Infectious Diseases

This centennial year update focuses primarily on immunization, but also reviews epidemiology, transmission, and treatment.

EPIDEMIOLOGY

2017–2018 was a bad season

The 2017–2018 influenza epidemic was memorable, dominated by influenza A(H3N2) viruses with morbidity and mortality rates approaching pandemic numbers. It lasted 19 weeks, killed more people than any other epidemic since 2010, particularly children, and was associated with 30,453 hospitalizations—almost twice the previous season high in some parts of the United States.²

Regrettably, 171 unvaccinated children died during 2017–2018, accounting for almost 80% of deaths.² The mean age of the children who died was 7.1 years; 51% had at least 1 underlying medical condition placing them at risk for influenza-related complications, and 57% died after hospitalization.²

Recent estimates of the incidence of symptomatic influenza among all ages ranged from 3% to 11%, which is slightly lower than historical estimates. The rates were higher for children under age 18 than for adults.³ Interestingly, influenza A(H3N2) accounted for 50% of cases of non-mumps viral parotitis during the 2014–2015 influenza season in the United States.⁴

Influenza C exists but is rare

Influenza A and B account for almost all influenza-related outpatient visits and hospitalizations. Surveillance data from May 2013 through December 2016 showed that influenza C accounts for 0.5% of influenza-related outpatient visits and hospitalizations, particularly affecting children ages 6 to 24 months. Medical comorbidities and copathogens were seen in all patients requiring intensive care and in most hospitalizations.⁵ Diagnostic tests for influenza C are not widely available.

Dogs and cats: Factories for new flu strains?

While pigs and birds are the major reservoirs of influenza viral genetic diversity from which infection is transmitted to humans, dogs and cats have recently emerged as possible sources of novel reassortant influenza A.⁶ With their frequent close contact with humans, our pets may prove to pose a significant threat.

Obesity a risk factor for influenza

Obesity emerged as a risk factor for severe influenza in the 2009 pandemic. Recent data also showed that obesity increases the duration of influenza A virus shedding, thus increasing duration of contagiousness.⁷

Influenza a cardiovascular risk factor

Previous data showed that influenza was a risk factor for cardiovascular events. Two recent epi­demiologic studies from the United Kingdom showed that laboratory-confirmed influenza was associated with higher rates of myocardial infarction and stroke for up to 4 weeks.^8,9

Which strain is the biggest threat?

Predicting which emerging influenza serotype may cause the next pandemic is difficult, but influenza A(H7N9), which had not infected humans until 2013 but has since infected about 1,600 people in China and killed 37% of them, appears to have the greatest potential.¹⁰

National influenza surveillance programs and influenza-related social media applications have been developed and may get a boost from technology. A smartphone equipped with a temperature sensor can instantly detect one’s temperature with great precision. A 2018 study suggested that a smartphone-driven thermometry application correlated well with national influenza-like illness activity and improved its forecast in real time and up to 3 weeks in advance.¹¹

TRANSMISSION

Humidity may not block transmission

Animal studies have suggested that humidity in the air interferes with transmission of airborne influenza virus, partially from biologic inactivation. But when a recent study used humidity-controlled chambers to investigate the stability of the 2009 influenza A(H1N1) virus in suspended aerosols and stationary droplets, the virus remained infectious in aerosols across a wide range of relative humidities, challenging the common belief that humidity destabilizes respiratory viruses in aerosols.¹²

One sick passenger may not infect the whole plane

Transmission of respiratory viruses on airplane flights has long been considered a potential avenue for spreading influenza. However, a recent study that monitored movements of individuals on 10 transcontinental US flights and simulated inflight transmission based on these data showed a low probability of direct transmission, except for passengers seated in close proximity to an infectious passenger.¹³

WHAT’S IN THE NEW FLU SHOT?

The 2018–2019 quadrivalent vaccine for the Northern Hemisphere¹⁴ contains the following strains:

• A/Michigan/45/2015 A(H1N1)pdm09-like virus
• A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus
• B/Colorado/06/2017-like virus (Victoria lineage)
• B/Phuket/3073/2013-like virus (Yamagata lineage).

The A(H3N2) (Singapore) and B/Victoria lineage components are new this year. The A(H3N2) strain was the main cause of the 2018 influenza epidemic in the Southern Hemisphere.

The quadrivalent live-attenuated vaccine, which was not recommended during the 2016–2017 and 2017–2018 influenza seasons, has made a comeback and is recommended for the 2018–2019 season in people for whom it is appropriate based on age and comorbidities.¹⁵ Although it was effective against influenza B and A(H3N2) viruses, it was less effective against the influenza A(H1N1)pdm09-like viruses during the 2013–2014 and 2015–2016 seasons.

A/Slovenia/2903/2015, the new A(H1N1)pdm09-like virus included in the 2018–2019 quadrivalent live-attenuated vaccine, is significantly more immunogenic than its predecessor, A/Bolivia/559/2013, but its clinical effectiveness remains to be seen.

How effective is it?

Influenza vaccine effectiveness in the 2017–2018 influenza season was 36% overall, 67% against A(H1N1), 42% against influenza B, and 25% against A(H3N2).¹⁶ It is estimated that influenza vaccine prevents 300 to 4,000 deaths annually in the United States alone.¹⁷

A 2018 Cochrane review¹⁷ concluded that vaccination reduced the incidence of influenza by about half, with 2.3% of the population contracting the flu without vaccination compared with 0.9% with vaccination (risk ratio 0.41, 95% confidence interval 0.36–0.47). The same review found that 71 healthy adults need to be vaccinated to prevent 1 from experiencing influenza, and 29 to prevent 1 influenza-like illness.

Several recent studies showed that influenza vaccine effectiveness varied based on age and influenza serotype, with higher effectiveness in people ages 5 to 17 and ages 18 to 64 than in those age 65 and older.^18–20 A mathematical model of influenza transmission and vaccination in the United States determined that even relatively low-efficacy influenza vaccines can be very useful if optimally distributed across age groups.²¹

Vaccination rates are low, and ‘antivaxxers’ are on the rise

Although the influenza vaccine is recommended in the United States for all people age 6 months and older regardless of the state of their health, vaccination rates remain low. In 2016, only 37% of employed adults were vaccinated. The highest rate was for government employees (45%), followed by private employees (36%), followed by the self-employed (30%).²²

A national goal is to immunize 80% of all Americans and 90% of at-risk populations (which include children and the elderly).²³ The number of US hospitals that require their employees to be vaccinated increased from 37.1% in 2013 to 61.4% in 2017.²⁴ Regrettably, as of March 2018, 14 lawsuits addressing religious objections to hospital influenza vaccination mandates have been filed.²⁵

Despite hundreds of studies demonstrating the efficacy, safety, and cost savings of influenza vaccination, the antivaccine movement has been growing in the United States and worldwide.²⁶ All US states except West Virginia, Mississippi, and California allow nonmedical exemptions from vaccination based on religious or personal belief.²⁷ Several US metropolitan areas represent “hot spots” for these exemptions.²⁸ This may render such areas vulnerable to vaccine-preventable diseases, including influenza.

Herd immunity: We’re all in this together

Some argue that the potential adverse effects and the cost of vaccination outweigh the benefits, but the protective benefits of herd immunity are significant for those with comorbidities or compromised immunity.

