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The Journal of Family Practice is a peer-reviewed and indexed journal that provides its 95,000 family physician readers with timely, practical, and evidence-based information that they can immediately put into practice. Research and applied evidence articles, plus patient-oriented departments like Practice Alert, PURLs, and Clinical Inquiries can be found in print and at jfponline.com. The Web site, which logs an average of 125,000 visitors every month, also offers audiocasts by physician specialists and interactive features like Instant Polls and Photo Rounds Friday—a weekly diagnostic puzzle.
gambling
compulsive behaviors
ammunition
assault rifle
black jack
Boko Haram
bondage
child abuse
cocaine
Daech
drug paraphernalia
explosion
gun
human trafficking
ISIL
ISIS
Islamic caliphate
Islamic state
mixed martial arts
MMA
molestation
national rifle association
NRA
nsfw
pedophile
pedophilia
poker
porn
pornography
psychedelic drug
recreational drug
sex slave rings
slot machine
terrorism
terrorist
Texas hold 'em
UFC
substance abuse
abuseed
abuseer
abusees
abuseing
abusely
abuses
aeolus
aeolused
aeoluser
aeoluses
aeolusing
aeolusly
aeoluss
ahole
aholeed
aholeer
aholees
aholeing
aholely
aholes
alcohol
alcoholed
alcoholer
alcoholes
alcoholing
alcoholly
alcohols
allman
allmaned
allmaner
allmanes
allmaning
allmanly
allmans
alted
altes
alting
altly
alts
analed
analer
anales
analing
anally
analprobe
analprobeed
analprobeer
analprobees
analprobeing
analprobely
analprobes
anals
anilingus
anilingused
anilinguser
anilinguses
anilingusing
anilingusly
anilinguss
anus
anused
anuser
anuses
anusing
anusly
anuss
areola
areolaed
areolaer
areolaes
areolaing
areolaly
areolas
areole
areoleed
areoleer
areolees
areoleing
areolely
areoles
arian
arianed
arianer
arianes
arianing
arianly
arians
aryan
aryaned
aryaner
aryanes
aryaning
aryanly
aryans
asiaed
asiaer
asiaes
asiaing
asialy
asias
ass
ass hole
ass lick
ass licked
ass licker
ass lickes
ass licking
ass lickly
ass licks
assbang
assbanged
assbangeded
assbangeder
assbangedes
assbangeding
assbangedly
assbangeds
assbanger
assbanges
assbanging
assbangly
assbangs
assbangsed
assbangser
assbangses
assbangsing
assbangsly
assbangss
assed
asser
asses
assesed
asseser
asseses
assesing
assesly
assess
assfuck
assfucked
assfucker
assfuckered
assfuckerer
assfuckeres
assfuckering
assfuckerly
assfuckers
assfuckes
assfucking
assfuckly
assfucks
asshat
asshated
asshater
asshates
asshating
asshatly
asshats
assholeed
assholeer
assholees
assholeing
assholely
assholes
assholesed
assholeser
assholeses
assholesing
assholesly
assholess
assing
assly
assmaster
assmastered
assmasterer
assmasteres
assmastering
assmasterly
assmasters
assmunch
assmunched
assmuncher
assmunches
assmunching
assmunchly
assmunchs
asss
asswipe
asswipeed
asswipeer
asswipees
asswipeing
asswipely
asswipes
asswipesed
asswipeser
asswipeses
asswipesing
asswipesly
asswipess
azz
azzed
azzer
azzes
azzing
azzly
azzs
babeed
babeer
babees
babeing
babely
babes
babesed
babeser
babeses
babesing
babesly
babess
ballsac
ballsaced
ballsacer
ballsaces
ballsacing
ballsack
ballsacked
ballsacker
ballsackes
ballsacking
ballsackly
ballsacks
ballsacly
ballsacs
ballsed
ballser
ballses
ballsing
ballsly
ballss
barf
barfed
barfer
barfes
barfing
barfly
barfs
bastard
bastarded
bastarder
bastardes
bastarding
bastardly
bastards
bastardsed
bastardser
bastardses
bastardsing
bastardsly
bastardss
bawdy
bawdyed
bawdyer
bawdyes
bawdying
bawdyly
bawdys
beaner
beanered
beanerer
beaneres
beanering
beanerly
beaners
beardedclam
beardedclamed
beardedclamer
beardedclames
beardedclaming
beardedclamly
beardedclams
beastiality
beastialityed
beastialityer
beastialityes
beastialitying
beastialityly
beastialitys
beatch
beatched
beatcher
beatches
beatching
beatchly
beatchs
beater
beatered
beaterer
beateres
beatering
beaterly
beaters
beered
beerer
beeres
beering
beerly
beeyotch
beeyotched
beeyotcher
beeyotches
beeyotching
beeyotchly
beeyotchs
beotch
beotched
beotcher
beotches
beotching
beotchly
beotchs
biatch
biatched
biatcher
biatches
biatching
biatchly
biatchs
big tits
big titsed
big titser
big titses
big titsing
big titsly
big titss
bigtits
bigtitsed
bigtitser
bigtitses
bigtitsing
bigtitsly
bigtitss
bimbo
bimboed
bimboer
bimboes
bimboing
bimboly
bimbos
bisexualed
bisexualer
bisexuales
bisexualing
bisexually
bisexuals
bitch
bitched
bitcheded
bitcheder
bitchedes
bitcheding
bitchedly
bitcheds
bitcher
bitches
bitchesed
bitcheser
bitcheses
bitchesing
bitchesly
bitchess
bitching
bitchly
bitchs
bitchy
bitchyed
bitchyer
bitchyes
bitchying
bitchyly
bitchys
bleached
bleacher
bleaches
bleaching
bleachly
bleachs
blow job
blow jobed
blow jober
blow jobes
blow jobing
blow jobly
blow jobs
blowed
blower
blowes
blowing
blowjob
blowjobed
blowjober
blowjobes
blowjobing
blowjobly
blowjobs
blowjobsed
blowjobser
blowjobses
blowjobsing
blowjobsly
blowjobss
blowly
blows
boink
boinked
boinker
boinkes
boinking
boinkly
boinks
bollock
bollocked
bollocker
bollockes
bollocking
bollockly
bollocks
bollocksed
bollockser
bollockses
bollocksing
bollocksly
bollockss
bollok
bolloked
bolloker
bollokes
bolloking
bollokly
bolloks
boner
bonered
bonerer
boneres
bonering
bonerly
boners
bonersed
bonerser
bonerses
bonersing
bonersly
bonerss
bong
bonged
bonger
bonges
bonging
bongly
bongs
boob
boobed
boober
boobes
boobies
boobiesed
boobieser
boobieses
boobiesing
boobiesly
boobiess
boobing
boobly
boobs
boobsed
boobser
boobses
boobsing
boobsly
boobss
booby
boobyed
boobyer
boobyes
boobying
boobyly
boobys
booger
boogered
boogerer
boogeres
boogering
boogerly
boogers
bookie
bookieed
bookieer
bookiees
bookieing
bookiely
bookies
bootee
booteeed
booteeer
booteees
booteeing
booteely
bootees
bootie
bootieed
bootieer
bootiees
bootieing
bootiely
booties
booty
bootyed
bootyer
bootyes
bootying
bootyly
bootys
boozeed
boozeer
boozees
boozeing
boozely
boozer
boozered
boozerer
boozeres
boozering
boozerly
boozers
boozes
boozy
boozyed
boozyer
boozyes
boozying
boozyly
boozys
bosomed
bosomer
bosomes
bosoming
bosomly
bosoms
bosomy
bosomyed
bosomyer
bosomyes
bosomying
bosomyly
bosomys
bugger
buggered
buggerer
buggeres
buggering
buggerly
buggers
bukkake
bukkakeed
bukkakeer
bukkakees
bukkakeing
bukkakely
bukkakes
bull shit
bull shited
bull shiter
bull shites
bull shiting
bull shitly
bull shits
bullshit
bullshited
bullshiter
bullshites
bullshiting
bullshitly
bullshits
bullshitsed
bullshitser
bullshitses
bullshitsing
bullshitsly
bullshitss
bullshitted
bullshitteded
bullshitteder
bullshittedes
bullshitteding
bullshittedly
bullshitteds
bullturds
bullturdsed
bullturdser
bullturdses
bullturdsing
bullturdsly
bullturdss
bung
bunged
bunger
bunges
bunging
bungly
bungs
busty
bustyed
bustyer
bustyes
bustying
bustyly
bustys
butt
butt fuck
butt fucked
butt fucker
butt fuckes
butt fucking
butt fuckly
butt fucks
butted
buttes
buttfuck
buttfucked
buttfucker
buttfuckered
buttfuckerer
buttfuckeres
buttfuckering
buttfuckerly
buttfuckers
buttfuckes
buttfucking
buttfuckly
buttfucks
butting
buttly
buttplug
buttpluged
buttpluger
buttpluges
buttpluging
buttplugly
buttplugs
butts
caca
cacaed
cacaer
cacaes
cacaing
cacaly
cacas
cahone
cahoneed
cahoneer
cahonees
cahoneing
cahonely
cahones
cameltoe
cameltoeed
cameltoeer
cameltoees
cameltoeing
cameltoely
cameltoes
carpetmuncher
carpetmunchered
carpetmuncherer
carpetmuncheres
carpetmunchering
carpetmuncherly
carpetmunchers
cawk
cawked
cawker
cawkes
cawking
cawkly
cawks
chinc
chinced
chincer
chinces
chincing
chincly
chincs
chincsed
chincser
chincses
chincsing
chincsly
chincss
chink
chinked
chinker
chinkes
chinking
chinkly
chinks
chode
chodeed
chodeer
chodees
chodeing
chodely
chodes
chodesed
chodeser
chodeses
chodesing
chodesly
chodess
clit
clited
cliter
clites
cliting
clitly
clitoris
clitorised
clitoriser
clitorises
clitorising
clitorisly
clitoriss
clitorus
clitorused
clitoruser
clitoruses
clitorusing
clitorusly
clitoruss
clits
clitsed
clitser
clitses
clitsing
clitsly
clitss
clitty
clittyed
clittyer
clittyes
clittying
clittyly
clittys
cocain
cocaine
cocained
cocaineed
cocaineer
cocainees
cocaineing
cocainely
cocainer
cocaines
cocaining
cocainly
cocains
cock
cock sucker
cock suckered
cock suckerer
cock suckeres
cock suckering
cock suckerly
cock suckers
cockblock
cockblocked
cockblocker
cockblockes
cockblocking
cockblockly
cockblocks
cocked
cocker
cockes
cockholster
cockholstered
cockholsterer
cockholsteres
cockholstering
cockholsterly
cockholsters
cocking
cockknocker
cockknockered
cockknockerer
cockknockeres
cockknockering
cockknockerly
cockknockers
cockly
cocks
cocksed
cockser
cockses
cocksing
cocksly
cocksmoker
cocksmokered
cocksmokerer
cocksmokeres
cocksmokering
cocksmokerly
cocksmokers
cockss
cocksucker
cocksuckered
cocksuckerer
cocksuckeres
cocksuckering
cocksuckerly
cocksuckers
coital
coitaled
coitaler
coitales
coitaling
coitally
coitals
commie
commieed
commieer
commiees
commieing
commiely
commies
condomed
condomer
condomes
condoming
condomly
condoms
coon
cooned
cooner
coones
cooning
coonly
coons
coonsed
coonser
coonses
coonsing
coonsly
coonss
corksucker
corksuckered
corksuckerer
corksuckeres
corksuckering
corksuckerly
corksuckers
cracked
crackwhore
crackwhoreed
crackwhoreer
crackwhorees
crackwhoreing
crackwhorely
crackwhores
crap
craped
craper
crapes
craping
craply
crappy
crappyed
crappyer
crappyes
crappying
crappyly
crappys
cum
cumed
cumer
cumes
cuming
cumly
cummin
cummined
cumminer
cummines
cumming
cumminged
cumminger
cumminges
cumminging
cummingly
cummings
cummining
cumminly
cummins
cums
cumshot
cumshoted
cumshoter
cumshotes
cumshoting
cumshotly
cumshots
cumshotsed
cumshotser
cumshotses
cumshotsing
cumshotsly
cumshotss
cumslut
cumsluted
cumsluter
cumslutes
cumsluting
cumslutly
cumsluts
cumstain
cumstained
cumstainer
cumstaines
cumstaining
cumstainly
cumstains
cunilingus
cunilingused
cunilinguser
cunilinguses
cunilingusing
cunilingusly
cunilinguss
cunnilingus
cunnilingused
cunnilinguser
cunnilinguses
cunnilingusing
cunnilingusly
cunnilinguss
cunny
cunnyed
cunnyer
cunnyes
cunnying
cunnyly
cunnys
cunt
cunted
cunter
cuntes
cuntface
cuntfaceed
cuntfaceer
cuntfacees
cuntfaceing
cuntfacely
cuntfaces
cunthunter
cunthuntered
cunthunterer
cunthunteres
cunthuntering
cunthunterly
cunthunters
cunting
cuntlick
cuntlicked
cuntlicker
cuntlickered
cuntlickerer
cuntlickeres
cuntlickering
cuntlickerly
cuntlickers
cuntlickes
cuntlicking
cuntlickly
cuntlicks
cuntly
cunts
cuntsed
cuntser
cuntses
cuntsing
cuntsly
cuntss
dago
dagoed
dagoer
dagoes
dagoing
dagoly
dagos
dagosed
dagoser
dagoses
dagosing
dagosly
dagoss
dammit
dammited
dammiter
dammites
dammiting
dammitly
dammits
damn
damned
damneded
damneder
damnedes
damneding
damnedly
damneds
damner
damnes
damning
damnit
damnited
damniter
damnites
damniting
damnitly
damnits
damnly
damns
dick
dickbag
dickbaged
dickbager
dickbages
dickbaging
dickbagly
dickbags
dickdipper
dickdippered
dickdipperer
dickdipperes
dickdippering
dickdipperly
dickdippers
dicked
dicker
dickes
dickface
dickfaceed
dickfaceer
dickfacees
dickfaceing
dickfacely
dickfaces
dickflipper
dickflippered
dickflipperer
dickflipperes
dickflippering
dickflipperly
dickflippers
dickhead
dickheaded
dickheader
dickheades
dickheading
dickheadly
dickheads
dickheadsed
dickheadser
dickheadses
dickheadsing
dickheadsly
dickheadss
dicking
dickish
dickished
dickisher
dickishes
dickishing
dickishly
dickishs
dickly
dickripper
dickrippered
dickripperer
dickripperes
dickrippering
dickripperly
dickrippers
dicks
dicksipper
dicksippered
dicksipperer
dicksipperes
dicksippering
dicksipperly
dicksippers
dickweed
dickweeded
dickweeder
dickweedes
dickweeding
dickweedly
dickweeds
dickwhipper
dickwhippered
dickwhipperer
dickwhipperes
dickwhippering
dickwhipperly
dickwhippers
dickzipper
dickzippered
dickzipperer
dickzipperes
dickzippering
dickzipperly
dickzippers
diddle
diddleed
diddleer
diddlees
diddleing
diddlely
diddles
dike
dikeed
dikeer
dikees
dikeing
dikely
dikes
dildo
dildoed
dildoer
dildoes
dildoing
dildoly
dildos
dildosed
dildoser
dildoses
dildosing
dildosly
dildoss
diligaf
diligafed
diligafer
diligafes
diligafing
diligafly
diligafs
dillweed
dillweeded
dillweeder
dillweedes
dillweeding
dillweedly
dillweeds
dimwit
dimwited
dimwiter
dimwites
dimwiting
dimwitly
dimwits
dingle
dingleed
dingleer
dinglees
dingleing
dinglely
dingles
dipship
dipshiped
dipshiper
dipshipes
dipshiping
dipshiply
dipships
dizzyed
dizzyer
dizzyes
dizzying
dizzyly
dizzys
doggiestyleed
doggiestyleer
doggiestylees
doggiestyleing
doggiestylely
doggiestyles
doggystyleed
doggystyleer
doggystylees
doggystyleing
doggystylely
doggystyles
dong
donged
donger
donges
donging
dongly
dongs
doofus
doofused
doofuser
doofuses
doofusing
doofusly
doofuss
doosh
dooshed
doosher
dooshes
dooshing
dooshly
dooshs
dopeyed
dopeyer
dopeyes
dopeying
dopeyly
dopeys
douchebag
douchebaged
douchebager
douchebages
douchebaging
douchebagly
douchebags
douchebagsed
douchebagser
douchebagses
douchebagsing
douchebagsly
douchebagss
doucheed
doucheer
douchees
doucheing
douchely
douches
douchey
doucheyed
doucheyer
doucheyes
doucheying
doucheyly
doucheys
drunk
drunked
drunker
drunkes
drunking
drunkly
drunks
dumass
dumassed
dumasser
dumasses
dumassing
dumassly
dumasss
dumbass
dumbassed
dumbasser
dumbasses
dumbassesed
dumbasseser
dumbasseses
dumbassesing
dumbassesly
dumbassess
dumbassing
dumbassly
dumbasss
dummy
dummyed
dummyer
dummyes
dummying
dummyly
dummys
dyke
dykeed
dykeer
dykees
dykeing
dykely
dykes
dykesed
dykeser
dykeses
dykesing
dykesly
dykess
erotic
eroticed
eroticer
erotices
eroticing
eroticly
erotics
extacy
extacyed
extacyer
extacyes
extacying
extacyly
extacys
extasy
extasyed
extasyer
extasyes
extasying
extasyly
extasys
fack
facked
facker
fackes
facking
fackly
facks
fag
faged
fager
fages
fagg
fagged
faggeded
faggeder
faggedes
faggeding
faggedly
faggeds
fagger
fagges
fagging
faggit
faggited
faggiter
faggites
faggiting
faggitly
faggits
faggly
faggot
faggoted
faggoter
faggotes
faggoting
faggotly
faggots
faggs
faging
fagly
fagot
fagoted
fagoter
fagotes
fagoting
fagotly
fagots
fags
fagsed
fagser
fagses
fagsing
fagsly
fagss
faig
faiged
faiger
faiges
faiging
faigly
faigs
faigt
faigted
faigter
faigtes
faigting
faigtly
faigts
fannybandit
fannybandited
fannybanditer
fannybandites
fannybanditing
fannybanditly
fannybandits
farted
farter
fartes
farting
fartknocker
fartknockered
fartknockerer
fartknockeres
fartknockering
fartknockerly
fartknockers
fartly
farts
felch
felched
felcher
felchered
felcherer
felcheres
felchering
felcherly
felchers
felches
felching
felchinged
felchinger
felchinges
felchinging
felchingly
felchings
felchly
felchs
fellate
fellateed
fellateer
fellatees
fellateing
fellately
fellates
fellatio
fellatioed
fellatioer
fellatioes
fellatioing
fellatioly
fellatios
feltch
feltched
feltcher
feltchered
feltcherer
feltcheres
feltchering
feltcherly
feltchers
feltches
feltching
feltchly
feltchs
feom
feomed
feomer
feomes
feoming
feomly
feoms
fisted
fisteded
fisteder
fistedes
fisteding
fistedly
fisteds
fisting
fistinged
fistinger
fistinges
fistinging
fistingly
fistings
fisty
fistyed
fistyer
fistyes
fistying
fistyly
fistys
floozy
floozyed
floozyer
floozyes
floozying
floozyly
floozys
foad
foaded
foader
foades
foading
foadly
foads
fondleed
fondleer
fondlees
fondleing
fondlely
fondles
foobar
foobared
foobarer
foobares
foobaring
foobarly
foobars
freex
freexed
freexer
freexes
freexing
freexly
freexs
frigg
frigga
friggaed
friggaer
friggaes
friggaing
friggaly
friggas
frigged
frigger
frigges
frigging
friggly
friggs
fubar
fubared
fubarer
fubares
fubaring
fubarly
fubars
fuck
fuckass
fuckassed
fuckasser
fuckasses
fuckassing
fuckassly
fuckasss
fucked
fuckeded
fuckeder
fuckedes
fuckeding
fuckedly
fuckeds
fucker
fuckered
fuckerer
fuckeres
fuckering
fuckerly
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37-year-old man • cough • increasing shortness of breath • pleuritic chest pain • Dx?
THE CASE
A 37-year-old man with a history of asthma, schizoaffective disorder, and tobacco use (36 packs per year) presented to the clinic after 5 days of worsening cough, reproducible left-sided chest pain, and increasing shortness of breath. He also experienced chills, fatigue, nausea, and vomiting but was afebrile. The patient had not travelled recently nor had direct contact with anyone sick. He also denied intravenous (IV) drug use, alcohol use, and bloody sputum. Recently, he had intentionally lost weight, as recommended by his psychiatrist.
Medication review revealed that he was taking many central-acting agents for schizoaffective disorder, including alprazolam, aripiprazole, desvenlafaxine, and quetiapine. Due to his intermittent asthma since childhood, he used an albuterol inhaler as needed, which currently offered only minimal relief. He denied any history of hospitalization or intubation for asthma.
During the clinic visit, his blood pressure was 90/60 mm Hg and his heart rate was normal. His pulse oximetry was 92% on room air. On physical examination, he had normal-appearing dentition. Auscultation revealed bilateral expiratory wheezes with decreased breath sounds at the left lower lobe.
A plain chest radiograph (CXR) performed in the clinic (FIGURE 1) showed a large, thick-walled cavitary lesion with an air-fluid level in the left lower lobe. The patient was directly admitted to the Family Medicine Inpatient Service. Computed tomography (CT) of the chest with contrast was ordered to rule out empyema or malignancy. The chest CT confirmed the previous findings while also revealing a surrounding satellite nodularity in the left lower lobe (FIGURE 2). QuantiFERON-TB Gold and HIV tests were both negative.
THE DIAGNOSIS
The patient was given a diagnosis of a lung abscess based on symptoms and imaging. An extensive smoking history, as well as multiple sedating medications, increased his likelihood of aspiration.
DISCUSSION
Lung abscess is the probable diagnosis in a patient with indolent infectious symptoms (cough, fever, night sweats) developing over days to weeks and a CXR finding of pulmonary opacity, often with an air-fluid level.1-4 A lung abscess is a circumscribed collection of pus in the lung parenchyma that develops as a result of microbial infection.4
Primary vs secondary abscess. Lung abscesses can be divided into 2 groups: primary and secondary abscesses. Primary abscesses (60%) occur without any other medical condition or in patients prone to aspiration.5 Secondary abscesses occur in the setting of a comorbid medical condition, such as lung disease, heart disease, bronchogenic neoplasm, or immunocompromised status.5
Continue to: With a primary lung abscess...
With a primary lung abscess, oropharyngeal contents are aspirated (generally while the patient is unconscious) and contain mixed flora.2 The aspirate typically migrates to the posterior segments of the upper lobes and to the superior segments of the lower lobes. These abscesses are usually singular and have an air-fluid level.1,2
Secondary lung abscesses occur in bronchial obstruction (by tumor, foreign body, or enlarged lymph nodes), with coexisting lung diseases (bronchiectasis, cystic fibrosis, infected pulmonary infarcts, lung contusion) or by direct spread (broncho-esophageal fistula, subphrenic abscess).6 Secondary abscesses are associated with a poorer prognosis, dependent on the patient’s general condition and underlying disease.7
What to rule out
The differential diagnosis of cavitary lung lesion includes tuberculosis, necrotizing pneumonia, bronchial carcinoma, pulmonary embolism, vasculitis (eg, Churg-Strauss syndrome), and localized pleural empyema.1,4 A CT scan is helpful to differentiate between a parenchymal lesion and pleural collection, which may not be as clear on CXR.1,4
Tuberculosis manifests with fatigue, weight loss, and night sweats; a chest CT will reveal a cavitating lesion (usually upper lobe) with a characteristic “rim sign” that includes caseous necrosis surrounded by a peripheral enhancing rim.8
Necrotizing pneumonia manifests as acute, fulminant infection. The most common causative organisms on sputum culture are Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas species. Plain radiography will reveal multiple cavities and often associated pleural effusion and empyema.9
Continue to: Excavating bronchogenic carcinomas
Excavating bronchogenic carcinomas differ from a lung abscess in that a patient with the latter is typically, but not always, febrile and has purulent sputum. On imaging, a bronchogenic carcinoma has a thicker and more irregular wall than a lung abscess.10
Treatment
When antibiotics first became available, penicillin was used to treat lung abscess.11 Then IV clindamycin became the drug of choice after 2 trials demonstrated its superiority to IV penicillin.12,13 More recently, clindamycin alone has fallen out of favor due to growing anaerobic resistance.14
Current therapy includes beta-lactam with beta-lactamase inhibitors.14 Lung abscesses are typically polymicrobial and thus carry different degrees of antibiotic resistance.15,16 If culture data are available, targeted therapy is preferred, especially for secondary abscesses.7 Antibiotic therapy is usually continued until a CXR reveals a small lesion or is clear, which may require several months of outpatient oral antibiotic therapy.4
Our patient was treated with IV clindamycin for 3 days in the hospital. Clindamycin was chosen due to his penicillin allergy and started empirically without any culture data. He was transitioned to oral clindamycin and completed a total 3-week course as his CXR continued to show improvement (FIGURE 3). He did not undergo bronchoscopy. A follow-up CXR showed resolution of lung abscess at 9 months. (FIGURE 4).
THE TAKEAWAY
All patients with lung abscesses should have sputum culture with gram stain done—ideally prior to starting antibiotics.3,4 Bronchoscopy should be considered for patients with atypical presentations or those who fail standard therapy, but may be used in other cases, as well.3
CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; [email protected]
1. Hassan M, Asciak R, Rizk R, et al. Lung abscess or empyema? Taking a closer look. Thorax. 2018;73:887-889. https://doi. org/10.1136/thoraxjnl-2018-211604
2. Moreira J da SM, Camargo J de JP, Felicetti JC, et al. Lung abscess: analysis of 252 consecutive cases diagnosed between 1968 and 2004. J Bras Pneumol. 2006;32:136-43. https://doi.org/10.1590/ s1806-37132006000200009
3. Schiza S, Siafakas NM. Clinical presentation and management of empyema, lung abscess and pleural effusion. Curr Opin Pulm Med. 2006;12:205-211. https://doi.org/10.1097/01. mcp.0000219270.73180.8b
4. Yazbeck MF, Dahdel M, Kalra A, et al. Lung abscess: update on microbiology and management. Am J Ther. 2014;21:217-221. https://doi.org/10.1097/MJT.0b013e3182383c9b
5. Nicolini A, Cilloniz C, Senarega R, et al. Lung abscess due to Streptococcus pneumoniae: a case series and brief review of the literature. Pneumonol Alergol Pol. 2014;82:276-285. https://doi. org/10.5603/PiAP.2014.0033
6. Puligandla PS, Laberge J-M. Respiratory infections: pneumonia, lung abscess, and empyema. Semin Pediatr Surg. 2008;17:42-52. https://doi.org/10.1053/j.sempedsurg.2007.10.007
7. Marra A, Hillejan L, Ukena D. [Management of Lung Abscess]. Zentralbl Chir. 2015;140 (suppl 1):S47-S53. https://doi. org/10.1055/s-0035-1557883
THE CASE
A 37-year-old man with a history of asthma, schizoaffective disorder, and tobacco use (36 packs per year) presented to the clinic after 5 days of worsening cough, reproducible left-sided chest pain, and increasing shortness of breath. He also experienced chills, fatigue, nausea, and vomiting but was afebrile. The patient had not travelled recently nor had direct contact with anyone sick. He also denied intravenous (IV) drug use, alcohol use, and bloody sputum. Recently, he had intentionally lost weight, as recommended by his psychiatrist.
Medication review revealed that he was taking many central-acting agents for schizoaffective disorder, including alprazolam, aripiprazole, desvenlafaxine, and quetiapine. Due to his intermittent asthma since childhood, he used an albuterol inhaler as needed, which currently offered only minimal relief. He denied any history of hospitalization or intubation for asthma.
During the clinic visit, his blood pressure was 90/60 mm Hg and his heart rate was normal. His pulse oximetry was 92% on room air. On physical examination, he had normal-appearing dentition. Auscultation revealed bilateral expiratory wheezes with decreased breath sounds at the left lower lobe.
A plain chest radiograph (CXR) performed in the clinic (FIGURE 1) showed a large, thick-walled cavitary lesion with an air-fluid level in the left lower lobe. The patient was directly admitted to the Family Medicine Inpatient Service. Computed tomography (CT) of the chest with contrast was ordered to rule out empyema or malignancy. The chest CT confirmed the previous findings while also revealing a surrounding satellite nodularity in the left lower lobe (FIGURE 2). QuantiFERON-TB Gold and HIV tests were both negative.
THE DIAGNOSIS
The patient was given a diagnosis of a lung abscess based on symptoms and imaging. An extensive smoking history, as well as multiple sedating medications, increased his likelihood of aspiration.
DISCUSSION
Lung abscess is the probable diagnosis in a patient with indolent infectious symptoms (cough, fever, night sweats) developing over days to weeks and a CXR finding of pulmonary opacity, often with an air-fluid level.1-4 A lung abscess is a circumscribed collection of pus in the lung parenchyma that develops as a result of microbial infection.4
Primary vs secondary abscess. Lung abscesses can be divided into 2 groups: primary and secondary abscesses. Primary abscesses (60%) occur without any other medical condition or in patients prone to aspiration.5 Secondary abscesses occur in the setting of a comorbid medical condition, such as lung disease, heart disease, bronchogenic neoplasm, or immunocompromised status.5
Continue to: With a primary lung abscess...
With a primary lung abscess, oropharyngeal contents are aspirated (generally while the patient is unconscious) and contain mixed flora.2 The aspirate typically migrates to the posterior segments of the upper lobes and to the superior segments of the lower lobes. These abscesses are usually singular and have an air-fluid level.1,2
Secondary lung abscesses occur in bronchial obstruction (by tumor, foreign body, or enlarged lymph nodes), with coexisting lung diseases (bronchiectasis, cystic fibrosis, infected pulmonary infarcts, lung contusion) or by direct spread (broncho-esophageal fistula, subphrenic abscess).6 Secondary abscesses are associated with a poorer prognosis, dependent on the patient’s general condition and underlying disease.7
What to rule out
The differential diagnosis of cavitary lung lesion includes tuberculosis, necrotizing pneumonia, bronchial carcinoma, pulmonary embolism, vasculitis (eg, Churg-Strauss syndrome), and localized pleural empyema.1,4 A CT scan is helpful to differentiate between a parenchymal lesion and pleural collection, which may not be as clear on CXR.1,4
Tuberculosis manifests with fatigue, weight loss, and night sweats; a chest CT will reveal a cavitating lesion (usually upper lobe) with a characteristic “rim sign” that includes caseous necrosis surrounded by a peripheral enhancing rim.8
Necrotizing pneumonia manifests as acute, fulminant infection. The most common causative organisms on sputum culture are Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas species. Plain radiography will reveal multiple cavities and often associated pleural effusion and empyema.9
Continue to: Excavating bronchogenic carcinomas
Excavating bronchogenic carcinomas differ from a lung abscess in that a patient with the latter is typically, but not always, febrile and has purulent sputum. On imaging, a bronchogenic carcinoma has a thicker and more irregular wall than a lung abscess.10
Treatment
When antibiotics first became available, penicillin was used to treat lung abscess.11 Then IV clindamycin became the drug of choice after 2 trials demonstrated its superiority to IV penicillin.12,13 More recently, clindamycin alone has fallen out of favor due to growing anaerobic resistance.14
Current therapy includes beta-lactam with beta-lactamase inhibitors.14 Lung abscesses are typically polymicrobial and thus carry different degrees of antibiotic resistance.15,16 If culture data are available, targeted therapy is preferred, especially for secondary abscesses.7 Antibiotic therapy is usually continued until a CXR reveals a small lesion or is clear, which may require several months of outpatient oral antibiotic therapy.4
Our patient was treated with IV clindamycin for 3 days in the hospital. Clindamycin was chosen due to his penicillin allergy and started empirically without any culture data. He was transitioned to oral clindamycin and completed a total 3-week course as his CXR continued to show improvement (FIGURE 3). He did not undergo bronchoscopy. A follow-up CXR showed resolution of lung abscess at 9 months. (FIGURE 4).
THE TAKEAWAY
All patients with lung abscesses should have sputum culture with gram stain done—ideally prior to starting antibiotics.3,4 Bronchoscopy should be considered for patients with atypical presentations or those who fail standard therapy, but may be used in other cases, as well.3
CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; [email protected]
THE CASE
A 37-year-old man with a history of asthma, schizoaffective disorder, and tobacco use (36 packs per year) presented to the clinic after 5 days of worsening cough, reproducible left-sided chest pain, and increasing shortness of breath. He also experienced chills, fatigue, nausea, and vomiting but was afebrile. The patient had not travelled recently nor had direct contact with anyone sick. He also denied intravenous (IV) drug use, alcohol use, and bloody sputum. Recently, he had intentionally lost weight, as recommended by his psychiatrist.
Medication review revealed that he was taking many central-acting agents for schizoaffective disorder, including alprazolam, aripiprazole, desvenlafaxine, and quetiapine. Due to his intermittent asthma since childhood, he used an albuterol inhaler as needed, which currently offered only minimal relief. He denied any history of hospitalization or intubation for asthma.
During the clinic visit, his blood pressure was 90/60 mm Hg and his heart rate was normal. His pulse oximetry was 92% on room air. On physical examination, he had normal-appearing dentition. Auscultation revealed bilateral expiratory wheezes with decreased breath sounds at the left lower lobe.
A plain chest radiograph (CXR) performed in the clinic (FIGURE 1) showed a large, thick-walled cavitary lesion with an air-fluid level in the left lower lobe. The patient was directly admitted to the Family Medicine Inpatient Service. Computed tomography (CT) of the chest with contrast was ordered to rule out empyema or malignancy. The chest CT confirmed the previous findings while also revealing a surrounding satellite nodularity in the left lower lobe (FIGURE 2). QuantiFERON-TB Gold and HIV tests were both negative.
THE DIAGNOSIS
The patient was given a diagnosis of a lung abscess based on symptoms and imaging. An extensive smoking history, as well as multiple sedating medications, increased his likelihood of aspiration.
DISCUSSION
Lung abscess is the probable diagnosis in a patient with indolent infectious symptoms (cough, fever, night sweats) developing over days to weeks and a CXR finding of pulmonary opacity, often with an air-fluid level.1-4 A lung abscess is a circumscribed collection of pus in the lung parenchyma that develops as a result of microbial infection.4
Primary vs secondary abscess. Lung abscesses can be divided into 2 groups: primary and secondary abscesses. Primary abscesses (60%) occur without any other medical condition or in patients prone to aspiration.5 Secondary abscesses occur in the setting of a comorbid medical condition, such as lung disease, heart disease, bronchogenic neoplasm, or immunocompromised status.5
Continue to: With a primary lung abscess...
With a primary lung abscess, oropharyngeal contents are aspirated (generally while the patient is unconscious) and contain mixed flora.2 The aspirate typically migrates to the posterior segments of the upper lobes and to the superior segments of the lower lobes. These abscesses are usually singular and have an air-fluid level.1,2
Secondary lung abscesses occur in bronchial obstruction (by tumor, foreign body, or enlarged lymph nodes), with coexisting lung diseases (bronchiectasis, cystic fibrosis, infected pulmonary infarcts, lung contusion) or by direct spread (broncho-esophageal fistula, subphrenic abscess).6 Secondary abscesses are associated with a poorer prognosis, dependent on the patient’s general condition and underlying disease.7
What to rule out
The differential diagnosis of cavitary lung lesion includes tuberculosis, necrotizing pneumonia, bronchial carcinoma, pulmonary embolism, vasculitis (eg, Churg-Strauss syndrome), and localized pleural empyema.1,4 A CT scan is helpful to differentiate between a parenchymal lesion and pleural collection, which may not be as clear on CXR.1,4
Tuberculosis manifests with fatigue, weight loss, and night sweats; a chest CT will reveal a cavitating lesion (usually upper lobe) with a characteristic “rim sign” that includes caseous necrosis surrounded by a peripheral enhancing rim.8
Necrotizing pneumonia manifests as acute, fulminant infection. The most common causative organisms on sputum culture are Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas species. Plain radiography will reveal multiple cavities and often associated pleural effusion and empyema.9
Continue to: Excavating bronchogenic carcinomas
Excavating bronchogenic carcinomas differ from a lung abscess in that a patient with the latter is typically, but not always, febrile and has purulent sputum. On imaging, a bronchogenic carcinoma has a thicker and more irregular wall than a lung abscess.10
Treatment
When antibiotics first became available, penicillin was used to treat lung abscess.11 Then IV clindamycin became the drug of choice after 2 trials demonstrated its superiority to IV penicillin.12,13 More recently, clindamycin alone has fallen out of favor due to growing anaerobic resistance.14
Current therapy includes beta-lactam with beta-lactamase inhibitors.14 Lung abscesses are typically polymicrobial and thus carry different degrees of antibiotic resistance.15,16 If culture data are available, targeted therapy is preferred, especially for secondary abscesses.7 Antibiotic therapy is usually continued until a CXR reveals a small lesion or is clear, which may require several months of outpatient oral antibiotic therapy.4
Our patient was treated with IV clindamycin for 3 days in the hospital. Clindamycin was chosen due to his penicillin allergy and started empirically without any culture data. He was transitioned to oral clindamycin and completed a total 3-week course as his CXR continued to show improvement (FIGURE 3). He did not undergo bronchoscopy. A follow-up CXR showed resolution of lung abscess at 9 months. (FIGURE 4).
THE TAKEAWAY
All patients with lung abscesses should have sputum culture with gram stain done—ideally prior to starting antibiotics.3,4 Bronchoscopy should be considered for patients with atypical presentations or those who fail standard therapy, but may be used in other cases, as well.3
CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; [email protected]
1. Hassan M, Asciak R, Rizk R, et al. Lung abscess or empyema? Taking a closer look. Thorax. 2018;73:887-889. https://doi. org/10.1136/thoraxjnl-2018-211604
2. Moreira J da SM, Camargo J de JP, Felicetti JC, et al. Lung abscess: analysis of 252 consecutive cases diagnosed between 1968 and 2004. J Bras Pneumol. 2006;32:136-43. https://doi.org/10.1590/ s1806-37132006000200009
3. Schiza S, Siafakas NM. Clinical presentation and management of empyema, lung abscess and pleural effusion. Curr Opin Pulm Med. 2006;12:205-211. https://doi.org/10.1097/01. mcp.0000219270.73180.8b
4. Yazbeck MF, Dahdel M, Kalra A, et al. Lung abscess: update on microbiology and management. Am J Ther. 2014;21:217-221. https://doi.org/10.1097/MJT.0b013e3182383c9b
5. Nicolini A, Cilloniz C, Senarega R, et al. Lung abscess due to Streptococcus pneumoniae: a case series and brief review of the literature. Pneumonol Alergol Pol. 2014;82:276-285. https://doi. org/10.5603/PiAP.2014.0033
6. Puligandla PS, Laberge J-M. Respiratory infections: pneumonia, lung abscess, and empyema. Semin Pediatr Surg. 2008;17:42-52. https://doi.org/10.1053/j.sempedsurg.2007.10.007
7. Marra A, Hillejan L, Ukena D. [Management of Lung Abscess]. Zentralbl Chir. 2015;140 (suppl 1):S47-S53. https://doi. org/10.1055/s-0035-1557883
1. Hassan M, Asciak R, Rizk R, et al. Lung abscess or empyema? Taking a closer look. Thorax. 2018;73:887-889. https://doi. org/10.1136/thoraxjnl-2018-211604
2. Moreira J da SM, Camargo J de JP, Felicetti JC, et al. Lung abscess: analysis of 252 consecutive cases diagnosed between 1968 and 2004. J Bras Pneumol. 2006;32:136-43. https://doi.org/10.1590/ s1806-37132006000200009
3. Schiza S, Siafakas NM. Clinical presentation and management of empyema, lung abscess and pleural effusion. Curr Opin Pulm Med. 2006;12:205-211. https://doi.org/10.1097/01. mcp.0000219270.73180.8b
4. Yazbeck MF, Dahdel M, Kalra A, et al. Lung abscess: update on microbiology and management. Am J Ther. 2014;21:217-221. https://doi.org/10.1097/MJT.0b013e3182383c9b
5. Nicolini A, Cilloniz C, Senarega R, et al. Lung abscess due to Streptococcus pneumoniae: a case series and brief review of the literature. Pneumonol Alergol Pol. 2014;82:276-285. https://doi. org/10.5603/PiAP.2014.0033
6. Puligandla PS, Laberge J-M. Respiratory infections: pneumonia, lung abscess, and empyema. Semin Pediatr Surg. 2008;17:42-52. https://doi.org/10.1053/j.sempedsurg.2007.10.007
7. Marra A, Hillejan L, Ukena D. [Management of Lung Abscess]. Zentralbl Chir. 2015;140 (suppl 1):S47-S53. https://doi. org/10.1055/s-0035-1557883
Confidently rule out CAP in the outpatient setting
ILLUSTRATIVE CASE
An otherwise healthy 56-year-old woman presents to the emergency department (ED) with a productive cough of 4 days’ duration. A review of her history is negative for recurrent upper respiratory infections, smoking, or environmental exposures. Her physical exam is unremarkable and, more specifically, her pulmonary exam and vital signs (temperature, respiratory rate, and heart rate) are within normal limits. The patient states that last year her friend had similar symptoms and was given a diagnosis of pneumonia. Is it necessary to order a chest x-ray in this patient to rule out community-acquired pneumonia (CAP)?
CAP is a common pulmonary condition seen in the outpatient setting in the United States, representing more than 4.5 million outpatient visits in the years 2009 to 2010.2 Historically, a diagnosis of CAP has been based on clinical findings in conjunction with infiltrates seen on chest x-ray.
In 2017, more than 5 million visits to the ED were due to a cough.3 The use of radiographic imaging in EDs has been increasing. There were 49 million x-rays and 2.7 million noncardiac chest computed tomography (CT) scans performed in 2016, many of which were for patients with cough.3,4 Although imaging is an extremely useful tool and indicated in many instances, the ability to rule out CAP in an adult who presents with a cough by using a set of simple, clinically based heuristics without requiring imaging would help to increase efficiency, limit cost, and decrease exposure of patients to unnecessary and potentially harmful diagnostic studies.
Clinical decision rules (CDRs) are simple heuristics that can stratify patients as either high risk or low risk for specific diseases. Two older large, prospective cross-sectional studies developed CDRs to determine the probability of CAP based on symptoms (eg, night sweats, myalgias, and sputum production) and clinical findings (eg, temperature > 37.8 °C [100 °F], tachypnea, tachycardia, rales, and decreased breath sounds).5,6 This meta-analysis includes these studies and more recent studies7-9 used to develop a CDR that focuses solely on a few specific signs and symptoms that can reliably rule out CAP without imaging, and so prove highly useful for busy primary care clinicians.
STUDY SUMMARY
This simple approach rules out CAP in outpatients 99.6% of the time
This systematic review and meta-analysis included studies that used 2 or more signs, symptoms, or point-of-care tests to determine the patient’s risk for CAP.1 Twelve studies (N = 10,254) met inclusion criteria by applying a CDR to adults or adolescents presenting with respiratory signs or symptoms potentially suggestive of CAP to either an outpatient setting or an ED. Prospective cohort, cross-sectional, and case-control studies were included when a chest x-ray or CT was utilized as the primary reference standard. Exclusion criteria included studies of military or nursing home populations and studies in which the majority of patients had hospital- or ventilator-associated pneumonia or were immunocompromised.
A simple, highly useful CDR emerged from 3 of the studies (N = 1865).7-9 Two of these studies were described as case-control studies with prospective enrollment of patients older than 17 years in both outpatient and ED settings.7,8 One study was conducted in the United States (mean age, 65 years) and the other in Iran (mean age, 60 years). The third was a Chilean prospective cohort study of ED patients older than 15 years (mean age, 53 years).9 In each of these studies, the outpatient or ED physicians collected all clinical data and documented their physical exam prior to receiving the chest radiograph results. The radiologists were masked to the clinical findings at the time of their interpretation.
Results. From the meta-analysis, a simple CDR emerged for patients with normal vital signs (temperature, respiratory rate, and heart rate) and a normal pulmonary exam that virtually ruled out CAP (sensitivity = 96%; 95% CI, 92%–98%; and negative likelihood ratio = 0.10; 95% CI, 0.07–0.13). In patients presenting to an outpatient clinic with acute cough with a 4% baseline prevalence rate of pneumonia, this CDR ruled out CAP 99.6% of the time.
Continue to: WHAT'S NEW
WHAT’S NEW
A clinical decision rule validated for accuracy
This is the first validated CDR that accurately rules out CAP in the outpatient or ED setting using parameters easily obtainable during a clinical exam.
CAVEATS
Proceed with caution in the young and the very old
Two of the 3 studies in this CDR had an overall moderate risk of bias, whereas the third study was determined to be at low risk of bias, based on appraisal with the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2) framework.10
The mean age range in these 3 studies was 53 to 66 years (without further data such as standard deviation), suggesting that application of the CDR to adults who fall at extremes of age should be done with a modicum of caution.
Additionally, although the symptom complex of COVID-19 pneumonia would suggest that this CDR would likely remain accurate today, it has not been validated in patients with COVID-19 infection.
CHALLENGES TO IMPLEMENTATION
Potential reluctance to forgo imaging
Beyond the caveats regarding COVID-19, the use of a simple CDR to reliably exclude pneumonia should have no barrier to implementation in an outpatient primary care setting or ED, although there could be reluctance on the part of both providers and patients to fully embrace this simple tool without a confirmatory chest x-ray.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
1. Marchello CS, Ebell MH, Dale AP, et al. Signs and symptoms that rule out community-acquired pneumonia in outpatient adults: a systematic review and meta-analysis. J Am Board Fam Med. 2019;32:234-247.
2. St Sauver JL, Warner DO, Yawn BP, et al. Why patients visit their doctors: assessing the most prevalent conditions in a defined American population. Mayo Clin Proc. 2013;88:56-67.
3. CDC. National Center for Health Statistics. National Hospital Ambulatory Medical Care Survey: 2017. Emergency Department Summary Tables. Accessed March 24, 2021. www.cdc.gov/nchs/data/nhamcs/web_tables/2017_ed_web_tables-508.pdf
4. Jain S, Self WH, Wunderink RG, et al; CDC EPIC Study Team. Community-acquired pneumonia requiring hospitalization among US adults. N Engl J Med. 2015;373:415-427.
5. Heckerling PS, Tape TG, Wigton RS, et al. Clinical prediction rule for pulmonary infiltrates. Ann Intern Med. 1990;113:664-670.
6. Diehr P, Wood RW, Bushyhead J, et al. Prediction of pneumonia in outpatients with acute cough—a statistical approach. J Chronic Dis. 1984;37:215-225.
7. O’Brien WT Sr, Rohweder DA, Lattin GE Jr, et al. Clinical indicators of radiographic findings in patients with suspected community-acquired pneumonia: who needs a chest x-ray? J Am Coll Radiol. 2006;3:703-706.
8. Ebrahimzadeh A, Mohammadifard M, Naseh G, et al. Clinical and laboratory findings in patients with acute respiratory symptoms that suggest the necessity of chest x-ray for community-acquired pneumonia. Iran J Radiol. 2015;12:e13547.
9. Saldías PF, Cabrera TD, de Solminihac LI, et al. Valor predictivo de la historia clínica y examen físico en el diagnóstico de neumonía del adulto adquirida en la comunidad [Predictive value of history and physical examination for the diagnosis of community-acquired pneumonia in adults]. Abstract in English. Rev Med Chil. 2007;135:143-152.
10. Whiting PF, Rutjes AWS, Westwood ME, et al; QUADAS-2 Group. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155:529-536.
ILLUSTRATIVE CASE
An otherwise healthy 56-year-old woman presents to the emergency department (ED) with a productive cough of 4 days’ duration. A review of her history is negative for recurrent upper respiratory infections, smoking, or environmental exposures. Her physical exam is unremarkable and, more specifically, her pulmonary exam and vital signs (temperature, respiratory rate, and heart rate) are within normal limits. The patient states that last year her friend had similar symptoms and was given a diagnosis of pneumonia. Is it necessary to order a chest x-ray in this patient to rule out community-acquired pneumonia (CAP)?
CAP is a common pulmonary condition seen in the outpatient setting in the United States, representing more than 4.5 million outpatient visits in the years 2009 to 2010.2 Historically, a diagnosis of CAP has been based on clinical findings in conjunction with infiltrates seen on chest x-ray.
In 2017, more than 5 million visits to the ED were due to a cough.3 The use of radiographic imaging in EDs has been increasing. There were 49 million x-rays and 2.7 million noncardiac chest computed tomography (CT) scans performed in 2016, many of which were for patients with cough.3,4 Although imaging is an extremely useful tool and indicated in many instances, the ability to rule out CAP in an adult who presents with a cough by using a set of simple, clinically based heuristics without requiring imaging would help to increase efficiency, limit cost, and decrease exposure of patients to unnecessary and potentially harmful diagnostic studies.
Clinical decision rules (CDRs) are simple heuristics that can stratify patients as either high risk or low risk for specific diseases. Two older large, prospective cross-sectional studies developed CDRs to determine the probability of CAP based on symptoms (eg, night sweats, myalgias, and sputum production) and clinical findings (eg, temperature > 37.8 °C [100 °F], tachypnea, tachycardia, rales, and decreased breath sounds).5,6 This meta-analysis includes these studies and more recent studies7-9 used to develop a CDR that focuses solely on a few specific signs and symptoms that can reliably rule out CAP without imaging, and so prove highly useful for busy primary care clinicians.
STUDY SUMMARY
This simple approach rules out CAP in outpatients 99.6% of the time
This systematic review and meta-analysis included studies that used 2 or more signs, symptoms, or point-of-care tests to determine the patient’s risk for CAP.1 Twelve studies (N = 10,254) met inclusion criteria by applying a CDR to adults or adolescents presenting with respiratory signs or symptoms potentially suggestive of CAP to either an outpatient setting or an ED. Prospective cohort, cross-sectional, and case-control studies were included when a chest x-ray or CT was utilized as the primary reference standard. Exclusion criteria included studies of military or nursing home populations and studies in which the majority of patients had hospital- or ventilator-associated pneumonia or were immunocompromised.
A simple, highly useful CDR emerged from 3 of the studies (N = 1865).7-9 Two of these studies were described as case-control studies with prospective enrollment of patients older than 17 years in both outpatient and ED settings.7,8 One study was conducted in the United States (mean age, 65 years) and the other in Iran (mean age, 60 years). The third was a Chilean prospective cohort study of ED patients older than 15 years (mean age, 53 years).9 In each of these studies, the outpatient or ED physicians collected all clinical data and documented their physical exam prior to receiving the chest radiograph results. The radiologists were masked to the clinical findings at the time of their interpretation.
Results. From the meta-analysis, a simple CDR emerged for patients with normal vital signs (temperature, respiratory rate, and heart rate) and a normal pulmonary exam that virtually ruled out CAP (sensitivity = 96%; 95% CI, 92%–98%; and negative likelihood ratio = 0.10; 95% CI, 0.07–0.13). In patients presenting to an outpatient clinic with acute cough with a 4% baseline prevalence rate of pneumonia, this CDR ruled out CAP 99.6% of the time.
Continue to: WHAT'S NEW
WHAT’S NEW
A clinical decision rule validated for accuracy
This is the first validated CDR that accurately rules out CAP in the outpatient or ED setting using parameters easily obtainable during a clinical exam.
CAVEATS
Proceed with caution in the young and the very old
Two of the 3 studies in this CDR had an overall moderate risk of bias, whereas the third study was determined to be at low risk of bias, based on appraisal with the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2) framework.10
The mean age range in these 3 studies was 53 to 66 years (without further data such as standard deviation), suggesting that application of the CDR to adults who fall at extremes of age should be done with a modicum of caution.
Additionally, although the symptom complex of COVID-19 pneumonia would suggest that this CDR would likely remain accurate today, it has not been validated in patients with COVID-19 infection.
CHALLENGES TO IMPLEMENTATION
Potential reluctance to forgo imaging
Beyond the caveats regarding COVID-19, the use of a simple CDR to reliably exclude pneumonia should have no barrier to implementation in an outpatient primary care setting or ED, although there could be reluctance on the part of both providers and patients to fully embrace this simple tool without a confirmatory chest x-ray.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
ILLUSTRATIVE CASE
An otherwise healthy 56-year-old woman presents to the emergency department (ED) with a productive cough of 4 days’ duration. A review of her history is negative for recurrent upper respiratory infections, smoking, or environmental exposures. Her physical exam is unremarkable and, more specifically, her pulmonary exam and vital signs (temperature, respiratory rate, and heart rate) are within normal limits. The patient states that last year her friend had similar symptoms and was given a diagnosis of pneumonia. Is it necessary to order a chest x-ray in this patient to rule out community-acquired pneumonia (CAP)?
CAP is a common pulmonary condition seen in the outpatient setting in the United States, representing more than 4.5 million outpatient visits in the years 2009 to 2010.2 Historically, a diagnosis of CAP has been based on clinical findings in conjunction with infiltrates seen on chest x-ray.
In 2017, more than 5 million visits to the ED were due to a cough.3 The use of radiographic imaging in EDs has been increasing. There were 49 million x-rays and 2.7 million noncardiac chest computed tomography (CT) scans performed in 2016, many of which were for patients with cough.3,4 Although imaging is an extremely useful tool and indicated in many instances, the ability to rule out CAP in an adult who presents with a cough by using a set of simple, clinically based heuristics without requiring imaging would help to increase efficiency, limit cost, and decrease exposure of patients to unnecessary and potentially harmful diagnostic studies.
Clinical decision rules (CDRs) are simple heuristics that can stratify patients as either high risk or low risk for specific diseases. Two older large, prospective cross-sectional studies developed CDRs to determine the probability of CAP based on symptoms (eg, night sweats, myalgias, and sputum production) and clinical findings (eg, temperature > 37.8 °C [100 °F], tachypnea, tachycardia, rales, and decreased breath sounds).5,6 This meta-analysis includes these studies and more recent studies7-9 used to develop a CDR that focuses solely on a few specific signs and symptoms that can reliably rule out CAP without imaging, and so prove highly useful for busy primary care clinicians.
STUDY SUMMARY
This simple approach rules out CAP in outpatients 99.6% of the time
This systematic review and meta-analysis included studies that used 2 or more signs, symptoms, or point-of-care tests to determine the patient’s risk for CAP.1 Twelve studies (N = 10,254) met inclusion criteria by applying a CDR to adults or adolescents presenting with respiratory signs or symptoms potentially suggestive of CAP to either an outpatient setting or an ED. Prospective cohort, cross-sectional, and case-control studies were included when a chest x-ray or CT was utilized as the primary reference standard. Exclusion criteria included studies of military or nursing home populations and studies in which the majority of patients had hospital- or ventilator-associated pneumonia or were immunocompromised.
A simple, highly useful CDR emerged from 3 of the studies (N = 1865).7-9 Two of these studies were described as case-control studies with prospective enrollment of patients older than 17 years in both outpatient and ED settings.7,8 One study was conducted in the United States (mean age, 65 years) and the other in Iran (mean age, 60 years). The third was a Chilean prospective cohort study of ED patients older than 15 years (mean age, 53 years).9 In each of these studies, the outpatient or ED physicians collected all clinical data and documented their physical exam prior to receiving the chest radiograph results. The radiologists were masked to the clinical findings at the time of their interpretation.
Results. From the meta-analysis, a simple CDR emerged for patients with normal vital signs (temperature, respiratory rate, and heart rate) and a normal pulmonary exam that virtually ruled out CAP (sensitivity = 96%; 95% CI, 92%–98%; and negative likelihood ratio = 0.10; 95% CI, 0.07–0.13). In patients presenting to an outpatient clinic with acute cough with a 4% baseline prevalence rate of pneumonia, this CDR ruled out CAP 99.6% of the time.
Continue to: WHAT'S NEW
WHAT’S NEW
A clinical decision rule validated for accuracy
This is the first validated CDR that accurately rules out CAP in the outpatient or ED setting using parameters easily obtainable during a clinical exam.
CAVEATS
Proceed with caution in the young and the very old
Two of the 3 studies in this CDR had an overall moderate risk of bias, whereas the third study was determined to be at low risk of bias, based on appraisal with the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2) framework.10
The mean age range in these 3 studies was 53 to 66 years (without further data such as standard deviation), suggesting that application of the CDR to adults who fall at extremes of age should be done with a modicum of caution.
Additionally, although the symptom complex of COVID-19 pneumonia would suggest that this CDR would likely remain accurate today, it has not been validated in patients with COVID-19 infection.
CHALLENGES TO IMPLEMENTATION
Potential reluctance to forgo imaging
Beyond the caveats regarding COVID-19, the use of a simple CDR to reliably exclude pneumonia should have no barrier to implementation in an outpatient primary care setting or ED, although there could be reluctance on the part of both providers and patients to fully embrace this simple tool without a confirmatory chest x-ray.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
1. Marchello CS, Ebell MH, Dale AP, et al. Signs and symptoms that rule out community-acquired pneumonia in outpatient adults: a systematic review and meta-analysis. J Am Board Fam Med. 2019;32:234-247.
2. St Sauver JL, Warner DO, Yawn BP, et al. Why patients visit their doctors: assessing the most prevalent conditions in a defined American population. Mayo Clin Proc. 2013;88:56-67.
3. CDC. National Center for Health Statistics. National Hospital Ambulatory Medical Care Survey: 2017. Emergency Department Summary Tables. Accessed March 24, 2021. www.cdc.gov/nchs/data/nhamcs/web_tables/2017_ed_web_tables-508.pdf
4. Jain S, Self WH, Wunderink RG, et al; CDC EPIC Study Team. Community-acquired pneumonia requiring hospitalization among US adults. N Engl J Med. 2015;373:415-427.
5. Heckerling PS, Tape TG, Wigton RS, et al. Clinical prediction rule for pulmonary infiltrates. Ann Intern Med. 1990;113:664-670.
6. Diehr P, Wood RW, Bushyhead J, et al. Prediction of pneumonia in outpatients with acute cough—a statistical approach. J Chronic Dis. 1984;37:215-225.
7. O’Brien WT Sr, Rohweder DA, Lattin GE Jr, et al. Clinical indicators of radiographic findings in patients with suspected community-acquired pneumonia: who needs a chest x-ray? J Am Coll Radiol. 2006;3:703-706.
8. Ebrahimzadeh A, Mohammadifard M, Naseh G, et al. Clinical and laboratory findings in patients with acute respiratory symptoms that suggest the necessity of chest x-ray for community-acquired pneumonia. Iran J Radiol. 2015;12:e13547.
9. Saldías PF, Cabrera TD, de Solminihac LI, et al. Valor predictivo de la historia clínica y examen físico en el diagnóstico de neumonía del adulto adquirida en la comunidad [Predictive value of history and physical examination for the diagnosis of community-acquired pneumonia in adults]. Abstract in English. Rev Med Chil. 2007;135:143-152.
10. Whiting PF, Rutjes AWS, Westwood ME, et al; QUADAS-2 Group. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155:529-536.
1. Marchello CS, Ebell MH, Dale AP, et al. Signs and symptoms that rule out community-acquired pneumonia in outpatient adults: a systematic review and meta-analysis. J Am Board Fam Med. 2019;32:234-247.
2. St Sauver JL, Warner DO, Yawn BP, et al. Why patients visit their doctors: assessing the most prevalent conditions in a defined American population. Mayo Clin Proc. 2013;88:56-67.
3. CDC. National Center for Health Statistics. National Hospital Ambulatory Medical Care Survey: 2017. Emergency Department Summary Tables. Accessed March 24, 2021. www.cdc.gov/nchs/data/nhamcs/web_tables/2017_ed_web_tables-508.pdf
4. Jain S, Self WH, Wunderink RG, et al; CDC EPIC Study Team. Community-acquired pneumonia requiring hospitalization among US adults. N Engl J Med. 2015;373:415-427.
5. Heckerling PS, Tape TG, Wigton RS, et al. Clinical prediction rule for pulmonary infiltrates. Ann Intern Med. 1990;113:664-670.
6. Diehr P, Wood RW, Bushyhead J, et al. Prediction of pneumonia in outpatients with acute cough—a statistical approach. J Chronic Dis. 1984;37:215-225.
7. O’Brien WT Sr, Rohweder DA, Lattin GE Jr, et al. Clinical indicators of radiographic findings in patients with suspected community-acquired pneumonia: who needs a chest x-ray? J Am Coll Radiol. 2006;3:703-706.
8. Ebrahimzadeh A, Mohammadifard M, Naseh G, et al. Clinical and laboratory findings in patients with acute respiratory symptoms that suggest the necessity of chest x-ray for community-acquired pneumonia. Iran J Radiol. 2015;12:e13547.
9. Saldías PF, Cabrera TD, de Solminihac LI, et al. Valor predictivo de la historia clínica y examen físico en el diagnóstico de neumonía del adulto adquirida en la comunidad [Predictive value of history and physical examination for the diagnosis of community-acquired pneumonia in adults]. Abstract in English. Rev Med Chil. 2007;135:143-152.
10. Whiting PF, Rutjes AWS, Westwood ME, et al; QUADAS-2 Group. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155:529-536.
PRACTICE CHANGER
You can safely rule out community-acquired pneumonia (CAP)—without requiring a chest x-ray—in an otherwise healthy adult outpatient who has an acute cough, a normal pulmonary exam, and normal vital signs using this simple clinical decision rule (CDR).1
STRENGTH OF RECOMMENDATION
A: Based on a systematic review of prospective case-control studies and randomized controlled trials in the outpatient setting.1
Marchello CS, Ebell MH, Dale AP, et al. Signs and symptoms that rule out community-acquired pneumonia in outpatient adults: a systematic review and meta-analysis. J Am Board Fam Med. 2019;32:234-247.
Integrating primary care into a community mental health center
THE CASE
John C* is a 57-year-old man with hypertension, hyperlipidemia, and schizophrenia who followed up with a psychiatrist monthly at the community mental health center (CMHC). He had no primary care doctor. His psychiatrist referred him to our new Integrated Behavioral Health (IBH) clinic, also located in the CMHC, to see a family physician for complaints of urinary frequency, blurred vision, thirst, and weight loss. An on-site fingerstick revealed his blood glucose to be 357 mg/dL. Given the presumptive diagnosis of diabetes, we checked his bloodwork, prescribed metformin, and referred him for diabetes education. That evening, his lab results showed a hemoglobin A1C > 17%, a basic metabolic panel with an anion gap, ketones in the urine, and a low C-peptide level. We were unable to reach Mr. C by phone for further management.
● How would you proceed with this patient?
* The patient’s name has been changed to protect his identity.
Coordination of behavioral health and primary care can take many forms, from simple synchronized care via referral, to co-located services, to fully integrated care.1 Reverse integration, the subject of this article, is the provision of primary care in mental health or substance use disorder treatment settings. Published evidence to date regarding this model is minimal. This article describes our experience in developing a model of reverse integration in which family physicians and nurse practitioners are embedded in a CMHC with psychiatric providers, counselors, and social workers to jointly address physical and behavioral health care issues and address social determinants of health.
The rationale for reverse integration
Many individuals with serious mental illness (SMI), including schizophrenia and bipolar disorder, have rates of comorbid chronic physical health conditions that are higher than in the general population. These conditions include obesity, diabetes, metabolic syndrome, cardiovascular disease, chronic obstructive pulmonary disease, HIV, viral hepatitis, and tuberculosis.2 Outcomes in the SMI group are also considerably worse than in the general population. People with SMI have a demonstrated loss of up to 32 years of potential life per patient compared with the general-population average, primarily due to poor physical health.2 Maladaptive health behaviors such as poor diet, lack of physical activity, tobacco use, and substance use contribute to this increased mortality.2,3 Social determinants of poor health are more prevalent among individuals with SMI, and a relative inability to collaborate in one’s own health care due to psychiatric symptoms further exacerbates the challenges.
Many individuals with SMI receive psychiatric care, case management, counseling, and psychosocial services in CMHCs. Their psychiatric caregiver may be their only regular health care provider. Family physicians—who receive residency training in behavioral health and social determinants of health in community settings—are distinctively capable of improving overall health care outcomes of patients with SMI.
THE ADVANTAGES OF A REVERSE-INTEGRATION PRACTICE MODEL
Delivering primary care in a CMHC with a behavioral health team can benefit patients with SMI and be a satisfying practice for family physicians. Specifically, family physicians
- find that caring for complex patients can be less stressful because they benefit from the knowledge and resources of the CMHC team. The CMHC team offers case management, counseling, employment services, and housing assistance, so the primary care provider and patient are well supported.
- see fewer patients per hour due to higher visit complexity (and coding). In our experience, team-based care and additional time with patients make complex patient care more enjoyable and less frustrating.
- benefit from a situation in which patients feel safe because the CMHC support staff knows them well.
Continue to: Other benefits
Other benefits. When primary care is delivered in a CMHC, there are “huddles” and warm handoffs that allow for bidirectional collaboration and care coordination between the primary care and behavioral health teams in real time. In addition, family medicine residents, medical students, and other learners can be successfully included in an IBH clinic for patients with SMI. The behavioral health team provides the mentorship, education, and modelling of skills needed to work with this population, including limit-setting, empathy, patience, and motivational interviewing.
For their part, learners self-report increased comfort and interest in working with underserved populations and improved awareness of the social determinants of health after these experiences.4,5 Many patients at CMHCs are comfortable working with learners if continuity is maintained with a primary care provider.
Challenges we’ve faced, tips we can offer
For primary care providers, the unique workplace culture, terminology, and patient population encountered in a CMHC can be challenging. Also challenging can be the combining of things such as electronic medical records (EMRs).
Culture. The CMHC model focuses on team-based care spearheaded by case managers, in contrast to the traditional family medicine model wherein the physician coordinates services. Case managers provide assessments of client stability and readiness to be seen. They also attend primary care visits to support patient interactions, provide important psychosocial information, and assess adherence to care.
Terminology. It’s not always easy to shift to different terminology in this culture. Thus, orientation needs to address things such as the use of the word “patient,” rather than “client,” when charting.
Continue to: The complexities of the patient population
The complexities of the patient population. Many patients treated at a CMHC have a history of trauma, anxiety, and paranoia, requiring adjustments to exam practices such as using smaller speculums, providing more physical space, and offering to leave examination room doors open while patients are waiting.
In addition, individuals with SMI often have multiple health conditions, but they may become uncomfortable with physical closeness, grow tired of conversation, or feel overwhelmed when asked to complete multiple tasks in 1 visit. As a result, visits may need to be shorter and more frequent.
It’s also worth noting that, in our experience, CMHC patients may have a higher no-show rate than typical primary care clinics, requiring flexibility in scheduling. To fill vacant primary care time slots, our front desk staff uses strategies such as waiting lists and offering walk-in visits to patients who are on site for other services.
Ideally, IBH clinics use a single, fully integrated EMR, but this is not always possible. If the primary care and CMHC EMR systems do not connect, then record review and repeat documentation is needed, while care is taken to adhere to the confidentiality standards of a particular state.
Standards of care and state policies. Written standards of care, procedures, and accreditation in CMHCs rarely include provisions for common primary care practice, such as vaccines, in-clinic medications, and implements for simple procedures. To provide these services in our clinic, we ordered/stocked the needed supplies and instituted protocols that mirrored our other outpatient family medicine clinical sites.
Continue to: Some states may have...
Some states may have policies that prevent reimbursement for mental health and primary care services billed on the same day. Seeing a family physician and a psychiatry provider on the same day is convenient for patients and allows for collaboration between providers. But reimbursement rules can vary by state, so starting an IBH clinic like this requires research into local billing regulations.
WANT TO START AN INTEGRATED BEHAVIORAL HEALTH CLINIC?
Detailed instruction on starting a primary care clinic in a CMHC is beyond the scope of this article. However, the Substance Abuse and Mental Health Services Administration provides guidance on integrating primary care services into a local CMHC.6 Start by performing a baseline needs assessment of the CMHC and its patients to help guide clinic design. Leadership buy-in is key.
Leadership must provide adequate time and financial and technological support. This includes identifying appropriate space for primary care, offering training on using the EMR, and obtaining support from Finance to develop a realistic and competent business plan with an appropriate budgetary runway for start-up. (This may include securing grants in the beginning.)
We recommend starting small and expanding slowly. Once the clinic is operational, formal pathways for good communication are necessary. This includes holding regular team meetings to develop and revise clinic workflows—eg, patient enrollment, protocols, and administrative procedures such as managing medications and vaccinations—as well as addressing space, staffing, and training issues that arise. The IBH transitional leadership structure must include clinicians from both primary care and behavioral health, support staff, and the administration. Finally, you need the right staff—people who are passionate, flexible, and interested in trying something new.
THE CASE
The next day, an outreach was made to the CMHC nurse, who had the case manager go to Mr. C’s house and bring him to the CMHC for education on insulin injection, glucometer use, and diabetes nutrition. Mr. C was prescribed long-acting insulin at bedtime; his metformin was stopped and he was monitored closely.
Continue to: Mr. C now calls...
Mr. C now calls the CMHC nurse every few weeks to report his blood sugar levels, have his insulin dose adjusted, or just say “hello.” He continues to see his psychiatrist every month and his family physician every 4 months. The team collaborates as issues arise. His diabetes has been well controlled for more than 3 years.
The IBH clinic has grown in number of patients and family medicine providers, is self-sustaining, and has expanded services to include hepatitis C treatment.
1. Rajesh R, Tampi R, Balachandran S. The case for behavioral health integration into primary care. J Fam Pract. 2019;68:278-284.
2. Parks J, Svendsen D, Singer P, et al. Morbidity and Mortality in People with Serious Mental Illness. 2006. Accessed March 24, 2021. www.nasmhpd.org/sites/default/files/Mortality%20and%20Morbidity%20Final%20Report%208.18.08_0.pdf
3. Dickerson F, Stallings, CR, Origoni AE, et al. Cigarette Smoking among persons with schizophrenia or bipolar disorder in routine clinical settings, 1999-2011. Psychiatr Serv. 2013;64:44-50.
4. Raddock M, Antenucci C, Chrisman L. Innovative primary care training: caring for the urban underserved. Innovations in Education Poster Session, Case School of Medicine Annual Education Retreat, Cleveland, OH, March 3, 2016.
5. Berg K, Antenucci C, Raddock M, et al. Deciding to care: medical students and patients’ social circumstances. Poster: Annual meeting of the Society for Medical Decision Making. Pittsburgh, PA. October 2017.
6. Heath B, Wise Romero P, and Reynolds K. A standard framework for levels of integrated healthcare. Washington, D.C. SAMHSA-HRSA Center for Integrated Health Solutions. March 2013. Accessed March 24, 2021. www.pcpcc.org/resource/standard-framework-levels-integrated-healthcare
THE CASE
John C* is a 57-year-old man with hypertension, hyperlipidemia, and schizophrenia who followed up with a psychiatrist monthly at the community mental health center (CMHC). He had no primary care doctor. His psychiatrist referred him to our new Integrated Behavioral Health (IBH) clinic, also located in the CMHC, to see a family physician for complaints of urinary frequency, blurred vision, thirst, and weight loss. An on-site fingerstick revealed his blood glucose to be 357 mg/dL. Given the presumptive diagnosis of diabetes, we checked his bloodwork, prescribed metformin, and referred him for diabetes education. That evening, his lab results showed a hemoglobin A1C > 17%, a basic metabolic panel with an anion gap, ketones in the urine, and a low C-peptide level. We were unable to reach Mr. C by phone for further management.
● How would you proceed with this patient?
* The patient’s name has been changed to protect his identity.
Coordination of behavioral health and primary care can take many forms, from simple synchronized care via referral, to co-located services, to fully integrated care.1 Reverse integration, the subject of this article, is the provision of primary care in mental health or substance use disorder treatment settings. Published evidence to date regarding this model is minimal. This article describes our experience in developing a model of reverse integration in which family physicians and nurse practitioners are embedded in a CMHC with psychiatric providers, counselors, and social workers to jointly address physical and behavioral health care issues and address social determinants of health.
The rationale for reverse integration
Many individuals with serious mental illness (SMI), including schizophrenia and bipolar disorder, have rates of comorbid chronic physical health conditions that are higher than in the general population. These conditions include obesity, diabetes, metabolic syndrome, cardiovascular disease, chronic obstructive pulmonary disease, HIV, viral hepatitis, and tuberculosis.2 Outcomes in the SMI group are also considerably worse than in the general population. People with SMI have a demonstrated loss of up to 32 years of potential life per patient compared with the general-population average, primarily due to poor physical health.2 Maladaptive health behaviors such as poor diet, lack of physical activity, tobacco use, and substance use contribute to this increased mortality.2,3 Social determinants of poor health are more prevalent among individuals with SMI, and a relative inability to collaborate in one’s own health care due to psychiatric symptoms further exacerbates the challenges.
Many individuals with SMI receive psychiatric care, case management, counseling, and psychosocial services in CMHCs. Their psychiatric caregiver may be their only regular health care provider. Family physicians—who receive residency training in behavioral health and social determinants of health in community settings—are distinctively capable of improving overall health care outcomes of patients with SMI.
THE ADVANTAGES OF A REVERSE-INTEGRATION PRACTICE MODEL
Delivering primary care in a CMHC with a behavioral health team can benefit patients with SMI and be a satisfying practice for family physicians. Specifically, family physicians
- find that caring for complex patients can be less stressful because they benefit from the knowledge and resources of the CMHC team. The CMHC team offers case management, counseling, employment services, and housing assistance, so the primary care provider and patient are well supported.
- see fewer patients per hour due to higher visit complexity (and coding). In our experience, team-based care and additional time with patients make complex patient care more enjoyable and less frustrating.
- benefit from a situation in which patients feel safe because the CMHC support staff knows them well.
Continue to: Other benefits
Other benefits. When primary care is delivered in a CMHC, there are “huddles” and warm handoffs that allow for bidirectional collaboration and care coordination between the primary care and behavioral health teams in real time. In addition, family medicine residents, medical students, and other learners can be successfully included in an IBH clinic for patients with SMI. The behavioral health team provides the mentorship, education, and modelling of skills needed to work with this population, including limit-setting, empathy, patience, and motivational interviewing.
For their part, learners self-report increased comfort and interest in working with underserved populations and improved awareness of the social determinants of health after these experiences.4,5 Many patients at CMHCs are comfortable working with learners if continuity is maintained with a primary care provider.
Challenges we’ve faced, tips we can offer
For primary care providers, the unique workplace culture, terminology, and patient population encountered in a CMHC can be challenging. Also challenging can be the combining of things such as electronic medical records (EMRs).
Culture. The CMHC model focuses on team-based care spearheaded by case managers, in contrast to the traditional family medicine model wherein the physician coordinates services. Case managers provide assessments of client stability and readiness to be seen. They also attend primary care visits to support patient interactions, provide important psychosocial information, and assess adherence to care.
Terminology. It’s not always easy to shift to different terminology in this culture. Thus, orientation needs to address things such as the use of the word “patient,” rather than “client,” when charting.
Continue to: The complexities of the patient population
The complexities of the patient population. Many patients treated at a CMHC have a history of trauma, anxiety, and paranoia, requiring adjustments to exam practices such as using smaller speculums, providing more physical space, and offering to leave examination room doors open while patients are waiting.
In addition, individuals with SMI often have multiple health conditions, but they may become uncomfortable with physical closeness, grow tired of conversation, or feel overwhelmed when asked to complete multiple tasks in 1 visit. As a result, visits may need to be shorter and more frequent.
It’s also worth noting that, in our experience, CMHC patients may have a higher no-show rate than typical primary care clinics, requiring flexibility in scheduling. To fill vacant primary care time slots, our front desk staff uses strategies such as waiting lists and offering walk-in visits to patients who are on site for other services.
Ideally, IBH clinics use a single, fully integrated EMR, but this is not always possible. If the primary care and CMHC EMR systems do not connect, then record review and repeat documentation is needed, while care is taken to adhere to the confidentiality standards of a particular state.
Standards of care and state policies. Written standards of care, procedures, and accreditation in CMHCs rarely include provisions for common primary care practice, such as vaccines, in-clinic medications, and implements for simple procedures. To provide these services in our clinic, we ordered/stocked the needed supplies and instituted protocols that mirrored our other outpatient family medicine clinical sites.
Continue to: Some states may have...
Some states may have policies that prevent reimbursement for mental health and primary care services billed on the same day. Seeing a family physician and a psychiatry provider on the same day is convenient for patients and allows for collaboration between providers. But reimbursement rules can vary by state, so starting an IBH clinic like this requires research into local billing regulations.
WANT TO START AN INTEGRATED BEHAVIORAL HEALTH CLINIC?
Detailed instruction on starting a primary care clinic in a CMHC is beyond the scope of this article. However, the Substance Abuse and Mental Health Services Administration provides guidance on integrating primary care services into a local CMHC.6 Start by performing a baseline needs assessment of the CMHC and its patients to help guide clinic design. Leadership buy-in is key.
Leadership must provide adequate time and financial and technological support. This includes identifying appropriate space for primary care, offering training on using the EMR, and obtaining support from Finance to develop a realistic and competent business plan with an appropriate budgetary runway for start-up. (This may include securing grants in the beginning.)
We recommend starting small and expanding slowly. Once the clinic is operational, formal pathways for good communication are necessary. This includes holding regular team meetings to develop and revise clinic workflows—eg, patient enrollment, protocols, and administrative procedures such as managing medications and vaccinations—as well as addressing space, staffing, and training issues that arise. The IBH transitional leadership structure must include clinicians from both primary care and behavioral health, support staff, and the administration. Finally, you need the right staff—people who are passionate, flexible, and interested in trying something new.
THE CASE
The next day, an outreach was made to the CMHC nurse, who had the case manager go to Mr. C’s house and bring him to the CMHC for education on insulin injection, glucometer use, and diabetes nutrition. Mr. C was prescribed long-acting insulin at bedtime; his metformin was stopped and he was monitored closely.
Continue to: Mr. C now calls...
Mr. C now calls the CMHC nurse every few weeks to report his blood sugar levels, have his insulin dose adjusted, or just say “hello.” He continues to see his psychiatrist every month and his family physician every 4 months. The team collaborates as issues arise. His diabetes has been well controlled for more than 3 years.
The IBH clinic has grown in number of patients and family medicine providers, is self-sustaining, and has expanded services to include hepatitis C treatment.
THE CASE
John C* is a 57-year-old man with hypertension, hyperlipidemia, and schizophrenia who followed up with a psychiatrist monthly at the community mental health center (CMHC). He had no primary care doctor. His psychiatrist referred him to our new Integrated Behavioral Health (IBH) clinic, also located in the CMHC, to see a family physician for complaints of urinary frequency, blurred vision, thirst, and weight loss. An on-site fingerstick revealed his blood glucose to be 357 mg/dL. Given the presumptive diagnosis of diabetes, we checked his bloodwork, prescribed metformin, and referred him for diabetes education. That evening, his lab results showed a hemoglobin A1C > 17%, a basic metabolic panel with an anion gap, ketones in the urine, and a low C-peptide level. We were unable to reach Mr. C by phone for further management.
● How would you proceed with this patient?
* The patient’s name has been changed to protect his identity.
Coordination of behavioral health and primary care can take many forms, from simple synchronized care via referral, to co-located services, to fully integrated care.1 Reverse integration, the subject of this article, is the provision of primary care in mental health or substance use disorder treatment settings. Published evidence to date regarding this model is minimal. This article describes our experience in developing a model of reverse integration in which family physicians and nurse practitioners are embedded in a CMHC with psychiatric providers, counselors, and social workers to jointly address physical and behavioral health care issues and address social determinants of health.
The rationale for reverse integration
Many individuals with serious mental illness (SMI), including schizophrenia and bipolar disorder, have rates of comorbid chronic physical health conditions that are higher than in the general population. These conditions include obesity, diabetes, metabolic syndrome, cardiovascular disease, chronic obstructive pulmonary disease, HIV, viral hepatitis, and tuberculosis.2 Outcomes in the SMI group are also considerably worse than in the general population. People with SMI have a demonstrated loss of up to 32 years of potential life per patient compared with the general-population average, primarily due to poor physical health.2 Maladaptive health behaviors such as poor diet, lack of physical activity, tobacco use, and substance use contribute to this increased mortality.2,3 Social determinants of poor health are more prevalent among individuals with SMI, and a relative inability to collaborate in one’s own health care due to psychiatric symptoms further exacerbates the challenges.
Many individuals with SMI receive psychiatric care, case management, counseling, and psychosocial services in CMHCs. Their psychiatric caregiver may be their only regular health care provider. Family physicians—who receive residency training in behavioral health and social determinants of health in community settings—are distinctively capable of improving overall health care outcomes of patients with SMI.
THE ADVANTAGES OF A REVERSE-INTEGRATION PRACTICE MODEL
Delivering primary care in a CMHC with a behavioral health team can benefit patients with SMI and be a satisfying practice for family physicians. Specifically, family physicians
- find that caring for complex patients can be less stressful because they benefit from the knowledge and resources of the CMHC team. The CMHC team offers case management, counseling, employment services, and housing assistance, so the primary care provider and patient are well supported.
- see fewer patients per hour due to higher visit complexity (and coding). In our experience, team-based care and additional time with patients make complex patient care more enjoyable and less frustrating.
- benefit from a situation in which patients feel safe because the CMHC support staff knows them well.
Continue to: Other benefits
Other benefits. When primary care is delivered in a CMHC, there are “huddles” and warm handoffs that allow for bidirectional collaboration and care coordination between the primary care and behavioral health teams in real time. In addition, family medicine residents, medical students, and other learners can be successfully included in an IBH clinic for patients with SMI. The behavioral health team provides the mentorship, education, and modelling of skills needed to work with this population, including limit-setting, empathy, patience, and motivational interviewing.
For their part, learners self-report increased comfort and interest in working with underserved populations and improved awareness of the social determinants of health after these experiences.4,5 Many patients at CMHCs are comfortable working with learners if continuity is maintained with a primary care provider.
Challenges we’ve faced, tips we can offer
For primary care providers, the unique workplace culture, terminology, and patient population encountered in a CMHC can be challenging. Also challenging can be the combining of things such as electronic medical records (EMRs).
Culture. The CMHC model focuses on team-based care spearheaded by case managers, in contrast to the traditional family medicine model wherein the physician coordinates services. Case managers provide assessments of client stability and readiness to be seen. They also attend primary care visits to support patient interactions, provide important psychosocial information, and assess adherence to care.
Terminology. It’s not always easy to shift to different terminology in this culture. Thus, orientation needs to address things such as the use of the word “patient,” rather than “client,” when charting.
Continue to: The complexities of the patient population
The complexities of the patient population. Many patients treated at a CMHC have a history of trauma, anxiety, and paranoia, requiring adjustments to exam practices such as using smaller speculums, providing more physical space, and offering to leave examination room doors open while patients are waiting.
In addition, individuals with SMI often have multiple health conditions, but they may become uncomfortable with physical closeness, grow tired of conversation, or feel overwhelmed when asked to complete multiple tasks in 1 visit. As a result, visits may need to be shorter and more frequent.
It’s also worth noting that, in our experience, CMHC patients may have a higher no-show rate than typical primary care clinics, requiring flexibility in scheduling. To fill vacant primary care time slots, our front desk staff uses strategies such as waiting lists and offering walk-in visits to patients who are on site for other services.
Ideally, IBH clinics use a single, fully integrated EMR, but this is not always possible. If the primary care and CMHC EMR systems do not connect, then record review and repeat documentation is needed, while care is taken to adhere to the confidentiality standards of a particular state.
Standards of care and state policies. Written standards of care, procedures, and accreditation in CMHCs rarely include provisions for common primary care practice, such as vaccines, in-clinic medications, and implements for simple procedures. To provide these services in our clinic, we ordered/stocked the needed supplies and instituted protocols that mirrored our other outpatient family medicine clinical sites.
Continue to: Some states may have...
Some states may have policies that prevent reimbursement for mental health and primary care services billed on the same day. Seeing a family physician and a psychiatry provider on the same day is convenient for patients and allows for collaboration between providers. But reimbursement rules can vary by state, so starting an IBH clinic like this requires research into local billing regulations.
WANT TO START AN INTEGRATED BEHAVIORAL HEALTH CLINIC?
Detailed instruction on starting a primary care clinic in a CMHC is beyond the scope of this article. However, the Substance Abuse and Mental Health Services Administration provides guidance on integrating primary care services into a local CMHC.6 Start by performing a baseline needs assessment of the CMHC and its patients to help guide clinic design. Leadership buy-in is key.
Leadership must provide adequate time and financial and technological support. This includes identifying appropriate space for primary care, offering training on using the EMR, and obtaining support from Finance to develop a realistic and competent business plan with an appropriate budgetary runway for start-up. (This may include securing grants in the beginning.)