Educating the public about herd immunity and local influenza vaccination uptake increases people’s willingness to be vaccinated.²⁹ A key educational point is that at least 70% of a community needs to be vaccinated to prevent community outbreaks; this protects everyone, including those who do not mount a protective antibody response to influenza vaccination and those who are not vaccinated.

DOES ANNUAL VACCINATION BLUNT ITS EFFECTIVENESS?

Some studies from the 1970s and 1980s raised concern over a possible negative effect of annual influenza vaccination on vaccine effectiveness. The “antigenic distance hypothesis” holds that vaccine effectiveness is influenced by antigenic similarity between the previous season’s vaccine serotypes and the epidemic serotypes, as well as the antigenic similarity between the serotypes of the current and previous seasons.

A meta-analysis of studies from 2010 through 2015 showed significant inconsistencies in repeat vaccination effects within and between seasons and serotypes. It also showed that vaccine effectiveness may be influenced by more than 1 previous season, particularly for influenza A(H3N2), in which repeated vaccination can blunt the hemagglutinin antibody response.³⁰

A study from Japan showed that people who needed medical attention for influenza in the previous season were at lower risk of a similar event in the current season.³¹ Prior-season influenza vaccination reduced current-season vaccine effectiveness only in those who did not have medically attended influenza in the prior season. This suggests that infection is more immunogenic than vaccination, but only against the serotype causing the infection and not the other serotypes included in the vaccine.

An Australian study showed that annual influenza vaccination did not decrease vaccine effectiveness against influenza-associated hospitalization. Rather, effectiveness increased by about 15% in those vaccinated in both current and previous seasons compared with those vaccinated in either season alone.³²

European investigators showed that repeated seasonal influenza vaccination in the elderly prevented the need for hospitalization due to influenza A(H3N2) and B, but not A(H1N1)pdm09.³³

High-dose vaccine for older adults

The high-dose influenza vaccine has been licensed since 2009 for use in the United States for people ages 65 and older.

Recent studies confirmed that high-dose vaccine is more effective than standard-dose vaccine in veterans³⁴ and US Medicare beneficiaries.³⁵

The high-dose vaccine is rapidly becoming the primary vaccine given to people ages 65 and older in retail pharmacies, where vaccination begins earlier in the season than in providers’ offices.³⁶ Some studies have shown that the standard-dose vaccine wanes in effectiveness toward the end of the influenza season (particularly if the season is long) if it is given very early. It remains to be seen whether the same applies to the high-dose influenza vaccine.

Some advocate twice-annual influenza vaccination, particularly for older adults living in tropical and subtropical areas, where influenza seasons are more prolonged. However, a recently published study observed reductions in influenza-specific hemagglutination inhibition and cell-mediated immunity after twice-annual vaccination.³⁷

Vaccination is beneficial during pregnancy

Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants.

One recently published study showed that 18% of infants who developed influenza required hospitalization.³⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively.

Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.³⁹

Some studies have shown that influenza virus infection can increase susceptibility to certain bacterial infections. A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.⁴⁰

Factors that make vaccination less effective

Several factors including age-related frailty and iatrogenic and disease-related immunosuppression can affect vaccine effectiveness.

Frailty. A recent study showed that vaccine effectiveness was 77.6% in nonfrail older adults but only 58.7% in frail older adults.⁴¹

Immunosuppression. Temporary discontinuation of methotrexate for 2 weeks after influenza vaccination in patients with rheumatoid arthritis improves vaccine immunogenicity without precipitating disease flare.⁴² Solid-organ and hematopoietic stem cell transplant recipients who received influenza vaccine were less likely to develop pneumonia and require intensive care unit admission.⁴³

The high-dose influenza vaccine is more immunogenic than the standard-dose vaccine in solid-organ transplant recipients.⁴⁴

Statins are widely prescribed and have recently been associated with reduced influenza vaccine effectiveness against medically attended acute respiratory illness, but their benefits in preventing cardiovascular events outweigh this risk.⁴⁵

FUTURE VACCINE CONSIDERATIONS

Moving away from eggs

During the annual egg-based production process, which takes several months, the influenza vaccine acquires antigenic changes that allow replication in eggs, particularly in the hemagglutinin protein, which mediates receptor binding. This process of egg adaptation may cause antigenic changes that decrease vaccine effectiveness against circulating viruses.

The cell-based baculovirus influenza vaccine grown in dog kidney cells has higher antigenic content and is not subject to the limitations of egg-based vaccine, although it still requires annual updates. A recombinant influenza vaccine reduces the probability of influenza-like illness by 30% compared with the egg-based influenza vaccine, but also still requires annual updates.⁴⁶ The market share of these non-egg-based vaccines is small, and thus their effectiveness has yet to be demonstrated.

The US Department of Defense administered the cell-based influenza vaccine to about one-third of Armed Forces personnel, their families, and retirees in the 2017–2018 influenza seasons, and data on its effectiveness are expected in the near future.⁴⁷

A universal vaccine would be ideal

The quest continues for a universal influenza vaccine, one that remains protective for several years and does not require annual updates.⁴⁸ Such a vaccine would protect against seasonal epidemic influenza drift variants and pandemic strains. More people could likely be persuaded to be vaccinated once rather than every year.

David Schumick, medical illustrator; adapted from reference 49; illustration of the influenza hemagglutinin created in part with data from reference 50.

An ideal universal vaccine would be suitable for all age groups, at least 75% effective against symptomatic influenza virus infection, protective against all influenza A viruses (influenza A, not B, causes pandemics and seasonal epidemics), and durable through multiple influenza seasons.⁵¹

Research and production of such a vaccine are expected to require funding of about $1 billion over the next 5 years.

Boosting effectiveness

Estimates of influenza vaccine effectiveness range from 40% to 60% in years when the vaccine viruses closely match the circulating viruses, and variably lower when they do not match. The efficacy of most other vaccines given to prevent other infections is much higher.

New technologies to improve influenza vaccine effectiveness are needed, particularly for influenza A(H3N2) viruses, which are rapidly evolving and are highly susceptible to egg-adaptive mutations in the manufacturing process.

In one study, a nanoparticle vaccine formulated with a saponin-based adjuvant induced hemagglutination inhibition responses that were even greater than those induced by the high-dose vaccine.⁵²

Immunoglobulin A (IgA) may be a more effective vaccine target than traditional influenza vaccines that target IgG, since different parts of IgA may engage the influenza virus simultaneously.⁵³

Vaccines can be developed more quickly than in the past. The timeline from viral sequencing to human studies with deoxyribonucleic acid plasmid vaccines decreased from 20 months in 2003 for the severe acquired respiratory syndrome coronavirus to 11 months in 2006 for influenza A/Indonesia/2006 (H5), to 4 months in 2009 for influenza A/California/2009 (H1), to 3.5 months in 2016 for Zika virus.⁵⁴ This is because it is possible today to sequence a virus and insert the genetic material into a vaccine platform without ever having to grow the virus.

Numerous studies have found anti-influenza medications to be effective. Nevertheless, in an analysis of the 2011–2016 influenza seasons, only 15% of high-risk patients were prescribed anti-influenza medications within 2 days of symptom onset, including 37% in those with laboratory-confirmed influenza.⁵⁵ Fever was associated with an increased rate of antiviral treatment, but 25% of high-risk outpatients were afebrile. Empiric treatment of 4 high-risk outpatients with acute respiratory illness was needed to treat 1 patient with influenza.⁵⁵

Treatment with a neuraminidase inhibitor within 2 days of illness has recently been shown to improve survival and shorten duration of viral shedding in patients with avian influenza A(H7N9) infection.⁵⁶ Antiviral treatment within 2 days of illness is associated with improved outcomes in transplant recipients⁵⁷ and with a lower risk of otitis media in children.⁵⁸

Appropriate anti-influenza treatment is as important as avoiding unnecessary antibiotics. Regrettably, as many as one-third of patients with laboratory-confirmed influenza are prescribed antibiotics.⁵⁹

The US Food and Drug Administration warns against fraudulent unapproved over-the-counter influenza products.⁶⁰

Baloxavir marboxil

Baloxavir marboxil is a new anti-influenza medication approved in Japan in February 2018 and anticipated to be available in the United States sometime in 2019.

This prodrug is hydrolyzed in vivo to the active metabolite, which selectively inhibits cap-dependent endonuclease enzyme, a key enzyme in initiation of messenger ribonucleic acid synthesis required for influenza viral replication.⁶¹

In a double-blind phase 3 trial, the median time to alleviation of influenza symptoms is 26.5 hours shorter with baloxavir marboxil than with placebo. One tablet was as effective as 5 days of the neuraminidase inhibitor oseltamivir and was associated with greater reduction in viral load 1 day after initiation, and similar side effects.⁶² Of concern is the emergence of nucleic acid substitutions conferring resistance to baloxavir; this occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 and 3 trials, respectively.

CLOSING THE GAPS

Several gaps in the management of influenza persist since the 1918 pandemic.¹ These include gaps in epidemiology, prevention, diagnosis, treatment, and prognosis.

• Global networks wider than current ones are needed to address this global disease and to prioritize coordination efforts.
• Establishing and strengthening clinical capacity is needed in limited resource settings. New technologies are needed to expedite vaccine development and to achieve progress toward a universal vaccine.
• Current diagnostic tests do not distinguish between seasonal and novel influenza A viruses of zoonotic origin, which are expected to cause the next pandemic.
• Current antivirals have been shown to shorten duration of illness in outpatients with uncomplicated influenza, but the benefit in hospitalized patients has been less well established.
• In 2007, resistance of seasonal influenza A(H1N1) to oseltamivir became widespread. In 2009, pandemic influenza A(H1N1), which is highly susceptible to oseltamivir, replaced the seasonal virus and remains the predominantly circulating A(H1N1) strain.
• A small-molecule fragment, N-cyclohexyaltaurine, binds to the conserved hemagglutinin receptor-binding site in a manner that mimics the binding mode of the natural receptor sialic acid. This can serve as a template to guide the development of novel broad-spectrum small-molecule anti-influenza drugs.⁶³
• Biomarkers that can accurately predict development of severe disease in patients with influenza are needed.

This centennial year update focuses primarily on immunization, but also reviews epidemiology, transmission, and treatment.

EPIDEMIOLOGY

2017–2018 was a bad season

The 2017–2018 influenza epidemic was memorable, dominated by influenza A(H3N2) viruses with morbidity and mortality rates approaching pandemic numbers. It lasted 19 weeks, killed more people than any other epidemic since 2010, particularly children, and was associated with 30,453 hospitalizations—almost twice the previous season high in some parts of the United States.²

Regrettably, 171 unvaccinated children died during 2017–2018, accounting for almost 80% of deaths.² The mean age of the children who died was 7.1 years; 51% had at least 1 underlying medical condition placing them at risk for influenza-related complications, and 57% died after hospitalization.²

Recent estimates of the incidence of symptomatic influenza among all ages ranged from 3% to 11%, which is slightly lower than historical estimates. The rates were higher for children under age 18 than for adults.³ Interestingly, influenza A(H3N2) accounted for 50% of cases of non-mumps viral parotitis during the 2014–2015 influenza season in the United States.⁴

Influenza C exists but is rare

Influenza A and B account for almost all influenza-related outpatient visits and hospitalizations. Surveillance data from May 2013 through December 2016 showed that influenza C accounts for 0.5% of influenza-related outpatient visits and hospitalizations, particularly affecting children ages 6 to 24 months. Medical comorbidities and copathogens were seen in all patients requiring intensive care and in most hospitalizations.⁵ Diagnostic tests for influenza C are not widely available.

Dogs and cats: Factories for new flu strains?

While pigs and birds are the major reservoirs of influenza viral genetic diversity from which infection is transmitted to humans, dogs and cats have recently emerged as possible sources of novel reassortant influenza A.⁶ With their frequent close contact with humans, our pets may prove to pose a significant threat.

Obesity a risk factor for influenza

Obesity emerged as a risk factor for severe influenza in the 2009 pandemic. Recent data also showed that obesity increases the duration of influenza A virus shedding, thus increasing duration of contagiousness.⁷

Influenza a cardiovascular risk factor

Previous data showed that influenza was a risk factor for cardiovascular events. Two recent epi­demiologic studies from the United Kingdom showed that laboratory-confirmed influenza was associated with higher rates of myocardial infarction and stroke for up to 4 weeks.^8,9

Which strain is the biggest threat?

Predicting which emerging influenza serotype may cause the next pandemic is difficult, but influenza A(H7N9), which had not infected humans until 2013 but has since infected about 1,600 people in China and killed 37% of them, appears to have the greatest potential.¹⁰

National influenza surveillance programs and influenza-related social media applications have been developed and may get a boost from technology. A smartphone equipped with a temperature sensor can instantly detect one’s temperature with great precision. A 2018 study suggested that a smartphone-driven thermometry application correlated well with national influenza-like illness activity and improved its forecast in real time and up to 3 weeks in advance.¹¹

TRANSMISSION

Humidity may not block transmission

Animal studies have suggested that humidity in the air interferes with transmission of airborne influenza virus, partially from biologic inactivation. But when a recent study used humidity-controlled chambers to investigate the stability of the 2009 influenza A(H1N1) virus in suspended aerosols and stationary droplets, the virus remained infectious in aerosols across a wide range of relative humidities, challenging the common belief that humidity destabilizes respiratory viruses in aerosols.¹²

One sick passenger may not infect the whole plane

Transmission of respiratory viruses on airplane flights has long been considered a potential avenue for spreading influenza. However, a recent study that monitored movements of individuals on 10 transcontinental US flights and simulated inflight transmission based on these data showed a low probability of direct transmission, except for passengers seated in close proximity to an infectious passenger.¹³

WHAT’S IN THE NEW FLU SHOT?

The 2018–2019 quadrivalent vaccine for the Northern Hemisphere¹⁴ contains the following strains:

• A/Michigan/45/2015 A(H1N1)pdm09-like virus
• A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus
• B/Colorado/06/2017-like virus (Victoria lineage)
• B/Phuket/3073/2013-like virus (Yamagata lineage).

The A(H3N2) (Singapore) and B/Victoria lineage components are new this year. The A(H3N2) strain was the main cause of the 2018 influenza epidemic in the Southern Hemisphere.