We recommend starting small and expanding slowly. Once the clinic is operational, formal pathways for good communication are necessary. This includes holding regular team meetings to develop and revise clinic workflows—eg, patient enrollment, protocols, and administrative procedures such as managing medications and vaccinations—as well as addressing space, staffing, and training issues that arise. The IBH transitional leadership structure must include clinicians from both primary care and behavioral health, support staff, and the administration. Finally, you need the right staff—people who are passionate, flexible, and interested in trying something new.
THE CASE
The next day, an outreach was made to the CMHC nurse, who had the case manager go to Mr. C’s house and bring him to the CMHC for education on insulin injection, glucometer use, and diabetes nutrition. Mr. C was prescribed long-acting insulin at bedtime; his metformin was stopped and he was monitored closely.
Continue to: Mr. C now calls...
Mr. C now calls the CMHC nurse every few weeks to report his blood sugar levels, have his insulin dose adjusted, or just say “hello.” He continues to see his psychiatrist every month and his family physician every 4 months. The team collaborates as issues arise. His diabetes has been well controlled for more than 3 years.
The IBH clinic has grown in number of patients and family medicine providers, is self-sustaining, and has expanded services to include hepatitis C treatment.
1. Rajesh R, Tampi R, Balachandran S. The case for behavioral health integration into primary care. J Fam Pract. 2019;68:278-284.
2. Parks J, Svendsen D, Singer P, et al. Morbidity and Mortality in People with Serious Mental Illness. 2006. Accessed March 24, 2021. www.nasmhpd.org/sites/default/files/Mortality%20and%20Morbidity%20Final%20Report%208.18.08_0.pdf
3. Dickerson F, Stallings, CR, Origoni AE, et al. Cigarette Smoking among persons with schizophrenia or bipolar disorder in routine clinical settings, 1999-2011. Psychiatr Serv. 2013;64:44-50.
4. Raddock M, Antenucci C, Chrisman L. Innovative primary care training: caring for the urban underserved. Innovations in Education Poster Session, Case School of Medicine Annual Education Retreat, Cleveland, OH, March 3, 2016.
5. Berg K, Antenucci C, Raddock M, et al. Deciding to care: medical students and patients’ social circumstances. Poster: Annual meeting of the Society for Medical Decision Making. Pittsburgh, PA. October 2017.
6. Heath B, Wise Romero P, and Reynolds K. A standard framework for levels of integrated healthcare. Washington, D.C. SAMHSA-HRSA Center for Integrated Health Solutions. March 2013. Accessed March 24, 2021. www.pcpcc.org/resource/standard-framework-levels-integrated-healthcare
1. Rajesh R, Tampi R, Balachandran S. The case for behavioral health integration into primary care. J Fam Pract. 2019;68:278-284.
2. Parks J, Svendsen D, Singer P, et al. Morbidity and Mortality in People with Serious Mental Illness. 2006. Accessed March 24, 2021. www.nasmhpd.org/sites/default/files/Mortality%20and%20Morbidity%20Final%20Report%208.18.08_0.pdf
3. Dickerson F, Stallings, CR, Origoni AE, et al. Cigarette Smoking among persons with schizophrenia or bipolar disorder in routine clinical settings, 1999-2011. Psychiatr Serv. 2013;64:44-50.
4. Raddock M, Antenucci C, Chrisman L. Innovative primary care training: caring for the urban underserved. Innovations in Education Poster Session, Case School of Medicine Annual Education Retreat, Cleveland, OH, March 3, 2016.
5. Berg K, Antenucci C, Raddock M, et al. Deciding to care: medical students and patients’ social circumstances. Poster: Annual meeting of the Society for Medical Decision Making. Pittsburgh, PA. October 2017.
6. Heath B, Wise Romero P, and Reynolds K. A standard framework for levels of integrated healthcare. Washington, D.C. SAMHSA-HRSA Center for Integrated Health Solutions. March 2013. Accessed March 24, 2021. www.pcpcc.org/resource/standard-framework-levels-integrated-healthcare
Helping your obese patient achieve a healthier weight
In 2015-2016, almost 40% of adults and 18.5% of children ages 2 to 19 years in the United States met the definition for obesity—a chronic, relapsing, multifactorial, neurobehavioral disease that results in adverse metabolic, biomechanical, and psychosocial health consequences.1,2
Tremendous resources have been invested in research, policy development, and public education to try to prevent obesity and its related complications. Despite this, the obesity epidemic has worsened. Here, we explore how to evaluate and treat obese patients in a primary care setting based on the evidence and our experience seeing patients specifically for weight management in a family medicine residency teaching clinic. Pharmacotherapy and surgery, while often helpful, are outside the scope of this article.
It begins withan obesity-friendly office
Patients may have reservations about health care interactions specific to obesity, so it is important to invite them into a setting that facilitates trust and encourages collaboration. Actively engage patients with unhealthy weight by creating an environment where they feel comfortable. Offer wide chairs without armrests, which will easily accommodate patients of all sizes, and ensure that scales have a weight capacity > 400 lb. Communicate a message to patients, via waiting room materials and videos, that focuses on health rather than on weight or body mass index (BMI).
Understand the patient’s goals and challenges
Most (although not all) family physicians will see obese patients in the context of a visit for diabetes, hypertension, or another condition. However, we feel that having visits specifically to address weight in the initial stages of weight management is helpful. The focus of an initial visit should be getting to know how obesity has affected the patient and what his or her motive is in attempting to lose weight. Explore previous attempts at weight loss and establish what the patient’s highest weight has been, as this will impact weight-loss goals. For example, if a patient has weighed > 300 lb all her adult life, it will be extremely difficult to maintain a weight loss of 150 lb.
What else to ask about. Discuss stressors that may be causing increased food intake or poor food choices, including hunger, anger, loneliness, and sleep difficulties. Multidisciplinary care including a psychologist can aid in addressing these issues. Ask patients if they keep a food diary (and if not, recommend that they start), as food diaries are often helpful in elucidating eating and drinking patterns. Determine a patient’s current and past levels of physical activity, as this will guide the fitness goals you develop for him or her.
Screen for psychosocial disorders
As noted earlier, the physical component of obesity is commonly associated with mood disorders such as anxiety and depression.2 This requires a multidisciplinary team effort to facilitate healing in the patient struggling with obesity.
Screening for depression and anxiety using standardized tools such as the Patient Health Questionnaire-9 or the Generalized Anxiety Disorder-7 is encouraged in patients who are overweight or obese. Positive screens should be addressed as part of the patient’s treatment plan, as untreated depression and anxiety can inhibit success with weight loss. Be mindful that many medications commonly used to treat these conditions can impair weight loss and even promote weight gain.
Continue to: Don't overlook binge-eating disorders
Don’t overlook binge-eating disorders. Screening specifically for binge-eating disorders is important, given the implications on treatment. The US Department of Veterans Affairs developed a single-item tool for this purpose, the VA Binge Eating Screener. The validated questionnaire asks, “On average, how often have you eaten extremely large amounts of food at one time and felt that your eating was out of control at that time?” Response options are: “Never,” “< 1 time/week,” “1 time/week,” “2-4 times/week,” and “5+ times/week.” A response of ≥ 2 times/week had a sensitivity of 88.9% and specificity of 83.2% for binge-eating disorder.3
Patients with positive screens should undergo psychotherapy and consider pharmacotherapy with lisdexamfetamine as part of their treatment plan. Caution should be used if recommending intermittent fasting for someone with binge-eating disorder.
Evaluate for underlying causes and assess for comorbidities
Review the patient’s current medication list and history. Many medications can cause weight gain, and weight loss can often be achieved by deprescribing such medications. When feasible, prescribe an alternative medication with a more favorable weight profile. A previous article in The Journal of Family Practice addresses this in more depth.4
Laboratory and other testing
Laboratory analysis should primarily be focused on determining treatment alterations specific to underlying pathophysiology. Tests to consider ordering are outlined in the Table
Diabetes and insulin resistance. The American Diabetes Association recommends screening patients who are overweight or obese and have an additional risk factor for diabetes.5 This can be done by obtaining a fasting glucose level, hemoglobin A1C, or a 2-hour oral glucose tolerance test.
Continue to: Since it is known that...
Since it is known that insulin resistance increases the risk for coronary heart disease6 and can be treated effectively,7 we recommend testing for insulin resistance in patients who do not already have impaired fasting glucose, prediabetes, type 2 diabetes, or impaired glucose tolerance. The homeostatic model assessment for insulin resistance (HOMA-IR)8 is a measure of insulin resistance and can be calculated from the fasting insulin and fasting glucose levels. This measure should not be done in isolation, but it can be a useful adjunct in identifying patients with insulin resistance and directing treatment.
If there is evidence of diabetes or insulin resistance, consider treatment with metformin ± initiation of a low-carbohydrate diet.
Hypothyroidism. Consider screening for thyroid dysfunction with a thyroid-stimulating hormone level, if it has not been checked previously.
Renal abnormalities. When serum creatinine levels and glomerular filtration rate indicate chronic kidney disease, consider recommending a protein-restricted diet and adjust medications according to renal dosing protocols, as indicated.
Liver abnormalities, including nonalcoholic fatty liver disease (NAFLD). Monitor aspartate aminotransferase and alanine aminotransferase for resolution of elevations as weight loss is achieved. If abnormalities persist, consider ordering a liver ultrasound. Traditionally, low-calorie diets have been prescribed to treat NAFLD, but evidence shows that low-carbohydrate diets can also be effective.9
Continue to: Hypertriglyceridemia and low high-density lipoprotein (HDL) levels
Hypertriglyceridemia and low high-density lipoprotein (HDL) levels. Obtain a lipid panel if one has not been completed within the past several years, as hypertriglyceridemia and low HDL can improve dramatically with specific dietary changes.7 Observe trends to assess for resolution of lipid abnormalities as weight loss is achieved.
Gout. Consider checking a uric acid level if you are thinking about recommending a low-carbohydrate diet, particularly in patients with a history of gout, as this may temporarily increase the risk of gout flare.
Hypovitaminosis D. If the patient’s vitamin D level is low, consider appropriate supplementation to support the patient’s overall health. While vitamin D deficiency is common in obesity, the role of supplementation in this population is unclear.
Cardiovascular disease. Consider ordering an electrocardiogram, particularly if you are thinking of prescribing medication therapy. Use caution with initiation of certain medications, such as phentermine or diethylproprion, in the presence of arrhythmias or active cardiovascular disease.
Obstructive sleep apnea. Sleep health is important to address, since obesity is one of the most significant risk factors for obstructive sleep apnea.10 If your patient is given a diagnosis of OSA following a sleep study, consider treatment with continuous positive airway pressure (CPAP), although there are conflicting studies regarding the effects of CPAP therapy in OSA on weight.11,12
Continue to: Provide guidance on lifestyle changes
Provide guidance on lifestyle changes
Addressing obesity with patients can be challenging in a busy primary care clinic, but it is imperative to helping patients achieve overall health. Counseling on nutrition and physical activity is an important part of this process.
There is no one-size-fits-all approach to nutrition counseling. Focus on creating individualized plans through which patients can achieve success. Some guidance follows, but also beware of common pitfalls that we have observed in clinical practice which, when addressed, can enable significant weight loss (see “Common pitfalls inhibiting weight loss”).
SIDEBAR
Common pitfalls inhibiting weight loss
On the part of the patient:
- Continuing to consume substantial amounts of high-calorie drinks.
- Taking in excessive amounts of sugar-rich foods, including cough drops.
- Using non-nutritive sweeteners (eg, aspartame, saccharin, sucralose, and erythritol). Although the mechanism is not certain, some people are able to lose weight while consuming these substances, while others are not.
On the part of the provider:
- Prescribing a diet that the patient cannot sustain long term.
- Overlooking the issue of food availability for the patient.
Choose an approach that works for the patient. Commonly prescribed diets to address obesity include, but are not limited to, Atkins, Dietary Approaches to Stop Hypertension (DASH), Glycemic Index, Mediterranean, Ornish, Paleolithic, Zone, whole food plant-based, and ketogenic. We attempt to engage patients in making the decision on what food choices are appropriate for them considering their food availability, culture, and belief systems. For patients who prefer a vegan or vegetarian whole food diet, it is important to note that these diets are generally deficient in vitamin B12 and omega 3 fatty acids, so supplementing these should be considered.
Rather than focus on a specific diet, which may not be sustainable long term, encourage healthy eating habits. Low-carbohydrate diets have been shown to promote greater weight loss compared to low-fat diets.13,14 Low-calorie diets can also be quite effective in promoting short-term weight loss. In our clinic, when weight loss is the primary goal, patients are typically encouraged to focus on either calorie or carbohydrate restriction in the initial stages of weight loss.
Eliminate sugar and refined carbohydrates. While rigorous mortality data are not available, more recent trials have demonstrated significant improvements in atherosclerotic cardiovascular disease risk markers, including weight reduction and diabetes reversal, when following a diet that markedly decreases carbohydrate intake, especially sugar and refined carbohydrates.7,14-17
Continue to: We recommend that patients focus...
We recommend that patients focus on eliminating sweetened beverages, such as soft drinks, sports drinks, energy drinks, vitamin water, sweet tea, chocolate milk, and Frappuccinos. We also recommend substantially limiting or eliminating fruit juices and fruit smoothies due to their high sugar content. For example, 8 oz of orange juice contains 26 g of carbohydrates, which is almost as much as 8 oz of soda.
Compared with eating whole fruit, consuming fruit juice has demonstrated a small amount of weight gain in young children and adults.18,19 It also has shown a higher insulin response compared with eating the same amount of carbohydrates in whole fruit.20 Better options to drink include water, unsweetened tea, and black coffee. Also, avoid ultra-processed carbohydrates from foods such as breads, cereals, and pastries, as they have similar effects on blood glucose when compared to sugar.21
Greatly restrict highly processed foods. The evidence suggests that the availability of processed food is associated with increasing obesity.22 Simple advice to offer your patients is to encourage them to shop the perimeter of the grocery store, where fresh produce, meat, and dairy products are primarily located, and avoid the inner aisles, which contain primarily processed foods. Choosing food items with 5 or fewer ingredients is a starting point when teaching patients to read labels.
Consider limiting saturated fats. In 1977, the Dietary Guidelines for Americans recommended that Americans eat no more than 30% of total energy intake from fat and less than 10% of total energy intake from saturated fat; however, no randomized controlled trials had been done that supported this recommendation and epidemiologic data supporting it were weak.23
The 2015 Dietary Guidelines continue to recommend limiting total energy intake from saturated fats.24 While there may be a small decrease in cardiovascular risk with a reduction of saturated fat intake and replacement with unsaturated fats, no overall mortality benefit has been demonstrated.24,25 More research is needed in this area to guide patients in decisions regarding consumption of saturated fats and what types of unsaturated fats are best for their health.
Continue to: Eat only 3 meals per day
Eat only 3 meals per day, but aim for fewer than that. The prescription of fasting is a modality that can be used for weight loss and improved health. Fasting has been a prescribed healing practice for thousands of years.26 It is a practice that virtually every major religion in the world embraces. Studies have demonstrated fasting to be safe and effective in the setting of obesity without significant comorbidities, and it may promote weight loss and metabolic health.26-29
There are multiple types of intermittent fasting. A practical way for patients to start is by restricting the number of hours in which they eat or drink calorie-containing beverages to 8 hours per day. In our experience, this regimen is easier for most patients to follow than alternate-day or other longer fasts. While there has been caution in the prescription of intermittent fasting due to concerns about causing eating disorders, a recent small study did not demonstrate increased risk of eating disorders with daily intermittent fasting.30
Participate in healthy exercise. Nonpharmacologic office-based strategies for treating obesity have generally focused on increasing exercise and decreasing caloric intake.31 While exercise has significant health benefits, including preventing weight regain, evidence does not support monotherapy with exercise as an effective long-term weight-loss strategy.32 There are no studies available that adequately support prescribing an exact dose of exercise.33 Generally, less than 150 minutes of exercise per week is not effective and more than that does have a dose-related response.33
Follow up to help patients stay on target
There is no ideal interval for follow-up visits. However, frequent visits—anywhere from weekly to monthly—in the initial stages of weight loss increase the patient’s sense of accountability and, in our experience, seem to be helpful.
Patients may also choose to track their progress by weighing themselves regularly. A small study published in the International Journal of Obesity found that patients who weighed themselves daily had greater and more sustained weight loss than those who didn’t.34 But the decision of whether to weigh one’s self at home should be individualized for each patient.
CORRESPONDENCE
Wesley Eichorn, DO, 1000 Oakland Drive, Kalamazoo, MI 49008; [email protected]
1. Hales CM, Carroll MD, Fryar CD, et al. Prevalence of obesity among adults and youth: United States, 2015-2016 key findings data from the National Health and Nutrition Examination Survey. NCHS Data Brief. 2017;(288):1-8.
2. Seger JC, Horn DB, Westman EC, et al. Obesity Algorithm, presented by the Obesity Medicine Association. Accessed March 5, 2021. www.obesityalgorithm.org. 2016-2017
3. Dorflinger LM, Ruser CB, Masheb RM. A brief screening measure for binge eating in primary care. Eat Behav. 2017;26:163-166. https://doi.org/10.1016/j.eatbeh.2017.03.009
4. Saunders KH, Igel LI, Shukla AP, et al. Drug-induced weight gain: rethinking our choices. J Fam Pract. 2016;65:780-788.
5. American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019;42(suppl 1):S13-S28. https://doi.org/10.2337/dc19-S002
6. Reaven G. Insulin resistance and coronary heart disease in nondiabetic individuals. Arterioscler Thromb Vasc Biol. 2012;32:1754-1759. https://doi.org/10.1161/ATVBAHA.111.241885/-/DC1
7. Hallberg S, McKenzie A, Williams P, et al. Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year: an open-label, non-randomized, controlled study. Diabetes Ther. 2018;9:583-612. https://doi.org/10.6084/m9.figshare
8. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27:1487-1495.
9. Vilar-Gomez E, Athinarayanan SJ, Adams RN, et al. Post hoc analyses of surrogate markers of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis in patients with type 2 diabetes in a digitally supported continuous care intervention: an open-label, non-randomised controlled study. BMJ Open. 2019;9:e023597. https://doi.org/10.1136/bmjopen-2018-023597
10. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea. Am J Respir Crit Care Med. 2002;165:1217-1239. https://doi.org/10.1164/rccm.2109080
11. Drager LF, Brunoni AR, Jenner R, et al. Effects of CPAP on body weight in patients with obstructive sleep apnoea: a meta-analysis of randomised trials. Thorax. 2015;70:258-264. https://doi.org/10.1136/thoraxjnl-2014-205361
12. Bosworth T. CPAP use associated with greater weight loss in obese patients with sleep apnea. CHEST Physician. Published March 29, 2019. Accessed March 5, 2021. www.mdedge.com/chestphysician/article/197827/sleep-medicine/cpap-use-associated-greater-weight-loss-obese-patients
13. Tobias DK, Chen M, Manson JAE, et al. Effect of low-fat diet interventions versus other diet interventions on long-term weight change in adults: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2015;3:968-979. https://doi.org/10.1016/S2213-8587(15)00367-8
14. Sackner-Bernstein J, Kanter D, Kaul S. Dietary intervention for overweight and obese adults: comparison of low-carbohydrate and low-fat diets: a meta-analysis. PLoS One. 2015;10:e0139817. https://doi.org/10.1371/journal.pone.0139817
15. Bezerra Bueno N, Vieira De Melo IS, Lima De Oliveira S, et al. Very-low-carbohydrate ketogenic diet v low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. Br J Nutr. 2013;110:1178-1187. https://doi.org/10.1017/S0007114513000548
16. Santos FL, Esteves SS, da Costa Pereira A, et al. Systematic review and meta-analysis of clinical trials of the effects of low carbohydrate diets on cardiovascular risk factors. Obes Rev. 2012;13:1048-1066. https://doi.org/10.1111/j.1467-789X.2012.01021.x
17. Athinarayanan SJ, Adams RN, Hallberg SJ, et al. Long-term effects of a novel continuous remote care intervention including nutritional ketosis for the management of type 2 diabetes: a 2-year non-randomized clinical trial. bioRxiv. 2018;10:348. https://doi.org/10.1101/476275
18. Auerbach BJ, Dibey S, Vallila-Buchman P, et al. Review of 100% fruit juice and chronic health conditions: implications for sugar-sweetened beverage policy. Adv Nutr. 2018;9:78-85. https://doi.org/10.1093/advances/nmx006
19. Faith MS, Dennison BA, Edmunds LS, et al. Fruit juice intake predicts increased adiposity gain in children from low-income families: weight status-by-environment interaction. Pediatrics. 2006;118:2066-2075. https://doi.org/10.1542/peds.2006-1117
20. Bolton RP, Burroughs LF, Heaton KW. The role of dietary fiber in satiety, insulin: studies with fruit and fruit. Am J Clin Nutr. 1981;84:211-217. https://doi.org/10.1093/ajcn/34.2.211
21. Unwin D, Haslam D, Livesey G. It is the glycaemic response to, not the carbohydrate content of food that matters in diabetes and obesity: the glycaemic index revisited. J Insul Resist. 2016;1(1):a8. https://doi.org/10.4102/jir.v1i1.8
22. Monteiro CA, Moubarac JC, Levy RB, et al. Household availability of ultra-processed foods and obesity in nineteen European countries. Public Health Nutr. 2018;21:18-26. https://doi.org/10.1017/S1368980017001379
23. Harcombe Z, Baker JS, Cooper SM, et al. Evidence from randomised controlled trials did not support the introduction of dietary fat guidelines in 1977 and 1983: a systematic review and meta-analysis. Open Hear. 2015;2:e000196. https://doi.org/10.1136/openhrt-2014
24. US Department of Health and Human Services and US Department of Agriculture. 2015-2020 Dietary Guidelines for Americans. 8th edition. Published December 2015. Accessed March 5, 2021. http://health.gov/dietaryguidelines/2015/guidelines/
25. Harcombe Z, Baker JS, DiNicolantonio JJ, et al. Evidence from randomised controlled trials does not support current dietary fat guidelines: a systematic review and meta-analysis. Open Hear. 2016;3:e000409. https://doi.org/10.1136/openhrt-2016-000409
26. Fung J. The Obesity Code: Unlocking the Secrets of Weight Loss. Greystone Books; 2016.
27. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58. https://doi.org/10.1016/j.arr.2016.10.005
28. Patterson RE, Sears DD. Metabolic Effects of Intermittent Fasting. Annu Rev Nutr. 2017; 37:371-393. https://doi.org/10.1146/annurev-nutr-071816-064634
29. Duncan GG. Intermittent fasts in the correction and control of intractable obesity. Trans Am Clin Climatol Assoc. 1962;74:121-129.
30. Gabel K, Hoddy KK, Varady KA. Safety of 8-h time restricted feeding in adults with obesity. Appl Physiol Nutr Metab. 2019;44:107-109. https://doi.org/10.1139/apnm-2018-0389
31. Erlandson M, Ivey LC, Seikel K. Update on office-based strategies for the management of obesity. Am Fam Physician. 2016;94:361-368.
32. Malhotra A, Noakes T, Phinney S. It is time to bust the myth of physical inactivity and obesity: you cannot outrun a bad diet. Br J Sports Med. 2015;49:967-968. https://doi.org/10.1136/bjsports-2015-094911
33. Donnelly JE, Blair SN, Jakicic JM, et al. Appropriate physical activity intervention strategies for weight loss and prevention of weight regain for adults. Med Sci Sports Exerc. 2009;41:459-471. https://doi.org/10.1249/MSS.0b013e3181949333
34. Zheng Y, Burke LE, Danford CA, et al. Patterns of self-weighing behavior and weight change in a weight loss trial. Int J Obes (Lond). 2016;40:1392-1396. https://doi.org/10.1038/ijo.2016.68
In 2015-2016, almost 40% of adults and 18.5% of children ages 2 to 19 years in the United States met the definition for obesity—a chronic, relapsing, multifactorial, neurobehavioral disease that results in adverse metabolic, biomechanical, and psychosocial health consequences.1,2
Tremendous resources have been invested in research, policy development, and public education to try to prevent obesity and its related complications. Despite this, the obesity epidemic has worsened. Here, we explore how to evaluate and treat obese patients in a primary care setting based on the evidence and our experience seeing patients specifically for weight management in a family medicine residency teaching clinic. Pharmacotherapy and surgery, while often helpful, are outside the scope of this article.
It begins withan obesity-friendly office
Patients may have reservations about health care interactions specific to obesity, so it is important to invite them into a setting that facilitates trust and encourages collaboration. Actively engage patients with unhealthy weight by creating an environment where they feel comfortable. Offer wide chairs without armrests, which will easily accommodate patients of all sizes, and ensure that scales have a weight capacity > 400 lb. Communicate a message to patients, via waiting room materials and videos, that focuses on health rather than on weight or body mass index (BMI).
Understand the patient’s goals and challenges
Most (although not all) family physicians will see obese patients in the context of a visit for diabetes, hypertension, or another condition. However, we feel that having visits specifically to address weight in the initial stages of weight management is helpful. The focus of an initial visit should be getting to know how obesity has affected the patient and what his or her motive is in attempting to lose weight. Explore previous attempts at weight loss and establish what the patient’s highest weight has been, as this will impact weight-loss goals. For example, if a patient has weighed > 300 lb all her adult life, it will be extremely difficult to maintain a weight loss of 150 lb.
What else to ask about. Discuss stressors that may be causing increased food intake or poor food choices, including hunger, anger, loneliness, and sleep difficulties. Multidisciplinary care including a psychologist can aid in addressing these issues. Ask patients if they keep a food diary (and if not, recommend that they start), as food diaries are often helpful in elucidating eating and drinking patterns. Determine a patient’s current and past levels of physical activity, as this will guide the fitness goals you develop for him or her.
Screen for psychosocial disorders
As noted earlier, the physical component of obesity is commonly associated with mood disorders such as anxiety and depression.2 This requires a multidisciplinary team effort to facilitate healing in the patient struggling with obesity.
Screening for depression and anxiety using standardized tools such as the Patient Health Questionnaire-9 or the Generalized Anxiety Disorder-7 is encouraged in patients who are overweight or obese. Positive screens should be addressed as part of the patient’s treatment plan, as untreated depression and anxiety can inhibit success with weight loss. Be mindful that many medications commonly used to treat these conditions can impair weight loss and even promote weight gain.
Continue to: Don't overlook binge-eating disorders
Don’t overlook binge-eating disorders. Screening specifically for binge-eating disorders is important, given the implications on treatment. The US Department of Veterans Affairs developed a single-item tool for this purpose, the VA Binge Eating Screener. The validated questionnaire asks, “On average, how often have you eaten extremely large amounts of food at one time and felt that your eating was out of control at that time?” Response options are: “Never,” “< 1 time/week,” “1 time/week,” “2-4 times/week,” and “5+ times/week.” A response of ≥ 2 times/week had a sensitivity of 88.9% and specificity of 83.2% for binge-eating disorder.3
Patients with positive screens should undergo psychotherapy and consider pharmacotherapy with lisdexamfetamine as part of their treatment plan. Caution should be used if recommending intermittent fasting for someone with binge-eating disorder.
Evaluate for underlying causes and assess for comorbidities
Review the patient’s current medication list and history. Many medications can cause weight gain, and weight loss can often be achieved by deprescribing such medications. When feasible, prescribe an alternative medication with a more favorable weight profile. A previous article in The Journal of Family Practice addresses this in more depth.4
Laboratory and other testing
Laboratory analysis should primarily be focused on determining treatment alterations specific to underlying pathophysiology. Tests to consider ordering are outlined in the Table
Diabetes and insulin resistance. The American Diabetes Association recommends screening patients who are overweight or obese and have an additional risk factor for diabetes.5 This can be done by obtaining a fasting glucose level, hemoglobin A1C, or a 2-hour oral glucose tolerance test.
Continue to: Since it is known that...
Since it is known that insulin resistance increases the risk for coronary heart disease6 and can be treated effectively,7 we recommend testing for insulin resistance in patients who do not already have impaired fasting glucose, prediabetes, type 2 diabetes, or impaired glucose tolerance. The homeostatic model assessment for insulin resistance (HOMA-IR)8 is a measure of insulin resistance and can be calculated from the fasting insulin and fasting glucose levels. This measure should not be done in isolation, but it can be a useful adjunct in identifying patients with insulin resistance and directing treatment.
If there is evidence of diabetes or insulin resistance, consider treatment with metformin ± initiation of a low-carbohydrate diet.
Hypothyroidism. Consider screening for thyroid dysfunction with a thyroid-stimulating hormone level, if it has not been checked previously.
Renal abnormalities. When serum creatinine levels and glomerular filtration rate indicate chronic kidney disease, consider recommending a protein-restricted diet and adjust medications according to renal dosing protocols, as indicated.
Liver abnormalities, including nonalcoholic fatty liver disease (NAFLD). Monitor aspartate aminotransferase and alanine aminotransferase for resolution of elevations as weight loss is achieved. If abnormalities persist, consider ordering a liver ultrasound. Traditionally, low-calorie diets have been prescribed to treat NAFLD, but evidence shows that low-carbohydrate diets can also be effective.9
Continue to: Hypertriglyceridemia and low high-density lipoprotein (HDL) levels
Hypertriglyceridemia and low high-density lipoprotein (HDL) levels. Obtain a lipid panel if one has not been completed within the past several years, as hypertriglyceridemia and low HDL can improve dramatically with specific dietary changes.7 Observe trends to assess for resolution of lipid abnormalities as weight loss is achieved.
Gout. Consider checking a uric acid level if you are thinking about recommending a low-carbohydrate diet, particularly in patients with a history of gout, as this may temporarily increase the risk of gout flare.
Hypovitaminosis D. If the patient’s vitamin D level is low, consider appropriate supplementation to support the patient’s overall health. While vitamin D deficiency is common in obesity, the role of supplementation in this population is unclear.
Cardiovascular disease. Consider ordering an electrocardiogram, particularly if you are thinking of prescribing medication therapy. Use caution with initiation of certain medications, such as phentermine or diethylproprion, in the presence of arrhythmias or active cardiovascular disease.
Obstructive sleep apnea. Sleep health is important to address, since obesity is one of the most significant risk factors for obstructive sleep apnea.10 If your patient is given a diagnosis of OSA following a sleep study, consider treatment with continuous positive airway pressure (CPAP), although there are conflicting studies regarding the effects of CPAP therapy in OSA on weight.11,12
Continue to: Provide guidance on lifestyle changes
Provide guidance on lifestyle changes
Addressing obesity with patients can be challenging in a busy primary care clinic, but it is imperative to helping patients achieve overall health. Counseling on nutrition and physical activity is an important part of this process.
There is no one-size-fits-all approach to nutrition counseling. Focus on creating individualized plans through which patients can achieve success. Some guidance follows, but also beware of common pitfalls that we have observed in clinical practice which, when addressed, can enable significant weight loss (see “Common pitfalls inhibiting weight loss”).
SIDEBAR
Common pitfalls inhibiting weight loss
On the part of the patient:
- Continuing to consume substantial amounts of high-calorie drinks.
- Taking in excessive amounts of sugar-rich foods, including cough drops.
- Using non-nutritive sweeteners (eg, aspartame, saccharin, sucralose, and erythritol). Although the mechanism is not certain, some people are able to lose weight while consuming these substances, while others are not.
On the part of the provider:
- Prescribing a diet that the patient cannot sustain long term.
- Overlooking the issue of food availability for the patient.
Choose an approach that works for the patient. Commonly prescribed diets to address obesity include, but are not limited to, Atkins, Dietary Approaches to Stop Hypertension (DASH), Glycemic Index, Mediterranean, Ornish, Paleolithic, Zone, whole food plant-based, and ketogenic. We attempt to engage patients in making the decision on what food choices are appropriate for them considering their food availability, culture, and belief systems. For patients who prefer a vegan or vegetarian whole food diet, it is important to note that these diets are generally deficient in vitamin B12 and omega 3 fatty acids, so supplementing these should be considered.
Rather than focus on a specific diet, which may not be sustainable long term, encourage healthy eating habits. Low-carbohydrate diets have been shown to promote greater weight loss compared to low-fat diets.13,14 Low-calorie diets can also be quite effective in promoting short-term weight loss. In our clinic, when weight loss is the primary goal, patients are typically encouraged to focus on either calorie or carbohydrate restriction in the initial stages of weight loss.
Eliminate sugar and refined carbohydrates. While rigorous mortality data are not available, more recent trials have demonstrated significant improvements in atherosclerotic cardiovascular disease risk markers, including weight reduction and diabetes reversal, when following a diet that markedly decreases carbohydrate intake, especially sugar and refined carbohydrates.7,14-17
Continue to: We recommend that patients focus...
We recommend that patients focus on eliminating sweetened beverages, such as soft drinks, sports drinks, energy drinks, vitamin water, sweet tea, chocolate milk, and Frappuccinos. We also recommend substantially limiting or eliminating fruit juices and fruit smoothies due to their high sugar content. For example, 8 oz of orange juice contains 26 g of carbohydrates, which is almost as much as 8 oz of soda.
Compared with eating whole fruit, consuming fruit juice has demonstrated a small amount of weight gain in young children and adults.18,19 It also has shown a higher insulin response compared with eating the same amount of carbohydrates in whole fruit.20 Better options to drink include water, unsweetened tea, and black coffee. Also, avoid ultra-processed carbohydrates from foods such as breads, cereals, and pastries, as they have similar effects on blood glucose when compared to sugar.21
Greatly restrict highly processed foods. The evidence suggests that the availability of processed food is associated with increasing obesity.22 Simple advice to offer your patients is to encourage them to shop the perimeter of the grocery store, where fresh produce, meat, and dairy products are primarily located, and avoid the inner aisles, which contain primarily processed foods. Choosing food items with 5 or fewer ingredients is a starting point when teaching patients to read labels.
Consider limiting saturated fats. In 1977, the Dietary Guidelines for Americans recommended that Americans eat no more than 30% of total energy intake from fat and less than 10% of total energy intake from saturated fat; however, no randomized controlled trials had been done that supported this recommendation and epidemiologic data supporting it were weak.23
The 2015 Dietary Guidelines continue to recommend limiting total energy intake from saturated fats.24 While there may be a small decrease in cardiovascular risk with a reduction of saturated fat intake and replacement with unsaturated fats, no overall mortality benefit has been demonstrated.24,25 More research is needed in this area to guide patients in decisions regarding consumption of saturated fats and what types of unsaturated fats are best for their health.
Continue to: Eat only 3 meals per day
Eat only 3 meals per day, but aim for fewer than that. The prescription of fasting is a modality that can be used for weight loss and improved health. Fasting has been a prescribed healing practice for thousands of years.26 It is a practice that virtually every major religion in the world embraces. Studies have demonstrated fasting to be safe and effective in the setting of obesity without significant comorbidities, and it may promote weight loss and metabolic health.26-29
There are multiple types of intermittent fasting. A practical way for patients to start is by restricting the number of hours in which they eat or drink calorie-containing beverages to 8 hours per day. In our experience, this regimen is easier for most patients to follow than alternate-day or other longer fasts. While there has been caution in the prescription of intermittent fasting due to concerns about causing eating disorders, a recent small study did not demonstrate increased risk of eating disorders with daily intermittent fasting.30
Participate in healthy exercise. Nonpharmacologic office-based strategies for treating obesity have generally focused on increasing exercise and decreasing caloric intake.31 While exercise has significant health benefits, including preventing weight regain, evidence does not support monotherapy with exercise as an effective long-term weight-loss strategy.32 There are no studies available that adequately support prescribing an exact dose of exercise.33 Generally, less than 150 minutes of exercise per week is not effective and more than that does have a dose-related response.33
Follow up to help patients stay on target
There is no ideal interval for follow-up visits. However, frequent visits—anywhere from weekly to monthly—in the initial stages of weight loss increase the patient’s sense of accountability and, in our experience, seem to be helpful.
Patients may also choose to track their progress by weighing themselves regularly. A small study published in the International Journal of Obesity found that patients who weighed themselves daily had greater and more sustained weight loss than those who didn’t.34 But the decision of whether to weigh one’s self at home should be individualized for each patient.
CORRESPONDENCE
Wesley Eichorn, DO, 1000 Oakland Drive, Kalamazoo, MI 49008; [email protected]
In 2015-2016, almost 40% of adults and 18.5% of children ages 2 to 19 years in the United States met the definition for obesity—a chronic, relapsing, multifactorial, neurobehavioral disease that results in adverse metabolic, biomechanical, and psychosocial health consequences.1,2
Tremendous resources have been invested in research, policy development, and public education to try to prevent obesity and its related complications. Despite this, the obesity epidemic has worsened. Here, we explore how to evaluate and treat obese patients in a primary care setting based on the evidence and our experience seeing patients specifically for weight management in a family medicine residency teaching clinic. Pharmacotherapy and surgery, while often helpful, are outside the scope of this article.
It begins withan obesity-friendly office
Patients may have reservations about health care interactions specific to obesity, so it is important to invite them into a setting that facilitates trust and encourages collaboration. Actively engage patients with unhealthy weight by creating an environment where they feel comfortable. Offer wide chairs without armrests, which will easily accommodate patients of all sizes, and ensure that scales have a weight capacity > 400 lb. Communicate a message to patients, via waiting room materials and videos, that focuses on health rather than on weight or body mass index (BMI).
Understand the patient’s goals and challenges
Most (although not all) family physicians will see obese patients in the context of a visit for diabetes, hypertension, or another condition. However, we feel that having visits specifically to address weight in the initial stages of weight management is helpful. The focus of an initial visit should be getting to know how obesity has affected the patient and what his or her motive is in attempting to lose weight. Explore previous attempts at weight loss and establish what the patient’s highest weight has been, as this will impact weight-loss goals. For example, if a patient has weighed > 300 lb all her adult life, it will be extremely difficult to maintain a weight loss of 150 lb.
What else to ask about. Discuss stressors that may be causing increased food intake or poor food choices, including hunger, anger, loneliness, and sleep difficulties. Multidisciplinary care including a psychologist can aid in addressing these issues. Ask patients if they keep a food diary (and if not, recommend that they start), as food diaries are often helpful in elucidating eating and drinking patterns. Determine a patient’s current and past levels of physical activity, as this will guide the fitness goals you develop for him or her.
Screen for psychosocial disorders
As noted earlier, the physical component of obesity is commonly associated with mood disorders such as anxiety and depression.2 This requires a multidisciplinary team effort to facilitate healing in the patient struggling with obesity.
Screening for depression and anxiety using standardized tools such as the Patient Health Questionnaire-9 or the Generalized Anxiety Disorder-7 is encouraged in patients who are overweight or obese. Positive screens should be addressed as part of the patient’s treatment plan, as untreated depression and anxiety can inhibit success with weight loss. Be mindful that many medications commonly used to treat these conditions can impair weight loss and even promote weight gain.
Continue to: Don't overlook binge-eating disorders
Don’t overlook binge-eating disorders. Screening specifically for binge-eating disorders is important, given the implications on treatment. The US Department of Veterans Affairs developed a single-item tool for this purpose, the VA Binge Eating Screener. The validated questionnaire asks, “On average, how often have you eaten extremely large amounts of food at one time and felt that your eating was out of control at that time?” Response options are: “Never,” “< 1 time/week,” “1 time/week,” “2-4 times/week,” and “5+ times/week.” A response of ≥ 2 times/week had a sensitivity of 88.9% and specificity of 83.2% for binge-eating disorder.3
Patients with positive screens should undergo psychotherapy and consider pharmacotherapy with lisdexamfetamine as part of their treatment plan. Caution should be used if recommending intermittent fasting for someone with binge-eating disorder.
Evaluate for underlying causes and assess for comorbidities
Review the patient’s current medication list and history. Many medications can cause weight gain, and weight loss can often be achieved by deprescribing such medications. When feasible, prescribe an alternative medication with a more favorable weight profile. A previous article in The Journal of Family Practice addresses this in more depth.4
Laboratory and other testing
Laboratory analysis should primarily be focused on determining treatment alterations specific to underlying pathophysiology. Tests to consider ordering are outlined in the Table
Diabetes and insulin resistance. The American Diabetes Association recommends screening patients who are overweight or obese and have an additional risk factor for diabetes.5 This can be done by obtaining a fasting glucose level, hemoglobin A1C, or a 2-hour oral glucose tolerance test.
Continue to: Since it is known that...
Since it is known that insulin resistance increases the risk for coronary heart disease6 and can be treated effectively,7 we recommend testing for insulin resistance in patients who do not already have impaired fasting glucose, prediabetes, type 2 diabetes, or impaired glucose tolerance. The homeostatic model assessment for insulin resistance (HOMA-IR)8 is a measure of insulin resistance and can be calculated from the fasting insulin and fasting glucose levels. This measure should not be done in isolation, but it can be a useful adjunct in identifying patients with insulin resistance and directing treatment.
If there is evidence of diabetes or insulin resistance, consider treatment with metformin ± initiation of a low-carbohydrate diet.
Hypothyroidism. Consider screening for thyroid dysfunction with a thyroid-stimulating hormone level, if it has not been checked previously.
Renal abnormalities. When serum creatinine levels and glomerular filtration rate indicate chronic kidney disease, consider recommending a protein-restricted diet and adjust medications according to renal dosing protocols, as indicated.
Liver abnormalities, including nonalcoholic fatty liver disease (NAFLD). Monitor aspartate aminotransferase and alanine aminotransferase for resolution of elevations as weight loss is achieved. If abnormalities persist, consider ordering a liver ultrasound. Traditionally, low-calorie diets have been prescribed to treat NAFLD, but evidence shows that low-carbohydrate diets can also be effective.9
Continue to: Hypertriglyceridemia and low high-density lipoprotein (HDL) levels
Hypertriglyceridemia and low high-density lipoprotein (HDL) levels. Obtain a lipid panel if one has not been completed within the past several years, as hypertriglyceridemia and low HDL can improve dramatically with specific dietary changes.7 Observe trends to assess for resolution of lipid abnormalities as weight loss is achieved.
Gout. Consider checking a uric acid level if you are thinking about recommending a low-carbohydrate diet, particularly in patients with a history of gout, as this may temporarily increase the risk of gout flare.
Hypovitaminosis D. If the patient’s vitamin D level is low, consider appropriate supplementation to support the patient’s overall health. While vitamin D deficiency is common in obesity, the role of supplementation in this population is unclear.
Cardiovascular disease. Consider ordering an electrocardiogram, particularly if you are thinking of prescribing medication therapy. Use caution with initiation of certain medications, such as phentermine or diethylproprion, in the presence of arrhythmias or active cardiovascular disease.