The quadrivalent live-attenuated vaccine, which was not recommended during the 2016–2017 and 2017–2018 influenza seasons, has made a comeback and is recommended for the 2018–2019 season in people for whom it is appropriate based on age and comorbidities.¹⁵ Although it was effective against influenza B and A(H3N2) viruses, it was less effective against the influenza A(H1N1)pdm09-like viruses during the 2013–2014 and 2015–2016 seasons.

A/Slovenia/2903/2015, the new A(H1N1)pdm09-like virus included in the 2018–2019 quadrivalent live-attenuated vaccine, is significantly more immunogenic than its predecessor, A/Bolivia/559/2013, but its clinical effectiveness remains to be seen.

How effective is it?

Influenza vaccine effectiveness in the 2017–2018 influenza season was 36% overall, 67% against A(H1N1), 42% against influenza B, and 25% against A(H3N2).¹⁶ It is estimated that influenza vaccine prevents 300 to 4,000 deaths annually in the United States alone.¹⁷

A 2018 Cochrane review¹⁷ concluded that vaccination reduced the incidence of influenza by about half, with 2.3% of the population contracting the flu without vaccination compared with 0.9% with vaccination (risk ratio 0.41, 95% confidence interval 0.36–0.47). The same review found that 71 healthy adults need to be vaccinated to prevent 1 from experiencing influenza, and 29 to prevent 1 influenza-like illness.

Several recent studies showed that influenza vaccine effectiveness varied based on age and influenza serotype, with higher effectiveness in people ages 5 to 17 and ages 18 to 64 than in those age 65 and older.^18–20 A mathematical model of influenza transmission and vaccination in the United States determined that even relatively low-efficacy influenza vaccines can be very useful if optimally distributed across age groups.²¹

Vaccination rates are low, and ‘antivaxxers’ are on the rise

Although the influenza vaccine is recommended in the United States for all people age 6 months and older regardless of the state of their health, vaccination rates remain low. In 2016, only 37% of employed adults were vaccinated. The highest rate was for government employees (45%), followed by private employees (36%), followed by the self-employed (30%).²²

A national goal is to immunize 80% of all Americans and 90% of at-risk populations (which include children and the elderly).²³ The number of US hospitals that require their employees to be vaccinated increased from 37.1% in 2013 to 61.4% in 2017.²⁴ Regrettably, as of March 2018, 14 lawsuits addressing religious objections to hospital influenza vaccination mandates have been filed.²⁵

Despite hundreds of studies demonstrating the efficacy, safety, and cost savings of influenza vaccination, the antivaccine movement has been growing in the United States and worldwide.²⁶ All US states except West Virginia, Mississippi, and California allow nonmedical exemptions from vaccination based on religious or personal belief.²⁷ Several US metropolitan areas represent “hot spots” for these exemptions.²⁸ This may render such areas vulnerable to vaccine-preventable diseases, including influenza.

Herd immunity: We’re all in this together

Some argue that the potential adverse effects and the cost of vaccination outweigh the benefits, but the protective benefits of herd immunity are significant for those with comorbidities or compromised immunity.

Educating the public about herd immunity and local influenza vaccination uptake increases people’s willingness to be vaccinated.²⁹ A key educational point is that at least 70% of a community needs to be vaccinated to prevent community outbreaks; this protects everyone, including those who do not mount a protective antibody response to influenza vaccination and those who are not vaccinated.

DOES ANNUAL VACCINATION BLUNT ITS EFFECTIVENESS?

Some studies from the 1970s and 1980s raised concern over a possible negative effect of annual influenza vaccination on vaccine effectiveness. The “antigenic distance hypothesis” holds that vaccine effectiveness is influenced by antigenic similarity between the previous season’s vaccine serotypes and the epidemic serotypes, as well as the antigenic similarity between the serotypes of the current and previous seasons.

A meta-analysis of studies from 2010 through 2015 showed significant inconsistencies in repeat vaccination effects within and between seasons and serotypes. It also showed that vaccine effectiveness may be influenced by more than 1 previous season, particularly for influenza A(H3N2), in which repeated vaccination can blunt the hemagglutinin antibody response.³⁰

A study from Japan showed that people who needed medical attention for influenza in the previous season were at lower risk of a similar event in the current season.³¹ Prior-season influenza vaccination reduced current-season vaccine effectiveness only in those who did not have medically attended influenza in the prior season. This suggests that infection is more immunogenic than vaccination, but only against the serotype causing the infection and not the other serotypes included in the vaccine.

An Australian study showed that annual influenza vaccination did not decrease vaccine effectiveness against influenza-associated hospitalization. Rather, effectiveness increased by about 15% in those vaccinated in both current and previous seasons compared with those vaccinated in either season alone.³²

European investigators showed that repeated seasonal influenza vaccination in the elderly prevented the need for hospitalization due to influenza A(H3N2) and B, but not A(H1N1)pdm09.³³

High-dose vaccine for older adults

The high-dose influenza vaccine has been licensed since 2009 for use in the United States for people ages 65 and older.

Recent studies confirmed that high-dose vaccine is more effective than standard-dose vaccine in veterans³⁴ and US Medicare beneficiaries.³⁵

The high-dose vaccine is rapidly becoming the primary vaccine given to people ages 65 and older in retail pharmacies, where vaccination begins earlier in the season than in providers’ offices.³⁶ Some studies have shown that the standard-dose vaccine wanes in effectiveness toward the end of the influenza season (particularly if the season is long) if it is given very early. It remains to be seen whether the same applies to the high-dose influenza vaccine.

Some advocate twice-annual influenza vaccination, particularly for older adults living in tropical and subtropical areas, where influenza seasons are more prolonged. However, a recently published study observed reductions in influenza-specific hemagglutination inhibition and cell-mediated immunity after twice-annual vaccination.³⁷

Vaccination is beneficial during pregnancy

Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants.

One recently published study showed that 18% of infants who developed influenza required hospitalization.³⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively.

Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.³⁹

Some studies have shown that influenza virus infection can increase susceptibility to certain bacterial infections. A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.⁴⁰

Factors that make vaccination less effective

Several factors including age-related frailty and iatrogenic and disease-related immunosuppression can affect vaccine effectiveness.

Frailty. A recent study showed that vaccine effectiveness was 77.6% in nonfrail older adults but only 58.7% in frail older adults.⁴¹

Immunosuppression. Temporary discontinuation of methotrexate for 2 weeks after influenza vaccination in patients with rheumatoid arthritis improves vaccine immunogenicity without precipitating disease flare.⁴² Solid-organ and hematopoietic stem cell transplant recipients who received influenza vaccine were less likely to develop pneumonia and require intensive care unit admission.⁴³

The high-dose influenza vaccine is more immunogenic than the standard-dose vaccine in solid-organ transplant recipients.⁴⁴

Statins are widely prescribed and have recently been associated with reduced influenza vaccine effectiveness against medically attended acute respiratory illness, but their benefits in preventing cardiovascular events outweigh this risk.⁴⁵

FUTURE VACCINE CONSIDERATIONS

Moving away from eggs

During the annual egg-based production process, which takes several months, the influenza vaccine acquires antigenic changes that allow replication in eggs, particularly in the hemagglutinin protein, which mediates receptor binding. This process of egg adaptation may cause antigenic changes that decrease vaccine effectiveness against circulating viruses.