Obstructive sleep apnea. Sleep health is important to address, since obesity is one of the most significant risk factors for obstructive sleep apnea.10 If your patient is given a diagnosis of OSA following a sleep study, consider treatment with continuous positive airway pressure (CPAP), although there are conflicting studies regarding the effects of CPAP therapy in OSA on weight.11,12
Continue to: Provide guidance on lifestyle changes
Provide guidance on lifestyle changes
Addressing obesity with patients can be challenging in a busy primary care clinic, but it is imperative to helping patients achieve overall health. Counseling on nutrition and physical activity is an important part of this process.
There is no one-size-fits-all approach to nutrition counseling. Focus on creating individualized plans through which patients can achieve success. Some guidance follows, but also beware of common pitfalls that we have observed in clinical practice which, when addressed, can enable significant weight loss (see “Common pitfalls inhibiting weight loss”).
SIDEBAR
Common pitfalls inhibiting weight loss
On the part of the patient:
- Continuing to consume substantial amounts of high-calorie drinks.
- Taking in excessive amounts of sugar-rich foods, including cough drops.
- Using non-nutritive sweeteners (eg, aspartame, saccharin, sucralose, and erythritol). Although the mechanism is not certain, some people are able to lose weight while consuming these substances, while others are not.
On the part of the provider:
- Prescribing a diet that the patient cannot sustain long term.
- Overlooking the issue of food availability for the patient.
Choose an approach that works for the patient. Commonly prescribed diets to address obesity include, but are not limited to, Atkins, Dietary Approaches to Stop Hypertension (DASH), Glycemic Index, Mediterranean, Ornish, Paleolithic, Zone, whole food plant-based, and ketogenic. We attempt to engage patients in making the decision on what food choices are appropriate for them considering their food availability, culture, and belief systems. For patients who prefer a vegan or vegetarian whole food diet, it is important to note that these diets are generally deficient in vitamin B12 and omega 3 fatty acids, so supplementing these should be considered.
Rather than focus on a specific diet, which may not be sustainable long term, encourage healthy eating habits. Low-carbohydrate diets have been shown to promote greater weight loss compared to low-fat diets.13,14 Low-calorie diets can also be quite effective in promoting short-term weight loss. In our clinic, when weight loss is the primary goal, patients are typically encouraged to focus on either calorie or carbohydrate restriction in the initial stages of weight loss.
Eliminate sugar and refined carbohydrates. While rigorous mortality data are not available, more recent trials have demonstrated significant improvements in atherosclerotic cardiovascular disease risk markers, including weight reduction and diabetes reversal, when following a diet that markedly decreases carbohydrate intake, especially sugar and refined carbohydrates.7,14-17
Continue to: We recommend that patients focus...
We recommend that patients focus on eliminating sweetened beverages, such as soft drinks, sports drinks, energy drinks, vitamin water, sweet tea, chocolate milk, and Frappuccinos. We also recommend substantially limiting or eliminating fruit juices and fruit smoothies due to their high sugar content. For example, 8 oz of orange juice contains 26 g of carbohydrates, which is almost as much as 8 oz of soda.
Compared with eating whole fruit, consuming fruit juice has demonstrated a small amount of weight gain in young children and adults.18,19 It also has shown a higher insulin response compared with eating the same amount of carbohydrates in whole fruit.20 Better options to drink include water, unsweetened tea, and black coffee. Also, avoid ultra-processed carbohydrates from foods such as breads, cereals, and pastries, as they have similar effects on blood glucose when compared to sugar.21
Greatly restrict highly processed foods. The evidence suggests that the availability of processed food is associated with increasing obesity.22 Simple advice to offer your patients is to encourage them to shop the perimeter of the grocery store, where fresh produce, meat, and dairy products are primarily located, and avoid the inner aisles, which contain primarily processed foods. Choosing food items with 5 or fewer ingredients is a starting point when teaching patients to read labels.
Consider limiting saturated fats. In 1977, the Dietary Guidelines for Americans recommended that Americans eat no more than 30% of total energy intake from fat and less than 10% of total energy intake from saturated fat; however, no randomized controlled trials had been done that supported this recommendation and epidemiologic data supporting it were weak.23
The 2015 Dietary Guidelines continue to recommend limiting total energy intake from saturated fats.24 While there may be a small decrease in cardiovascular risk with a reduction of saturated fat intake and replacement with unsaturated fats, no overall mortality benefit has been demonstrated.24,25 More research is needed in this area to guide patients in decisions regarding consumption of saturated fats and what types of unsaturated fats are best for their health.
Continue to: Eat only 3 meals per day
Eat only 3 meals per day, but aim for fewer than that. The prescription of fasting is a modality that can be used for weight loss and improved health. Fasting has been a prescribed healing practice for thousands of years.26 It is a practice that virtually every major religion in the world embraces. Studies have demonstrated fasting to be safe and effective in the setting of obesity without significant comorbidities, and it may promote weight loss and metabolic health.26-29
There are multiple types of intermittent fasting. A practical way for patients to start is by restricting the number of hours in which they eat or drink calorie-containing beverages to 8 hours per day. In our experience, this regimen is easier for most patients to follow than alternate-day or other longer fasts. While there has been caution in the prescription of intermittent fasting due to concerns about causing eating disorders, a recent small study did not demonstrate increased risk of eating disorders with daily intermittent fasting.30
Participate in healthy exercise. Nonpharmacologic office-based strategies for treating obesity have generally focused on increasing exercise and decreasing caloric intake.31 While exercise has significant health benefits, including preventing weight regain, evidence does not support monotherapy with exercise as an effective long-term weight-loss strategy.32 There are no studies available that adequately support prescribing an exact dose of exercise.33 Generally, less than 150 minutes of exercise per week is not effective and more than that does have a dose-related response.33
Follow up to help patients stay on target
There is no ideal interval for follow-up visits. However, frequent visits—anywhere from weekly to monthly—in the initial stages of weight loss increase the patient’s sense of accountability and, in our experience, seem to be helpful.
Patients may also choose to track their progress by weighing themselves regularly. A small study published in the International Journal of Obesity found that patients who weighed themselves daily had greater and more sustained weight loss than those who didn’t.34 But the decision of whether to weigh one’s self at home should be individualized for each patient.
CORRESPONDENCE
Wesley Eichorn, DO, 1000 Oakland Drive, Kalamazoo, MI 49008; [email protected]
1. Hales CM, Carroll MD, Fryar CD, et al. Prevalence of obesity among adults and youth: United States, 2015-2016 key findings data from the National Health and Nutrition Examination Survey. NCHS Data Brief. 2017;(288):1-8.
2. Seger JC, Horn DB, Westman EC, et al. Obesity Algorithm, presented by the Obesity Medicine Association. Accessed March 5, 2021. www.obesityalgorithm.org. 2016-2017
3. Dorflinger LM, Ruser CB, Masheb RM. A brief screening measure for binge eating in primary care. Eat Behav. 2017;26:163-166. https://doi.org/10.1016/j.eatbeh.2017.03.009
4. Saunders KH, Igel LI, Shukla AP, et al. Drug-induced weight gain: rethinking our choices. J Fam Pract. 2016;65:780-788.
5. American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019;42(suppl 1):S13-S28. https://doi.org/10.2337/dc19-S002
6. Reaven G. Insulin resistance and coronary heart disease in nondiabetic individuals. Arterioscler Thromb Vasc Biol. 2012;32:1754-1759. https://doi.org/10.1161/ATVBAHA.111.241885/-/DC1
7. Hallberg S, McKenzie A, Williams P, et al. Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year: an open-label, non-randomized, controlled study. Diabetes Ther. 2018;9:583-612. https://doi.org/10.6084/m9.figshare
8. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27:1487-1495.
9. Vilar-Gomez E, Athinarayanan SJ, Adams RN, et al. Post hoc analyses of surrogate markers of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis in patients with type 2 diabetes in a digitally supported continuous care intervention: an open-label, non-randomised controlled study. BMJ Open. 2019;9:e023597. https://doi.org/10.1136/bmjopen-2018-023597
10. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea. Am J Respir Crit Care Med. 2002;165:1217-1239. https://doi.org/10.1164/rccm.2109080
11. Drager LF, Brunoni AR, Jenner R, et al. Effects of CPAP on body weight in patients with obstructive sleep apnoea: a meta-analysis of randomised trials. Thorax. 2015;70:258-264. https://doi.org/10.1136/thoraxjnl-2014-205361
12. Bosworth T. CPAP use associated with greater weight loss in obese patients with sleep apnea. CHEST Physician. Published March 29, 2019. Accessed March 5, 2021. www.mdedge.com/chestphysician/article/197827/sleep-medicine/cpap-use-associated-greater-weight-loss-obese-patients
13. Tobias DK, Chen M, Manson JAE, et al. Effect of low-fat diet interventions versus other diet interventions on long-term weight change in adults: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2015;3:968-979. https://doi.org/10.1016/S2213-8587(15)00367-8
14. Sackner-Bernstein J, Kanter D, Kaul S. Dietary intervention for overweight and obese adults: comparison of low-carbohydrate and low-fat diets: a meta-analysis. PLoS One. 2015;10:e0139817. https://doi.org/10.1371/journal.pone.0139817
15. Bezerra Bueno N, Vieira De Melo IS, Lima De Oliveira S, et al. Very-low-carbohydrate ketogenic diet v low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. Br J Nutr. 2013;110:1178-1187. https://doi.org/10.1017/S0007114513000548
16. Santos FL, Esteves SS, da Costa Pereira A, et al. Systematic review and meta-analysis of clinical trials of the effects of low carbohydrate diets on cardiovascular risk factors. Obes Rev. 2012;13:1048-1066. https://doi.org/10.1111/j.1467-789X.2012.01021.x
17. Athinarayanan SJ, Adams RN, Hallberg SJ, et al. Long-term effects of a novel continuous remote care intervention including nutritional ketosis for the management of type 2 diabetes: a 2-year non-randomized clinical trial. bioRxiv. 2018;10:348. https://doi.org/10.1101/476275
18. Auerbach BJ, Dibey S, Vallila-Buchman P, et al. Review of 100% fruit juice and chronic health conditions: implications for sugar-sweetened beverage policy. Adv Nutr. 2018;9:78-85. https://doi.org/10.1093/advances/nmx006
19. Faith MS, Dennison BA, Edmunds LS, et al. Fruit juice intake predicts increased adiposity gain in children from low-income families: weight status-by-environment interaction. Pediatrics. 2006;118:2066-2075. https://doi.org/10.1542/peds.2006-1117
20. Bolton RP, Burroughs LF, Heaton KW. The role of dietary fiber in satiety, insulin: studies with fruit and fruit. Am J Clin Nutr. 1981;84:211-217. https://doi.org/10.1093/ajcn/34.2.211
21. Unwin D, Haslam D, Livesey G. It is the glycaemic response to, not the carbohydrate content of food that matters in diabetes and obesity: the glycaemic index revisited. J Insul Resist. 2016;1(1):a8. https://doi.org/10.4102/jir.v1i1.8
22. Monteiro CA, Moubarac JC, Levy RB, et al. Household availability of ultra-processed foods and obesity in nineteen European countries. Public Health Nutr. 2018;21:18-26. https://doi.org/10.1017/S1368980017001379
23. Harcombe Z, Baker JS, Cooper SM, et al. Evidence from randomised controlled trials did not support the introduction of dietary fat guidelines in 1977 and 1983: a systematic review and meta-analysis. Open Hear. 2015;2:e000196. https://doi.org/10.1136/openhrt-2014
24. US Department of Health and Human Services and US Department of Agriculture. 2015-2020 Dietary Guidelines for Americans. 8th edition. Published December 2015. Accessed March 5, 2021. http://health.gov/dietaryguidelines/2015/guidelines/
25. Harcombe Z, Baker JS, DiNicolantonio JJ, et al. Evidence from randomised controlled trials does not support current dietary fat guidelines: a systematic review and meta-analysis. Open Hear. 2016;3:e000409. https://doi.org/10.1136/openhrt-2016-000409
26. Fung J. The Obesity Code: Unlocking the Secrets of Weight Loss. Greystone Books; 2016.
27. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58. https://doi.org/10.1016/j.arr.2016.10.005
28. Patterson RE, Sears DD. Metabolic Effects of Intermittent Fasting. Annu Rev Nutr. 2017; 37:371-393. https://doi.org/10.1146/annurev-nutr-071816-064634
29. Duncan GG. Intermittent fasts in the correction and control of intractable obesity. Trans Am Clin Climatol Assoc. 1962;74:121-129.
30. Gabel K, Hoddy KK, Varady KA. Safety of 8-h time restricted feeding in adults with obesity. Appl Physiol Nutr Metab. 2019;44:107-109. https://doi.org/10.1139/apnm-2018-0389
31. Erlandson M, Ivey LC, Seikel K. Update on office-based strategies for the management of obesity. Am Fam Physician. 2016;94:361-368.
32. Malhotra A, Noakes T, Phinney S. It is time to bust the myth of physical inactivity and obesity: you cannot outrun a bad diet. Br J Sports Med. 2015;49:967-968. https://doi.org/10.1136/bjsports-2015-094911
33. Donnelly JE, Blair SN, Jakicic JM, et al. Appropriate physical activity intervention strategies for weight loss and prevention of weight regain for adults. Med Sci Sports Exerc. 2009;41:459-471. https://doi.org/10.1249/MSS.0b013e3181949333
34. Zheng Y, Burke LE, Danford CA, et al. Patterns of self-weighing behavior and weight change in a weight loss trial. Int J Obes (Lond). 2016;40:1392-1396. https://doi.org/10.1038/ijo.2016.68
1. Hales CM, Carroll MD, Fryar CD, et al. Prevalence of obesity among adults and youth: United States, 2015-2016 key findings data from the National Health and Nutrition Examination Survey. NCHS Data Brief. 2017;(288):1-8.
2. Seger JC, Horn DB, Westman EC, et al. Obesity Algorithm, presented by the Obesity Medicine Association. Accessed March 5, 2021. www.obesityalgorithm.org. 2016-2017
3. Dorflinger LM, Ruser CB, Masheb RM. A brief screening measure for binge eating in primary care. Eat Behav. 2017;26:163-166. https://doi.org/10.1016/j.eatbeh.2017.03.009
4. Saunders KH, Igel LI, Shukla AP, et al. Drug-induced weight gain: rethinking our choices. J Fam Pract. 2016;65:780-788.
5. American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019;42(suppl 1):S13-S28. https://doi.org/10.2337/dc19-S002
6. Reaven G. Insulin resistance and coronary heart disease in nondiabetic individuals. Arterioscler Thromb Vasc Biol. 2012;32:1754-1759. https://doi.org/10.1161/ATVBAHA.111.241885/-/DC1
7. Hallberg S, McKenzie A, Williams P, et al. Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year: an open-label, non-randomized, controlled study. Diabetes Ther. 2018;9:583-612. https://doi.org/10.6084/m9.figshare
8. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27:1487-1495.
9. Vilar-Gomez E, Athinarayanan SJ, Adams RN, et al. Post hoc analyses of surrogate markers of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis in patients with type 2 diabetes in a digitally supported continuous care intervention: an open-label, non-randomised controlled study. BMJ Open. 2019;9:e023597. https://doi.org/10.1136/bmjopen-2018-023597
10. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea. Am J Respir Crit Care Med. 2002;165:1217-1239. https://doi.org/10.1164/rccm.2109080
11. Drager LF, Brunoni AR, Jenner R, et al. Effects of CPAP on body weight in patients with obstructive sleep apnoea: a meta-analysis of randomised trials. Thorax. 2015;70:258-264. https://doi.org/10.1136/thoraxjnl-2014-205361
12. Bosworth T. CPAP use associated with greater weight loss in obese patients with sleep apnea. CHEST Physician. Published March 29, 2019. Accessed March 5, 2021. www.mdedge.com/chestphysician/article/197827/sleep-medicine/cpap-use-associated-greater-weight-loss-obese-patients
13. Tobias DK, Chen M, Manson JAE, et al. Effect of low-fat diet interventions versus other diet interventions on long-term weight change in adults: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2015;3:968-979. https://doi.org/10.1016/S2213-8587(15)00367-8
14. Sackner-Bernstein J, Kanter D, Kaul S. Dietary intervention for overweight and obese adults: comparison of low-carbohydrate and low-fat diets: a meta-analysis. PLoS One. 2015;10:e0139817. https://doi.org/10.1371/journal.pone.0139817
15. Bezerra Bueno N, Vieira De Melo IS, Lima De Oliveira S, et al. Very-low-carbohydrate ketogenic diet v low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. Br J Nutr. 2013;110:1178-1187. https://doi.org/10.1017/S0007114513000548
16. Santos FL, Esteves SS, da Costa Pereira A, et al. Systematic review and meta-analysis of clinical trials of the effects of low carbohydrate diets on cardiovascular risk factors. Obes Rev. 2012;13:1048-1066. https://doi.org/10.1111/j.1467-789X.2012.01021.x
17. Athinarayanan SJ, Adams RN, Hallberg SJ, et al. Long-term effects of a novel continuous remote care intervention including nutritional ketosis for the management of type 2 diabetes: a 2-year non-randomized clinical trial. bioRxiv. 2018;10:348. https://doi.org/10.1101/476275
18. Auerbach BJ, Dibey S, Vallila-Buchman P, et al. Review of 100% fruit juice and chronic health conditions: implications for sugar-sweetened beverage policy. Adv Nutr. 2018;9:78-85. https://doi.org/10.1093/advances/nmx006
19. Faith MS, Dennison BA, Edmunds LS, et al. Fruit juice intake predicts increased adiposity gain in children from low-income families: weight status-by-environment interaction. Pediatrics. 2006;118:2066-2075. https://doi.org/10.1542/peds.2006-1117
20. Bolton RP, Burroughs LF, Heaton KW. The role of dietary fiber in satiety, insulin: studies with fruit and fruit. Am J Clin Nutr. 1981;84:211-217. https://doi.org/10.1093/ajcn/34.2.211
21. Unwin D, Haslam D, Livesey G. It is the glycaemic response to, not the carbohydrate content of food that matters in diabetes and obesity: the glycaemic index revisited. J Insul Resist. 2016;1(1):a8. https://doi.org/10.4102/jir.v1i1.8
22. Monteiro CA, Moubarac JC, Levy RB, et al. Household availability of ultra-processed foods and obesity in nineteen European countries. Public Health Nutr. 2018;21:18-26. https://doi.org/10.1017/S1368980017001379
23. Harcombe Z, Baker JS, Cooper SM, et al. Evidence from randomised controlled trials did not support the introduction of dietary fat guidelines in 1977 and 1983: a systematic review and meta-analysis. Open Hear. 2015;2:e000196. https://doi.org/10.1136/openhrt-2014
24. US Department of Health and Human Services and US Department of Agriculture. 2015-2020 Dietary Guidelines for Americans. 8th edition. Published December 2015. Accessed March 5, 2021. http://health.gov/dietaryguidelines/2015/guidelines/
25. Harcombe Z, Baker JS, DiNicolantonio JJ, et al. Evidence from randomised controlled trials does not support current dietary fat guidelines: a systematic review and meta-analysis. Open Hear. 2016;3:e000409. https://doi.org/10.1136/openhrt-2016-000409
26. Fung J. The Obesity Code: Unlocking the Secrets of Weight Loss. Greystone Books; 2016.
27. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58. https://doi.org/10.1016/j.arr.2016.10.005
28. Patterson RE, Sears DD. Metabolic Effects of Intermittent Fasting. Annu Rev Nutr. 2017; 37:371-393. https://doi.org/10.1146/annurev-nutr-071816-064634
29. Duncan GG. Intermittent fasts in the correction and control of intractable obesity. Trans Am Clin Climatol Assoc. 1962;74:121-129.
30. Gabel K, Hoddy KK, Varady KA. Safety of 8-h time restricted feeding in adults with obesity. Appl Physiol Nutr Metab. 2019;44:107-109. https://doi.org/10.1139/apnm-2018-0389
31. Erlandson M, Ivey LC, Seikel K. Update on office-based strategies for the management of obesity. Am Fam Physician. 2016;94:361-368.
32. Malhotra A, Noakes T, Phinney S. It is time to bust the myth of physical inactivity and obesity: you cannot outrun a bad diet. Br J Sports Med. 2015;49:967-968. https://doi.org/10.1136/bjsports-2015-094911
33. Donnelly JE, Blair SN, Jakicic JM, et al. Appropriate physical activity intervention strategies for weight loss and prevention of weight regain for adults. Med Sci Sports Exerc. 2009;41:459-471. https://doi.org/10.1249/MSS.0b013e3181949333
34. Zheng Y, Burke LE, Danford CA, et al. Patterns of self-weighing behavior and weight change in a weight loss trial. Int J Obes (Lond). 2016;40:1392-1396. https://doi.org/10.1038/ijo.2016.68
PRACTICE RECOMMENDATIONS
› Create an office environment where patients feel comfortable discussing their weight. C
› Screen overweight and obese patients for comorbidities. B
› Focus on nutritional changes more than exercise when working with patients who want to lose weight. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Guarding against nonmelanoma skin cancer in solid organ transplant recipients
The incidence of posttransplant malignancy among solid organ transplant recipients (SOTRs) is 10%; skin cancer, primarily nonmelanoma skin cancer (NMSC), constitutes 49.5% of all malignancies in this population.1 The etiology of the increased risk of cutaneous malignancy in SOTR is multifactorial:
- The skin of SOTRs is photosensitive, compared to that of immunocompetent patients, thus predisposing SOTRs to carcinogenic damage resulting from exposure to UV light.2
- Immunosuppression plays a key role in increasing the risk of cutaneous malignancy by inhibiting the ability of the immune system to recognize and destroy tumor cells.3
- Human papillomavirus (HPV) can play a role in carcinogenesis by promoting molecular pathways to proliferation and survival of nascent tumor cells4;Times New Romanβ-HPV strains are disseminated ubiquitously in the skin of immunosuppressed patients.5
- Some medications administered after transplantation can be directly carcinogenic.
NMSC in SOTRs also differs qualitatively from NMSC in immunocompetent patients. Cutaneous squamous cell carcinoma (cSCC) (FIGUREs 1 and 2) is the most common skin cancer among SOTRs, whereas basal cell carcinoma (BCC) is the most common skin cancer in the general population.3 cSCC in the SOTR population tends to be more aggressive, with more rapid local invasion and an increased rate of both in-transit and distant metastases, leading to an increase in morbidity and mortality. Mortality of metastatic cSCC among SOTRs is approximately 50%, compared to 20% in an otherwise healthy population.3,6-8
The problem is relevant to primary care
Screening. Because there is a demonstrated reduction in morbidity and mortality associated with early detection and treatment of NMSC, regular screening of skin is important in the SOTR population.9 A study in Ontario, Canada, from 1994 to 2012 and comprising 10,183 SOTRs, found that adherence to an annual skin check regimen for ≥ 75% of the observation period was associated with a 34% reduction in cutaneous BCC- and cSCC-related morbidity or death (adjusted hazard ratio = 0.66; 95% CI, 0.48-0.92).10 Although routine follow-up with a dermatologist is recommended for SOTRs,9,11-15 only 2.1% of patients in the Canadian study were fully adherent with annual skin examination, and 55% never visited a dermatologist.10 Consequently, primary care physicians can play a key role in skin cancer screening for SOTRs.
Education regarding the importance of protection from the sun is also an essential part of primary care. A 2018 study of SOTRs in Turkey demonstrated that16
- 46% expressed a lack of knowledge of the hazards of sun exposure
- 44% did not recall ever receiving medical advice regarding sun protection
- 89% did not wear sun-protective clothing
- 86% did not use sunscreen daily.
Multiple studies have demonstrated the positive effect that preventive education and attendance at a dermatology or skin cancer screening clinic can have on sun-protective behaviors among SOTRs.9,16-18 In the Turkish study, 100% of patients who reported using sunscreen daily had been undergoing regular dermatologic examination.16
In this article, we review current management guidelines regarding the prevention and treatment of NMSC in SOTRs.
Recommendations for prevention
Screening skin exams (TABLE 11,11,12,15,19-23). Although definitive guidelines do not exist regarding the frequency of a screening skin exam for SOTRs, multiple frequency-determining algorithms have been proposed.11,12,15,19 The recommended frequency of a skin exam is based on history of skin cancer; for SOTRs, the most common recommendation19 is a full-body skin examination as follows:
- annually—when there is no history of skin cancer
- every 6 months—when there is a history of actinic keratoses (AKs; precancerous lesions that carry a risk of transforming into cSCC) or a single low-risk NMSC
- every 3 months—when there is a history of multiple NMSCs or a single high-risk NMSC
- every 1 to 3 months—when there is a history of metastatic disease.
Continue to: Other risk factors...
Other risk factors for NMSC to consider in SOTRs when determining an appropriate follow-up regimen include any of the following1,20,21,24-26:
- male gender, fair skin, history of childhood sunburn, history of smoking
- lung or heart transplantation, history of episodes of transplant rejection, age ≥ 50 years at transplantation
- immunosuppression with calcineurin inhibitors, compared to mammalian target of rapamycin (mTOR) inhibitors
- immunosuppression with cyclosporine, compared to tacrolimus
- an immunosuppressive regimen with > 1 immunosuppressant or an increased degree of immunosuppression
- antithymocyte globulin within the first year posttransplantation.
Because the intensity of immunosuppression and individual immunosuppressants used affect the risk of NMSC, conduct a thorough medication review with SOTRs at all visits. Ask about new, changing, or symptomatic (pruritic, painful, bleeding) skin lesions, and perform a full-body skin exam. Palpate draining lymph nodes if the patient has a history of NMSC.15 AKs (FIGURE 3) should be treated aggressively with liquid nitrogen or field therapy. Lesions suspicious for NMSC should be biopsied and sent for histologic evaluation.22 Shave, punch, and excisional biopsies are all adequate techniques; however, because all cSCCs in SOTRs are considered high risk for aggressive features, biopsy should extend at least into the reticular dermis to allow evaluation for invasive disease.22
Sun-protective measures (TABLE 11,11,12,15,19-23). Inquire about patients’ habits related to protection from the sun, their knowledge of recommended sun-protective measures, and risks associated with nonadherence. Recommended sun-protective measures include
- daily broad-spectrum sunscreen (SPF ≥ 30), reapplied every 2 hours of sun exposure, in accordance with labeling instructions23
- sun-protective clothing (pants, long sleeves, hat, sunglasses)23
- avoidance of tanning salons.15
SOTRs who adequately adhere to sun-protective measures might need vitamin D supplementation because sunscreen and sun-protective clothing inhibit cutaneous synthesis of vitamin D.15
Recommendations for treatment
Consider chemoprophylactic therapy for SOTRs who have had multiple prior cutaneous malignancies or multiple AKs.
Continue to: Topical chemoprophylaxis
Topical chemoprophylaxis
Topical medications used for cSCC chemoprophylaxis include 5-fluorouracil (5-FU), photodynamic therapy (PDT), imiquimod, ingenol mebutate, topical retinoids, and diclofenac.27 (See TABLE 2.27-40) Of these, the latter 3 are used less commonly because of the small packaging size of ingenol mebutate and the relative lack of efficacy data for topical retinoids and diclofenac.27 Imiquimod is often avoided when treating large surface areas because of the risk of systemic adverse effects associated with cytokine release.27
5-FU is US Food and Drug Administration (FDA)-approved for the treatment of AKs, and is used off-label for treating cSCC in situ (Bowen disease). It is the most commonly used topical therapy for field disease.27-29 5-FU is typically applied once or twice daily for 3 to 4 weeks. Common adverse effects include transient skin irritation and erythema.27
PDT involves topical application of a photosensitizer, such as 5-aminolevulinic acid or methyl aminolevulinate, followed by exposure to a visible light source, leading to antitumor effects on gene expression and destruction of proliferating cells through production of reactive oxygen species.30,31 Evidence is sufficient to support routine use of PDT for AKs and Bowen disease.30 A mild sunburn-like reaction is common following PDT, with transient erythema and discomfort typically lasting 1 to 2 weeks but not typically necessitating analgesic therapy.27
Imiquimod is a ligand that binds to and activates Toll-like receptor 7, leading to enhancement of the cell-mediated antitumor immune response and resultant tissue-specific apoptosis coordinated by type 1 T-helper lymphocytes.32 Topical imiquimod cream is FDA approved for field treatment of AKs at 2.5%, 3.75%, and 5% concentrations; efficacy has been demonstrated in the SOTR population.33,41 Multiple studies in immunocompetent patients have suggested that imiquimod might be slightly less efficacious than 5-FU.42-44
The tolerability of field treatment with imiquimod has been called into question.27 However, in a 2019 study comparing adverse reactions among 513 immunocompetent patients with field disease who were treated with either 5-FU 5% cream; imiquimod 5% cream; PDT with methyl aminolevulinate; or ingenol mebutate 0.015% gel, a similar or smaller percentage of patients treated with imiquimod reported moderate-to-severe itching, moderate-to-severe pain, and any adverse events, compared to patients treated with the other options.44
Continue to: Diclofenac
Diclofenac is a nonsteroidal anti-inflammatory drug that reversibly inhibits the enzymes cyclooxygenase-1 and cyclooxygenase-2, resulting in a decrease in the formation of inflammatory prostaglandins, which have been observed in chronically sun-damaged skin, AKs, and cSCC.34,45 Diclofenac 3% gel, applied topically twice daily for 60 to 90 days has been approved by the FDA for treatment of AKs, in conjunction with sun avoidance.34 Topical diclofenac has been demonstrated to be efficacious in treating AKs in the SOTR population46,47; however, multiple meta-analyses using data from immunocompetent patients have demonstrated that topical diclofenac is inferior to other treatment options, particularly 5-FU, at achieving complete clearance of AKs.43,48,49 Diclofenac might be a useful option when patient adherence is expected to be difficult because of adverse effects of therapy: Multiple studies have suggested that diclofenac might be more tolerable than other options.43,48,50
Systemic chemoprophylaxis
Systemic therapies that have been used for chemoprophylaxis against cutaneous malignancy include nicotinamide, oral retinoids, capecitabine, and HPV vaccination. (See TABLE 2.27-40)
Nicotinamide, the amide form of vitamin B3, protects against cutaneous malignancy by aiding repair of DNA damaged by ionizing radiation, such as UV light.27 Efficacy has been demonstrated in reducing development of new AKs and cSCC in immunocompetent patients with a history of more than 2 keratinocyte carcinomas within a 5-year span.27,35 Nicotinamide is especially relevant to the SOTR population because it reduces the level of cutaneous immunity suppression induced by UV radiation without altering patients’ baseline immunity.27,36
There are insufficient long-term follow-up data in the literature to assess the sustainability of the antitumor effects of nicotinamide; studies specific to the SOTR population have been underpowered for assessing its impact on formation of cSCC.27,35Patients taking nicotinamide should be informed of the risk of liver failure at dosages > 3 g/d (antitumor efficacy has been demonstrated at 500 mg twice daily) and advised to avoid purchasing over-the-counter nicotinic acid or niacin as a substitute for nicotinamide, because of the increased incidence of flushing associated with their use.27
Oral retinoids. Systemic retinoids—in particular, acitretin—are efficacious in reducing the risk of cSCC in SOTRs.27,37,38 The primary drawback to cSCC prophylaxis with oral retinoids is a rebound effect, in which treatment discontinuation leads to a rapid return to baseline cSCC formation.27
Continue to: Pregnancy must be avoided...
Pregnancy must be avoided while taking an oral retinoid. Because acitretin can persist in the body for years after discontinuation, its use should generally be avoided in patients of childbearing potential. An FDA black box warning states that patients of childbearing potential must be counseled to use 2 forms of birth control to avoid pregnancy for ≥ 3 years after cessation of oral acitretin. Prior to initiation of oral retinoid therapy, the following baseline laboratory tests should be obtained: complete blood count, creatinine, lipid panel, and liver function tests. For patients with a history of chronic kidney disease or renal transplantation, the lipid panel, liver function tests, and creatinine assay should be repeated with each dosage adjustment and every 3 months once goal-dosing is achieved.27
Capecitabine is typically initiated with the help of Medical Oncology.27,40 A prodrug metabolized by dihydropyrimidine dehydrogenase to 5-FU, capecitabine interacts with warfarin, leading to a significant increase in prothrombin time.39 Other adverse effects associated with oral capecitabine include fatigue, palmar-plantar erythrodysesthesia, diarrhea, and, rarely, neutropenia. Although dihydropyrimidine dehydrogenase deficiency is rare, treatment with capecitabine in patients who have this enzyme deficiency might lead to severe toxicity or death.27
HPV vaccination. HPV might play a role in the development of cutaneous malignancy, especially in immunosuppressed patients.4,5 The utility of HPV vaccination in the prevention of NMSC has yet to be determined, but vaccination has been shown, in case reports, to be helpful in immunocompetent patients.51,52 The immunogenicity of HPV vaccination in the SOTR population is uncertain, and the most common HPV types found in SOTRs are not specifically covered by available HPV vaccines.19
The role of immunosuppression reduction and immunosuppressive replacement
Both the degree of immunosuppression and the individual agents used can affect a patient’s risk of NMSC. Immunosuppression reduction should be considered if skin cancer poses a major risk to the patient’s health and if that risk outweighs the risk of graft rejection associated with immunosuppression reduction.27 In a cohort of 180 kidney and liver SOTRs who developed de novo carcinoma (excluding NMSC) after transplantation, neither reduction of immunosuppression nor introduction of an mTOR inhibitor affected graft survival or oncologic treatment tolerance.53 Because mTOR inhibitors have a protective effect against development of NMSC, they are the preferred choice of immunosuppressive agent from a dermatologic perspective.1,27,54-57 Decisions regarding changes in immunosuppression are generally made by, or in collaboration with, the patient’s transplant physician.
Recommendations: Treating cSCC
Risk should guide strategy
Small lesions of the trunk and extremities without high-risk features can be treated with a destructive method (eg, electrodessication and curettage). However, lesions of the head and neck and those found to have features consistent with an increased risk of recurrence or metastasis should be treated aggressively.3,58,59
Continue to: Risk factors for invasive growth...
Risk factors for invasive growth, recurrence, or metastasis of cSCC in SOTRs are multiple lesions or satellite lesions, indistinct clinical borders, rapid growth, ulceration, and recurrence after treatment.60 The risk of invasive growth, recurrence, and metastasis of cSCC also increases with size and location of the lesion, according to this framework60:
- any size in scar tissue, areas of chronic inflammation, and fields of prior radiation therapy
- ≥ 0.6 cm on hands, feet, genitalia, and mask areas of the face (central face, eyelids, eyebrows, nose, lips, chin, mandible, and temporal, preauricular, postauricular, and periorbital areas)
- > 1 cm on cheeks, forehead, neck, and scalp
- > 2 cm on the trunk and extremities.
In addition, specific findings on histologic analysis portend increased risk of invasive growth, recurrence, or metastasis:
- poor differentiation
- deep extension of the tumor into subcutaneous fat
- perineural invasion or inflammation
- perivascular or intravascular invasion.
Treatment modalities
Mohs surgery is preferred to ensure margin clearance while preserving noninvolved tissue3,7 (FIGURE 4). If Mohs surgery is not possible, the lesion should be excised with 3- to 10-mm margins.3,60 Based on current literature, the roles of nodal staging, sentinel lymph node biopsy, and adjuvant therapy are not well defined, but it is likely that these interventions will play a pivotal role in the management of advanced cSCC in SOTRs in the future.3
Nonsurgical therapeutic options for primary or adjuvant treatment of cSCC include systemic chemotherapy, radiotherapy, and programmed cell death protein 1 inhibitors. (For more on treatment modalities, see TABLE 3.3,7,58-61)
Recommendations: Treating BCC
BCC in SOTRs is treated similarly (TABLE 33,7,58-61) to how it is treated in the immunocompetent population—except that SOTRs require closer follow-up than nontransplant patients because they are at higher risk of recurrence and new NMSCs.3 Standard management after biopsy is either3,61:
- Mohs surgery to ensure margin control (for most BCCs on the head and neck and those with clinical or histologic risk factors for recurrence or aggressive behavior)
- excision with a 4- or 5-mm margin or a destructive modality (for BCCs on the trunk and extremities without risk factors for recurrence).
Radiotherapy is an alternative for patients with high-risk BCCs who are unable to tolerate surgery.3
CORRESPONDENCE
Lindsey Collins, MD, Department of Dermatology, University of Oklahoma Health Sciences Center, 619 NE 13th Steet, Oklahoma City, OK 73104; [email protected]
1. Bhat M, Mara K, Dierkhising R, et al. Immunosuppression, race, and donor-related risk factors affect de novo cancer incidence across solid organ transplant recipients. Mayo Clin Proc. 2018;93:1236-1246. doi: 10.1016/j.mayocp.2018.04.025
2. Togsverd-Bo K, Philipsen PA, Haedersdal M, et al. Organ transplant recipients express enhanced skin autofluorescence and pigmentation at skin cancer sites. J Photochem Photobiol B. 2018;188:1-5. doi: 10.1016/j.jphotobiol.2018.08.008
3. Kearney L, Hogan D, Conlon P, et al. High-risk cutaneous malignancies and immunosuppression: challenges for the reconstructive surgeon in the renal transplant population. J Plast Reconstr Aesthet Surg. 2017;70:922-930. doi: 10.1016/j.bjps.2017.03.005
4. Borgogna C, Olivero C, Lanfredini S, et al. β-HPV infection correlates with early stages of carcinogenesis in skin tumors and patient-derived xenografts from a kidney transplant recipient cohort. Front Microbiol. 2018;9:117. doi: 10.3389/fmicb.2018.00117
5. Nunes EM, Talpe-Nunes V, Sichero L. Epidemiology and biology of cutaneous human papillomavirus. Clinics (Sao Paulo). 2018;73(suppl 1):e489s. doi: 10.6061/clinics/2018/e489s
6. Pini AM, Koch S, J Am Acad Dermatol. 2008;59(suppl 5):S116-S117. doi: 10.1016/j.jaad.2008.06.018
L, et al. Eruptive keratoacanthoma following topical imiquimod for in situ squamous cell carcinoma of the skin in a renal transplant recipient.7. Ilyas M, Zhang N, Sharma A. Residual squamous cell carcinoma after shave biopsy in solid organ transplant recipients. Dermatol Surg. 2018;44:370-374. doi: 10.1097/DSS.0000000000001340
8. Brunner M, Veness MJ, Ch‘ng S, et al. Distant metastases from cutaneous squamous cell carcinoma—analysis of AJCC stage IV. Head Neck. 2013;35:72-75. doi: 10.1002/hed.22913
9. Hartman RI, Green AC, Gordon LG; JAMA Dermatol. 2018;154:842-844. doi: 10.1001/jamadermatol.2018.1164
. Sun protection among organ transplant recipients after participation in a skin cancer research study.10. Chan A-W, Fung K, Austin PC, et al. Improved keratinocyte carcinoma outcomes with annual dermatology assessment after solid organ transplantation: population-based cohort study. Am J Transplant. 2018;19:522-531. doi: 10.1111/ajt.14966
11. Hofbauer GF, Anliker M, Arnold A, et al. Swiss clinical practice guidelines for skin cancer in organ transplant recipients. Swiss Med Wkly. 2009;139:407-415. doi: https://doi.org/10.4414/smw.2014.14026
12. Ulrich C, Kanitakis J, Stockfleth E, et al. Skin cancer in organ transplant recipients—where do we stand today? Am J Transplant. 2008;8:2192-2198. doi: 10.1111/j.1600-6143.2008.02386.x
13. Chen SC, Pennie ML, Kolm P, et al. Diagnosing and managing cutaneous pigmented lesions: primary care physicians versus dermatologists. J Gen Intern Med. 2006;21:678-682. doi: 10.1111/j.1525-1497.2006.00462.x
14. Ismail F, Mitchell L, Casabonne D, et al. Specialist dermatology clinics for organ transplant recipients significantly improve compliance with photoprotection and levels of skin cancer awareness. Br J Dermatol. 2006;155:916-925. doi: 10.1111/j.1365-2133.2006.07454.x
15. O‘Reilly Zwald F, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: part II. Management of skin cancer in solid organ transplant recipients. J Am Acad Dermatol. 2011;65:263-279. doi: 10.1016/j.jaad.2010.11.063
16. Exp Clin Transplant. 2018;16(suppl 1):203-207. doi: 10.6002/ect.TOND-TDTD2017.P65
Vural A, A, Kirnap M, et al. Skin cancer risk awareness and sun-protective behavior among solid-organ transplant recipients.17. Papier K, Gordon LG, Khosrotehrani K, et al. Increase in preventive behaviour by organ transplant recipients after sun protection information in a skin cancer surveillance clinic. Br J Dermatol. 2018;179:1195-1196. doi: 10.1111/bjd.16836
18. Wu SZ, Jiang P, DeCaro JE, et al. A qualitative systematic review of the efficacy of sun protection education in organ transplant recipients. J Am Acad Dermatol. 2016;75:1238-1244.e5. doi: 10.1016/j.jaad.2016.06.031
19. Blomberg M, He SY, Harwood C, et al; Br J Dermatol. 2017;177:1225-1233. doi: 10.1111/bjd.15950
. Research gaps in the management and prevention of cutaneous squamous cell carcinoma in organ transplant recipients.20. Urwin HR, Jones PW, Harden PN, et al. Predicting risk of nonmelanoma skin cancer and premalignant skin lesions in renal transplant recipients. Transplantation. 2009;87:1667-1671. doi: 10.1097/TP.0b013e3181a5ce2e
21. Infusino SD, Loi C, Ravaioli GM, et al. Cutaneous complications of immunosuppression in 812 transplant recipients: a 40-year single center experience. G Ital Dermatol Venereol. 2020;155:662-668. doi: 10.23736/S0392-0488.18.06091-1
22. Naldi L, Venturuzzo A, Invernizzi P. Dermatological complications after solid organ transplantation. Clin Rev Allergy Immunol. 2018;54:185-212. doi: 10.1007/s12016-017-8657-9
23. Sunscreen FAQs. American Academy of Dermatology Web site. Accessed February 25, 2021. www.aad.org/media/stats/prevention-and-care/sunscreen-faqs
24. Vos M, Plasmeijer EI, van Bemmel BC, et al. Azathioprine to mycophenolate mofetil transition and risk of squamous cell carcinoma after lung transplantation. J Heart Lung Transplant. 2018;37:853-859. doi: 10.1016/j.healun.2018.03.012
25. Puza CJ, Myers SA, Cardones AR, et al. The impact of transplant rejection on cutaneous squamous cell carcinoma in renal transplant recipients. Clin Exp Dermatol. 2018;44:265-269. doi: 10.1111/ced.13699
26. Abikhair Burgo M, Roudiani N, Chen J, et al. Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma. JCI Insight. 2018;3:e120750. doi: 10.1172/jci.insight.120750
27. Que SKT, Zwald FO, Schmults CD. Cutaneous squamous cell carcinoma: management of advanced and high-stage tumors. J Am Acad Dermatol. 2018;78:249-261. doi: 10.1016/j.jaad.2017.08.058
28. Askew DA, Mickan SM, Soyer HP, et al. Effectiveness of 5-fluorouracil treatment for actinic keratosis—a systematic review of randomized controlled trials. Int J Dermatol. 2009;48:453-463. doi: 10.1111/j.1365-4632.2009.04045.x
29. Salim A, Leman JA, McColl JH, et al. Randomized comparison of photodynamic therapy with topical 5-fluorouracil in Bowen‘s disease. Br J Dermatol. 2003;148:539-543. doi: 10.1046/j.1365-2133.2003.05033.x
30. Morton CA. A synthesis of the world‘s guidelines on photodynamic therapy for non-melanoma skin cancer. G Ital Dermatol Venereol. 2018;153:783-792. doi: 10.23736/S0392-0488.18.05896-0
31. Joly F, Deret S, Gamboa B, et al. Photodynamic therapy corrects abnormal cancer-associated gene expression observed in actinic keratosis lesions and induces a remodeling effect in photodamaged skin. J Dermatol Sci. 2018;S0923-1811(17)30775-2. doi: 10.1016/j.jdermsci.2018.05.002
32. Patel GK, Goodwin R, Chawla M, et al. Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in situ (Bowen‘s disease): a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2006;54:1025-1032. doi: 10.1016/j.jaad.2006.01.055
33. Imiquimod. Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed August 6, 2019. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7077?cesid=aRo1Yh9sd0Q&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dimiquimod%26t%3Dname%26va%3Dimiquimod
34. Diclofenac. Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed August 6th, 2019. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/1772965?cesid=5vTk7J3Vmvc&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Ddiclofenac%26t%3Dname%26va%3Ddiclofenac
35. Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373:1618-1626. doi: 10.1056/NEJMoa1506197
36. Yiasemides E, Sivapirabu G, Halliday GM, et al. Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans. Carcinogenesis. 2009;30:101-105. doi: 10.1093/carcin/bgn248
37. Otley CC, Stasko T, Tope WD, et al. Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects. Dermatol Surg. 2006;32:562-568. doi: 10.1111/j.1524-4725.2006.32115.x
38. McKenna DB, Murphy GM. Skin cancer chemoprophylaxis in renal transplant recipients: 5 years of experience using low-dose acitretin. Br J Dermatol. 1999;140:656-660. doi: 10.1046/j.1365-2133.1999.02765.x
39. Capecitabine. Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed February 13, 2019. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6519?cesid=7WMsK72X7T7&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dcapecitabine%26t%3Dname%26va%3Dcapecitabine
40. Wollina U, Hansel G, Koch A, et al. Oral capecitabine plus subcutaneous interferon alpha in advanced squamous cell carcinoma of the skin. J Cancer Res Clin Oncol. 2005;131:300-304. doi: 10.1007/s00432-004-0656-6
41. Zavattaro E, Veronese F, Landucci G, et al. Efficacy of topical imiquimod 3.75% in the treatment of actinic keratosis of the scalp in immunosuppressed patients: our case series. J Dermatol Treat. 2020;31:285-289. doi: 10.1080/09546634.2019.1590524
42. Neugebauer R, Su KA, Zhu Z, et al. Comparative effectiveness of treatment of actinic keratosis with topical fluorouracil and imiquimod in the prevention of keratinocyte carcinoma: a cohort study. J Am Acad Dermatol. 2019;80:998-1005. doi: 10.1016/j.jaad.2018.11.024
43. Gupta AK, Paquet M. Network meta-analysis of the outcome ‚participant complete clearance in nonimmunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review. Br J Dermatol. 2013;169:250-259. doi: 10.1111/bjd.12343
44. Jansen MHE, Kessels JPHM, Nelemans PJ, et al. Randomized trial of four treatment approaches for actinic keratosis. N Engl J Med. 2019;380:935-946. doi: 10.1056/NEJMoa1811850
45. Bangash HK, Colegio OR. Management of non-melanoma skin cancer in immunocompromised solid organ transplant recipients. Curr Treat Options Oncol. 2012;13:354-376. doi: 10.1007/s11864-012-0195-3
46. Ulrich C, Johannsen A, Eur J Dermatol. 2010;20:482-488. doi: 10.1684/ejd.2010.1010
J, et al. Results of a randomized, placebo-controlled safety and efficacy study of topical diclofenac 3% gel in organ transplant patients with multiple actinic keratoses.47. Ulrich C, Hackethal M, Ulrich M, et al. Treatment of multiple actinic keratoses with topical diclofenac 3% gel in organ transplant recipients: a series of six cases. Br J Dermatol. 2007;156(suppl 3):40-42. doi: 10.1111/j.1365-2133.2007.07864.x
48. Wu Y, Tang N, Cai L, et al. Relative efficacy of 5-fluorouracil compared with other treatments among patients with actinic keratosis: a network meta-analysis. Dermatol Ther. 2019;32:e12822. doi: 10.1111/dth.12822
49. Stockfleth E, Kerl H, Zwingers T, et al. Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results. Br J Dermatol. 2011;165:1101-1108. doi: 10.1111/j.1365-2133.2011.10387.x
50. Smith SR, Morhenn VB, Piacquadio DJ. Bilateral comparison of the efficacy and tolerability of 3% diclofenac sodium gel and 5% 5-fluorouracil cream in the treatment of actinic keratoses of the face and scalp. J Drug Dermatol. 2006;5:156-159.
51. Nichols AJ, Allen AH, Shareef S, et al. Association of human papillomavirus vaccine with the development of keratinocyte carcinomas. JAMA Dermatol. 2017;153:571-574. doi: 10.1001/jamadermatol.2016.5703
52. Nichols AJ, Gonzalez A, Clark ES, et al. Combined systemic and intratumoral administration of human papillomavirus vaccine to treat multiple cutaneous basaloid squamous cell carcinomas. JAMA Dermatol. 2018;154:927-930. doi: 10.1001/jamadermatol.2018.1748
53. Rousseau B, Guillemin A, Duvoux C, et al. Optimal oncologic management and mTOR inhibitor introduction are safe and improve survival in kidney and liver allograft recipients with de novo carcinoma. Int J Cancer. 2019;144:886-896. doi: 10.1002/ijc.31769
54. Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant. 2004;18:446-449. doi: 10.1111/j.1399-0012.2004.00188.x
55. Euvrard S, Morelon E, Rostaing L, et al; N Engl J Med. 2012;367:329-339. doi: 10.1056/NEJMoa1204166
Sirolimus and secondary skin-cancer prevention in kidney transplantation.56. Hoogendijk-van den Akker JM, Harden PN, Hoitsma AJ, et al. Two-year randomized controlled prospective trial converting treatment of stable renal transplant recipients with cutaneous invasive squamous cell carcinomas to sirolimus. J Clin Oncol. 2013;31:1317-1323. doi: 10.1200/JCO.2012.45.6376
57. Karia PS, Azzi JR, Heher EC, et al. Association of sirolimus use with risk for skin cancer in a mixed-organ cohort of solid-organ transplant recipients with a history of cancer. JAMA Dermatol. 2016;152:533-540. doi: 10.1001/jamadermatol.2015.5548
58. Stratigos A, Garbe C, Lebbe C, et al; . Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline. Eur J Cancer. 2015;51:1989-2007. doi: 10.1016/j.ejca.2015.06.110
59. Goldman G. The current status of curettage and electrodesiccation. Dermatol Clin. 2002;20:569-578, ix. doi: 10.1016/s0733-8635(02)00022-0
60. Stasko T, Brown MD, Carucci JA, et al; ; . Guidelines for the management of squamous cell carcinoma in organ transplant recipients. Derm Surg. 2004;30:642-650. doi: 10.1111/j.1524-4725.2004.30150.x
61. Telfer NR, Colver GB, Morton CA; Br J Dermatol. 2008;159:35-48. doi: 10.1111/j.1365-2133.2008.08666.x
. Guidelines for the management of basal cell carcinoma.The incidence of posttransplant malignancy among solid organ transplant recipients (SOTRs) is 10%; skin cancer, primarily nonmelanoma skin cancer (NMSC), constitutes 49.5% of all malignancies in this population.1 The etiology of the increased risk of cutaneous malignancy in SOTR is multifactorial:
- The skin of SOTRs is photosensitive, compared to that of immunocompetent patients, thus predisposing SOTRs to carcinogenic damage resulting from exposure to UV light.2
- Immunosuppression plays a key role in increasing the risk of cutaneous malignancy by inhibiting the ability of the immune system to recognize and destroy tumor cells.3
- Human papillomavirus (HPV) can play a role in carcinogenesis by promoting molecular pathways to proliferation and survival of nascent tumor cells4;Times New Romanβ-HPV strains are disseminated ubiquitously in the skin of immunosuppressed patients.5
- Some medications administered after transplantation can be directly carcinogenic.
NMSC in SOTRs also differs qualitatively from NMSC in immunocompetent patients. Cutaneous squamous cell carcinoma (cSCC) (FIGUREs 1 and 2) is the most common skin cancer among SOTRs, whereas basal cell carcinoma (BCC) is the most common skin cancer in the general population.3 cSCC in the SOTR population tends to be more aggressive, with more rapid local invasion and an increased rate of both in-transit and distant metastases, leading to an increase in morbidity and mortality. Mortality of metastatic cSCC among SOTRs is approximately 50%, compared to 20% in an otherwise healthy population.3,6-8
The problem is relevant to primary care
Screening. Because there is a demonstrated reduction in morbidity and mortality associated with early detection and treatment of NMSC, regular screening of skin is important in the SOTR population.9 A study in Ontario, Canada, from 1994 to 2012 and comprising 10,183 SOTRs, found that adherence to an annual skin check regimen for ≥ 75% of the observation period was associated with a 34% reduction in cutaneous BCC- and cSCC-related morbidity or death (adjusted hazard ratio = 0.66; 95% CI, 0.48-0.92).10 Although routine follow-up with a dermatologist is recommended for SOTRs,9,11-15 only 2.1% of patients in the Canadian study were fully adherent with annual skin examination, and 55% never visited a dermatologist.10 Consequently, primary care physicians can play a key role in skin cancer screening for SOTRs.
Education regarding the importance of protection from the sun is also an essential part of primary care. A 2018 study of SOTRs in Turkey demonstrated that16
- 46% expressed a lack of knowledge of the hazards of sun exposure
- 44% did not recall ever receiving medical advice regarding sun protection
- 89% did not wear sun-protective clothing
- 86% did not use sunscreen daily.
Multiple studies have demonstrated the positive effect that preventive education and attendance at a dermatology or skin cancer screening clinic can have on sun-protective behaviors among SOTRs.9,16-18 In the Turkish study, 100% of patients who reported using sunscreen daily had been undergoing regular dermatologic examination.16
In this article, we review current management guidelines regarding the prevention and treatment of NMSC in SOTRs.
Recommendations for prevention
Screening skin exams (TABLE 11,11,12,15,19-23). Although definitive guidelines do not exist regarding the frequency of a screening skin exam for SOTRs, multiple frequency-determining algorithms have been proposed.11,12,15,19 The recommended frequency of a skin exam is based on history of skin cancer; for SOTRs, the most common recommendation19 is a full-body skin examination as follows:
- annually—when there is no history of skin cancer
- every 6 months—when there is a history of actinic keratoses (AKs; precancerous lesions that carry a risk of transforming into cSCC) or a single low-risk NMSC
- every 3 months—when there is a history of multiple NMSCs or a single high-risk NMSC
- every 1 to 3 months—when there is a history of metastatic disease.
Continue to: Other risk factors...
Other risk factors for NMSC to consider in SOTRs when determining an appropriate follow-up regimen include any of the following1,20,21,24-26:
- male gender, fair skin, history of childhood sunburn, history of smoking
- lung or heart transplantation, history of episodes of transplant rejection, age ≥ 50 years at transplantation
- immunosuppression with calcineurin inhibitors, compared to mammalian target of rapamycin (mTOR) inhibitors
- immunosuppression with cyclosporine, compared to tacrolimus
- an immunosuppressive regimen with > 1 immunosuppressant or an increased degree of immunosuppression
- antithymocyte globulin within the first year posttransplantation.
Because the intensity of immunosuppression and individual immunosuppressants used affect the risk of NMSC, conduct a thorough medication review with SOTRs at all visits. Ask about new, changing, or symptomatic (pruritic, painful, bleeding) skin lesions, and perform a full-body skin exam. Palpate draining lymph nodes if the patient has a history of NMSC.15 AKs (FIGURE 3) should be treated aggressively with liquid nitrogen or field therapy. Lesions suspicious for NMSC should be biopsied and sent for histologic evaluation.22 Shave, punch, and excisional biopsies are all adequate techniques; however, because all cSCCs in SOTRs are considered high risk for aggressive features, biopsy should extend at least into the reticular dermis to allow evaluation for invasive disease.22
Sun-protective measures (TABLE 11,11,12,15,19-23). Inquire about patients’ habits related to protection from the sun, their knowledge of recommended sun-protective measures, and risks associated with nonadherence. Recommended sun-protective measures include
- daily broad-spectrum sunscreen (SPF ≥ 30), reapplied every 2 hours of sun exposure, in accordance with labeling instructions23
- sun-protective clothing (pants, long sleeves, hat, sunglasses)23
- avoidance of tanning salons.15
SOTRs who adequately adhere to sun-protective measures might need vitamin D supplementation because sunscreen and sun-protective clothing inhibit cutaneous synthesis of vitamin D.15
Recommendations for treatment
Consider chemoprophylactic therapy for SOTRs who have had multiple prior cutaneous malignancies or multiple AKs.
Continue to: Topical chemoprophylaxis
Topical chemoprophylaxis
Topical medications used for cSCC chemoprophylaxis include 5-fluorouracil (5-FU), photodynamic therapy (PDT), imiquimod, ingenol mebutate, topical retinoids, and diclofenac.27 (See TABLE 2.27-40) Of these, the latter 3 are used less commonly because of the small packaging size of ingenol mebutate and the relative lack of efficacy data for topical retinoids and diclofenac.27 Imiquimod is often avoided when treating large surface areas because of the risk of systemic adverse effects associated with cytokine release.27
5-FU is US Food and Drug Administration (FDA)-approved for the treatment of AKs, and is used off-label for treating cSCC in situ (Bowen disease). It is the most commonly used topical therapy for field disease.27-29 5-FU is typically applied once or twice daily for 3 to 4 weeks. Common adverse effects include transient skin irritation and erythema.27
PDT involves topical application of a photosensitizer, such as 5-aminolevulinic acid or methyl aminolevulinate, followed by exposure to a visible light source, leading to antitumor effects on gene expression and destruction of proliferating cells through production of reactive oxygen species.30,31 Evidence is sufficient to support routine use of PDT for AKs and Bowen disease.30 A mild sunburn-like reaction is common following PDT, with transient erythema and discomfort typically lasting 1 to 2 weeks but not typically necessitating analgesic therapy.27
Imiquimod is a ligand that binds to and activates Toll-like receptor 7, leading to enhancement of the cell-mediated antitumor immune response and resultant tissue-specific apoptosis coordinated by type 1 T-helper lymphocytes.32 Topical imiquimod cream is FDA approved for field treatment of AKs at 2.5%, 3.75%, and 5% concentrations; efficacy has been demonstrated in the SOTR population.33,41 Multiple studies in immunocompetent patients have suggested that imiquimod might be slightly less efficacious than 5-FU.42-44
The tolerability of field treatment with imiquimod has been called into question.27 However, in a 2019 study comparing adverse reactions among 513 immunocompetent patients with field disease who were treated with either 5-FU 5% cream; imiquimod 5% cream; PDT with methyl aminolevulinate; or ingenol mebutate 0.015% gel, a similar or smaller percentage of patients treated with imiquimod reported moderate-to-severe itching, moderate-to-severe pain, and any adverse events, compared to patients treated with the other options.44
Continue to: Diclofenac
Diclofenac is a nonsteroidal anti-inflammatory drug that reversibly inhibits the enzymes cyclooxygenase-1 and cyclooxygenase-2, resulting in a decrease in the formation of inflammatory prostaglandins, which have been observed in chronically sun-damaged skin, AKs, and cSCC.34,45 Diclofenac 3% gel, applied topically twice daily for 60 to 90 days has been approved by the FDA for treatment of AKs, in conjunction with sun avoidance.34 Topical diclofenac has been demonstrated to be efficacious in treating AKs in the SOTR population46,47; however, multiple meta-analyses using data from immunocompetent patients have demonstrated that topical diclofenac is inferior to other treatment options, particularly 5-FU, at achieving complete clearance of AKs.43,48,49 Diclofenac might be a useful option when patient adherence is expected to be difficult because of adverse effects of therapy: Multiple studies have suggested that diclofenac might be more tolerable than other options.43,48,50
Systemic chemoprophylaxis
Systemic therapies that have been used for chemoprophylaxis against cutaneous malignancy include nicotinamide, oral retinoids, capecitabine, and HPV vaccination. (See TABLE 2.27-40)
Nicotinamide, the amide form of vitamin B3, protects against cutaneous malignancy by aiding repair of DNA damaged by ionizing radiation, such as UV light.27 Efficacy has been demonstrated in reducing development of new AKs and cSCC in immunocompetent patients with a history of more than 2 keratinocyte carcinomas within a 5-year span.27,35 Nicotinamide is especially relevant to the SOTR population because it reduces the level of cutaneous immunity suppression induced by UV radiation without altering patients’ baseline immunity.27,36
There are insufficient long-term follow-up data in the literature to assess the sustainability of the antitumor effects of nicotinamide; studies specific to the SOTR population have been underpowered for assessing its impact on formation of cSCC.27,35Patients taking nicotinamide should be informed of the risk of liver failure at dosages > 3 g/d (antitumor efficacy has been demonstrated at 500 mg twice daily) and advised to avoid purchasing over-the-counter nicotinic acid or niacin as a substitute for nicotinamide, because of the increased incidence of flushing associated with their use.27
Oral retinoids. Systemic retinoids—in particular, acitretin—are efficacious in reducing the risk of cSCC in SOTRs.27,37,38 The primary drawback to cSCC prophylaxis with oral retinoids is a rebound effect, in which treatment discontinuation leads to a rapid return to baseline cSCC formation.27
Continue to: Pregnancy must be avoided...
Pregnancy must be avoided while taking an oral retinoid. Because acitretin can persist in the body for years after discontinuation, its use should generally be avoided in patients of childbearing potential. An FDA black box warning states that patients of childbearing potential must be counseled to use 2 forms of birth control to avoid pregnancy for ≥ 3 years after cessation of oral acitretin. Prior to initiation of oral retinoid therapy, the following baseline laboratory tests should be obtained: complete blood count, creatinine, lipid panel, and liver function tests. For patients with a history of chronic kidney disease or renal transplantation, the lipid panel, liver function tests, and creatinine assay should be repeated with each dosage adjustment and every 3 months once goal-dosing is achieved.27
Capecitabine is typically initiated with the help of Medical Oncology.27,40 A prodrug metabolized by dihydropyrimidine dehydrogenase to 5-FU, capecitabine interacts with warfarin, leading to a significant increase in prothrombin time.39 Other adverse effects associated with oral capecitabine include fatigue, palmar-plantar erythrodysesthesia, diarrhea, and, rarely, neutropenia. Although dihydropyrimidine dehydrogenase deficiency is rare, treatment with capecitabine in patients who have this enzyme deficiency might lead to severe toxicity or death.27
HPV vaccination. HPV might play a role in the development of cutaneous malignancy, especially in immunosuppressed patients.4,5 The utility of HPV vaccination in the prevention of NMSC has yet to be determined, but vaccination has been shown, in case reports, to be helpful in immunocompetent patients.51,52 The immunogenicity of HPV vaccination in the SOTR population is uncertain, and the most common HPV types found in SOTRs are not specifically covered by available HPV vaccines.19
The role of immunosuppression reduction and immunosuppressive replacement
Both the degree of immunosuppression and the individual agents used can affect a patient’s risk of NMSC. Immunosuppression reduction should be considered if skin cancer poses a major risk to the patient’s health and if that risk outweighs the risk of graft rejection associated with immunosuppression reduction.27 In a cohort of 180 kidney and liver SOTRs who developed de novo carcinoma (excluding NMSC) after transplantation, neither reduction of immunosuppression nor introduction of an mTOR inhibitor affected graft survival or oncologic treatment tolerance.53 Because mTOR inhibitors have a protective effect against development of NMSC, they are the preferred choice of immunosuppressive agent from a dermatologic perspective.1,27,54-57 Decisions regarding changes in immunosuppression are generally made by, or in collaboration with, the patient’s transplant physician.
Recommendations: Treating cSCC
Risk should guide strategy
Small lesions of the trunk and extremities without high-risk features can be treated with a destructive method (eg, electrodessication and curettage). However, lesions of the head and neck and those found to have features consistent with an increased risk of recurrence or metastasis should be treated aggressively.3,58,59
Continue to: Risk factors for invasive growth...
Risk factors for invasive growth, recurrence, or metastasis of cSCC in SOTRs are multiple lesions or satellite lesions, indistinct clinical borders, rapid growth, ulceration, and recurrence after treatment.60 The risk of invasive growth, recurrence, and metastasis of cSCC also increases with size and location of the lesion, according to this framework60:
- any size in scar tissue, areas of chronic inflammation, and fields of prior radiation therapy
- ≥ 0.6 cm on hands, feet, genitalia, and mask areas of the face (central face, eyelids, eyebrows, nose, lips, chin, mandible, and temporal, preauricular, postauricular, and periorbital areas)
- > 1 cm on cheeks, forehead, neck, and scalp
- > 2 cm on the trunk and extremities.
In addition, specific findings on histologic analysis portend increased risk of invasive growth, recurrence, or metastasis:
- poor differentiation
- deep extension of the tumor into subcutaneous fat
- perineural invasion or inflammation
- perivascular or intravascular invasion.
Treatment modalities
Mohs surgery is preferred to ensure margin clearance while preserving noninvolved tissue3,7 (FIGURE 4). If Mohs surgery is not possible, the lesion should be excised with 3- to 10-mm margins.3,60 Based on current literature, the roles of nodal staging, sentinel lymph node biopsy, and adjuvant therapy are not well defined, but it is likely that these interventions will play a pivotal role in the management of advanced cSCC in SOTRs in the future.3
Nonsurgical therapeutic options for primary or adjuvant treatment of cSCC include systemic chemotherapy, radiotherapy, and programmed cell death protein 1 inhibitors. (For more on treatment modalities, see TABLE 3.3,7,58-61)
Recommendations: Treating BCC
BCC in SOTRs is treated similarly (TABLE 33,7,58-61) to how it is treated in the immunocompetent population—except that SOTRs require closer follow-up than nontransplant patients because they are at higher risk of recurrence and new NMSCs.3 Standard management after biopsy is either3,61:
- Mohs surgery to ensure margin control (for most BCCs on the head and neck and those with clinical or histologic risk factors for recurrence or aggressive behavior)
- excision with a 4- or 5-mm margin or a destructive modality (for BCCs on the trunk and extremities without risk factors for recurrence).
Radiotherapy is an alternative for patients with high-risk BCCs who are unable to tolerate surgery.3
CORRESPONDENCE
Lindsey Collins, MD, Department of Dermatology, University of Oklahoma Health Sciences Center, 619 NE 13th Steet, Oklahoma City, OK 73104; [email protected]
The incidence of posttransplant malignancy among solid organ transplant recipients (SOTRs) is 10%; skin cancer, primarily nonmelanoma skin cancer (NMSC), constitutes 49.5% of all malignancies in this population.1 The etiology of the increased risk of cutaneous malignancy in SOTR is multifactorial:
- The skin of SOTRs is photosensitive, compared to that of immunocompetent patients, thus predisposing SOTRs to carcinogenic damage resulting from exposure to UV light.2
- Immunosuppression plays a key role in increasing the risk of cutaneous malignancy by inhibiting the ability of the immune system to recognize and destroy tumor cells.3
- Human papillomavirus (HPV) can play a role in carcinogenesis by promoting molecular pathways to proliferation and survival of nascent tumor cells4;Times New Romanβ-HPV strains are disseminated ubiquitously in the skin of immunosuppressed patients.5
- Some medications administered after transplantation can be directly carcinogenic.
NMSC in SOTRs also differs qualitatively from NMSC in immunocompetent patients. Cutaneous squamous cell carcinoma (cSCC) (FIGUREs 1 and 2) is the most common skin cancer among SOTRs, whereas basal cell carcinoma (BCC) is the most common skin cancer in the general population.3 cSCC in the SOTR population tends to be more aggressive, with more rapid local invasion and an increased rate of both in-transit and distant metastases, leading to an increase in morbidity and mortality. Mortality of metastatic cSCC among SOTRs is approximately 50%, compared to 20% in an otherwise healthy population.3,6-8
The problem is relevant to primary care
Screening. Because there is a demonstrated reduction in morbidity and mortality associated with early detection and treatment of NMSC, regular screening of skin is important in the SOTR population.9 A study in Ontario, Canada, from 1994 to 2012 and comprising 10,183 SOTRs, found that adherence to an annual skin check regimen for ≥ 75% of the observation period was associated with a 34% reduction in cutaneous BCC- and cSCC-related morbidity or death (adjusted hazard ratio = 0.66; 95% CI, 0.48-0.92).10 Although routine follow-up with a dermatologist is recommended for SOTRs,9,11-15 only 2.1% of patients in the Canadian study were fully adherent with annual skin examination, and 55% never visited a dermatologist.10 Consequently, primary care physicians can play a key role in skin cancer screening for SOTRs.
Education regarding the importance of protection from the sun is also an essential part of primary care. A 2018 study of SOTRs in Turkey demonstrated that16
- 46% expressed a lack of knowledge of the hazards of sun exposure
- 44% did not recall ever receiving medical advice regarding sun protection
- 89% did not wear sun-protective clothing
- 86% did not use sunscreen daily.
Multiple studies have demonstrated the positive effect that preventive education and attendance at a dermatology or skin cancer screening clinic can have on sun-protective behaviors among SOTRs.9,16-18 In the Turkish study, 100% of patients who reported using sunscreen daily had been undergoing regular dermatologic examination.16
In this article, we review current management guidelines regarding the prevention and treatment of NMSC in SOTRs.
Recommendations for prevention
Screening skin exams (TABLE 11,11,12,15,19-23). Although definitive guidelines do not exist regarding the frequency of a screening skin exam for SOTRs, multiple frequency-determining algorithms have been proposed.11,12,15,19 The recommended frequency of a skin exam is based on history of skin cancer; for SOTRs, the most common recommendation19 is a full-body skin examination as follows:
- annually—when there is no history of skin cancer
- every 6 months—when there is a history of actinic keratoses (AKs; precancerous lesions that carry a risk of transforming into cSCC) or a single low-risk NMSC
- every 3 months—when there is a history of multiple NMSCs or a single high-risk NMSC
- every 1 to 3 months—when there is a history of metastatic disease.
Continue to: Other risk factors...
Other risk factors for NMSC to consider in SOTRs when determining an appropriate follow-up regimen include any of the following1,20,21,24-26:
- male gender, fair skin, history of childhood sunburn, history of smoking
- lung or heart transplantation, history of episodes of transplant rejection, age ≥ 50 years at transplantation
- immunosuppression with calcineurin inhibitors, compared to mammalian target of rapamycin (mTOR) inhibitors
- immunosuppression with cyclosporine, compared to tacrolimus
- an immunosuppressive regimen with > 1 immunosuppressant or an increased degree of immunosuppression
- antithymocyte globulin within the first year posttransplantation.
Because the intensity of immunosuppression and individual immunosuppressants used affect the risk of NMSC, conduct a thorough medication review with SOTRs at all visits. Ask about new, changing, or symptomatic (pruritic, painful, bleeding) skin lesions, and perform a full-body skin exam. Palpate draining lymph nodes if the patient has a history of NMSC.15 AKs (FIGURE 3) should be treated aggressively with liquid nitrogen or field therapy. Lesions suspicious for NMSC should be biopsied and sent for histologic evaluation.22 Shave, punch, and excisional biopsies are all adequate techniques; however, because all cSCCs in SOTRs are considered high risk for aggressive features, biopsy should extend at least into the reticular dermis to allow evaluation for invasive disease.22
Sun-protective measures (TABLE 11,11,12,15,19-23). Inquire about patients’ habits related to protection from the sun, their knowledge of recommended sun-protective measures, and risks associated with nonadherence. Recommended sun-protective measures include
- daily broad-spectrum sunscreen (SPF ≥ 30), reapplied every 2 hours of sun exposure, in accordance with labeling instructions23
- sun-protective clothing (pants, long sleeves, hat, sunglasses)23
- avoidance of tanning salons.15
SOTRs who adequately adhere to sun-protective measures might need vitamin D supplementation because sunscreen and sun-protective clothing inhibit cutaneous synthesis of vitamin D.15
Recommendations for treatment
Consider chemoprophylactic therapy for SOTRs who have had multiple prior cutaneous malignancies or multiple AKs.
Continue to: Topical chemoprophylaxis
Topical chemoprophylaxis
Topical medications used for cSCC chemoprophylaxis include 5-fluorouracil (5-FU), photodynamic therapy (PDT), imiquimod, ingenol mebutate, topical retinoids, and diclofenac.27 (See TABLE 2.27-40) Of these, the latter 3 are used less commonly because of the small packaging size of ingenol mebutate and the relative lack of efficacy data for topical retinoids and diclofenac.27 Imiquimod is often avoided when treating large surface areas because of the risk of systemic adverse effects associated with cytokine release.27
5-FU is US Food and Drug Administration (FDA)-approved for the treatment of AKs, and is used off-label for treating cSCC in situ (Bowen disease). It is the most commonly used topical therapy for field disease.27-29 5-FU is typically applied once or twice daily for 3 to 4 weeks. Common adverse effects include transient skin irritation and erythema.27
PDT involves topical application of a photosensitizer, such as 5-aminolevulinic acid or methyl aminolevulinate, followed by exposure to a visible light source, leading to antitumor effects on gene expression and destruction of proliferating cells through production of reactive oxygen species.30,31 Evidence is sufficient to support routine use of PDT for AKs and Bowen disease.30 A mild sunburn-like reaction is common following PDT, with transient erythema and discomfort typically lasting 1 to 2 weeks but not typically necessitating analgesic therapy.27
Imiquimod is a ligand that binds to and activates Toll-like receptor 7, leading to enhancement of the cell-mediated antitumor immune response and resultant tissue-specific apoptosis coordinated by type 1 T-helper lymphocytes.32 Topical imiquimod cream is FDA approved for field treatment of AKs at 2.5%, 3.75%, and 5% concentrations; efficacy has been demonstrated in the SOTR population.33,41 Multiple studies in immunocompetent patients have suggested that imiquimod might be slightly less efficacious than 5-FU.42-44
The tolerability of field treatment with imiquimod has been called into question.27 However, in a 2019 study comparing adverse reactions among 513 immunocompetent patients with field disease who were treated with either 5-FU 5% cream; imiquimod 5% cream; PDT with methyl aminolevulinate; or ingenol mebutate 0.015% gel, a similar or smaller percentage of patients treated with imiquimod reported moderate-to-severe itching, moderate-to-severe pain, and any adverse events, compared to patients treated with the other options.44
Continue to: Diclofenac
Diclofenac is a nonsteroidal anti-inflammatory drug that reversibly inhibits the enzymes cyclooxygenase-1 and cyclooxygenase-2, resulting in a decrease in the formation of inflammatory prostaglandins, which have been observed in chronically sun-damaged skin, AKs, and cSCC.34,45 Diclofenac 3% gel, applied topically twice daily for 60 to 90 days has been approved by the FDA for treatment of AKs, in conjunction with sun avoidance.34 Topical diclofenac has been demonstrated to be efficacious in treating AKs in the SOTR population46,47; however, multiple meta-analyses using data from immunocompetent patients have demonstrated that topical diclofenac is inferior to other treatment options, particularly 5-FU, at achieving complete clearance of AKs.43,48,49 Diclofenac might be a useful option when patient adherence is expected to be difficult because of adverse effects of therapy: Multiple studies have suggested that diclofenac might be more tolerable than other options.43,48,50
Systemic chemoprophylaxis
Systemic therapies that have been used for chemoprophylaxis against cutaneous malignancy include nicotinamide, oral retinoids, capecitabine, and HPV vaccination. (See TABLE 2.27-40)
Nicotinamide, the amide form of vitamin B3, protects against cutaneous malignancy by aiding repair of DNA damaged by ionizing radiation, such as UV light.27 Efficacy has been demonstrated in reducing development of new AKs and cSCC in immunocompetent patients with a history of more than 2 keratinocyte carcinomas within a 5-year span.27,35 Nicotinamide is especially relevant to the SOTR population because it reduces the level of cutaneous immunity suppression induced by UV radiation without altering patients’ baseline immunity.27,36
There are insufficient long-term follow-up data in the literature to assess the sustainability of the antitumor effects of nicotinamide; studies specific to the SOTR population have been underpowered for assessing its impact on formation of cSCC.27,35Patients taking nicotinamide should be informed of the risk of liver failure at dosages > 3 g/d (antitumor efficacy has been demonstrated at 500 mg twice daily) and advised to avoid purchasing over-the-counter nicotinic acid or niacin as a substitute for nicotinamide, because of the increased incidence of flushing associated with their use.27
Oral retinoids. Systemic retinoids—in particular, acitretin—are efficacious in reducing the risk of cSCC in SOTRs.27,37,38 The primary drawback to cSCC prophylaxis with oral retinoids is a rebound effect, in which treatment discontinuation leads to a rapid return to baseline cSCC formation.27
Continue to: Pregnancy must be avoided...
Pregnancy must be avoided while taking an oral retinoid. Because acitretin can persist in the body for years after discontinuation, its use should generally be avoided in patients of childbearing potential. An FDA black box warning states that patients of childbearing potential must be counseled to use 2 forms of birth control to avoid pregnancy for ≥ 3 years after cessation of oral acitretin. Prior to initiation of oral retinoid therapy, the following baseline laboratory tests should be obtained: complete blood count, creatinine, lipid panel, and liver function tests. For patients with a history of chronic kidney disease or renal transplantation, the lipid panel, liver function tests, and creatinine assay should be repeated with each dosage adjustment and every 3 months once goal-dosing is achieved.27
Capecitabine is typically initiated with the help of Medical Oncology.27,40 A prodrug metabolized by dihydropyrimidine dehydrogenase to 5-FU, capecitabine interacts with warfarin, leading to a significant increase in prothrombin time.39 Other adverse effects associated with oral capecitabine include fatigue, palmar-plantar erythrodysesthesia, diarrhea, and, rarely, neutropenia. Although dihydropyrimidine dehydrogenase deficiency is rare, treatment with capecitabine in patients who have this enzyme deficiency might lead to severe toxicity or death.27
HPV vaccination. HPV might play a role in the development of cutaneous malignancy, especially in immunosuppressed patients.4,5 The utility of HPV vaccination in the prevention of NMSC has yet to be determined, but vaccination has been shown, in case reports, to be helpful in immunocompetent patients.51,52 The immunogenicity of HPV vaccination in the SOTR population is uncertain, and the most common HPV types found in SOTRs are not specifically covered by available HPV vaccines.19
The role of immunosuppression reduction and immunosuppressive replacement
Both the degree of immunosuppression and the individual agents used can affect a patient’s risk of NMSC. Immunosuppression reduction should be considered if skin cancer poses a major risk to the patient’s health and if that risk outweighs the risk of graft rejection associated with immunosuppression reduction.27 In a cohort of 180 kidney and liver SOTRs who developed de novo carcinoma (excluding NMSC) after transplantation, neither reduction of immunosuppression nor introduction of an mTOR inhibitor affected graft survival or oncologic treatment tolerance.53 Because mTOR inhibitors have a protective effect against development of NMSC, they are the preferred choice of immunosuppressive agent from a dermatologic perspective.1,27,54-57 Decisions regarding changes in immunosuppression are generally made by, or in collaboration with, the patient’s transplant physician.
Recommendations: Treating cSCC
Risk should guide strategy
Small lesions of the trunk and extremities without high-risk features can be treated with a destructive method (eg, electrodessication and curettage). However, lesions of the head and neck and those found to have features consistent with an increased risk of recurrence or metastasis should be treated aggressively.3,58,59
Continue to: Risk factors for invasive growth...
Risk factors for invasive growth, recurrence, or metastasis of cSCC in SOTRs are multiple lesions or satellite lesions, indistinct clinical borders, rapid growth, ulceration, and recurrence after treatment.60 The risk of invasive growth, recurrence, and metastasis of cSCC also increases with size and location of the lesion, according to this framework60:
- any size in scar tissue, areas of chronic inflammation, and fields of prior radiation therapy
- ≥ 0.6 cm on hands, feet, genitalia, and mask areas of the face (central face, eyelids, eyebrows, nose, lips, chin, mandible, and temporal, preauricular, postauricular, and periorbital areas)
- > 1 cm on cheeks, forehead, neck, and scalp
- > 2 cm on the trunk and extremities.
In addition, specific findings on histologic analysis portend increased risk of invasive growth, recurrence, or metastasis:
- poor differentiation
- deep extension of the tumor into subcutaneous fat
- perineural invasion or inflammation
- perivascular or intravascular invasion.
Treatment modalities
Mohs surgery is preferred to ensure margin clearance while preserving noninvolved tissue3,7 (FIGURE 4). If Mohs surgery is not possible, the lesion should be excised with 3- to 10-mm margins.3,60 Based on current literature, the roles of nodal staging, sentinel lymph node biopsy, and adjuvant therapy are not well defined, but it is likely that these interventions will play a pivotal role in the management of advanced cSCC in SOTRs in the future.3
Nonsurgical therapeutic options for primary or adjuvant treatment of cSCC include systemic chemotherapy, radiotherapy, and programmed cell death protein 1 inhibitors. (For more on treatment modalities, see TABLE 3.3,7,58-61)
Recommendations: Treating BCC
BCC in SOTRs is treated similarly (TABLE 33,7,58-61) to how it is treated in the immunocompetent population—except that SOTRs require closer follow-up than nontransplant patients because they are at higher risk of recurrence and new NMSCs.3 Standard management after biopsy is either3,61:
- Mohs surgery to ensure margin control (for most BCCs on the head and neck and those with clinical or histologic risk factors for recurrence or aggressive behavior)
- excision with a 4- or 5-mm margin or a destructive modality (for BCCs on the trunk and extremities without risk factors for recurrence).