The cell-based baculovirus influenza vaccine grown in dog kidney cells has higher antigenic content and is not subject to the limitations of egg-based vaccine, although it still requires annual updates. A recombinant influenza vaccine reduces the probability of influenza-like illness by 30% compared with the egg-based influenza vaccine, but also still requires annual updates.⁴⁶ The market share of these non-egg-based vaccines is small, and thus their effectiveness has yet to be demonstrated.

The US Department of Defense administered the cell-based influenza vaccine to about one-third of Armed Forces personnel, their families, and retirees in the 2017–2018 influenza seasons, and data on its effectiveness are expected in the near future.⁴⁷

A universal vaccine would be ideal

The quest continues for a universal influenza vaccine, one that remains protective for several years and does not require annual updates.⁴⁸ Such a vaccine would protect against seasonal epidemic influenza drift variants and pandemic strains. More people could likely be persuaded to be vaccinated once rather than every year.

David Schumick, medical illustrator; adapted from reference 49; illustration of the influenza hemagglutinin created in part with data from reference 50.

An ideal universal vaccine would be suitable for all age groups, at least 75% effective against symptomatic influenza virus infection, protective against all influenza A viruses (influenza A, not B, causes pandemics and seasonal epidemics), and durable through multiple influenza seasons.⁵¹

Research and production of such a vaccine are expected to require funding of about $1 billion over the next 5 years.

Boosting effectiveness

Estimates of influenza vaccine effectiveness range from 40% to 60% in years when the vaccine viruses closely match the circulating viruses, and variably lower when they do not match. The efficacy of most other vaccines given to prevent other infections is much higher.

New technologies to improve influenza vaccine effectiveness are needed, particularly for influenza A(H3N2) viruses, which are rapidly evolving and are highly susceptible to egg-adaptive mutations in the manufacturing process.

In one study, a nanoparticle vaccine formulated with a saponin-based adjuvant induced hemagglutination inhibition responses that were even greater than those induced by the high-dose vaccine.⁵²

Immunoglobulin A (IgA) may be a more effective vaccine target than traditional influenza vaccines that target IgG, since different parts of IgA may engage the influenza virus simultaneously.⁵³

Vaccines can be developed more quickly than in the past. The timeline from viral sequencing to human studies with deoxyribonucleic acid plasmid vaccines decreased from 20 months in 2003 for the severe acquired respiratory syndrome coronavirus to 11 months in 2006 for influenza A/Indonesia/2006 (H5), to 4 months in 2009 for influenza A/California/2009 (H1), to 3.5 months in 2016 for Zika virus.⁵⁴ This is because it is possible today to sequence a virus and insert the genetic material into a vaccine platform without ever having to grow the virus.

Numerous studies have found anti-influenza medications to be effective. Nevertheless, in an analysis of the 2011–2016 influenza seasons, only 15% of high-risk patients were prescribed anti-influenza medications within 2 days of symptom onset, including 37% in those with laboratory-confirmed influenza.⁵⁵ Fever was associated with an increased rate of antiviral treatment, but 25% of high-risk outpatients were afebrile. Empiric treatment of 4 high-risk outpatients with acute respiratory illness was needed to treat 1 patient with influenza.⁵⁵

Treatment with a neuraminidase inhibitor within 2 days of illness has recently been shown to improve survival and shorten duration of viral shedding in patients with avian influenza A(H7N9) infection.⁵⁶ Antiviral treatment within 2 days of illness is associated with improved outcomes in transplant recipients⁵⁷ and with a lower risk of otitis media in children.⁵⁸

Appropriate anti-influenza treatment is as important as avoiding unnecessary antibiotics. Regrettably, as many as one-third of patients with laboratory-confirmed influenza are prescribed antibiotics.⁵⁹

The US Food and Drug Administration warns against fraudulent unapproved over-the-counter influenza products.⁶⁰

Baloxavir marboxil

Baloxavir marboxil is a new anti-influenza medication approved in Japan in February 2018 and anticipated to be available in the United States sometime in 2019.

This prodrug is hydrolyzed in vivo to the active metabolite, which selectively inhibits cap-dependent endonuclease enzyme, a key enzyme in initiation of messenger ribonucleic acid synthesis required for influenza viral replication.⁶¹

In a double-blind phase 3 trial, the median time to alleviation of influenza symptoms is 26.5 hours shorter with baloxavir marboxil than with placebo. One tablet was as effective as 5 days of the neuraminidase inhibitor oseltamivir and was associated with greater reduction in viral load 1 day after initiation, and similar side effects.⁶² Of concern is the emergence of nucleic acid substitutions conferring resistance to baloxavir; this occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 and 3 trials, respectively.

CLOSING THE GAPS

Several gaps in the management of influenza persist since the 1918 pandemic.¹ These include gaps in epidemiology, prevention, diagnosis, treatment, and prognosis.

• Global networks wider than current ones are needed to address this global disease and to prioritize coordination efforts.
• Establishing and strengthening clinical capacity is needed in limited resource settings. New technologies are needed to expedite vaccine development and to achieve progress toward a universal vaccine.
• Current diagnostic tests do not distinguish between seasonal and novel influenza A viruses of zoonotic origin, which are expected to cause the next pandemic.
• Current antivirals have been shown to shorten duration of illness in outpatients with uncomplicated influenza, but the benefit in hospitalized patients has been less well established.
• In 2007, resistance of seasonal influenza A(H1N1) to oseltamivir became widespread. In 2009, pandemic influenza A(H1N1), which is highly susceptible to oseltamivir, replaced the seasonal virus and remains the predominantly circulating A(H1N1) strain.
• A small-molecule fragment, N-cyclohexyaltaurine, binds to the conserved hemagglutinin receptor-binding site in a manner that mimics the binding mode of the natural receptor sialic acid. This can serve as a template to guide the development of novel broad-spectrum small-molecule anti-influenza drugs.⁶³
• Biomarkers that can accurately predict development of severe disease in patients with influenza are needed.

This centennial year update focuses primarily on immunization, but also reviews epidemiology, transmission, and treatment.

EPIDEMIOLOGY

2017–2018 was a bad season

The 2017–2018 influenza epidemic was memorable, dominated by influenza A(H3N2) viruses with morbidity and mortality rates approaching pandemic numbers. It lasted 19 weeks, killed more people than any other epidemic since 2010, particularly children, and was associated with 30,453 hospitalizations—almost twice the previous season high in some parts of the United States.²

Regrettably, 171 unvaccinated children died during 2017–2018, accounting for almost 80% of deaths.² The mean age of the children who died was 7.1 years; 51% had at least 1 underlying medical condition placing them at risk for influenza-related complications, and 57% died after hospitalization.²

Recent estimates of the incidence of symptomatic influenza among all ages ranged from 3% to 11%, which is slightly lower than historical estimates. The rates were higher for children under age 18 than for adults.³ Interestingly, influenza A(H3N2) accounted for 50% of cases of non-mumps viral parotitis during the 2014–2015 influenza season in the United States.⁴

Influenza C exists but is rare

Influenza A and B account for almost all influenza-related outpatient visits and hospitalizations. Surveillance data from May 2013 through December 2016 showed that influenza C accounts for 0.5% of influenza-related outpatient visits and hospitalizations, particularly affecting children ages 6 to 24 months. Medical comorbidities and copathogens were seen in all patients requiring intensive care and in most hospitalizations.⁵ Diagnostic tests for influenza C are not widely available.

Dogs and cats: Factories for new flu strains?

While pigs and birds are the major reservoirs of influenza viral genetic diversity from which infection is transmitted to humans, dogs and cats have recently emerged as possible sources of novel reassortant influenza A.⁶ With their frequent close contact with humans, our pets may prove to pose a significant threat.

Obesity a risk factor for influenza

Obesity emerged as a risk factor for severe influenza in the 2009 pandemic. Recent data also showed that obesity increases the duration of influenza A virus shedding, thus increasing duration of contagiousness.⁷

Influenza a cardiovascular risk factor

Previous data showed that influenza was a risk factor for cardiovascular events. Two recent epi­demiologic studies from the United Kingdom showed that laboratory-confirmed influenza was associated with higher rates of myocardial infarction and stroke for up to 4 weeks.^8,9

Which strain is the biggest threat?

Predicting which emerging influenza serotype may cause the next pandemic is difficult, but influenza A(H7N9), which had not infected humans until 2013 but has since infected about 1,600 people in China and killed 37% of them, appears to have the greatest potential.¹⁰

National influenza surveillance programs and influenza-related social media applications have been developed and may get a boost from technology. A smartphone equipped with a temperature sensor can instantly detect one’s temperature with great precision. A 2018 study suggested that a smartphone-driven thermometry application correlated well with national influenza-like illness activity and improved its forecast in real time and up to 3 weeks in advance.¹¹

TRANSMISSION

Humidity may not block transmission

Animal studies have suggested that humidity in the air interferes with transmission of airborne influenza virus, partially from biologic inactivation. But when a recent study used humidity-controlled chambers to investigate the stability of the 2009 influenza A(H1N1) virus in suspended aerosols and stationary droplets, the virus remained infectious in aerosols across a wide range of relative humidities, challenging the common belief that humidity destabilizes respiratory viruses in aerosols.¹²

One sick passenger may not infect the whole plane

Transmission of respiratory viruses on airplane flights has long been considered a potential avenue for spreading influenza. However, a recent study that monitored movements of individuals on 10 transcontinental US flights and simulated inflight transmission based on these data showed a low probability of direct transmission, except for passengers seated in close proximity to an infectious passenger.¹³

WHAT’S IN THE NEW FLU SHOT?

The 2018–2019 quadrivalent vaccine for the Northern Hemisphere¹⁴ contains the following strains:

• A/Michigan/45/2015 A(H1N1)pdm09-like virus
• A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus
• B/Colorado/06/2017-like virus (Victoria lineage)
• B/Phuket/3073/2013-like virus (Yamagata lineage).

The A(H3N2) (Singapore) and B/Victoria lineage components are new this year. The A(H3N2) strain was the main cause of the 2018 influenza epidemic in the Southern Hemisphere.

The quadrivalent live-attenuated vaccine, which was not recommended during the 2016–2017 and 2017–2018 influenza seasons, has made a comeback and is recommended for the 2018–2019 season in people for whom it is appropriate based on age and comorbidities.¹⁵ Although it was effective against influenza B and A(H3N2) viruses, it was less effective against the influenza A(H1N1)pdm09-like viruses during the 2013–2014 and 2015–2016 seasons.

A/Slovenia/2903/2015, the new A(H1N1)pdm09-like virus included in the 2018–2019 quadrivalent live-attenuated vaccine, is significantly more immunogenic than its predecessor, A/Bolivia/559/2013, but its clinical effectiveness remains to be seen.

How effective is it?

Influenza vaccine effectiveness in the 2017–2018 influenza season was 36% overall, 67% against A(H1N1), 42% against influenza B, and 25% against A(H3N2).¹⁶ It is estimated that influenza vaccine prevents 300 to 4,000 deaths annually in the United States alone.¹⁷

A 2018 Cochrane review¹⁷ concluded that vaccination reduced the incidence of influenza by about half, with 2.3% of the population contracting the flu without vaccination compared with 0.9% with vaccination (risk ratio 0.41, 95% confidence interval 0.36–0.47). The same review found that 71 healthy adults need to be vaccinated to prevent 1 from experiencing influenza, and 29 to prevent 1 influenza-like illness.

Several recent studies showed that influenza vaccine effectiveness varied based on age and influenza serotype, with higher effectiveness in people ages 5 to 17 and ages 18 to 64 than in those age 65 and older.^18–20 A mathematical model of influenza transmission and vaccination in the United States determined that even relatively low-efficacy influenza vaccines can be very useful if optimally distributed across age groups.²¹

Vaccination rates are low, and ‘antivaxxers’ are on the rise

Although the influenza vaccine is recommended in the United States for all people age 6 months and older regardless of the state of their health, vaccination rates remain low. In 2016, only 37% of employed adults were vaccinated. The highest rate was for government employees (45%), followed by private employees (36%), followed by the self-employed (30%).²²

A national goal is to immunize 80% of all Americans and 90% of at-risk populations (which include children and the elderly).²³ The number of US hospitals that require their employees to be vaccinated increased from 37.1% in 2013 to 61.4% in 2017.²⁴ Regrettably, as of March 2018, 14 lawsuits addressing religious objections to hospital influenza vaccination mandates have been filed.²⁵

Despite hundreds of studies demonstrating the efficacy, safety, and cost savings of influenza vaccination, the antivaccine movement has been growing in the United States and worldwide.²⁶ All US states except West Virginia, Mississippi, and California allow nonmedical exemptions from vaccination based on religious or personal belief.²⁷ Several US metropolitan areas represent “hot spots” for these exemptions.²⁸ This may render such areas vulnerable to vaccine-preventable diseases, including influenza.

Herd immunity: We’re all in this together

Some argue that the potential adverse effects and the cost of vaccination outweigh the benefits, but the protective benefits of herd immunity are significant for those with comorbidities or compromised immunity.

Educating the public about herd immunity and local influenza vaccination uptake increases people’s willingness to be vaccinated.²⁹ A key educational point is that at least 70% of a community needs to be vaccinated to prevent community outbreaks; this protects everyone, including those who do not mount a protective antibody response to influenza vaccination and those who are not vaccinated.

DOES ANNUAL VACCINATION BLUNT ITS EFFECTIVENESS?

Some studies from the 1970s and 1980s raised concern over a possible negative effect of annual influenza vaccination on vaccine effectiveness. The “antigenic distance hypothesis” holds that vaccine effectiveness is influenced by antigenic similarity between the previous season’s vaccine serotypes and the epidemic serotypes, as well as the antigenic similarity between the serotypes of the current and previous seasons.

A meta-analysis of studies from 2010 through 2015 showed significant inconsistencies in repeat vaccination effects within and between seasons and serotypes. It also showed that vaccine effectiveness may be influenced by more than 1 previous season, particularly for influenza A(H3N2), in which repeated vaccination can blunt the hemagglutinin antibody response.³⁰

A study from Japan showed that people who needed medical attention for influenza in the previous season were at lower risk of a similar event in the current season.³¹ Prior-season influenza vaccination reduced current-season vaccine effectiveness only in those who did not have medically attended influenza in the prior season. This suggests that infection is more immunogenic than vaccination, but only against the serotype causing the infection and not the other serotypes included in the vaccine.