Radiotherapy is an alternative for patients with high-risk BCCs who are unable to tolerate surgery.3
CORRESPONDENCE
Lindsey Collins, MD, Department of Dermatology, University of Oklahoma Health Sciences Center, 619 NE 13th Steet, Oklahoma City, OK 73104; [email protected]
1. Bhat M, Mara K, Dierkhising R, et al. Immunosuppression, race, and donor-related risk factors affect de novo cancer incidence across solid organ transplant recipients. Mayo Clin Proc. 2018;93:1236-1246. doi: 10.1016/j.mayocp.2018.04.025
2. Togsverd-Bo K, Philipsen PA, Haedersdal M, et al. Organ transplant recipients express enhanced skin autofluorescence and pigmentation at skin cancer sites. J Photochem Photobiol B. 2018;188:1-5. doi: 10.1016/j.jphotobiol.2018.08.008
3. Kearney L, Hogan D, Conlon P, et al. High-risk cutaneous malignancies and immunosuppression: challenges for the reconstructive surgeon in the renal transplant population. J Plast Reconstr Aesthet Surg. 2017;70:922-930. doi: 10.1016/j.bjps.2017.03.005
4. Borgogna C, Olivero C, Lanfredini S, et al. β-HPV infection correlates with early stages of carcinogenesis in skin tumors and patient-derived xenografts from a kidney transplant recipient cohort. Front Microbiol. 2018;9:117. doi: 10.3389/fmicb.2018.00117
5. Nunes EM, Talpe-Nunes V, Sichero L. Epidemiology and biology of cutaneous human papillomavirus. Clinics (Sao Paulo). 2018;73(suppl 1):e489s. doi: 10.6061/clinics/2018/e489s
6. Pini AM, Koch S, J Am Acad Dermatol. 2008;59(suppl 5):S116-S117. doi: 10.1016/j.jaad.2008.06.018
L, et al. Eruptive keratoacanthoma following topical imiquimod for in situ squamous cell carcinoma of the skin in a renal transplant recipient.7. Ilyas M, Zhang N, Sharma A. Residual squamous cell carcinoma after shave biopsy in solid organ transplant recipients. Dermatol Surg. 2018;44:370-374. doi: 10.1097/DSS.0000000000001340
8. Brunner M, Veness MJ, Ch‘ng S, et al. Distant metastases from cutaneous squamous cell carcinoma—analysis of AJCC stage IV. Head Neck. 2013;35:72-75. doi: 10.1002/hed.22913
9. Hartman RI, Green AC, Gordon LG; JAMA Dermatol. 2018;154:842-844. doi: 10.1001/jamadermatol.2018.1164
. Sun protection among organ transplant recipients after participation in a skin cancer research study.10. Chan A-W, Fung K, Austin PC, et al. Improved keratinocyte carcinoma outcomes with annual dermatology assessment after solid organ transplantation: population-based cohort study. Am J Transplant. 2018;19:522-531. doi: 10.1111/ajt.14966
11. Hofbauer GF, Anliker M, Arnold A, et al. Swiss clinical practice guidelines for skin cancer in organ transplant recipients. Swiss Med Wkly. 2009;139:407-415. doi: https://doi.org/10.4414/smw.2014.14026
12. Ulrich C, Kanitakis J, Stockfleth E, et al. Skin cancer in organ transplant recipients—where do we stand today? Am J Transplant. 2008;8:2192-2198. doi: 10.1111/j.1600-6143.2008.02386.x
13. Chen SC, Pennie ML, Kolm P, et al. Diagnosing and managing cutaneous pigmented lesions: primary care physicians versus dermatologists. J Gen Intern Med. 2006;21:678-682. doi: 10.1111/j.1525-1497.2006.00462.x
14. Ismail F, Mitchell L, Casabonne D, et al. Specialist dermatology clinics for organ transplant recipients significantly improve compliance with photoprotection and levels of skin cancer awareness. Br J Dermatol. 2006;155:916-925. doi: 10.1111/j.1365-2133.2006.07454.x
15. O‘Reilly Zwald F, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: part II. Management of skin cancer in solid organ transplant recipients. J Am Acad Dermatol. 2011;65:263-279. doi: 10.1016/j.jaad.2010.11.063
16. Exp Clin Transplant. 2018;16(suppl 1):203-207. doi: 10.6002/ect.TOND-TDTD2017.P65
Vural A, A, Kirnap M, et al. Skin cancer risk awareness and sun-protective behavior among solid-organ transplant recipients.17. Papier K, Gordon LG, Khosrotehrani K, et al. Increase in preventive behaviour by organ transplant recipients after sun protection information in a skin cancer surveillance clinic. Br J Dermatol. 2018;179:1195-1196. doi: 10.1111/bjd.16836
18. Wu SZ, Jiang P, DeCaro JE, et al. A qualitative systematic review of the efficacy of sun protection education in organ transplant recipients. J Am Acad Dermatol. 2016;75:1238-1244.e5. doi: 10.1016/j.jaad.2016.06.031
19. Blomberg M, He SY, Harwood C, et al; Br J Dermatol. 2017;177:1225-1233. doi: 10.1111/bjd.15950
. Research gaps in the management and prevention of cutaneous squamous cell carcinoma in organ transplant recipients.20. Urwin HR, Jones PW, Harden PN, et al. Predicting risk of nonmelanoma skin cancer and premalignant skin lesions in renal transplant recipients. Transplantation. 2009;87:1667-1671. doi: 10.1097/TP.0b013e3181a5ce2e
21. Infusino SD, Loi C, Ravaioli GM, et al. Cutaneous complications of immunosuppression in 812 transplant recipients: a 40-year single center experience. G Ital Dermatol Venereol. 2020;155:662-668. doi: 10.23736/S0392-0488.18.06091-1
22. Naldi L, Venturuzzo A, Invernizzi P. Dermatological complications after solid organ transplantation. Clin Rev Allergy Immunol. 2018;54:185-212. doi: 10.1007/s12016-017-8657-9
23. Sunscreen FAQs. American Academy of Dermatology Web site. Accessed February 25, 2021. www.aad.org/media/stats/prevention-and-care/sunscreen-faqs
24. Vos M, Plasmeijer EI, van Bemmel BC, et al. Azathioprine to mycophenolate mofetil transition and risk of squamous cell carcinoma after lung transplantation. J Heart Lung Transplant. 2018;37:853-859. doi: 10.1016/j.healun.2018.03.012
25. Puza CJ, Myers SA, Cardones AR, et al. The impact of transplant rejection on cutaneous squamous cell carcinoma in renal transplant recipients. Clin Exp Dermatol. 2018;44:265-269. doi: 10.1111/ced.13699
26. Abikhair Burgo M, Roudiani N, Chen J, et al. Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma. JCI Insight. 2018;3:e120750. doi: 10.1172/jci.insight.120750
27. Que SKT, Zwald FO, Schmults CD. Cutaneous squamous cell carcinoma: management of advanced and high-stage tumors. J Am Acad Dermatol. 2018;78:249-261. doi: 10.1016/j.jaad.2017.08.058
28. Askew DA, Mickan SM, Soyer HP, et al. Effectiveness of 5-fluorouracil treatment for actinic keratosis—a systematic review of randomized controlled trials. Int J Dermatol. 2009;48:453-463. doi: 10.1111/j.1365-4632.2009.04045.x
29. Salim A, Leman JA, McColl JH, et al. Randomized comparison of photodynamic therapy with topical 5-fluorouracil in Bowen‘s disease. Br J Dermatol. 2003;148:539-543. doi: 10.1046/j.1365-2133.2003.05033.x
30. Morton CA. A synthesis of the world‘s guidelines on photodynamic therapy for non-melanoma skin cancer. G Ital Dermatol Venereol. 2018;153:783-792. doi: 10.23736/S0392-0488.18.05896-0
31. Joly F, Deret S, Gamboa B, et al. Photodynamic therapy corrects abnormal cancer-associated gene expression observed in actinic keratosis lesions and induces a remodeling effect in photodamaged skin. J Dermatol Sci. 2018;S0923-1811(17)30775-2. doi: 10.1016/j.jdermsci.2018.05.002
32. Patel GK, Goodwin R, Chawla M, et al. Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in situ (Bowen‘s disease): a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2006;54:1025-1032. doi: 10.1016/j.jaad.2006.01.055
33. Imiquimod. Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed August 6, 2019. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7077?cesid=aRo1Yh9sd0Q&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dimiquimod%26t%3Dname%26va%3Dimiquimod
34. Diclofenac. Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed August 6th, 2019. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/1772965?cesid=5vTk7J3Vmvc&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Ddiclofenac%26t%3Dname%26va%3Ddiclofenac
35. Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373:1618-1626. doi: 10.1056/NEJMoa1506197
36. Yiasemides E, Sivapirabu G, Halliday GM, et al. Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans. Carcinogenesis. 2009;30:101-105. doi: 10.1093/carcin/bgn248
37. Otley CC, Stasko T, Tope WD, et al. Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects. Dermatol Surg. 2006;32:562-568. doi: 10.1111/j.1524-4725.2006.32115.x
38. McKenna DB, Murphy GM. Skin cancer chemoprophylaxis in renal transplant recipients: 5 years of experience using low-dose acitretin. Br J Dermatol. 1999;140:656-660. doi: 10.1046/j.1365-2133.1999.02765.x
39. Capecitabine. Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed February 13, 2019. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6519?cesid=7WMsK72X7T7&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dcapecitabine%26t%3Dname%26va%3Dcapecitabine
40. Wollina U, Hansel G, Koch A, et al. Oral capecitabine plus subcutaneous interferon alpha in advanced squamous cell carcinoma of the skin. J Cancer Res Clin Oncol. 2005;131:300-304. doi: 10.1007/s00432-004-0656-6
41. Zavattaro E, Veronese F, Landucci G, et al. Efficacy of topical imiquimod 3.75% in the treatment of actinic keratosis of the scalp in immunosuppressed patients: our case series. J Dermatol Treat. 2020;31:285-289. doi: 10.1080/09546634.2019.1590524
42. Neugebauer R, Su KA, Zhu Z, et al. Comparative effectiveness of treatment of actinic keratosis with topical fluorouracil and imiquimod in the prevention of keratinocyte carcinoma: a cohort study. J Am Acad Dermatol. 2019;80:998-1005. doi: 10.1016/j.jaad.2018.11.024
43. Gupta AK, Paquet M. Network meta-analysis of the outcome ‚participant complete clearance in nonimmunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review. Br J Dermatol. 2013;169:250-259. doi: 10.1111/bjd.12343
44. Jansen MHE, Kessels JPHM, Nelemans PJ, et al. Randomized trial of four treatment approaches for actinic keratosis. N Engl J Med. 2019;380:935-946. doi: 10.1056/NEJMoa1811850
45. Bangash HK, Colegio OR. Management of non-melanoma skin cancer in immunocompromised solid organ transplant recipients. Curr Treat Options Oncol. 2012;13:354-376. doi: 10.1007/s11864-012-0195-3
46. Ulrich C, Johannsen A, Eur J Dermatol. 2010;20:482-488. doi: 10.1684/ejd.2010.1010
J, et al. Results of a randomized, placebo-controlled safety and efficacy study of topical diclofenac 3% gel in organ transplant patients with multiple actinic keratoses.47. Ulrich C, Hackethal M, Ulrich M, et al. Treatment of multiple actinic keratoses with topical diclofenac 3% gel in organ transplant recipients: a series of six cases. Br J Dermatol. 2007;156(suppl 3):40-42. doi: 10.1111/j.1365-2133.2007.07864.x
48. Wu Y, Tang N, Cai L, et al. Relative efficacy of 5-fluorouracil compared with other treatments among patients with actinic keratosis: a network meta-analysis. Dermatol Ther. 2019;32:e12822. doi: 10.1111/dth.12822
49. Stockfleth E, Kerl H, Zwingers T, et al. Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results. Br J Dermatol. 2011;165:1101-1108. doi: 10.1111/j.1365-2133.2011.10387.x
50. Smith SR, Morhenn VB, Piacquadio DJ. Bilateral comparison of the efficacy and tolerability of 3% diclofenac sodium gel and 5% 5-fluorouracil cream in the treatment of actinic keratoses of the face and scalp. J Drug Dermatol. 2006;5:156-159.
51. Nichols AJ, Allen AH, Shareef S, et al. Association of human papillomavirus vaccine with the development of keratinocyte carcinomas. JAMA Dermatol. 2017;153:571-574. doi: 10.1001/jamadermatol.2016.5703
52. Nichols AJ, Gonzalez A, Clark ES, et al. Combined systemic and intratumoral administration of human papillomavirus vaccine to treat multiple cutaneous basaloid squamous cell carcinomas. JAMA Dermatol. 2018;154:927-930. doi: 10.1001/jamadermatol.2018.1748
53. Rousseau B, Guillemin A, Duvoux C, et al. Optimal oncologic management and mTOR inhibitor introduction are safe and improve survival in kidney and liver allograft recipients with de novo carcinoma. Int J Cancer. 2019;144:886-896. doi: 10.1002/ijc.31769
54. Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant. 2004;18:446-449. doi: 10.1111/j.1399-0012.2004.00188.x
55. Euvrard S, Morelon E, Rostaing L, et al; N Engl J Med. 2012;367:329-339. doi: 10.1056/NEJMoa1204166
Sirolimus and secondary skin-cancer prevention in kidney transplantation.56. Hoogendijk-van den Akker JM, Harden PN, Hoitsma AJ, et al. Two-year randomized controlled prospective trial converting treatment of stable renal transplant recipients with cutaneous invasive squamous cell carcinomas to sirolimus. J Clin Oncol. 2013;31:1317-1323. doi: 10.1200/JCO.2012.45.6376
57. Karia PS, Azzi JR, Heher EC, et al. Association of sirolimus use with risk for skin cancer in a mixed-organ cohort of solid-organ transplant recipients with a history of cancer. JAMA Dermatol. 2016;152:533-540. doi: 10.1001/jamadermatol.2015.5548
58. Stratigos A, Garbe C, Lebbe C, et al; . Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline. Eur J Cancer. 2015;51:1989-2007. doi: 10.1016/j.ejca.2015.06.110
59. Goldman G. The current status of curettage and electrodesiccation. Dermatol Clin. 2002;20:569-578, ix. doi: 10.1016/s0733-8635(02)00022-0
60. Stasko T, Brown MD, Carucci JA, et al; ; . Guidelines for the management of squamous cell carcinoma in organ transplant recipients. Derm Surg. 2004;30:642-650. doi: 10.1111/j.1524-4725.2004.30150.x
61. Telfer NR, Colver GB, Morton CA; Br J Dermatol. 2008;159:35-48. doi: 10.1111/j.1365-2133.2008.08666.x
. Guidelines for the management of basal cell carcinoma.1. Bhat M, Mara K, Dierkhising R, et al. Immunosuppression, race, and donor-related risk factors affect de novo cancer incidence across solid organ transplant recipients. Mayo Clin Proc. 2018;93:1236-1246. doi: 10.1016/j.mayocp.2018.04.025
2. Togsverd-Bo K, Philipsen PA, Haedersdal M, et al. Organ transplant recipients express enhanced skin autofluorescence and pigmentation at skin cancer sites. J Photochem Photobiol B. 2018;188:1-5. doi: 10.1016/j.jphotobiol.2018.08.008
3. Kearney L, Hogan D, Conlon P, et al. High-risk cutaneous malignancies and immunosuppression: challenges for the reconstructive surgeon in the renal transplant population. J Plast Reconstr Aesthet Surg. 2017;70:922-930. doi: 10.1016/j.bjps.2017.03.005
4. Borgogna C, Olivero C, Lanfredini S, et al. β-HPV infection correlates with early stages of carcinogenesis in skin tumors and patient-derived xenografts from a kidney transplant recipient cohort. Front Microbiol. 2018;9:117. doi: 10.3389/fmicb.2018.00117
5. Nunes EM, Talpe-Nunes V, Sichero L. Epidemiology and biology of cutaneous human papillomavirus. Clinics (Sao Paulo). 2018;73(suppl 1):e489s. doi: 10.6061/clinics/2018/e489s
6. Pini AM, Koch S, J Am Acad Dermatol. 2008;59(suppl 5):S116-S117. doi: 10.1016/j.jaad.2008.06.018
L, et al. Eruptive keratoacanthoma following topical imiquimod for in situ squamous cell carcinoma of the skin in a renal transplant recipient.7. Ilyas M, Zhang N, Sharma A. Residual squamous cell carcinoma after shave biopsy in solid organ transplant recipients. Dermatol Surg. 2018;44:370-374. doi: 10.1097/DSS.0000000000001340
8. Brunner M, Veness MJ, Ch‘ng S, et al. Distant metastases from cutaneous squamous cell carcinoma—analysis of AJCC stage IV. Head Neck. 2013;35:72-75. doi: 10.1002/hed.22913
9. Hartman RI, Green AC, Gordon LG; JAMA Dermatol. 2018;154:842-844. doi: 10.1001/jamadermatol.2018.1164
. Sun protection among organ transplant recipients after participation in a skin cancer research study.10. Chan A-W, Fung K, Austin PC, et al. Improved keratinocyte carcinoma outcomes with annual dermatology assessment after solid organ transplantation: population-based cohort study. Am J Transplant. 2018;19:522-531. doi: 10.1111/ajt.14966
11. Hofbauer GF, Anliker M, Arnold A, et al. Swiss clinical practice guidelines for skin cancer in organ transplant recipients. Swiss Med Wkly. 2009;139:407-415. doi: https://doi.org/10.4414/smw.2014.14026
12. Ulrich C, Kanitakis J, Stockfleth E, et al. Skin cancer in organ transplant recipients—where do we stand today? Am J Transplant. 2008;8:2192-2198. doi: 10.1111/j.1600-6143.2008.02386.x
13. Chen SC, Pennie ML, Kolm P, et al. Diagnosing and managing cutaneous pigmented lesions: primary care physicians versus dermatologists. J Gen Intern Med. 2006;21:678-682. doi: 10.1111/j.1525-1497.2006.00462.x
14. Ismail F, Mitchell L, Casabonne D, et al. Specialist dermatology clinics for organ transplant recipients significantly improve compliance with photoprotection and levels of skin cancer awareness. Br J Dermatol. 2006;155:916-925. doi: 10.1111/j.1365-2133.2006.07454.x
15. O‘Reilly Zwald F, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: part II. Management of skin cancer in solid organ transplant recipients. J Am Acad Dermatol. 2011;65:263-279. doi: 10.1016/j.jaad.2010.11.063
16. Exp Clin Transplant. 2018;16(suppl 1):203-207. doi: 10.6002/ect.TOND-TDTD2017.P65
Vural A, A, Kirnap M, et al. Skin cancer risk awareness and sun-protective behavior among solid-organ transplant recipients.17. Papier K, Gordon LG, Khosrotehrani K, et al. Increase in preventive behaviour by organ transplant recipients after sun protection information in a skin cancer surveillance clinic. Br J Dermatol. 2018;179:1195-1196. doi: 10.1111/bjd.16836
18. Wu SZ, Jiang P, DeCaro JE, et al. A qualitative systematic review of the efficacy of sun protection education in organ transplant recipients. J Am Acad Dermatol. 2016;75:1238-1244.e5. doi: 10.1016/j.jaad.2016.06.031
19. Blomberg M, He SY, Harwood C, et al; Br J Dermatol. 2017;177:1225-1233. doi: 10.1111/bjd.15950
. Research gaps in the management and prevention of cutaneous squamous cell carcinoma in organ transplant recipients.20. Urwin HR, Jones PW, Harden PN, et al. Predicting risk of nonmelanoma skin cancer and premalignant skin lesions in renal transplant recipients. Transplantation. 2009;87:1667-1671. doi: 10.1097/TP.0b013e3181a5ce2e
21. Infusino SD, Loi C, Ravaioli GM, et al. Cutaneous complications of immunosuppression in 812 transplant recipients: a 40-year single center experience. G Ital Dermatol Venereol. 2020;155:662-668. doi: 10.23736/S0392-0488.18.06091-1
22. Naldi L, Venturuzzo A, Invernizzi P. Dermatological complications after solid organ transplantation. Clin Rev Allergy Immunol. 2018;54:185-212. doi: 10.1007/s12016-017-8657-9
23. Sunscreen FAQs. American Academy of Dermatology Web site. Accessed February 25, 2021. www.aad.org/media/stats/prevention-and-care/sunscreen-faqs
24. Vos M, Plasmeijer EI, van Bemmel BC, et al. Azathioprine to mycophenolate mofetil transition and risk of squamous cell carcinoma after lung transplantation. J Heart Lung Transplant. 2018;37:853-859. doi: 10.1016/j.healun.2018.03.012
25. Puza CJ, Myers SA, Cardones AR, et al. The impact of transplant rejection on cutaneous squamous cell carcinoma in renal transplant recipients. Clin Exp Dermatol. 2018;44:265-269. doi: 10.1111/ced.13699
26. Abikhair Burgo M, Roudiani N, Chen J, et al. Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma. JCI Insight. 2018;3:e120750. doi: 10.1172/jci.insight.120750
27. Que SKT, Zwald FO, Schmults CD. Cutaneous squamous cell carcinoma: management of advanced and high-stage tumors. J Am Acad Dermatol. 2018;78:249-261. doi: 10.1016/j.jaad.2017.08.058
28. Askew DA, Mickan SM, Soyer HP, et al. Effectiveness of 5-fluorouracil treatment for actinic keratosis—a systematic review of randomized controlled trials. Int J Dermatol. 2009;48:453-463. doi: 10.1111/j.1365-4632.2009.04045.x
29. Salim A, Leman JA, McColl JH, et al. Randomized comparison of photodynamic therapy with topical 5-fluorouracil in Bowen‘s disease. Br J Dermatol. 2003;148:539-543. doi: 10.1046/j.1365-2133.2003.05033.x
30. Morton CA. A synthesis of the world‘s guidelines on photodynamic therapy for non-melanoma skin cancer. G Ital Dermatol Venereol. 2018;153:783-792. doi: 10.23736/S0392-0488.18.05896-0
31. Joly F, Deret S, Gamboa B, et al. Photodynamic therapy corrects abnormal cancer-associated gene expression observed in actinic keratosis lesions and induces a remodeling effect in photodamaged skin. J Dermatol Sci. 2018;S0923-1811(17)30775-2. doi: 10.1016/j.jdermsci.2018.05.002
32. Patel GK, Goodwin R, Chawla M, et al. Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in situ (Bowen‘s disease): a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2006;54:1025-1032. doi: 10.1016/j.jaad.2006.01.055
33. Imiquimod. Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed August 6, 2019. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7077?cesid=aRo1Yh9sd0Q&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dimiquimod%26t%3Dname%26va%3Dimiquimod
34. Diclofenac. Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed August 6th, 2019. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/1772965?cesid=5vTk7J3Vmvc&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Ddiclofenac%26t%3Dname%26va%3Ddiclofenac
35. Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373:1618-1626. doi: 10.1056/NEJMoa1506197
36. Yiasemides E, Sivapirabu G, Halliday GM, et al. Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans. Carcinogenesis. 2009;30:101-105. doi: 10.1093/carcin/bgn248
37. Otley CC, Stasko T, Tope WD, et al. Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects. Dermatol Surg. 2006;32:562-568. doi: 10.1111/j.1524-4725.2006.32115.x
38. McKenna DB, Murphy GM. Skin cancer chemoprophylaxis in renal transplant recipients: 5 years of experience using low-dose acitretin. Br J Dermatol. 1999;140:656-660. doi: 10.1046/j.1365-2133.1999.02765.x
39. Capecitabine. Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed February 13, 2019. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6519?cesid=7WMsK72X7T7&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dcapecitabine%26t%3Dname%26va%3Dcapecitabine
40. Wollina U, Hansel G, Koch A, et al. Oral capecitabine plus subcutaneous interferon alpha in advanced squamous cell carcinoma of the skin. J Cancer Res Clin Oncol. 2005;131:300-304. doi: 10.1007/s00432-004-0656-6
41. Zavattaro E, Veronese F, Landucci G, et al. Efficacy of topical imiquimod 3.75% in the treatment of actinic keratosis of the scalp in immunosuppressed patients: our case series. J Dermatol Treat. 2020;31:285-289. doi: 10.1080/09546634.2019.1590524
42. Neugebauer R, Su KA, Zhu Z, et al. Comparative effectiveness of treatment of actinic keratosis with topical fluorouracil and imiquimod in the prevention of keratinocyte carcinoma: a cohort study. J Am Acad Dermatol. 2019;80:998-1005. doi: 10.1016/j.jaad.2018.11.024
43. Gupta AK, Paquet M. Network meta-analysis of the outcome ‚participant complete clearance in nonimmunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review. Br J Dermatol. 2013;169:250-259. doi: 10.1111/bjd.12343
44. Jansen MHE, Kessels JPHM, Nelemans PJ, et al. Randomized trial of four treatment approaches for actinic keratosis. N Engl J Med. 2019;380:935-946. doi: 10.1056/NEJMoa1811850
45. Bangash HK, Colegio OR. Management of non-melanoma skin cancer in immunocompromised solid organ transplant recipients. Curr Treat Options Oncol. 2012;13:354-376. doi: 10.1007/s11864-012-0195-3
46. Ulrich C, Johannsen A, Eur J Dermatol. 2010;20:482-488. doi: 10.1684/ejd.2010.1010
J, et al. Results of a randomized, placebo-controlled safety and efficacy study of topical diclofenac 3% gel in organ transplant patients with multiple actinic keratoses.47. Ulrich C, Hackethal M, Ulrich M, et al. Treatment of multiple actinic keratoses with topical diclofenac 3% gel in organ transplant recipients: a series of six cases. Br J Dermatol. 2007;156(suppl 3):40-42. doi: 10.1111/j.1365-2133.2007.07864.x
48. Wu Y, Tang N, Cai L, et al. Relative efficacy of 5-fluorouracil compared with other treatments among patients with actinic keratosis: a network meta-analysis. Dermatol Ther. 2019;32:e12822. doi: 10.1111/dth.12822
49. Stockfleth E, Kerl H, Zwingers T, et al. Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results. Br J Dermatol. 2011;165:1101-1108. doi: 10.1111/j.1365-2133.2011.10387.x
50. Smith SR, Morhenn VB, Piacquadio DJ. Bilateral comparison of the efficacy and tolerability of 3% diclofenac sodium gel and 5% 5-fluorouracil cream in the treatment of actinic keratoses of the face and scalp. J Drug Dermatol. 2006;5:156-159.
51. Nichols AJ, Allen AH, Shareef S, et al. Association of human papillomavirus vaccine with the development of keratinocyte carcinomas. JAMA Dermatol. 2017;153:571-574. doi: 10.1001/jamadermatol.2016.5703
52. Nichols AJ, Gonzalez A, Clark ES, et al. Combined systemic and intratumoral administration of human papillomavirus vaccine to treat multiple cutaneous basaloid squamous cell carcinomas. JAMA Dermatol. 2018;154:927-930. doi: 10.1001/jamadermatol.2018.1748
53. Rousseau B, Guillemin A, Duvoux C, et al. Optimal oncologic management and mTOR inhibitor introduction are safe and improve survival in kidney and liver allograft recipients with de novo carcinoma. Int J Cancer. 2019;144:886-896. doi: 10.1002/ijc.31769
54. Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant. 2004;18:446-449. doi: 10.1111/j.1399-0012.2004.00188.x
55. Euvrard S, Morelon E, Rostaing L, et al; N Engl J Med. 2012;367:329-339. doi: 10.1056/NEJMoa1204166
Sirolimus and secondary skin-cancer prevention in kidney transplantation.56. Hoogendijk-van den Akker JM, Harden PN, Hoitsma AJ, et al. Two-year randomized controlled prospective trial converting treatment of stable renal transplant recipients with cutaneous invasive squamous cell carcinomas to sirolimus. J Clin Oncol. 2013;31:1317-1323. doi: 10.1200/JCO.2012.45.6376
57. Karia PS, Azzi JR, Heher EC, et al. Association of sirolimus use with risk for skin cancer in a mixed-organ cohort of solid-organ transplant recipients with a history of cancer. JAMA Dermatol. 2016;152:533-540. doi: 10.1001/jamadermatol.2015.5548
58. Stratigos A, Garbe C, Lebbe C, et al; . Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline. Eur J Cancer. 2015;51:1989-2007. doi: 10.1016/j.ejca.2015.06.110
59. Goldman G. The current status of curettage and electrodesiccation. Dermatol Clin. 2002;20:569-578, ix. doi: 10.1016/s0733-8635(02)00022-0
60. Stasko T, Brown MD, Carucci JA, et al; ; . Guidelines for the management of squamous cell carcinoma in organ transplant recipients. Derm Surg. 2004;30:642-650. doi: 10.1111/j.1524-4725.2004.30150.x
61. Telfer NR, Colver GB, Morton CA; Br J Dermatol. 2008;159:35-48. doi: 10.1111/j.1365-2133.2008.08666.x
. Guidelines for the management of basal cell carcinoma.PRACTICE RECOMMENDATIONS
› Conduct a full-body skin examination at least once annually for solid organ transplant recipients. C
› Encourage daily use of broad-spectrum SPF ≥ 30 sunscreen and sun-protective clothing (long sleeves, pants, wide-brimmed hats) for these patients. A
› Consider chemoprophylactic agents for patients at especially high risk of nonmelanoma skin cancer. A
› Treat nonmelanoma skin cancer in a solid organ transplant recipient aggressively because of their increased risk of recurrence, local invasion, and metastasis. B
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Urine drug screening: A guide to monitoring Tx with controlled substances
An estimated 20 million patients in the United States have a substance use disorder (SUD), with hundreds of millions of prescriptions for controlled substances written annually. Consequently, urine drug screening (UDS) has become widely utilized to evaluate and treat patients with an SUD or on chronic opioid or benzodiazepine therapy.1
Used appropriately, UDS can be a valuable tool; there is ample evidence, however, that it has been misused, by some physicians, to stigmatize patients who use drugs of abuse,2 profile patients racially,2 profit from excessive testing,3 and inappropriately discontinue treatment.4
A patient-centered approach. We have extensive clinical experience in the use and interpretation of urine toxicology, serving as clinical leads in busy family medicine residency practices that care for patients with SUDs, and are often consulted regarding patients on chronic opioid or benzodiazepine therapy. We have encountered countless situations in which the correct interpretation of UDS is critical to providing care.
Over time, and after considerable trial and error, we developed the patient-centered approach to urine toxicology described in this article. We believe that the medical evidence strongly supports our approach to the appropriate use and interpretation of urine toxicology in clinical practice. Our review here is intended as a resource when you consider implementing a UDS protocol or are struggling with the management of unexpected results.
Urine toxicology for therapeutic drug monitoring
Prescribing a controlled substance carries inherent risks, including diversion, nonmedical use, and development of an SUD. Prescribed medications, particularly opioids and benzodiazepines, have been linked to a large increase in overdose deaths over the past decade.5 Several strategies have been investigated to mitigate risk (see “How frequently should a patient be tested?,” later in the article).
Clinical judgment—ie, when a physician orders a drug test upon suspecting that a patient is diverting a prescribed drug or has developed an SUD—has been shown to be highly inaccurate. Implicit racial bias might affect the physician’s judgment, leading to changes in testing and test interpretation. For example, Black patients were found to be 10% more likely to have drug screening ordered while being treated with long-term opioid therapy and 2 to 3 times more likely to have their medication discontinued as a result of a marijuana- or cocaine-positive test.2
Other studies have shown that testing patients for “bad behavior,” so to speak—reporting a prescription lost or stolen, consuming more than the prescribed dosage, visiting the office without an appointment, having multiple drug intolerances and allergies, and making frequent telephone calls to the practice—is ineffective.6 Patients with these behaviors were slightly more likely to unexpectedly test positive, or negative, on their UDS; however, many patients without suspect behavior also were found to have abnormal toxicology results.6 Data do not support therapeutic drug monitoring only of patients selected on the basis of aberrant behavior.6
Continue to: Questions and concerns about urine drug screening
Questions and concerns about urine drug screening
Why not just ask the patient? Studies have evaluated whether patient self-reporting of adherence is a feasible alternative to laboratory drug screening. Regrettably, patients have repeatedly been shown to underreport their use of both prescribed and illicit drugs.7,8
That question leads to another: Why do patients lie to their physician? It is easy to assume malicious intent, but a variety of obstacles might dissuade a patient from being fully truthful with their physician:
- Monetary gain. A small, but real, percentage of medications are diverted by patients for this reason.9
- Addiction, pseudo-addiction due to tolerance, and self-medication for psychological symptoms are clinically treatable syndromes that can lead to underreporting of prescribed and nonprescribed drug and alcohol use.
- Shame. Addiction is a highly stigmatized disease, and patients might simply be ashamed to admit that they need treatment: 13% to 38% of patients receiving chronic opioid therapy in a pain management or primary care setting have a clinically diagnosable SUD.10,11
Is consent needed to test or to share test results? Historically, UDS has been performed on patients without their consent or knowledge.12 Patients give a urine specimen to their physician for a variety of reasons; it seems easy to “add on” UDS. Evidence is clear, however, that confronting a patient about an unexpected test result can make the clinical outcome worse—often resulting in irreparable damage to the patient–physician relationship.12,13 Unless the patient is experiencing a medical emergency, guidelines unanimously recommend obtaining consent prior to testing.1,5,14
Federal law requires written permission from the patient for the physician to disclose information about alcohol or substance use, unless the information is expressly needed to provide care during a medical emergency. Substance use is highly stigmatized, and patients might—legitimately—fear that sharing their history could undermine their care.1,12,14
How frequently should a patient be tested? Experts recommend utilizing a risk-based strategy to determine the frequency of UDS.1,5,15 Validated risk-assessment questionnaires include:
- Opioid Risk Tool for Opioid Use Disorder (ORT-OUD)a
- Screener and Opioid Assessment for Patients With Pain–Revised (SOAPP-R)b
- Diagnosis, Intractability, Risk and Efficacy (DIRE)c
- Addiction Behaviors Checklist (ABC).d
Continue to: Each of these tools...
Each of these tools takes less than 5 minutes to administer and can be used by a primary care physician to objectively quantify the risk of prescribing; there is no evidence for the use of 1 of these screeners over the others.15 It is recommended that you choose a questionnaire that works for you and incorporate the risk assessment into prescribing any high-risk medication.1,5,15
Once you have completed an initial risk assessment, the frequency of UDS can be based on ongoing assessment that incorporates baseline testing, patient self-reporting, toxicology results, behavioral monitoring, and state database monitoring through a prescription drug monitoring program. Annual screening is appropriate in low-risk patients; moderate-risk patients should be screened twice a year, and high-risk patients should be screened at least every 4 months (FIGURE).15
Many state and federal agencies, health systems, employers, and insurers mandate the frequency of testing through guidelines or legislation. These regulations often are inconsistent with the newest medical evidence.15 Consult local guidelines and review the medical evidence and consensus recommendations on UDS.
What are the cost considerations in providing UDS? Insurers have been billed as much as $4000 for definitive chromatography testing (described later).3 This has led to insurance fraud, when drug-testing practices with a financial interest routinely use large and expensive test panels, test too frequently, or unnecessarily send for confirmatory or quantitative analysis of all positive tests.3,14 Often, insurers refuse to pay for unnecessary testing, leaving patients with significant indebtedness.3,14 Take time to review the evidence and consensus recommendations on UDS to avoid waste, potential accusations of fraud, and financial burden on your patients.
Urine toxicology for addiction treatment
UDS protocols in addiction settings are often different from those in which a controlled substance is being prescribed.
Continue to: Routine and random testing
Routine and random testing. Two common practices when treating addiction are to perform UDS on all patients, at every visit, or to test randomly.1 These practices can be problematic, however. Routine testing at every visit can make urine-tampering more likely and is often unnecessary for stable patients. Random testing can reduce the risk of urine-tampering, but it is often difficult for primary care clinics to institute such a protocol. Some clinics have patients provide a urine specimen at every visit and then only send tests to the lab based on randomization.1
Contingency management—a behavioral intervention in which a patient is rewarded, or their performance is reinforced, when they display evidence of positive change—is the most effective strategy used in addiction medicine to determine the frequency of patient visits and UDS.14,16 High-risk patients with self-reported active substance use or UDS results consistent with substance use, or both, are seen more often; as their addiction behavior diminishes, visits and UDS become less frequent. If addiction behavior increases, the patient is seen more often. Keep in mind that addiction behavior decreases over months of treatment, not immediately upon initiation.14,17 For contingency management to be successful, patient-centered interviewing and UDS will need to be employed frequently as the patient works toward meaningful change.14
The technology of urine drug screening
Two general techniques are used for UDS: immunoassay and chromatography. Each plays an important role in clinical practice; physicians must therefore maintain a basic understanding of the mechanism of each technique and their comparable advantages and disadvantages. Such an understanding allows for (1) matching the appropriate technique to the individual clinical scenario and (2) correctly interpreting results.
Immunoassay technology is used for point-of-care and rapid laboratory UDS, using antibodies to detect the drug or drug metabolite of interest. Antibodies utilized in immunoassays are designed to selectively bind a specific antigen—ie, a unique chemical structure within the drug of choice. Once bound, the antigen–antibody complex can be exploited for detection through various methods.
Chromatography–mass spectrometry is considered the gold standard for UDS, yielding confirmatory results. This is a 2-step process: Chromatography separates components within a specimen; mass spectrometry then identifies those components. Most laboratories employ liquid, rather than gas, chromatography. The specificity of the liquid chromatography–mass spectrometry method is such that a false-positive result is, essentially, impossible.18
Continue to: How is the appropriate tests elected for urine drug screening?
How is the appropriate tests elected for urine drug screening?
Variables that influence your choice of the proper test method include the clinical question at hand; cost; the urgency of obtaining results; and the stakes in that decision (ie, will the results be used to simply change the dosage of a medication or, of greater consequence, to determine fitness for employment or inform criminal justice decisions?). Each method of UDS has advantages that can be utilized and disadvantages that must be considered to obtain an accurate and useful result.
Immunoassay provides rapid results, is relatively easy to perform, and is, comparatively, inexpensive.1,14 The speed of results makes this method particularly useful in settings such as the emergency department, where rapid results are crucial. Ease of use makes immunoassay ideal for the office, where non-laboratory staff can be trained to properly administer the test.
A major disadvantage of immunoassay technology, however, is interference resulting in both false-positive and false-negative results, which is discussed in detail in the next section. Immunoassay should be considered a screening test that yields presumptive results.
Liquid chromatography–mass spectrometry is exquisitely specific and provides confirmatory test results—major advantages of the method. However, specificity comes at a price: significantly increased cost and longer wait time for results (typically days, if specimens are sent out to a laboratory). These barriers can make it impractical to employ this method in routine practice.
Interpretation of results: Not so fast
Interpreting UDS results is not as simple as noting a positive or negative result. Physicians must understand the concept of interference, so that results can be appropriately interpreted and confirmed. This is crucial when results influence clinical decisions; inappropriate action, taken on the basis of presumptive results, can have severe consequences for the patient–provider relationship and the treatment plan.1,14
Continue to: Interference falls into 2 categories...
Interference falls into 2 categories: variables inherent in the testing process and patient variables.
Antibody cross-reactivity. A major disadvantage of immunoassay technology is interference that results in false-positive and false-negative results.19,20 The source of this interference is antibody cross-reactivity—the degree to which an antibody binds to structurally similar compounds. Antibody–antigen interactions are incredibly complex; although assay antibodies are engineered to specifically detect a drug class of interest, reactivity with other, structurally similar compounds is unavoidable.
Nevertheless, cross-reactivity is a useful phenomenon that allows broad testing for multiple drugs within a class. For example, most point-of-care tests for benzodiazepines reliably detect diazepam and chlordiazepoxide. Likewise, opiate tests reliably detect natural opiates, such as morphine and codeine. Cross-reactivity is not limitless, however; most benzodiazepine immunoassays have poor reactivity to clonazepam and lorazepam, making it possible that a patient taking clonazepam tests negative for benzodiazepine on an immunoassay.14,20 Similarly, standard opioid tests have only moderate cross-reactivity for semisynthetic opioids, such as hydrocodone and hydromorphone; poor cross-reactivity for oxycodone and oxymorphone; and essentially no cross-reactivity for full synthetics, such as fentanyl and methadone.14
It is the responsibility of the ordering physician to understand cross-reactivity to various drugs within a testing class.
Whereas weak cross-reactivity to drugs within a class can be a source of false-negative results, cross-reactivity to drugs outside the class of interest is a source of false-positive results. An extensive review of drugs that cause false-positive immunoassay screening tests is outside the scope of this article; commonly prescribed medications implicated in false-positive results are listed in TABLE 1.19
Continue to: In general...
In general, amphetamine immunoassays produce frequent false-positive results, whereas cocaine and cannabinoid assays are more specific.1,18 Common over-the-counter medications, including nonsteroidal anti-inflammatory drugs, decongestants, and antacids, can yield false-positive results, highlighting the need to obtain a comprehensive medication list from patients, including over-the-counter and herbal medications, before ordering UDS. Because of the complexity of cross-reactivity, it might not be possible to identify the source of a false-positive result.14
Patient variables. Intentional effort to skew results is another source of interference. The frequency of this effort varies by setting and the potential consequences of results—eg, employment testing or substance use treatment—and a range of attempts have been reported in the literature.21,22 Common practices are dilution, adulteration, and substitution.20,23
- Dilution lowers the concentration of the drug of interest below the detection limit of the assay by directly adding water to the urine specimen, drinking copious amounts of fluid, taking a diuretic, or a combination of these practices.
- Adulteration involves adding a substance to urine that interferes with the testing mechanism: for example, bleach, household cleaners, eye drops, and even commercially available products expressly marketed to interfere with UDS.24
- Substitution involves providing urine or a urine-like substance for testing that did not originate from the patient.
Methods to minimize patient-related interference include observed collection and specimen validity testing for pH, creatinine, and adulterants (TABLE 2).1,15 Efforts to detect patient interference must be balanced against concerns about privacy, personnel resources, and the cost of expanded testing.14,19,20
Additional aspects inherent to the testing process, such as cutoff concentrations and detection windows, can lead to interference. Laboratories must set reporting cutoffs, and specimens with a drug concentration present but below the cutoff value are reported as a negative result. Detection windows are complex and are influenced by inherent properties of the drug, including metabolic pathway and route and frequency of use.1 A given patient might well be using a substance, but if the specimen was obtained outside the detection window, a false-negative result might be reported (TABLE 31,23).
Managing test results
Appropriate management of UDS results is built on the foundation of understanding the testing mechanism, selecting the correct test, and properly interpreting results. Drug testing is, ultimately, a therapeutic tool used to monitor treatment, provide reinforcement, and explore substance use behavior; results of testing should be employed to achieve those objectives.1,4,14 A negative or expected UDS result can be utilized as positive reinforcement for a patient who is adherent to the treatment plan—much the way objective weight loss in an obese patient can provide encouragement to continue lifestyle changes.
Continue to: Test results should be presented...
Test results should be presented in an objective, nonconfrontational, and compassionate manner, not with stigmatizing language, such as “clean” or “dirty.”1,13,14 Using stigmatizing terms such as “substance abuser” instead of “person with a substance use disorder” has been shown, even among highly trained health care professionals, to have a negative effect on patient care.13
Inevitably, you will encounter an unexpected result, and therefore must develop a rational, systematic, and compassionate management approach. “Unexpected result” is a broad term that includes results that conflict with
- a patient’s self-report
- your understanding of what the patient is taking (using)
- prescribed medications
- a patient’s typical substance use pattern.
When faced with an unexpected test result, first, ensure that the result in question is reliable. If a screening test yields an unanticipated finding—especially if it conflicts with the patient’s self-reporting—make every effort to seek confirmation if you are going to be making a significant clinical decision because of the result.1,14
Second, use your understanding of interference to consider the result in a broader context. If confirmatory results are inconsistent with a patient’s self-report, discuss whether there has been a break in the physician–patient relationship and emphasize that recurrent use or failure to adhere to a treatment plan has clear consequences.1,14 Modify the treatment plan to address the inconsistent finding by escalating care, adjusting medications, and connecting the patient to additional resources.
Third, keep in mind that a positive urine test is not diagnostic of an SUD. Occasional drug use is extremely common17 and should not categorically lead to a change in the treatment plan. Addiction is, fundamentally, a disease of disordered reward, motivation, and behavior that is defined by the consequences of substance use, not substance use per se,25 and an SUD diagnosis is complex, based on clinical history, physical examination, and laboratory testing. Similarly, a negative UDS result does not rule out an SUD.4,10
Continue to: Fourth, patient dismissal...
Fourth, patient dismissal is rarely an appropriate initial response to UDS results. Regrettably, some physicians misinterpret urine toxicology results and inappropriately discharge patients on that basis.