An Australian study showed that annual influenza vaccination did not decrease vaccine effectiveness against influenza-associated hospitalization. Rather, effectiveness increased by about 15% in those vaccinated in both current and previous seasons compared with those vaccinated in either season alone.³²

European investigators showed that repeated seasonal influenza vaccination in the elderly prevented the need for hospitalization due to influenza A(H3N2) and B, but not A(H1N1)pdm09.³³

High-dose vaccine for older adults

The high-dose influenza vaccine has been licensed since 2009 for use in the United States for people ages 65 and older.

Recent studies confirmed that high-dose vaccine is more effective than standard-dose vaccine in veterans³⁴ and US Medicare beneficiaries.³⁵

The high-dose vaccine is rapidly becoming the primary vaccine given to people ages 65 and older in retail pharmacies, where vaccination begins earlier in the season than in providers’ offices.³⁶ Some studies have shown that the standard-dose vaccine wanes in effectiveness toward the end of the influenza season (particularly if the season is long) if it is given very early. It remains to be seen whether the same applies to the high-dose influenza vaccine.

Some advocate twice-annual influenza vaccination, particularly for older adults living in tropical and subtropical areas, where influenza seasons are more prolonged. However, a recently published study observed reductions in influenza-specific hemagglutination inhibition and cell-mediated immunity after twice-annual vaccination.³⁷

Vaccination is beneficial during pregnancy

Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants.

One recently published study showed that 18% of infants who developed influenza required hospitalization.³⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively.

Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.³⁹

Some studies have shown that influenza virus infection can increase susceptibility to certain bacterial infections. A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.⁴⁰

Factors that make vaccination less effective

Several factors including age-related frailty and iatrogenic and disease-related immunosuppression can affect vaccine effectiveness.

Frailty. A recent study showed that vaccine effectiveness was 77.6% in nonfrail older adults but only 58.7% in frail older adults.⁴¹

Immunosuppression. Temporary discontinuation of methotrexate for 2 weeks after influenza vaccination in patients with rheumatoid arthritis improves vaccine immunogenicity without precipitating disease flare.⁴² Solid-organ and hematopoietic stem cell transplant recipients who received influenza vaccine were less likely to develop pneumonia and require intensive care unit admission.⁴³

The high-dose influenza vaccine is more immunogenic than the standard-dose vaccine in solid-organ transplant recipients.⁴⁴

Statins are widely prescribed and have recently been associated with reduced influenza vaccine effectiveness against medically attended acute respiratory illness, but their benefits in preventing cardiovascular events outweigh this risk.⁴⁵

FUTURE VACCINE CONSIDERATIONS

Moving away from eggs

During the annual egg-based production process, which takes several months, the influenza vaccine acquires antigenic changes that allow replication in eggs, particularly in the hemagglutinin protein, which mediates receptor binding. This process of egg adaptation may cause antigenic changes that decrease vaccine effectiveness against circulating viruses.

The cell-based baculovirus influenza vaccine grown in dog kidney cells has higher antigenic content and is not subject to the limitations of egg-based vaccine, although it still requires annual updates. A recombinant influenza vaccine reduces the probability of influenza-like illness by 30% compared with the egg-based influenza vaccine, but also still requires annual updates.⁴⁶ The market share of these non-egg-based vaccines is small, and thus their effectiveness has yet to be demonstrated.

The US Department of Defense administered the cell-based influenza vaccine to about one-third of Armed Forces personnel, their families, and retirees in the 2017–2018 influenza seasons, and data on its effectiveness are expected in the near future.⁴⁷

A universal vaccine would be ideal

The quest continues for a universal influenza vaccine, one that remains protective for several years and does not require annual updates.⁴⁸ Such a vaccine would protect against seasonal epidemic influenza drift variants and pandemic strains. More people could likely be persuaded to be vaccinated once rather than every year.

David Schumick, medical illustrator; adapted from reference 49; illustration of the influenza hemagglutinin created in part with data from reference 50.

An ideal universal vaccine would be suitable for all age groups, at least 75% effective against symptomatic influenza virus infection, protective against all influenza A viruses (influenza A, not B, causes pandemics and seasonal epidemics), and durable through multiple influenza seasons.⁵¹

Research and production of such a vaccine are expected to require funding of about $1 billion over the next 5 years.

Boosting effectiveness

Estimates of influenza vaccine effectiveness range from 40% to 60% in years when the vaccine viruses closely match the circulating viruses, and variably lower when they do not match. The efficacy of most other vaccines given to prevent other infections is much higher.

New technologies to improve influenza vaccine effectiveness are needed, particularly for influenza A(H3N2) viruses, which are rapidly evolving and are highly susceptible to egg-adaptive mutations in the manufacturing process.

In one study, a nanoparticle vaccine formulated with a saponin-based adjuvant induced hemagglutination inhibition responses that were even greater than those induced by the high-dose vaccine.⁵²

Immunoglobulin A (IgA) may be a more effective vaccine target than traditional influenza vaccines that target IgG, since different parts of IgA may engage the influenza virus simultaneously.⁵³

Vaccines can be developed more quickly than in the past. The timeline from viral sequencing to human studies with deoxyribonucleic acid plasmid vaccines decreased from 20 months in 2003 for the severe acquired respiratory syndrome coronavirus to 11 months in 2006 for influenza A/Indonesia/2006 (H5), to 4 months in 2009 for influenza A/California/2009 (H1), to 3.5 months in 2016 for Zika virus.⁵⁴ This is because it is possible today to sequence a virus and insert the genetic material into a vaccine platform without ever having to grow the virus.

Numerous studies have found anti-influenza medications to be effective. Nevertheless, in an analysis of the 2011–2016 influenza seasons, only 15% of high-risk patients were prescribed anti-influenza medications within 2 days of symptom onset, including 37% in those with laboratory-confirmed influenza.⁵⁵ Fever was associated with an increased rate of antiviral treatment, but 25% of high-risk outpatients were afebrile. Empiric treatment of 4 high-risk outpatients with acute respiratory illness was needed to treat 1 patient with influenza.⁵⁵

Treatment with a neuraminidase inhibitor within 2 days of illness has recently been shown to improve survival and shorten duration of viral shedding in patients with avian influenza A(H7N9) infection.⁵⁶ Antiviral treatment within 2 days of illness is associated with improved outcomes in transplant recipients⁵⁷ and with a lower risk of otitis media in children.⁵⁸

Appropriate anti-influenza treatment is as important as avoiding unnecessary antibiotics. Regrettably, as many as one-third of patients with laboratory-confirmed influenza are prescribed antibiotics.⁵⁹

The US Food and Drug Administration warns against fraudulent unapproved over-the-counter influenza products.⁶⁰

Baloxavir marboxil

Baloxavir marboxil is a new anti-influenza medication approved in Japan in February 2018 and anticipated to be available in the United States sometime in 2019.

This prodrug is hydrolyzed in vivo to the active metabolite, which selectively inhibits cap-dependent endonuclease enzyme, a key enzyme in initiation of messenger ribonucleic acid synthesis required for influenza viral replication.⁶¹

In a double-blind phase 3 trial, the median time to alleviation of influenza symptoms is 26.5 hours shorter with baloxavir marboxil than with placebo. One tablet was as effective as 5 days of the neuraminidase inhibitor oseltamivir and was associated with greater reduction in viral load 1 day after initiation, and similar side effects.⁶² Of concern is the emergence of nucleic acid substitutions conferring resistance to baloxavir; this occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 and 3 trials, respectively.