The Centers for Disease Control and Prevention guideline for prescribing opioids has increased utilization of UDS in primary care settings but does not provide the necessary education on proper use of the tool, which has resulted in a rise in misinterpretation and inappropriate discharge.13,26
If recurrent aberrant behavior is detected (by history or urine toxicology), do not abruptly discontinue the patient’s medication(s). Inform the patient of your concern, taper medication, and refer the patient to addiction treatment. Abrupt discontinuation of an opioid or benzodiazepine can lead to significant harm.1,14
CORRESPONDENCE
John Hayes, DO, Department of Family and Community Medicine, Medical College of Wisconsin, 1121 E North Avenue, Milwaukee, WI, 53212; [email protected]
1. TAP 32: Clinical drug testing in primary care. Rockville, MD: Substance Abuse and Mental Health Services Administration, US Department of Health & Human Services; 2012. Technical Assistance Publication (TAP) 32; HHS Publication No. (SMA) 12-4668. 2012. Accessed March 19, 2021. https://store.samhsa.gov/sites/default/files/d7/priv/sma12-4668.pdf
2. Gaither JR, Gordon K, Crystal S, et al. Racial disparities in discontinuation of long-term opioid therapy following illicit drug use among black and white patients. Drug Alcohol Depend. 2018;192:371-376. https://doi.org/10.1016/j.drugalcdep.2018.05.033
3. Segal, David. In pursuit of liquid gold. The New York Times. December 27, 2017. Accessed March 19, 2021. https://nyti.ms/2E2GTOU
4. Ceasar R, Chang J, Zamora K, et al. Primary care providers’ experiences with urine toxicology tests to manage prescription opioid misuse and substance use among chronic noncancer pain patients in safety net health care settings. Subst Abus. 2016;37:154-160. https://doi.org/10.1080/08897077.2015.1132293
5. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain — United States, 2016. MMWR Recomm Rep. 2016;65:1-49. https://doi.org/10.15585/mmwr.rr6501e1
6. Katz NP, Sherburne S, Beach M, et al. Behavioral monitoring and urine toxicology testing in patients receiving long-term opioid therapy. Anesth Analg. 2003;97:1097-1102. https://doi.org/ 10.1213/01.ane.0000080159.83342.b5
7. Wilcox CE, Bogenschutz MP, Nakazawa M, et al. Concordance between self-report and urine drug screen data in adolescent opioid dependent clinical trial participants. Addict Behav. 2013;38:2568-2574. https://doi.org/10.1016/j.addbeh.2013.05.015
8. Zanis DA, McLellan AT, Randall M. Can you trust patient self-reports of drug use during treatment? Drug Alcohol Depend. 1994;35:127-132. https://doi.org/10.1016/0376-8716(94)90119-8
9. Jones CM, Paulozzi LJ, Mack KA. Sources of prescription opioid pain relievers by frequency of past-year nonmedical use: United States, 2008-2011. JAMA Intern Med. 2014;174:802-803. https://doi.org/10.1001/jamainternmed.2013.12809
10. Katz N, Fanciullo GJ. Role of urine toxicology testing in the management of chronic opioid therapy. Clin J Pain. 2002;18(4 suppl):S76-S82. https://doi.org/10.1097/00002508-200207001-00009
11. Vowles KE, McEntee ML, Julnes PS, et al. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain. 2015;156:569-576. https://doi.org/10.1097/01.j.pain.0000460357.01998.f1
12. Warner EA, Walker RM, Friedmann PD. Should informed consent be required for laboratory testing for drugs of abuse in medical settings? Am J Med. 2003;115:54-58. https://doi.org/10.1016/s0002-9343(03)00236-5
13. Kelly JF, Wakeman SE, Saitz R. Stop talking ‘dirty’: clinicians, language, and quality of care for the leading cause of preventable death in the United States. Am J Med. 2015;128:8-9. https://doi.org/10.1016/j.amjmed.2014.07.043
14. Jarvis M, Williams J, Hurford M, et al. Appropriate use of drug testing in clinical addiction medicine. J Addict Med. 2017;11:163-173. https://doi.org/10.1097/ADM.0000000000000323
15. Argoff CE, Alford DP, Fudin J, et al. Rational urine drug monitoring in patients receiving opioids for chronic pain: consensus recommendations. Pain Med. 2018;19:97-117. https://doi.org/10.1093/pm/pnx285
16 Ainscough TS, McNeill A, Strang J, et al. Contingency management interventions for non-prescribed drug use during treatment for opiate addiction: a systematic review and meta-analysis. Drug Alcohol Depend. 2017;178:318-339. https://doi.org/10.1016/j.drugalcdep.2017.05.028
17. Blum K, Han D, Femino J, et al. Systematic evaluation of “compliance” to prescribed treatment medications and “abstinence” from psychoactive drug abuse in chemical dependence programs: data from the comprehensive analysis of reported drugs. PLoS One. 2014;9:e104275. https://doi.org/10.1371/journal.pone.0104275
18. Miller SC, Fiellin DA, Rosenthal RN, et al. The ASAM Principles of Addiction Medicine. 6th ed. Wolters Kluwer; 2018.
19. Saitman A, Park H-D, Fitzgerald RL. False-positive interferences of common urine drug screen immunoassays: a review. J Anal Toxicol. 2014;38:387-396. https://doi.org/10.1093/jat/bku075
20. Smith MP, Bluth MH. Common interferences in drug testing. Clin Lab Med. 2016;36:663-671. https://doi.org/10.1016/j.cll.2016.07.006
21. George S, Braithwaite RA. An investigation into the extent of possible dilution of specimens received for urinary drugs of abuse screening. Addiction. 1995;90:967-970. https://doi.org/10.1046/j.1360-0443.1995.9079679.x
22. Beck O, Bohlin M, Bragd F, et al. Adulteration of urine drug testing—an exaggerated cause of concern. [Article in Swedish] Lakartidningen. 2000;97:703-706.
23. Kale N. Urine drug tests: ordering and interpreting results. Am Fam Physician. 2019;99:33-39.
24. Dasgupta A. The effects of adulterants and selected ingested compounds on drugs-of-abuse testing in urine. Am J Clin Pathol. 2007;128:491-503. https://doi.org/10.1309/FQY06F8XKTQPM149
25. Definition of addiction. American Society of Addiction Medicine Web site. Updated October 21, 2019. Accessed February 20, 2021. https://www.asam.org/resources/definition-of-addiction
26. Kroenke K, Alford DP, Argoff C, et al. Challenges with Implementing the Centers for Disease Control and Prevention Opioid Guideline: A Consensus Panel Report. Pain Med. 2019;20:724-735. https://doi.org/10.1093/pm/pny307
An estimated 20 million patients in the United States have a substance use disorder (SUD), with hundreds of millions of prescriptions for controlled substances written annually. Consequently, urine drug screening (UDS) has become widely utilized to evaluate and treat patients with an SUD or on chronic opioid or benzodiazepine therapy.1
Used appropriately, UDS can be a valuable tool; there is ample evidence, however, that it has been misused, by some physicians, to stigmatize patients who use drugs of abuse,2 profile patients racially,2 profit from excessive testing,3 and inappropriately discontinue treatment.4
A patient-centered approach. We have extensive clinical experience in the use and interpretation of urine toxicology, serving as clinical leads in busy family medicine residency practices that care for patients with SUDs, and are often consulted regarding patients on chronic opioid or benzodiazepine therapy. We have encountered countless situations in which the correct interpretation of UDS is critical to providing care.
Over time, and after considerable trial and error, we developed the patient-centered approach to urine toxicology described in this article. We believe that the medical evidence strongly supports our approach to the appropriate use and interpretation of urine toxicology in clinical practice. Our review here is intended as a resource when you consider implementing a UDS protocol or are struggling with the management of unexpected results.
Urine toxicology for therapeutic drug monitoring
Prescribing a controlled substance carries inherent risks, including diversion, nonmedical use, and development of an SUD. Prescribed medications, particularly opioids and benzodiazepines, have been linked to a large increase in overdose deaths over the past decade.5 Several strategies have been investigated to mitigate risk (see “How frequently should a patient be tested?,” later in the article).
Clinical judgment—ie, when a physician orders a drug test upon suspecting that a patient is diverting a prescribed drug or has developed an SUD—has been shown to be highly inaccurate. Implicit racial bias might affect the physician’s judgment, leading to changes in testing and test interpretation. For example, Black patients were found to be 10% more likely to have drug screening ordered while being treated with long-term opioid therapy and 2 to 3 times more likely to have their medication discontinued as a result of a marijuana- or cocaine-positive test.2
Other studies have shown that testing patients for “bad behavior,” so to speak—reporting a prescription lost or stolen, consuming more than the prescribed dosage, visiting the office without an appointment, having multiple drug intolerances and allergies, and making frequent telephone calls to the practice—is ineffective.6 Patients with these behaviors were slightly more likely to unexpectedly test positive, or negative, on their UDS; however, many patients without suspect behavior also were found to have abnormal toxicology results.6 Data do not support therapeutic drug monitoring only of patients selected on the basis of aberrant behavior.6
Continue to: Questions and concerns about urine drug screening
Questions and concerns about urine drug screening
Why not just ask the patient? Studies have evaluated whether patient self-reporting of adherence is a feasible alternative to laboratory drug screening. Regrettably, patients have repeatedly been shown to underreport their use of both prescribed and illicit drugs.7,8
That question leads to another: Why do patients lie to their physician? It is easy to assume malicious intent, but a variety of obstacles might dissuade a patient from being fully truthful with their physician:
- Monetary gain. A small, but real, percentage of medications are diverted by patients for this reason.9
- Addiction, pseudo-addiction due to tolerance, and self-medication for psychological symptoms are clinically treatable syndromes that can lead to underreporting of prescribed and nonprescribed drug and alcohol use.
- Shame. Addiction is a highly stigmatized disease, and patients might simply be ashamed to admit that they need treatment: 13% to 38% of patients receiving chronic opioid therapy in a pain management or primary care setting have a clinically diagnosable SUD.10,11
Is consent needed to test or to share test results? Historically, UDS has been performed on patients without their consent or knowledge.12 Patients give a urine specimen to their physician for a variety of reasons; it seems easy to “add on” UDS. Evidence is clear, however, that confronting a patient about an unexpected test result can make the clinical outcome worse—often resulting in irreparable damage to the patient–physician relationship.12,13 Unless the patient is experiencing a medical emergency, guidelines unanimously recommend obtaining consent prior to testing.1,5,14
Federal law requires written permission from the patient for the physician to disclose information about alcohol or substance use, unless the information is expressly needed to provide care during a medical emergency. Substance use is highly stigmatized, and patients might—legitimately—fear that sharing their history could undermine their care.1,12,14
How frequently should a patient be tested? Experts recommend utilizing a risk-based strategy to determine the frequency of UDS.1,5,15 Validated risk-assessment questionnaires include:
- Opioid Risk Tool for Opioid Use Disorder (ORT-OUD)a
- Screener and Opioid Assessment for Patients With Pain–Revised (SOAPP-R)b
- Diagnosis, Intractability, Risk and Efficacy (DIRE)c
- Addiction Behaviors Checklist (ABC).d
Continue to: Each of these tools...
Each of these tools takes less than 5 minutes to administer and can be used by a primary care physician to objectively quantify the risk of prescribing; there is no evidence for the use of 1 of these screeners over the others.15 It is recommended that you choose a questionnaire that works for you and incorporate the risk assessment into prescribing any high-risk medication.1,5,15
Once you have completed an initial risk assessment, the frequency of UDS can be based on ongoing assessment that incorporates baseline testing, patient self-reporting, toxicology results, behavioral monitoring, and state database monitoring through a prescription drug monitoring program. Annual screening is appropriate in low-risk patients; moderate-risk patients should be screened twice a year, and high-risk patients should be screened at least every 4 months (FIGURE).15
Many state and federal agencies, health systems, employers, and insurers mandate the frequency of testing through guidelines or legislation. These regulations often are inconsistent with the newest medical evidence.15 Consult local guidelines and review the medical evidence and consensus recommendations on UDS.
What are the cost considerations in providing UDS? Insurers have been billed as much as $4000 for definitive chromatography testing (described later).3 This has led to insurance fraud, when drug-testing practices with a financial interest routinely use large and expensive test panels, test too frequently, or unnecessarily send for confirmatory or quantitative analysis of all positive tests.3,14 Often, insurers refuse to pay for unnecessary testing, leaving patients with significant indebtedness.3,14 Take time to review the evidence and consensus recommendations on UDS to avoid waste, potential accusations of fraud, and financial burden on your patients.
Urine toxicology for addiction treatment
UDS protocols in addiction settings are often different from those in which a controlled substance is being prescribed.
Continue to: Routine and random testing
Routine and random testing. Two common practices when treating addiction are to perform UDS on all patients, at every visit, or to test randomly.1 These practices can be problematic, however. Routine testing at every visit can make urine-tampering more likely and is often unnecessary for stable patients. Random testing can reduce the risk of urine-tampering, but it is often difficult for primary care clinics to institute such a protocol. Some clinics have patients provide a urine specimen at every visit and then only send tests to the lab based on randomization.1
Contingency management—a behavioral intervention in which a patient is rewarded, or their performance is reinforced, when they display evidence of positive change—is the most effective strategy used in addiction medicine to determine the frequency of patient visits and UDS.14,16 High-risk patients with self-reported active substance use or UDS results consistent with substance use, or both, are seen more often; as their addiction behavior diminishes, visits and UDS become less frequent. If addiction behavior increases, the patient is seen more often. Keep in mind that addiction behavior decreases over months of treatment, not immediately upon initiation.14,17 For contingency management to be successful, patient-centered interviewing and UDS will need to be employed frequently as the patient works toward meaningful change.14
The technology of urine drug screening
Two general techniques are used for UDS: immunoassay and chromatography. Each plays an important role in clinical practice; physicians must therefore maintain a basic understanding of the mechanism of each technique and their comparable advantages and disadvantages. Such an understanding allows for (1) matching the appropriate technique to the individual clinical scenario and (2) correctly interpreting results.
Immunoassay technology is used for point-of-care and rapid laboratory UDS, using antibodies to detect the drug or drug metabolite of interest. Antibodies utilized in immunoassays are designed to selectively bind a specific antigen—ie, a unique chemical structure within the drug of choice. Once bound, the antigen–antibody complex can be exploited for detection through various methods.
Chromatography–mass spectrometry is considered the gold standard for UDS, yielding confirmatory results. This is a 2-step process: Chromatography separates components within a specimen; mass spectrometry then identifies those components. Most laboratories employ liquid, rather than gas, chromatography. The specificity of the liquid chromatography–mass spectrometry method is such that a false-positive result is, essentially, impossible.18
Continue to: How is the appropriate tests elected for urine drug screening?
How is the appropriate tests elected for urine drug screening?
Variables that influence your choice of the proper test method include the clinical question at hand; cost; the urgency of obtaining results; and the stakes in that decision (ie, will the results be used to simply change the dosage of a medication or, of greater consequence, to determine fitness for employment or inform criminal justice decisions?). Each method of UDS has advantages that can be utilized and disadvantages that must be considered to obtain an accurate and useful result.
Immunoassay provides rapid results, is relatively easy to perform, and is, comparatively, inexpensive.1,14 The speed of results makes this method particularly useful in settings such as the emergency department, where rapid results are crucial. Ease of use makes immunoassay ideal for the office, where non-laboratory staff can be trained to properly administer the test.
A major disadvantage of immunoassay technology, however, is interference resulting in both false-positive and false-negative results, which is discussed in detail in the next section. Immunoassay should be considered a screening test that yields presumptive results.
Liquid chromatography–mass spectrometry is exquisitely specific and provides confirmatory test results—major advantages of the method. However, specificity comes at a price: significantly increased cost and longer wait time for results (typically days, if specimens are sent out to a laboratory). These barriers can make it impractical to employ this method in routine practice.
Interpretation of results: Not so fast
Interpreting UDS results is not as simple as noting a positive or negative result. Physicians must understand the concept of interference, so that results can be appropriately interpreted and confirmed. This is crucial when results influence clinical decisions; inappropriate action, taken on the basis of presumptive results, can have severe consequences for the patient–provider relationship and the treatment plan.1,14
Continue to: Interference falls into 2 categories...
Interference falls into 2 categories: variables inherent in the testing process and patient variables.
Antibody cross-reactivity. A major disadvantage of immunoassay technology is interference that results in false-positive and false-negative results.19,20 The source of this interference is antibody cross-reactivity—the degree to which an antibody binds to structurally similar compounds. Antibody–antigen interactions are incredibly complex; although assay antibodies are engineered to specifically detect a drug class of interest, reactivity with other, structurally similar compounds is unavoidable.
Nevertheless, cross-reactivity is a useful phenomenon that allows broad testing for multiple drugs within a class. For example, most point-of-care tests for benzodiazepines reliably detect diazepam and chlordiazepoxide. Likewise, opiate tests reliably detect natural opiates, such as morphine and codeine. Cross-reactivity is not limitless, however; most benzodiazepine immunoassays have poor reactivity to clonazepam and lorazepam, making it possible that a patient taking clonazepam tests negative for benzodiazepine on an immunoassay.14,20 Similarly, standard opioid tests have only moderate cross-reactivity for semisynthetic opioids, such as hydrocodone and hydromorphone; poor cross-reactivity for oxycodone and oxymorphone; and essentially no cross-reactivity for full synthetics, such as fentanyl and methadone.14
It is the responsibility of the ordering physician to understand cross-reactivity to various drugs within a testing class.
Whereas weak cross-reactivity to drugs within a class can be a source of false-negative results, cross-reactivity to drugs outside the class of interest is a source of false-positive results. An extensive review of drugs that cause false-positive immunoassay screening tests is outside the scope of this article; commonly prescribed medications implicated in false-positive results are listed in TABLE 1.19
Continue to: In general...
In general, amphetamine immunoassays produce frequent false-positive results, whereas cocaine and cannabinoid assays are more specific.1,18 Common over-the-counter medications, including nonsteroidal anti-inflammatory drugs, decongestants, and antacids, can yield false-positive results, highlighting the need to obtain a comprehensive medication list from patients, including over-the-counter and herbal medications, before ordering UDS. Because of the complexity of cross-reactivity, it might not be possible to identify the source of a false-positive result.14
Patient variables. Intentional effort to skew results is another source of interference. The frequency of this effort varies by setting and the potential consequences of results—eg, employment testing or substance use treatment—and a range of attempts have been reported in the literature.21,22 Common practices are dilution, adulteration, and substitution.20,23
- Dilution lowers the concentration of the drug of interest below the detection limit of the assay by directly adding water to the urine specimen, drinking copious amounts of fluid, taking a diuretic, or a combination of these practices.
- Adulteration involves adding a substance to urine that interferes with the testing mechanism: for example, bleach, household cleaners, eye drops, and even commercially available products expressly marketed to interfere with UDS.24
- Substitution involves providing urine or a urine-like substance for testing that did not originate from the patient.
Methods to minimize patient-related interference include observed collection and specimen validity testing for pH, creatinine, and adulterants (TABLE 2).1,15 Efforts to detect patient interference must be balanced against concerns about privacy, personnel resources, and the cost of expanded testing.14,19,20
Additional aspects inherent to the testing process, such as cutoff concentrations and detection windows, can lead to interference. Laboratories must set reporting cutoffs, and specimens with a drug concentration present but below the cutoff value are reported as a negative result. Detection windows are complex and are influenced by inherent properties of the drug, including metabolic pathway and route and frequency of use.1 A given patient might well be using a substance, but if the specimen was obtained outside the detection window, a false-negative result might be reported (TABLE 31,23).
Managing test results
Appropriate management of UDS results is built on the foundation of understanding the testing mechanism, selecting the correct test, and properly interpreting results. Drug testing is, ultimately, a therapeutic tool used to monitor treatment, provide reinforcement, and explore substance use behavior; results of testing should be employed to achieve those objectives.1,4,14 A negative or expected UDS result can be utilized as positive reinforcement for a patient who is adherent to the treatment plan—much the way objective weight loss in an obese patient can provide encouragement to continue lifestyle changes.
Continue to: Test results should be presented...
Test results should be presented in an objective, nonconfrontational, and compassionate manner, not with stigmatizing language, such as “clean” or “dirty.”1,13,14 Using stigmatizing terms such as “substance abuser” instead of “person with a substance use disorder” has been shown, even among highly trained health care professionals, to have a negative effect on patient care.13
Inevitably, you will encounter an unexpected result, and therefore must develop a rational, systematic, and compassionate management approach. “Unexpected result” is a broad term that includes results that conflict with
- a patient’s self-report
- your understanding of what the patient is taking (using)
- prescribed medications
- a patient’s typical substance use pattern.
When faced with an unexpected test result, first, ensure that the result in question is reliable. If a screening test yields an unanticipated finding—especially if it conflicts with the patient’s self-reporting—make every effort to seek confirmation if you are going to be making a significant clinical decision because of the result.1,14
Second, use your understanding of interference to consider the result in a broader context. If confirmatory results are inconsistent with a patient’s self-report, discuss whether there has been a break in the physician–patient relationship and emphasize that recurrent use or failure to adhere to a treatment plan has clear consequences.1,14 Modify the treatment plan to address the inconsistent finding by escalating care, adjusting medications, and connecting the patient to additional resources.
Third, keep in mind that a positive urine test is not diagnostic of an SUD. Occasional drug use is extremely common17 and should not categorically lead to a change in the treatment plan. Addiction is, fundamentally, a disease of disordered reward, motivation, and behavior that is defined by the consequences of substance use, not substance use per se,25 and an SUD diagnosis is complex, based on clinical history, physical examination, and laboratory testing. Similarly, a negative UDS result does not rule out an SUD.4,10
Continue to: Fourth, patient dismissal...
Fourth, patient dismissal is rarely an appropriate initial response to UDS results. Regrettably, some physicians misinterpret urine toxicology results and inappropriately discharge patients on that basis.
The Centers for Disease Control and Prevention guideline for prescribing opioids has increased utilization of UDS in primary care settings but does not provide the necessary education on proper use of the tool, which has resulted in a rise in misinterpretation and inappropriate discharge.13,26
If recurrent aberrant behavior is detected (by history or urine toxicology), do not abruptly discontinue the patient’s medication(s). Inform the patient of your concern, taper medication, and refer the patient to addiction treatment. Abrupt discontinuation of an opioid or benzodiazepine can lead to significant harm.1,14
CORRESPONDENCE
John Hayes, DO, Department of Family and Community Medicine, Medical College of Wisconsin, 1121 E North Avenue, Milwaukee, WI, 53212; [email protected]
An estimated 20 million patients in the United States have a substance use disorder (SUD), with hundreds of millions of prescriptions for controlled substances written annually. Consequently, urine drug screening (UDS) has become widely utilized to evaluate and treat patients with an SUD or on chronic opioid or benzodiazepine therapy.1
Used appropriately, UDS can be a valuable tool; there is ample evidence, however, that it has been misused, by some physicians, to stigmatize patients who use drugs of abuse,2 profile patients racially,2 profit from excessive testing,3 and inappropriately discontinue treatment.4
A patient-centered approach. We have extensive clinical experience in the use and interpretation of urine toxicology, serving as clinical leads in busy family medicine residency practices that care for patients with SUDs, and are often consulted regarding patients on chronic opioid or benzodiazepine therapy. We have encountered countless situations in which the correct interpretation of UDS is critical to providing care.
Over time, and after considerable trial and error, we developed the patient-centered approach to urine toxicology described in this article. We believe that the medical evidence strongly supports our approach to the appropriate use and interpretation of urine toxicology in clinical practice. Our review here is intended as a resource when you consider implementing a UDS protocol or are struggling with the management of unexpected results.
Urine toxicology for therapeutic drug monitoring
Prescribing a controlled substance carries inherent risks, including diversion, nonmedical use, and development of an SUD. Prescribed medications, particularly opioids and benzodiazepines, have been linked to a large increase in overdose deaths over the past decade.5 Several strategies have been investigated to mitigate risk (see “How frequently should a patient be tested?,” later in the article).
Clinical judgment—ie, when a physician orders a drug test upon suspecting that a patient is diverting a prescribed drug or has developed an SUD—has been shown to be highly inaccurate. Implicit racial bias might affect the physician’s judgment, leading to changes in testing and test interpretation. For example, Black patients were found to be 10% more likely to have drug screening ordered while being treated with long-term opioid therapy and 2 to 3 times more likely to have their medication discontinued as a result of a marijuana- or cocaine-positive test.2
Other studies have shown that testing patients for “bad behavior,” so to speak—reporting a prescription lost or stolen, consuming more than the prescribed dosage, visiting the office without an appointment, having multiple drug intolerances and allergies, and making frequent telephone calls to the practice—is ineffective.6 Patients with these behaviors were slightly more likely to unexpectedly test positive, or negative, on their UDS; however, many patients without suspect behavior also were found to have abnormal toxicology results.6 Data do not support therapeutic drug monitoring only of patients selected on the basis of aberrant behavior.6
Continue to: Questions and concerns about urine drug screening
Questions and concerns about urine drug screening
Why not just ask the patient? Studies have evaluated whether patient self-reporting of adherence is a feasible alternative to laboratory drug screening. Regrettably, patients have repeatedly been shown to underreport their use of both prescribed and illicit drugs.7,8
That question leads to another: Why do patients lie to their physician? It is easy to assume malicious intent, but a variety of obstacles might dissuade a patient from being fully truthful with their physician:
- Monetary gain. A small, but real, percentage of medications are diverted by patients for this reason.9
- Addiction, pseudo-addiction due to tolerance, and self-medication for psychological symptoms are clinically treatable syndromes that can lead to underreporting of prescribed and nonprescribed drug and alcohol use.
- Shame. Addiction is a highly stigmatized disease, and patients might simply be ashamed to admit that they need treatment: 13% to 38% of patients receiving chronic opioid therapy in a pain management or primary care setting have a clinically diagnosable SUD.10,11
Is consent needed to test or to share test results? Historically, UDS has been performed on patients without their consent or knowledge.12 Patients give a urine specimen to their physician for a variety of reasons; it seems easy to “add on” UDS. Evidence is clear, however, that confronting a patient about an unexpected test result can make the clinical outcome worse—often resulting in irreparable damage to the patient–physician relationship.12,13 Unless the patient is experiencing a medical emergency, guidelines unanimously recommend obtaining consent prior to testing.1,5,14
Federal law requires written permission from the patient for the physician to disclose information about alcohol or substance use, unless the information is expressly needed to provide care during a medical emergency. Substance use is highly stigmatized, and patients might—legitimately—fear that sharing their history could undermine their care.1,12,14
How frequently should a patient be tested? Experts recommend utilizing a risk-based strategy to determine the frequency of UDS.1,5,15 Validated risk-assessment questionnaires include:
- Opioid Risk Tool for Opioid Use Disorder (ORT-OUD)a
- Screener and Opioid Assessment for Patients With Pain–Revised (SOAPP-R)b
- Diagnosis, Intractability, Risk and Efficacy (DIRE)c
- Addiction Behaviors Checklist (ABC).d
Continue to: Each of these tools...
Each of these tools takes less than 5 minutes to administer and can be used by a primary care physician to objectively quantify the risk of prescribing; there is no evidence for the use of 1 of these screeners over the others.15 It is recommended that you choose a questionnaire that works for you and incorporate the risk assessment into prescribing any high-risk medication.1,5,15
Once you have completed an initial risk assessment, the frequency of UDS can be based on ongoing assessment that incorporates baseline testing, patient self-reporting, toxicology results, behavioral monitoring, and state database monitoring through a prescription drug monitoring program. Annual screening is appropriate in low-risk patients; moderate-risk patients should be screened twice a year, and high-risk patients should be screened at least every 4 months (FIGURE).15
Many state and federal agencies, health systems, employers, and insurers mandate the frequency of testing through guidelines or legislation. These regulations often are inconsistent with the newest medical evidence.15 Consult local guidelines and review the medical evidence and consensus recommendations on UDS.
What are the cost considerations in providing UDS? Insurers have been billed as much as $4000 for definitive chromatography testing (described later).3 This has led to insurance fraud, when drug-testing practices with a financial interest routinely use large and expensive test panels, test too frequently, or unnecessarily send for confirmatory or quantitative analysis of all positive tests.3,14 Often, insurers refuse to pay for unnecessary testing, leaving patients with significant indebtedness.3,14 Take time to review the evidence and consensus recommendations on UDS to avoid waste, potential accusations of fraud, and financial burden on your patients.
Urine toxicology for addiction treatment
UDS protocols in addiction settings are often different from those in which a controlled substance is being prescribed.
Continue to: Routine and random testing
Routine and random testing. Two common practices when treating addiction are to perform UDS on all patients, at every visit, or to test randomly.1 These practices can be problematic, however. Routine testing at every visit can make urine-tampering more likely and is often unnecessary for stable patients. Random testing can reduce the risk of urine-tampering, but it is often difficult for primary care clinics to institute such a protocol. Some clinics have patients provide a urine specimen at every visit and then only send tests to the lab based on randomization.1
Contingency management—a behavioral intervention in which a patient is rewarded, or their performance is reinforced, when they display evidence of positive change—is the most effective strategy used in addiction medicine to determine the frequency of patient visits and UDS.14,16 High-risk patients with self-reported active substance use or UDS results consistent with substance use, or both, are seen more often; as their addiction behavior diminishes, visits and UDS become less frequent. If addiction behavior increases, the patient is seen more often. Keep in mind that addiction behavior decreases over months of treatment, not immediately upon initiation.14,17 For contingency management to be successful, patient-centered interviewing and UDS will need to be employed frequently as the patient works toward meaningful change.14
The technology of urine drug screening
Two general techniques are used for UDS: immunoassay and chromatography. Each plays an important role in clinical practice; physicians must therefore maintain a basic understanding of the mechanism of each technique and their comparable advantages and disadvantages. Such an understanding allows for (1) matching the appropriate technique to the individual clinical scenario and (2) correctly interpreting results.
Immunoassay technology is used for point-of-care and rapid laboratory UDS, using antibodies to detect the drug or drug metabolite of interest. Antibodies utilized in immunoassays are designed to selectively bind a specific antigen—ie, a unique chemical structure within the drug of choice. Once bound, the antigen–antibody complex can be exploited for detection through various methods.
Chromatography–mass spectrometry is considered the gold standard for UDS, yielding confirmatory results. This is a 2-step process: Chromatography separates components within a specimen; mass spectrometry then identifies those components. Most laboratories employ liquid, rather than gas, chromatography. The specificity of the liquid chromatography–mass spectrometry method is such that a false-positive result is, essentially, impossible.18
Continue to: How is the appropriate tests elected for urine drug screening?
How is the appropriate tests elected for urine drug screening?
Variables that influence your choice of the proper test method include the clinical question at hand; cost; the urgency of obtaining results; and the stakes in that decision (ie, will the results be used to simply change the dosage of a medication or, of greater consequence, to determine fitness for employment or inform criminal justice decisions?). Each method of UDS has advantages that can be utilized and disadvantages that must be considered to obtain an accurate and useful result.
Immunoassay provides rapid results, is relatively easy to perform, and is, comparatively, inexpensive.1,14 The speed of results makes this method particularly useful in settings such as the emergency department, where rapid results are crucial. Ease of use makes immunoassay ideal for the office, where non-laboratory staff can be trained to properly administer the test.
A major disadvantage of immunoassay technology, however, is interference resulting in both false-positive and false-negative results, which is discussed in detail in the next section. Immunoassay should be considered a screening test that yields presumptive results.
Liquid chromatography–mass spectrometry is exquisitely specific and provides confirmatory test results—major advantages of the method. However, specificity comes at a price: significantly increased cost and longer wait time for results (typically days, if specimens are sent out to a laboratory). These barriers can make it impractical to employ this method in routine practice.
Interpretation of results: Not so fast
Interpreting UDS results is not as simple as noting a positive or negative result. Physicians must understand the concept of interference, so that results can be appropriately interpreted and confirmed. This is crucial when results influence clinical decisions; inappropriate action, taken on the basis of presumptive results, can have severe consequences for the patient–provider relationship and the treatment plan.1,14
Continue to: Interference falls into 2 categories...
Interference falls into 2 categories: variables inherent in the testing process and patient variables.
Antibody cross-reactivity. A major disadvantage of immunoassay technology is interference that results in false-positive and false-negative results.19,20 The source of this interference is antibody cross-reactivity—the degree to which an antibody binds to structurally similar compounds. Antibody–antigen interactions are incredibly complex; although assay antibodies are engineered to specifically detect a drug class of interest, reactivity with other, structurally similar compounds is unavoidable.
Nevertheless, cross-reactivity is a useful phenomenon that allows broad testing for multiple drugs within a class. For example, most point-of-care tests for benzodiazepines reliably detect diazepam and chlordiazepoxide. Likewise, opiate tests reliably detect natural opiates, such as morphine and codeine. Cross-reactivity is not limitless, however; most benzodiazepine immunoassays have poor reactivity to clonazepam and lorazepam, making it possible that a patient taking clonazepam tests negative for benzodiazepine on an immunoassay.14,20 Similarly, standard opioid tests have only moderate cross-reactivity for semisynthetic opioids, such as hydrocodone and hydromorphone; poor cross-reactivity for oxycodone and oxymorphone; and essentially no cross-reactivity for full synthetics, such as fentanyl and methadone.14
It is the responsibility of the ordering physician to understand cross-reactivity to various drugs within a testing class.
Whereas weak cross-reactivity to drugs within a class can be a source of false-negative results, cross-reactivity to drugs outside the class of interest is a source of false-positive results. An extensive review of drugs that cause false-positive immunoassay screening tests is outside the scope of this article; commonly prescribed medications implicated in false-positive results are listed in TABLE 1.19
Continue to: In general...
In general, amphetamine immunoassays produce frequent false-positive results, whereas cocaine and cannabinoid assays are more specific.1,18 Common over-the-counter medications, including nonsteroidal anti-inflammatory drugs, decongestants, and antacids, can yield false-positive results, highlighting the need to obtain a comprehensive medication list from patients, including over-the-counter and herbal medications, before ordering UDS. Because of the complexity of cross-reactivity, it might not be possible to identify the source of a false-positive result.14
Patient variables. Intentional effort to skew results is another source of interference. The frequency of this effort varies by setting and the potential consequences of results—eg, employment testing or substance use treatment—and a range of attempts have been reported in the literature.21,22 Common practices are dilution, adulteration, and substitution.20,23
- Dilution lowers the concentration of the drug of interest below the detection limit of the assay by directly adding water to the urine specimen, drinking copious amounts of fluid, taking a diuretic, or a combination of these practices.
- Adulteration involves adding a substance to urine that interferes with the testing mechanism: for example, bleach, household cleaners, eye drops, and even commercially available products expressly marketed to interfere with UDS.24
- Substitution involves providing urine or a urine-like substance for testing that did not originate from the patient.
Methods to minimize patient-related interference include observed collection and specimen validity testing for pH, creatinine, and adulterants (TABLE 2).1,15 Efforts to detect patient interference must be balanced against concerns about privacy, personnel resources, and the cost of expanded testing.14,19,20
Additional aspects inherent to the testing process, such as cutoff concentrations and detection windows, can lead to interference. Laboratories must set reporting cutoffs, and specimens with a drug concentration present but below the cutoff value are reported as a negative result. Detection windows are complex and are influenced by inherent properties of the drug, including metabolic pathway and route and frequency of use.1 A given patient might well be using a substance, but if the specimen was obtained outside the detection window, a false-negative result might be reported (TABLE 31,23).
Managing test results
Appropriate management of UDS results is built on the foundation of understanding the testing mechanism, selecting the correct test, and properly interpreting results. Drug testing is, ultimately, a therapeutic tool used to monitor treatment, provide reinforcement, and explore substance use behavior; results of testing should be employed to achieve those objectives.1,4,14 A negative or expected UDS result can be utilized as positive reinforcement for a patient who is adherent to the treatment plan—much the way objective weight loss in an obese patient can provide encouragement to continue lifestyle changes.
Continue to: Test results should be presented...
Test results should be presented in an objective, nonconfrontational, and compassionate manner, not with stigmatizing language, such as “clean” or “dirty.”1,13,14 Using stigmatizing terms such as “substance abuser” instead of “person with a substance use disorder” has been shown, even among highly trained health care professionals, to have a negative effect on patient care.13
Inevitably, you will encounter an unexpected result, and therefore must develop a rational, systematic, and compassionate management approach. “Unexpected result” is a broad term that includes results that conflict with
- a patient’s self-report
- your understanding of what the patient is taking (using)
- prescribed medications
- a patient’s typical substance use pattern.
When faced with an unexpected test result, first, ensure that the result in question is reliable. If a screening test yields an unanticipated finding—especially if it conflicts with the patient’s self-reporting—make every effort to seek confirmation if you are going to be making a significant clinical decision because of the result.1,14
Second, use your understanding of interference to consider the result in a broader context. If confirmatory results are inconsistent with a patient’s self-report, discuss whether there has been a break in the physician–patient relationship and emphasize that recurrent use or failure to adhere to a treatment plan has clear consequences.1,14 Modify the treatment plan to address the inconsistent finding by escalating care, adjusting medications, and connecting the patient to additional resources.
Third, keep in mind that a positive urine test is not diagnostic of an SUD. Occasional drug use is extremely common17 and should not categorically lead to a change in the treatment plan. Addiction is, fundamentally, a disease of disordered reward, motivation, and behavior that is defined by the consequences of substance use, not substance use per se,25 and an SUD diagnosis is complex, based on clinical history, physical examination, and laboratory testing. Similarly, a negative UDS result does not rule out an SUD.4,10
Continue to: Fourth, patient dismissal...
Fourth, patient dismissal is rarely an appropriate initial response to UDS results. Regrettably, some physicians misinterpret urine toxicology results and inappropriately discharge patients on that basis.
The Centers for Disease Control and Prevention guideline for prescribing opioids has increased utilization of UDS in primary care settings but does not provide the necessary education on proper use of the tool, which has resulted in a rise in misinterpretation and inappropriate discharge.13,26
If recurrent aberrant behavior is detected (by history or urine toxicology), do not abruptly discontinue the patient’s medication(s). Inform the patient of your concern, taper medication, and refer the patient to addiction treatment. Abrupt discontinuation of an opioid or benzodiazepine can lead to significant harm.1,14
CORRESPONDENCE
John Hayes, DO, Department of Family and Community Medicine, Medical College of Wisconsin, 1121 E North Avenue, Milwaukee, WI, 53212; [email protected]
1. TAP 32: Clinical drug testing in primary care. Rockville, MD: Substance Abuse and Mental Health Services Administration, US Department of Health & Human Services; 2012. Technical Assistance Publication (TAP) 32; HHS Publication No. (SMA) 12-4668. 2012. Accessed March 19, 2021. https://store.samhsa.gov/sites/default/files/d7/priv/sma12-4668.pdf
2. Gaither JR, Gordon K, Crystal S, et al. Racial disparities in discontinuation of long-term opioid therapy following illicit drug use among black and white patients. Drug Alcohol Depend. 2018;192:371-376. https://doi.org/10.1016/j.drugalcdep.2018.05.033
3. Segal, David. In pursuit of liquid gold. The New York Times. December 27, 2017. Accessed March 19, 2021. https://nyti.ms/2E2GTOU
4. Ceasar R, Chang J, Zamora K, et al. Primary care providers’ experiences with urine toxicology tests to manage prescription opioid misuse and substance use among chronic noncancer pain patients in safety net health care settings. Subst Abus. 2016;37:154-160. https://doi.org/10.1080/08897077.2015.1132293
5. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain — United States, 2016. MMWR Recomm Rep. 2016;65:1-49. https://doi.org/10.15585/mmwr.rr6501e1
6. Katz NP, Sherburne S, Beach M, et al. Behavioral monitoring and urine toxicology testing in patients receiving long-term opioid therapy. Anesth Analg. 2003;97:1097-1102. https://doi.org/ 10.1213/01.ane.0000080159.83342.b5
7. Wilcox CE, Bogenschutz MP, Nakazawa M, et al. Concordance between self-report and urine drug screen data in adolescent opioid dependent clinical trial participants. Addict Behav. 2013;38:2568-2574. https://doi.org/10.1016/j.addbeh.2013.05.015
8. Zanis DA, McLellan AT, Randall M. Can you trust patient self-reports of drug use during treatment? Drug Alcohol Depend. 1994;35:127-132. https://doi.org/10.1016/0376-8716(94)90119-8
9. Jones CM, Paulozzi LJ, Mack KA. Sources of prescription opioid pain relievers by frequency of past-year nonmedical use: United States, 2008-2011. JAMA Intern Med. 2014;174:802-803. https://doi.org/10.1001/jamainternmed.2013.12809
10. Katz N, Fanciullo GJ. Role of urine toxicology testing in the management of chronic opioid therapy. Clin J Pain. 2002;18(4 suppl):S76-S82. https://doi.org/10.1097/00002508-200207001-00009
11. Vowles KE, McEntee ML, Julnes PS, et al. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain. 2015;156:569-576. https://doi.org/10.1097/01.j.pain.0000460357.01998.f1
12. Warner EA, Walker RM, Friedmann PD. Should informed consent be required for laboratory testing for drugs of abuse in medical settings? Am J Med. 2003;115:54-58. https://doi.org/10.1016/s0002-9343(03)00236-5
13. Kelly JF, Wakeman SE, Saitz R. Stop talking ‘dirty’: clinicians, language, and quality of care for the leading cause of preventable death in the United States. Am J Med. 2015;128:8-9. https://doi.org/10.1016/j.amjmed.2014.07.043
14. Jarvis M, Williams J, Hurford M, et al. Appropriate use of drug testing in clinical addiction medicine. J Addict Med. 2017;11:163-173. https://doi.org/10.1097/ADM.0000000000000323
15. Argoff CE, Alford DP, Fudin J, et al. Rational urine drug monitoring in patients receiving opioids for chronic pain: consensus recommendations. Pain Med. 2018;19:97-117. https://doi.org/10.1093/pm/pnx285
16 Ainscough TS, McNeill A, Strang J, et al. Contingency management interventions for non-prescribed drug use during treatment for opiate addiction: a systematic review and meta-analysis. Drug Alcohol Depend. 2017;178:318-339. https://doi.org/10.1016/j.drugalcdep.2017.05.028
17. Blum K, Han D, Femino J, et al. Systematic evaluation of “compliance” to prescribed treatment medications and “abstinence” from psychoactive drug abuse in chemical dependence programs: data from the comprehensive analysis of reported drugs. PLoS One. 2014;9:e104275. https://doi.org/10.1371/journal.pone.0104275
18. Miller SC, Fiellin DA, Rosenthal RN, et al. The ASAM Principles of Addiction Medicine. 6th ed. Wolters Kluwer; 2018.
19. Saitman A, Park H-D, Fitzgerald RL. False-positive interferences of common urine drug screen immunoassays: a review. J Anal Toxicol. 2014;38:387-396. https://doi.org/10.1093/jat/bku075
20. Smith MP, Bluth MH. Common interferences in drug testing. Clin Lab Med. 2016;36:663-671. https://doi.org/10.1016/j.cll.2016.07.006
21. George S, Braithwaite RA. An investigation into the extent of possible dilution of specimens received for urinary drugs of abuse screening. Addiction. 1995;90:967-970. https://doi.org/10.1046/j.1360-0443.1995.9079679.x
22. Beck O, Bohlin M, Bragd F, et al. Adulteration of urine drug testing—an exaggerated cause of concern. [Article in Swedish] Lakartidningen. 2000;97:703-706.
23. Kale N. Urine drug tests: ordering and interpreting results. Am Fam Physician. 2019;99:33-39.
24. Dasgupta A. The effects of adulterants and selected ingested compounds on drugs-of-abuse testing in urine. Am J Clin Pathol. 2007;128:491-503. https://doi.org/10.1309/FQY06F8XKTQPM149
25. Definition of addiction. American Society of Addiction Medicine Web site. Updated October 21, 2019. Accessed February 20, 2021. https://www.asam.org/resources/definition-of-addiction
26. Kroenke K, Alford DP, Argoff C, et al. Challenges with Implementing the Centers for Disease Control and Prevention Opioid Guideline: A Consensus Panel Report. Pain Med. 2019;20:724-735. https://doi.org/10.1093/pm/pny307
1. TAP 32: Clinical drug testing in primary care. Rockville, MD: Substance Abuse and Mental Health Services Administration, US Department of Health & Human Services; 2012. Technical Assistance Publication (TAP) 32; HHS Publication No. (SMA) 12-4668. 2012. Accessed March 19, 2021. https://store.samhsa.gov/sites/default/files/d7/priv/sma12-4668.pdf
2. Gaither JR, Gordon K, Crystal S, et al. Racial disparities in discontinuation of long-term opioid therapy following illicit drug use among black and white patients. Drug Alcohol Depend. 2018;192:371-376. https://doi.org/10.1016/j.drugalcdep.2018.05.033
3. Segal, David. In pursuit of liquid gold. The New York Times. December 27, 2017. Accessed March 19, 2021. https://nyti.ms/2E2GTOU
4. Ceasar R, Chang J, Zamora K, et al. Primary care providers’ experiences with urine toxicology tests to manage prescription opioid misuse and substance use among chronic noncancer pain patients in safety net health care settings. Subst Abus. 2016;37:154-160. https://doi.org/10.1080/08897077.2015.1132293
5. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain — United States, 2016. MMWR Recomm Rep. 2016;65:1-49. https://doi.org/10.15585/mmwr.rr6501e1
6. Katz NP, Sherburne S, Beach M, et al. Behavioral monitoring and urine toxicology testing in patients receiving long-term opioid therapy. Anesth Analg. 2003;97:1097-1102. https://doi.org/ 10.1213/01.ane.0000080159.83342.b5
7. Wilcox CE, Bogenschutz MP, Nakazawa M, et al. Concordance between self-report and urine drug screen data in adolescent opioid dependent clinical trial participants. Addict Behav. 2013;38:2568-2574. https://doi.org/10.1016/j.addbeh.2013.05.015
8. Zanis DA, McLellan AT, Randall M. Can you trust patient self-reports of drug use during treatment? Drug Alcohol Depend. 1994;35:127-132. https://doi.org/10.1016/0376-8716(94)90119-8
9. Jones CM, Paulozzi LJ, Mack KA. Sources of prescription opioid pain relievers by frequency of past-year nonmedical use: United States, 2008-2011. JAMA Intern Med. 2014;174:802-803. https://doi.org/10.1001/jamainternmed.2013.12809
10. Katz N, Fanciullo GJ. Role of urine toxicology testing in the management of chronic opioid therapy. Clin J Pain. 2002;18(4 suppl):S76-S82. https://doi.org/10.1097/00002508-200207001-00009
11. Vowles KE, McEntee ML, Julnes PS, et al. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain. 2015;156:569-576. https://doi.org/10.1097/01.j.pain.0000460357.01998.f1
12. Warner EA, Walker RM, Friedmann PD. Should informed consent be required for laboratory testing for drugs of abuse in medical settings? Am J Med. 2003;115:54-58. https://doi.org/10.1016/s0002-9343(03)00236-5
13. Kelly JF, Wakeman SE, Saitz R. Stop talking ‘dirty’: clinicians, language, and quality of care for the leading cause of preventable death in the United States. Am J Med. 2015;128:8-9. https://doi.org/10.1016/j.amjmed.2014.07.043
14. Jarvis M, Williams J, Hurford M, et al. Appropriate use of drug testing in clinical addiction medicine. J Addict Med. 2017;11:163-173. https://doi.org/10.1097/ADM.0000000000000323
15. Argoff CE, Alford DP, Fudin J, et al. Rational urine drug monitoring in patients receiving opioids for chronic pain: consensus recommendations. Pain Med. 2018;19:97-117. https://doi.org/10.1093/pm/pnx285
16 Ainscough TS, McNeill A, Strang J, et al. Contingency management interventions for non-prescribed drug use during treatment for opiate addiction: a systematic review and meta-analysis. Drug Alcohol Depend. 2017;178:318-339. https://doi.org/10.1016/j.drugalcdep.2017.05.028
17. Blum K, Han D, Femino J, et al. Systematic evaluation of “compliance” to prescribed treatment medications and “abstinence” from psychoactive drug abuse in chemical dependence programs: data from the comprehensive analysis of reported drugs. PLoS One. 2014;9:e104275. https://doi.org/10.1371/journal.pone.0104275
18. Miller SC, Fiellin DA, Rosenthal RN, et al. The ASAM Principles of Addiction Medicine. 6th ed. Wolters Kluwer; 2018.
19. Saitman A, Park H-D, Fitzgerald RL. False-positive interferences of common urine drug screen immunoassays: a review. J Anal Toxicol. 2014;38:387-396. https://doi.org/10.1093/jat/bku075
20. Smith MP, Bluth MH. Common interferences in drug testing. Clin Lab Med. 2016;36:663-671. https://doi.org/10.1016/j.cll.2016.07.006
21. George S, Braithwaite RA. An investigation into the extent of possible dilution of specimens received for urinary drugs of abuse screening. Addiction. 1995;90:967-970. https://doi.org/10.1046/j.1360-0443.1995.9079679.x
22. Beck O, Bohlin M, Bragd F, et al. Adulteration of urine drug testing—an exaggerated cause of concern. [Article in Swedish] Lakartidningen. 2000;97:703-706.
23. Kale N. Urine drug tests: ordering and interpreting results. Am Fam Physician. 2019;99:33-39.
24. Dasgupta A. The effects of adulterants and selected ingested compounds on drugs-of-abuse testing in urine. Am J Clin Pathol. 2007;128:491-503. https://doi.org/10.1309/FQY06F8XKTQPM149
25. Definition of addiction. American Society of Addiction Medicine Web site. Updated October 21, 2019. Accessed February 20, 2021. https://www.asam.org/resources/definition-of-addiction
26. Kroenke K, Alford DP, Argoff C, et al. Challenges with Implementing the Centers for Disease Control and Prevention Opioid Guideline: A Consensus Panel Report. Pain Med. 2019;20:724-735. https://doi.org/10.1093/pm/pny307
PRACTICE RECOMMENDATIONS
› Consider developing a risk-based urine drug testing protocol for all patients who are on chronic opioid therapy. C
› Consider urine drug testing to augment a thorough history when identifying and offering treatment to patients with a substance use disorder. A
› Do not change your management plan based on results of a single screening urine test. Revisit unexpected positive or negative results with a thorough history or confirmatory testing. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Itchy rash on back
A unilateral, neuropathic itch accompanied by postinflammatory pigmentation changes or lichenification at the medial inferior tip of the scapula are the hallmarks of notalgia paresthetica (NP).
NP is thought to result from nerve impingement or chronic nerve trauma to the posterior rami of the upper thoracic spinal nerves. The hyperpigmentation and lichenification arise from repeated scratching or rubbing of the skin.
NP is a clinical diagnosis and does not require biopsy or imaging. The differential diagnosis includes brachioradial pruritus, postherpetic neuralgia, multiple sclerosis, and other small fiber neuropathies.
The standard treatment is topical capsaicin 0.025% tid for 5 weeks, with repeat treatments (for a few days or weeks) if there are relapses. Higher doses (0.075%) may work more quickly but may also lead to more burning. A lidocaine 5% patch bid can also be considered. Second-line treatment options include cutaneous electrical field stimulation or transcutaneous electrical nerve stimulation, gabapentin, or oxcarbazepine. Topical steroids are considered ineffective for this condition.1
The patient in this case was started on capsaicin 0.025%. She was encouraged to keep her skin moisturized and well hydrated because dyshidrosis can exacerbate itching. A prescription for gabapentin was offered in case topical treatments were unsuccessful, but she declined after she weighed the risks of adverse effects against her current symptoms.
Photo courtesy of Daniel Stulberg, MD, and text courtesy of Nathan Birnbaum, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque
1. Lebwohl MG, Heymann WR, Berth-Jones J, et al, eds. Treatment of Skin Disease: Comprehensive Therapeutic Strategies. 5th ed. Elsevier; 2017.
A unilateral, neuropathic itch accompanied by postinflammatory pigmentation changes or lichenification at the medial inferior tip of the scapula are the hallmarks of notalgia paresthetica (NP).
NP is thought to result from nerve impingement or chronic nerve trauma to the posterior rami of the upper thoracic spinal nerves. The hyperpigmentation and lichenification arise from repeated scratching or rubbing of the skin.
NP is a clinical diagnosis and does not require biopsy or imaging. The differential diagnosis includes brachioradial pruritus, postherpetic neuralgia, multiple sclerosis, and other small fiber neuropathies.
The standard treatment is topical capsaicin 0.025% tid for 5 weeks, with repeat treatments (for a few days or weeks) if there are relapses. Higher doses (0.075%) may work more quickly but may also lead to more burning. A lidocaine 5% patch bid can also be considered. Second-line treatment options include cutaneous electrical field stimulation or transcutaneous electrical nerve stimulation, gabapentin, or oxcarbazepine. Topical steroids are considered ineffective for this condition.1
The patient in this case was started on capsaicin 0.025%. She was encouraged to keep her skin moisturized and well hydrated because dyshidrosis can exacerbate itching. A prescription for gabapentin was offered in case topical treatments were unsuccessful, but she declined after she weighed the risks of adverse effects against her current symptoms.
Photo courtesy of Daniel Stulberg, MD, and text courtesy of Nathan Birnbaum, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque
A unilateral, neuropathic itch accompanied by postinflammatory pigmentation changes or lichenification at the medial inferior tip of the scapula are the hallmarks of notalgia paresthetica (NP).
NP is thought to result from nerve impingement or chronic nerve trauma to the posterior rami of the upper thoracic spinal nerves. The hyperpigmentation and lichenification arise from repeated scratching or rubbing of the skin.
NP is a clinical diagnosis and does not require biopsy or imaging. The differential diagnosis includes brachioradial pruritus, postherpetic neuralgia, multiple sclerosis, and other small fiber neuropathies.
The standard treatment is topical capsaicin 0.025% tid for 5 weeks, with repeat treatments (for a few days or weeks) if there are relapses. Higher doses (0.075%) may work more quickly but may also lead to more burning. A lidocaine 5% patch bid can also be considered. Second-line treatment options include cutaneous electrical field stimulation or transcutaneous electrical nerve stimulation, gabapentin, or oxcarbazepine. Topical steroids are considered ineffective for this condition.1
The patient in this case was started on capsaicin 0.025%. She was encouraged to keep her skin moisturized and well hydrated because dyshidrosis can exacerbate itching. A prescription for gabapentin was offered in case topical treatments were unsuccessful, but she declined after she weighed the risks of adverse effects against her current symptoms.
Photo courtesy of Daniel Stulberg, MD, and text courtesy of Nathan Birnbaum, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque
1. Lebwohl MG, Heymann WR, Berth-Jones J, et al, eds. Treatment of Skin Disease: Comprehensive Therapeutic Strategies. 5th ed. Elsevier; 2017.
1. Lebwohl MG, Heymann WR, Berth-Jones J, et al, eds. Treatment of Skin Disease: Comprehensive Therapeutic Strategies. 5th ed. Elsevier; 2017.
Is ketamine effective and safe for treatment-resistant depression?
Evidence Summary
Single-dose IV ketamine elicits a short-term response
A meta-analysis of RCTs evaluating a single dose of IV ketamine vs placebo for severe depression found that it increased the chance of a treatment response for up to 1 week afterward. Studies included patients with severe (N = 30), treatment-resistant (N = 40), and psychotic depression (N = 10), based on Diagnostic and Statistical Manual of Mental Disorders–Fifth Edition criteria.1
The primary outcome was treatment response: either an improvement of > 50% on a standardized depression scale or a Clinical Global Impression–Improvement scale score of 1 or 2 (“very much” and “much” improved, respectively, as assessed by a clinician). Ketamine increased the likelihood of short-term response or improvement at 24 hours (3 RCTs; N = 56; odds ratio [OR] = 11; 95% CI, 2-58); at 72 hours (3 RCTs; N = 56; OR = 13; 95% CI, 2-66); and at 7 days (4 RCTs; N = 88; OR = 2.6; 95% CI, 1.1-6.2).1 Response rates equaled placebo at 2 weeks. The authors rated the RCTs as low quality.
Another systematic review of single-dose IV ketamine vs placebo for major depression and bipolar disorder included 3 additional small, low-quality RCTs, 2 of which showed short-term response to ketamine. The authors used Hedge’s g statistic to standardize effect size (a score of magnitude 0.2 indicates a small effect; 0.6, moderate; 1.2, large; and 2, very large). One RCT (n = 26) found a very large 1-day response (effect size: –2; 95% CI, –2.8 to –1.3), and 2 RCTs found conflicting responses at 12 days (RCT with N = 18: effect size: –0.2; 95% CI, –0.4 to 0.02 [no significant response] vs RCT with N = 8: effect size: –1.5; 95% CI, –2.5 to –0.5).2
More frequent dosing of IV ketamine improves symptoms
An RCT (N = 67) evaluating twice- or thrice-weekly IV ketamine vs placebo in patients with recurrent depression (with at least 1 treatment failure) found that ketamine significantly improved standardized depression scores and response rates at 15 days. Patients with clinically significant suicidality were excluded.3
Researchers randomized patients to IV ketamine (0.05 mg/kg) twice or thrice weekly or to saline control and used the 60-point Montgomery-Asberg Depression Rating Scale (MADRS). A response was defined as a reduction of the MADRS score by 50%.
Both ketamine arms produced greater symptom improvement at 15 days, compared to placebo (twice weekly: −18.4 vs −5.7; P < 0.001; thrice weekly: −17.7 vs −3.1; P < 0.001) in addition to higher response rates (twice weekly: 69% vs 15%; P = .005; number needed to treat [NNT] = 2; and thrice-weekly: 54% vs 6%; P = .004; NNT = 2).3 There was no significant difference between twice- or thrice-weekly dosing. The study was flawed by dropouts (N = 57 at 15 days and N = 25 at 28 days), primarily attributed to ketamine adverse effects, that prevented assessment beyond 2 weeks.
Oral ketamine has a moderate effecton depression
A systematic review included 2 low-quality RCTs evaluating oral ketamine vs placebo as adjunctive treatment with sertraline, and oral ketamine vs diclofenac, and found improvement in patients with moderate depression.4 In the first RCT (n = 45), researchers found that oral ketamine (25 mg bid) plus sertraline (25 mg titrated up to 150 mg/d) produced more treatment responses (> 50% reduction on a standardized depression rating scale) than placebo plus sertraline (2 weeks: 85.4% vs 42.5%; P < .001; 6 weeks: 85.4% vs 57.5%; P = .005).4
In the second RCT (n = 23), researchers randomized patients with mild-to-moderate depression and comorbid chronic headaches to take oral ketamine (50 mg tid) or oral diclofenac (50 mg tid) and measured effect size on standardized depression scores at 3 weeks (no difference) and 6 weeks (Cohen d effect size = 0.79 [rated as a moderate effect]; P = .017).4
Nasal esketamine + oral antidepressants boosts treatment response rates
A meta-analysis with 4 RCTs (N = 708) evaluating intranasal esketamine vs placebo as an adjunct to oral antidepressants for patients with predominantly treatment-resistant major depression found that it boosted response rates by about 40%. Researchers randomized patients to intranasal esketamine (mostly 28-84 mg twice weekly for 28 days) or placebo spray as an adjunct to oral antidepressants (duloxetine, escitalopram, sertraline, venlafaxine).
The primary outcomes were treatment response (≥ 50% reduction in depression scores) or remission (a MADRS score < 12). Adjunctive intranasal esketamine produced greater rates of treatment response compared to placebo at 24 hours (21% vs 7%; relative risk [RR] = 8.4; 95% CI, 1.4 to 21.2; P < .02; NNT = 7) and at 28 days (59% vs 43%; RR = 1.4; 95% CI, 1.2 to 1.60; P < .0001; NNT = 6).5 Adjunctive intranasal esketamine also produced greater rates of remission at the end of the study (mostly at 28 days), compared with placebo (41% vs 25%; RR = 1.4; 95% CI, 1.2 to 1.7; P = .0004; NNT = 7).5 The authors rated study quality as moderate to high.
Adverse effects are common, may cause Tx discontinuation
Ketamine-produced adverse effects (AEs) included confusion (2 trials; N = 76; OR = 3.7; 95% CI, 1.1-12) and emotional blunting (1 trial; N = 30; OR = 23; 95% CI, 1.1-489).1
A 2018 systematic review assessed the safety of ketamine in depression after single and repeated dose in 60 studies (N = 899; 20 RCTs, 17 open-label-trials, 20 case series, and 3 retrospective studies). The most common AEs reported were headache (35% of studies), dizziness (33%), dissociation (28%), elevated blood pressure (28%), and blurred vision (23%), with the majority reported to resolve shortly after administration. The most common psychiatric AE was anxiety (15%).6 Included studies varied greatly in design and dosage form, and no meta-analysis could be performed.
Nasal esketamine produced more AEs causing discontinuation than did placebo (5.8% vs 1.5%; RR = 3.5; 95% CI, 1.34-8.9; number needed to harm [NNH] = 23), including blurred vision, dizziness, sedation, nausea, and dysphoria.5A review (5 RCTs and 1 open-label trial; N = 1708) analyzing the cardiac safety profile of intranasal esketamine adjuvant therapy found that it produced transient and asymptomatic blood pressure elevations (OR = 3.2; 95% CI, 1.9-5.8; NNH = 13).7
Recommendations from others
A clinical practice guideline from the US Veterans Administration lists IV ketamine as 1 of the therapeutic options for patients with treatment-resistant depression and suicidal ideation.8 However, a Department of Veterans Affairs Panel restricted its use to a pre-approved case-by-case basis.8
Editor’s takeaway
Physicians with patients facing the all-too-common problem of treatment-resistant major depression will be wondering if ketamine, either by itself or as an augmentation therapy, can help. Unfortunately, the outcomes we report here are too short term to answer that question, and we must await the results of further studies. Augmentation with intranasal esketamine, at a cost of $370/month, might offer some promise.
1. Caddy C, Amit BH, McCloud TL, et al. Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database Syst Rev. 2015;(9):CD011612.
2. Coyle CM, Laws KR. The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum Psychopharmacol. 2015;30:152‐163.
3. Singh JB, Fedgchin M, Daly EJ, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry. 2016;173:816‐826.
4. Rosenblat JD, Carvalho AF, Li M, et al. Oral ketamine for depression: a systematic review. J Clin Psychiatry. 2019;80:18r12475.
5. Zheng W, Cai DB, Xiang YQ, et al. Adjunctive intranasal esketamine for major depressive disorder: a systematic review of randomized double-blind controlled-placebo studies. J Affect Disord. 2020;265:63‐70.
6. Short B, Fong J, Galvez V, et al. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018;5:65‐78.
7. Doherty T, Wajs E, Melkote R, et al. Cardiac safety of esketamine nasal spray in treatment-resistant depression: results from the Clinical Development Program. CNS Drugs. 2020;34:299‐310.
8. Sall J, Brenner L, Millikan Bell AM, et al. Assessment and management of patients at risk for suicide: synopsis of the 2019 US Department of Veterans Affairs and US Department of Defense Clinical Practice Guidelines. Ann Intern Med. 2019;171:343-353.
Evidence Summary
Single-dose IV ketamine elicits a short-term response
A meta-analysis of RCTs evaluating a single dose of IV ketamine vs placebo for severe depression found that it increased the chance of a treatment response for up to 1 week afterward. Studies included patients with severe (N = 30), treatment-resistant (N = 40), and psychotic depression (N = 10), based on Diagnostic and Statistical Manual of Mental Disorders–Fifth Edition criteria.1
The primary outcome was treatment response: either an improvement of > 50% on a standardized depression scale or a Clinical Global Impression–Improvement scale score of 1 or 2 (“very much” and “much” improved, respectively, as assessed by a clinician). Ketamine increased the likelihood of short-term response or improvement at 24 hours (3 RCTs; N = 56; odds ratio [OR] = 11; 95% CI, 2-58); at 72 hours (3 RCTs; N = 56; OR = 13; 95% CI, 2-66); and at 7 days (4 RCTs; N = 88; OR = 2.6; 95% CI, 1.1-6.2).1 Response rates equaled placebo at 2 weeks. The authors rated the RCTs as low quality.
Another systematic review of single-dose IV ketamine vs placebo for major depression and bipolar disorder included 3 additional small, low-quality RCTs, 2 of which showed short-term response to ketamine. The authors used Hedge’s g statistic to standardize effect size (a score of magnitude 0.2 indicates a small effect; 0.6, moderate; 1.2, large; and 2, very large). One RCT (n = 26) found a very large 1-day response (effect size: –2; 95% CI, –2.8 to –1.3), and 2 RCTs found conflicting responses at 12 days (RCT with N = 18: effect size: –0.2; 95% CI, –0.4 to 0.02 [no significant response] vs RCT with N = 8: effect size: –1.5; 95% CI, –2.5 to –0.5).2
More frequent dosing of IV ketamine improves symptoms
An RCT (N = 67) evaluating twice- or thrice-weekly IV ketamine vs placebo in patients with recurrent depression (with at least 1 treatment failure) found that ketamine significantly improved standardized depression scores and response rates at 15 days. Patients with clinically significant suicidality were excluded.3
Researchers randomized patients to IV ketamine (0.05 mg/kg) twice or thrice weekly or to saline control and used the 60-point Montgomery-Asberg Depression Rating Scale (MADRS). A response was defined as a reduction of the MADRS score by 50%.
Both ketamine arms produced greater symptom improvement at 15 days, compared to placebo (twice weekly: −18.4 vs −5.7; P < 0.001; thrice weekly: −17.7 vs −3.1; P < 0.001) in addition to higher response rates (twice weekly: 69% vs 15%; P = .005; number needed to treat [NNT] = 2; and thrice-weekly: 54% vs 6%; P = .004; NNT = 2).3 There was no significant difference between twice- or thrice-weekly dosing. The study was flawed by dropouts (N = 57 at 15 days and N = 25 at 28 days), primarily attributed to ketamine adverse effects, that prevented assessment beyond 2 weeks.
Oral ketamine has a moderate effecton depression
A systematic review included 2 low-quality RCTs evaluating oral ketamine vs placebo as adjunctive treatment with sertraline, and oral ketamine vs diclofenac, and found improvement in patients with moderate depression.4 In the first RCT (n = 45), researchers found that oral ketamine (25 mg bid) plus sertraline (25 mg titrated up to 150 mg/d) produced more treatment responses (> 50% reduction on a standardized depression rating scale) than placebo plus sertraline (2 weeks: 85.4% vs 42.5%; P < .001; 6 weeks: 85.4% vs 57.5%; P = .005).4
In the second RCT (n = 23), researchers randomized patients with mild-to-moderate depression and comorbid chronic headaches to take oral ketamine (50 mg tid) or oral diclofenac (50 mg tid) and measured effect size on standardized depression scores at 3 weeks (no difference) and 6 weeks (Cohen d effect size = 0.79 [rated as a moderate effect]; P = .017).4
Nasal esketamine + oral antidepressants boosts treatment response rates
A meta-analysis with 4 RCTs (N = 708) evaluating intranasal esketamine vs placebo as an adjunct to oral antidepressants for patients with predominantly treatment-resistant major depression found that it boosted response rates by about 40%. Researchers randomized patients to intranasal esketamine (mostly 28-84 mg twice weekly for 28 days) or placebo spray as an adjunct to oral antidepressants (duloxetine, escitalopram, sertraline, venlafaxine).
The primary outcomes were treatment response (≥ 50% reduction in depression scores) or remission (a MADRS score < 12). Adjunctive intranasal esketamine produced greater rates of treatment response compared to placebo at 24 hours (21% vs 7%; relative risk [RR] = 8.4; 95% CI, 1.4 to 21.2; P < .02; NNT = 7) and at 28 days (59% vs 43%; RR = 1.4; 95% CI, 1.2 to 1.60; P < .0001; NNT = 6).5 Adjunctive intranasal esketamine also produced greater rates of remission at the end of the study (mostly at 28 days), compared with placebo (41% vs 25%; RR = 1.4; 95% CI, 1.2 to 1.7; P = .0004; NNT = 7).5 The authors rated study quality as moderate to high.
Adverse effects are common, may cause Tx discontinuation
Ketamine-produced adverse effects (AEs) included confusion (2 trials; N = 76; OR = 3.7; 95% CI, 1.1-12) and emotional blunting (1 trial; N = 30; OR = 23; 95% CI, 1.1-489).1
A 2018 systematic review assessed the safety of ketamine in depression after single and repeated dose in 60 studies (N = 899; 20 RCTs, 17 open-label-trials, 20 case series, and 3 retrospective studies). The most common AEs reported were headache (35% of studies), dizziness (33%), dissociation (28%), elevated blood pressure (28%), and blurred vision (23%), with the majority reported to resolve shortly after administration. The most common psychiatric AE was anxiety (15%).6 Included studies varied greatly in design and dosage form, and no meta-analysis could be performed.
Nasal esketamine produced more AEs causing discontinuation than did placebo (5.8% vs 1.5%; RR = 3.5; 95% CI, 1.34-8.9; number needed to harm [NNH] = 23), including blurred vision, dizziness, sedation, nausea, and dysphoria.5A review (5 RCTs and 1 open-label trial; N = 1708) analyzing the cardiac safety profile of intranasal esketamine adjuvant therapy found that it produced transient and asymptomatic blood pressure elevations (OR = 3.2; 95% CI, 1.9-5.8; NNH = 13).7
Recommendations from others
A clinical practice guideline from the US Veterans Administration lists IV ketamine as 1 of the therapeutic options for patients with treatment-resistant depression and suicidal ideation.8 However, a Department of Veterans Affairs Panel restricted its use to a pre-approved case-by-case basis.8
Editor’s takeaway
Physicians with patients facing the all-too-common problem of treatment-resistant major depression will be wondering if ketamine, either by itself or as an augmentation therapy, can help. Unfortunately, the outcomes we report here are too short term to answer that question, and we must await the results of further studies. Augmentation with intranasal esketamine, at a cost of $370/month, might offer some promise.
Evidence Summary
Single-dose IV ketamine elicits a short-term response
A meta-analysis of RCTs evaluating a single dose of IV ketamine vs placebo for severe depression found that it increased the chance of a treatment response for up to 1 week afterward. Studies included patients with severe (N = 30), treatment-resistant (N = 40), and psychotic depression (N = 10), based on Diagnostic and Statistical Manual of Mental Disorders–Fifth Edition criteria.1
The primary outcome was treatment response: either an improvement of > 50% on a standardized depression scale or a Clinical Global Impression–Improvement scale score of 1 or 2 (“very much” and “much” improved, respectively, as assessed by a clinician). Ketamine increased the likelihood of short-term response or improvement at 24 hours (3 RCTs; N = 56; odds ratio [OR] = 11; 95% CI, 2-58); at 72 hours (3 RCTs; N = 56; OR = 13; 95% CI, 2-66); and at 7 days (4 RCTs; N = 88; OR = 2.6; 95% CI, 1.1-6.2).1 Response rates equaled placebo at 2 weeks. The authors rated the RCTs as low quality.
Another systematic review of single-dose IV ketamine vs placebo for major depression and bipolar disorder included 3 additional small, low-quality RCTs, 2 of which showed short-term response to ketamine. The authors used Hedge’s g statistic to standardize effect size (a score of magnitude 0.2 indicates a small effect; 0.6, moderate; 1.2, large; and 2, very large). One RCT (n = 26) found a very large 1-day response (effect size: –2; 95% CI, –2.8 to –1.3), and 2 RCTs found conflicting responses at 12 days (RCT with N = 18: effect size: –0.2; 95% CI, –0.4 to 0.02 [no significant response] vs RCT with N = 8: effect size: –1.5; 95% CI, –2.5 to –0.5).2
More frequent dosing of IV ketamine improves symptoms
An RCT (N = 67) evaluating twice- or thrice-weekly IV ketamine vs placebo in patients with recurrent depression (with at least 1 treatment failure) found that ketamine significantly improved standardized depression scores and response rates at 15 days. Patients with clinically significant suicidality were excluded.3
Researchers randomized patients to IV ketamine (0.05 mg/kg) twice or thrice weekly or to saline control and used the 60-point Montgomery-Asberg Depression Rating Scale (MADRS). A response was defined as a reduction of the MADRS score by 50%.
Both ketamine arms produced greater symptom improvement at 15 days, compared to placebo (twice weekly: −18.4 vs −5.7; P < 0.001; thrice weekly: −17.7 vs −3.1; P < 0.001) in addition to higher response rates (twice weekly: 69% vs 15%; P = .005; number needed to treat [NNT] = 2; and thrice-weekly: 54% vs 6%; P = .004; NNT = 2).3 There was no significant difference between twice- or thrice-weekly dosing. The study was flawed by dropouts (N = 57 at 15 days and N = 25 at 28 days), primarily attributed to ketamine adverse effects, that prevented assessment beyond 2 weeks.
Oral ketamine has a moderate effecton depression
A systematic review included 2 low-quality RCTs evaluating oral ketamine vs placebo as adjunctive treatment with sertraline, and oral ketamine vs diclofenac, and found improvement in patients with moderate depression.4 In the first RCT (n = 45), researchers found that oral ketamine (25 mg bid) plus sertraline (25 mg titrated up to 150 mg/d) produced more treatment responses (> 50% reduction on a standardized depression rating scale) than placebo plus sertraline (2 weeks: 85.4% vs 42.5%; P < .001; 6 weeks: 85.4% vs 57.5%; P = .005).4
In the second RCT (n = 23), researchers randomized patients with mild-to-moderate depression and comorbid chronic headaches to take oral ketamine (50 mg tid) or oral diclofenac (50 mg tid) and measured effect size on standardized depression scores at 3 weeks (no difference) and 6 weeks (Cohen d effect size = 0.79 [rated as a moderate effect]; P = .017).4
Nasal esketamine + oral antidepressants boosts treatment response rates
A meta-analysis with 4 RCTs (N = 708) evaluating intranasal esketamine vs placebo as an adjunct to oral antidepressants for patients with predominantly treatment-resistant major depression found that it boosted response rates by about 40%. Researchers randomized patients to intranasal esketamine (mostly 28-84 mg twice weekly for 28 days) or placebo spray as an adjunct to oral antidepressants (duloxetine, escitalopram, sertraline, venlafaxine).
The primary outcomes were treatment response (≥ 50% reduction in depression scores) or remission (a MADRS score < 12). Adjunctive intranasal esketamine produced greater rates of treatment response compared to placebo at 24 hours (21% vs 7%; relative risk [RR] = 8.4; 95% CI, 1.4 to 21.2; P < .02; NNT = 7) and at 28 days (59% vs 43%; RR = 1.4; 95% CI, 1.2 to 1.60; P < .0001; NNT = 6).5 Adjunctive intranasal esketamine also produced greater rates of remission at the end of the study (mostly at 28 days), compared with placebo (41% vs 25%; RR = 1.4; 95% CI, 1.2 to 1.7; P = .0004; NNT = 7).5 The authors rated study quality as moderate to high.
Adverse effects are common, may cause Tx discontinuation
Ketamine-produced adverse effects (AEs) included confusion (2 trials; N = 76; OR = 3.7; 95% CI, 1.1-12) and emotional blunting (1 trial; N = 30; OR = 23; 95% CI, 1.1-489).1
A 2018 systematic review assessed the safety of ketamine in depression after single and repeated dose in 60 studies (N = 899; 20 RCTs, 17 open-label-trials, 20 case series, and 3 retrospective studies). The most common AEs reported were headache (35% of studies), dizziness (33%), dissociation (28%), elevated blood pressure (28%), and blurred vision (23%), with the majority reported to resolve shortly after administration. The most common psychiatric AE was anxiety (15%).6 Included studies varied greatly in design and dosage form, and no meta-analysis could be performed.
Nasal esketamine produced more AEs causing discontinuation than did placebo (5.8% vs 1.5%; RR = 3.5; 95% CI, 1.34-8.9; number needed to harm [NNH] = 23), including blurred vision, dizziness, sedation, nausea, and dysphoria.5A review (5 RCTs and 1 open-label trial; N = 1708) analyzing the cardiac safety profile of intranasal esketamine adjuvant therapy found that it produced transient and asymptomatic blood pressure elevations (OR = 3.2; 95% CI, 1.9-5.8; NNH = 13).7
Recommendations from others
A clinical practice guideline from the US Veterans Administration lists IV ketamine as 1 of the therapeutic options for patients with treatment-resistant depression and suicidal ideation.8 However, a Department of Veterans Affairs Panel restricted its use to a pre-approved case-by-case basis.8
Editor’s takeaway
Physicians with patients facing the all-too-common problem of treatment-resistant major depression will be wondering if ketamine, either by itself or as an augmentation therapy, can help. Unfortunately, the outcomes we report here are too short term to answer that question, and we must await the results of further studies. Augmentation with intranasal esketamine, at a cost of $370/month, might offer some promise.
1. Caddy C, Amit BH, McCloud TL, et al. Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database Syst Rev. 2015;(9):CD011612.
2. Coyle CM, Laws KR. The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum Psychopharmacol. 2015;30:152‐163.
3. Singh JB, Fedgchin M, Daly EJ, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry. 2016;173:816‐826.
4. Rosenblat JD, Carvalho AF, Li M, et al. Oral ketamine for depression: a systematic review. J Clin Psychiatry. 2019;80:18r12475.
5. Zheng W, Cai DB, Xiang YQ, et al. Adjunctive intranasal esketamine for major depressive disorder: a systematic review of randomized double-blind controlled-placebo studies. J Affect Disord. 2020;265:63‐70.
6. Short B, Fong J, Galvez V, et al. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018;5:65‐78.
7. Doherty T, Wajs E, Melkote R, et al. Cardiac safety of esketamine nasal spray in treatment-resistant depression: results from the Clinical Development Program. CNS Drugs. 2020;34:299‐310.
8. Sall J, Brenner L, Millikan Bell AM, et al. Assessment and management of patients at risk for suicide: synopsis of the 2019 US Department of Veterans Affairs and US Department of Defense Clinical Practice Guidelines. Ann Intern Med. 2019;171:343-353.
1. Caddy C, Amit BH, McCloud TL, et al. Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database Syst Rev. 2015;(9):CD011612.
2. Coyle CM, Laws KR. The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum Psychopharmacol. 2015;30:152‐163.
3. Singh JB, Fedgchin M, Daly EJ, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry. 2016;173:816‐826.
4. Rosenblat JD, Carvalho AF, Li M, et al. Oral ketamine for depression: a systematic review. J Clin Psychiatry. 2019;80:18r12475.
5. Zheng W, Cai DB, Xiang YQ, et al. Adjunctive intranasal esketamine for major depressive disorder: a systematic review of randomized double-blind controlled-placebo studies. J Affect Disord. 2020;265:63‐70.
6. Short B, Fong J, Galvez V, et al. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018;5:65‐78.
7. Doherty T, Wajs E, Melkote R, et al. Cardiac safety of esketamine nasal spray in treatment-resistant depression: results from the Clinical Development Program. CNS Drugs. 2020;34:299‐310.
8. Sall J, Brenner L, Millikan Bell AM, et al. Assessment and management of patients at risk for suicide: synopsis of the 2019 US Department of Veterans Affairs and US Department of Defense Clinical Practice Guidelines. Ann Intern Med. 2019;171:343-353.
EVIDENCE-BASED ANSWER:
MAYBE, but it’s too soon to tell. There is limited evidence that ketamine by itself is effective in the very short term. Single-dose intravenous (IV) ketamine is more likely than placebo (odds ratio = 11-13) to produce improvement (> 50%) in standardized depression scores in 1 to 3 days, lasting up to a week. Twice- or thrice-weekly IV ketamine improves symptom scores by 20%-25% over 2 weeks (strength of recommendation [SOR]: B, meta-analysis of small, low-quality, randomized controlled trials [RCTs] and a single small RCT).
Augmentation of sertraline with daily oral ketamine moderately improves symptom scores for 6 weeks in patients with moderate depression (SOR: B, small, low-quality RCTs).
Augmentation of oral antidepressants (duloxetine, escitalopram, sertraline, venlafaxine) with intranasal esketamine spray improves response and remission rates at 4 weeks (16% for both outcomes) in patients with predominantly treatment-resistant major depression (SOR: A, meta-analysis of RCTs).
Ketamine therapy is associated with confusion, emotional blunting, headache, dizziness, and blurred vision (SOR: A, meta-analyses).
Nasal esketamine spray produces the adverse effects of dizziness, vertigo, and blurred vision severe enough to cause discontinuation in 4% of patients; it also can produce transient elevation of blood pressure (SOR: A, meta-analyses).
Painful thickened breast lesion
Treatment was attempted for both a suspected spider bite (2 weeks of topical triamcinolone 0.1%) and presumed cellulitis (oral doxycycline 100 mg bid/5 d), but neither improved her condition. Concerned for the possibility of cutaneous breast cancer, a punch biopsy was ordered and revealed diffuse dermal angiomatosis (DDA).
DDA is an uncommon proliferation of cutaneous blood vessels causing a reticular blood vessel pattern, as seen in this image. Typically, DDA is associated with tissue hypoxia due to arterial insufficiency from peripheral artery disease. In recent years, there have been numerous case reports of painful ulcerated lesions and reticular blood vessels occurring in women with large, pendulous breasts, increased body mass index, and a history of smoking. One theory suggests that the weight of the breasts causes tissue to stretch, compressing the blood vessels. This, combined with smoking, leads to localized hypoxia and DDA.
Treatments have included oral isotretinoin, calcium channel blockers, aspirin, or pentoxifylline to help circulation. Smoking cessation is recommended, as well as reduction mammoplasty to decrease the stretch on the tissues and relieve the local hypoxia. Although invasive, breast reduction surgery has moved to the forefront of therapy, with reports having shown resolution of the ulcers and pain.1
Two important aspects of clinical medicine are highlighted by this case. First, nonhealing lesions that are not responding to prescribed therapies may require biopsy to rule out malignancy. Second, when there is difficulty making a diagnosis, especially with uncommon diseases, biopsy and input from a pathologist can be extremely helpful.
In this case, the patient was referred to Plastic Surgery and scheduled for reduction mammoplasty. The patient was advised to stop smoking for at least 4 weeks prior to the surgery to possibly improve her condition and reduce the likelihood of postoperative complications.
Photo courtesy of Michael Louie, MD, and text courtesy of Michael Louie, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque
Galambos J, Meuli-Simmen C, Schmid R, et al. Diffuse dermal angiomatosis of the breast: a distinct entity in the spectrum of cutaneous reactive angiomatoses—clinicopathologic study of two cases and comprehensive review of the literature. Case Rep Dermatol 2017;9:194-205. https://doi.org/10.1159/000480721
Treatment was attempted for both a suspected spider bite (2 weeks of topical triamcinolone 0.1%) and presumed cellulitis (oral doxycycline 100 mg bid/5 d), but neither improved her condition. Concerned for the possibility of cutaneous breast cancer, a punch biopsy was ordered and revealed diffuse dermal angiomatosis (DDA).
DDA is an uncommon proliferation of cutaneous blood vessels causing a reticular blood vessel pattern, as seen in this image. Typically, DDA is associated with tissue hypoxia due to arterial insufficiency from peripheral artery disease. In recent years, there have been numerous case reports of painful ulcerated lesions and reticular blood vessels occurring in women with large, pendulous breasts, increased body mass index, and a history of smoking. One theory suggests that the weight of the breasts causes tissue to stretch, compressing the blood vessels. This, combined with smoking, leads to localized hypoxia and DDA.
Treatments have included oral isotretinoin, calcium channel blockers, aspirin, or pentoxifylline to help circulation. Smoking cessation is recommended, as well as reduction mammoplasty to decrease the stretch on the tissues and relieve the local hypoxia. Although invasive, breast reduction surgery has moved to the forefront of therapy, with reports having shown resolution of the ulcers and pain.1
Two important aspects of clinical medicine are highlighted by this case. First, nonhealing lesions that are not responding to prescribed therapies may require biopsy to rule out malignancy. Second, when there is difficulty making a diagnosis, especially with uncommon diseases, biopsy and input from a pathologist can be extremely helpful.
In this case, the patient was referred to Plastic Surgery and scheduled for reduction mammoplasty. The patient was advised to stop smoking for at least 4 weeks prior to the surgery to possibly improve her condition and reduce the likelihood of postoperative complications.
Photo courtesy of Michael Louie, MD, and text courtesy of Michael Louie, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque
Treatment was attempted for both a suspected spider bite (2 weeks of topical triamcinolone 0.1%) and presumed cellulitis (oral doxycycline 100 mg bid/5 d), but neither improved her condition. Concerned for the possibility of cutaneous breast cancer, a punch biopsy was ordered and revealed diffuse dermal angiomatosis (DDA).
DDA is an uncommon proliferation of cutaneous blood vessels causing a reticular blood vessel pattern, as seen in this image. Typically, DDA is associated with tissue hypoxia due to arterial insufficiency from peripheral artery disease. In recent years, there have been numerous case reports of painful ulcerated lesions and reticular blood vessels occurring in women with large, pendulous breasts, increased body mass index, and a history of smoking. One theory suggests that the weight of the breasts causes tissue to stretch, compressing the blood vessels. This, combined with smoking, leads to localized hypoxia and DDA.
Treatments have included oral isotretinoin, calcium channel blockers, aspirin, or pentoxifylline to help circulation. Smoking cessation is recommended, as well as reduction mammoplasty to decrease the stretch on the tissues and relieve the local hypoxia. Although invasive, breast reduction surgery has moved to the forefront of therapy, with reports having shown resolution of the ulcers and pain.1
Two important aspects of clinical medicine are highlighted by this case. First, nonhealing lesions that are not responding to prescribed therapies may require biopsy to rule out malignancy. Second, when there is difficulty making a diagnosis, especially with uncommon diseases, biopsy and input from a pathologist can be extremely helpful.
In this case, the patient was referred to Plastic Surgery and scheduled for reduction mammoplasty. The patient was advised to stop smoking for at least 4 weeks prior to the surgery to possibly improve her condition and reduce the likelihood of postoperative complications.
Photo courtesy of Michael Louie, MD, and text courtesy of Michael Louie, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque
Galambos J, Meuli-Simmen C, Schmid R, et al. Diffuse dermal angiomatosis of the breast: a distinct entity in the spectrum of cutaneous reactive angiomatoses—clinicopathologic study of two cases and comprehensive review of the literature. Case Rep Dermatol 2017;9:194-205. https://doi.org/10.1159/000480721
Galambos J, Meuli-Simmen C, Schmid R, et al. Diffuse dermal angiomatosis of the breast: a distinct entity in the spectrum of cutaneous reactive angiomatoses—clinicopathologic study of two cases and comprehensive review of the literature. Case Rep Dermatol 2017;9:194-205. https://doi.org/10.1159/000480721