CLOSING THE GAPS

Several gaps in the management of influenza persist since the 1918 pandemic.¹ These include gaps in epidemiology, prevention, diagnosis, treatment, and prognosis.

• Global networks wider than current ones are needed to address this global disease and to prioritize coordination efforts.
• Establishing and strengthening clinical capacity is needed in limited resource settings. New technologies are needed to expedite vaccine development and to achieve progress toward a universal vaccine.
• Current diagnostic tests do not distinguish between seasonal and novel influenza A viruses of zoonotic origin, which are expected to cause the next pandemic.
• Current antivirals have been shown to shorten duration of illness in outpatients with uncomplicated influenza, but the benefit in hospitalized patients has been less well established.
• In 2007, resistance of seasonal influenza A(H1N1) to oseltamivir became widespread. In 2009, pandemic influenza A(H1N1), which is highly susceptible to oseltamivir, replaced the seasonal virus and remains the predominantly circulating A(H1N1) strain.
• A small-molecule fragment, N-cyclohexyaltaurine, binds to the conserved hemagglutinin receptor-binding site in a manner that mimics the binding mode of the natural receptor sialic acid. This can serve as a template to guide the development of novel broad-spectrum small-molecule anti-influenza drugs.⁶³
• Biomarkers that can accurately predict development of severe disease in patients with influenza are needed.

Crohn’s disease was significantly associated with anal canal high-risk human papillomavirus (HPV) infection in a prospective, single-center study of patients undergoing colonoscopy for various indications.

xrender/Thinkstock

High-risk HPV and HPV strain 16 were detected in 30% of patients with Crohn’s disease and 18% of patients without Crohn’s disease (P = .005), said Lucine Vuitton, MD, of University Hospital of Besançon (France) and her associates. “Increasing our knowledge of HPV infection of anal tissues could help physicians identify populations at risk and promote prophylaxis with vaccination and adequate screening,” the investigators wrote in the November issue of Clinical Gastroenterology and Hepatology.

Most anal cancers are squamous cell carcinomas, for which infection with high-risk HPV (especially high-risk HPV16) is a driving risk factor. Case studies and literature reviews have linked Crohn’s disease to increased rates of anal canal cancers, but population-based data were lacking, the researchers wrote. Therefore, they prospectively analyzed anal tissue samples from 467 consecutive patients undergoing colonoscopy at a tertiary care center in France. Median age was 54 years (interquartile range, 18-86 years), and 52% of patients were women. No patient had detectable macroscopic neoplastic lesions at the anal margin at baseline.

The researchers used the QIAamp DNA Blood minikit (Qiagen) for DNA extraction and the INNO-LiPA HPV Genotyping Extra kit (Fujirebio Diagnostics) for HPV DNA detection and genotyping. These methods identified HPV DNA in anal tissue samples from 34% of the patients and high-risk HPV DNA in 18% of patients. The most prevalent genotype was HPV16 (detected in 7% of samples), followed by HPV51, HPV52, and HPV39.

A total of 112 patients were receiving at least one immunosuppressive treatment for inflammatory bowel disease or another condition. Seventy patients had Crohn’s disease, and 29 patients had ulcerative colitis. The prevalence of anal canal high-risk HPV and HPV16 infection in patients with ulcerative colitis was similar to that seen in those without inflammatory bowel disease. However, patients with Crohn’s disease were more likely to have anal canal high-risk HPV infection (30%) and HPV16 infection (14%), compared with patients without Crohn’s disease (18% and 7%, respectively). Additionally, among 22 patients with Crohn’s disease and perianal involvement, 11 had HPV DNA in the anal canal versus 30% of other patients with inflammatory bowel disease.

Women were more likely to have anal canal high-risk HPV (23%) infection than were men (13%; P = .004). In a multivariable analysis of self-reported data and medical data, significant risk factors for high-risk HPV infection included female sex, a history of sexually transmitted infections, having more than 10 sexual partners over the life course, having at least one sexual partner during the past year, current smoking, and immunosuppressive therapy. The multivariable analysis also linked Crohn’s disease with anal canal high-risk HPV16 infection (odds ratio, 3.8), but the association did not reach statistical significance (95% confidence interval, 0.9-16.9).

Most patients with Crohn’s disease were on immunosuppressive therapy, “which markedly affected statistical power,” the researchers commented. Nonetheless, their findings support HPV vaccination for patients with Crohn’s disease, as well as efforts to target high-risk patients who could benefit from anal cancer screening, they said.

The work was funded by the APICHU research grant from Besançon (France) University Hospital and by the Région de Franche-Comté. Dr. Vuitton disclosed ties to AbbVie, Ferring, MSD, Hospira, Janssen, and Takeda. Three coinvestigators disclosed relationships with AbbVie, MSD, Hospira, Mayoli, and Roche.

SOURCE: Vuitton L et al. Clin Gastroenterol Hepatol. 2018 Nov. doi: 10.1016/j.cgh.2018.03.008.

Crohn’s disease was significantly associated with anal canal high-risk human papillomavirus (HPV) infection in a prospective, single-center study of patients undergoing colonoscopy for various indications.

xrender/Thinkstock

High-risk HPV and HPV strain 16 were detected in 30% of patients with Crohn’s disease and 18% of patients without Crohn’s disease (P = .005), said Lucine Vuitton, MD, of University Hospital of Besançon (France) and her associates. “Increasing our knowledge of HPV infection of anal tissues could help physicians identify populations at risk and promote prophylaxis with vaccination and adequate screening,” the investigators wrote in the November issue of Clinical Gastroenterology and Hepatology.

Most anal cancers are squamous cell carcinomas, for which infection with high-risk HPV (especially high-risk HPV16) is a driving risk factor. Case studies and literature reviews have linked Crohn’s disease to increased rates of anal canal cancers, but population-based data were lacking, the researchers wrote. Therefore, they prospectively analyzed anal tissue samples from 467 consecutive patients undergoing colonoscopy at a tertiary care center in France. Median age was 54 years (interquartile range, 18-86 years), and 52% of patients were women. No patient had detectable macroscopic neoplastic lesions at the anal margin at baseline.

The researchers used the QIAamp DNA Blood minikit (Qiagen) for DNA extraction and the INNO-LiPA HPV Genotyping Extra kit (Fujirebio Diagnostics) for HPV DNA detection and genotyping. These methods identified HPV DNA in anal tissue samples from 34% of the patients and high-risk HPV DNA in 18% of patients. The most prevalent genotype was HPV16 (detected in 7% of samples), followed by HPV51, HPV52, and HPV39.

A total of 112 patients were receiving at least one immunosuppressive treatment for inflammatory bowel disease or another condition. Seventy patients had Crohn’s disease, and 29 patients had ulcerative colitis. The prevalence of anal canal high-risk HPV and HPV16 infection in patients with ulcerative colitis was similar to that seen in those without inflammatory bowel disease. However, patients with Crohn’s disease were more likely to have anal canal high-risk HPV infection (30%) and HPV16 infection (14%), compared with patients without Crohn’s disease (18% and 7%, respectively). Additionally, among 22 patients with Crohn’s disease and perianal involvement, 11 had HPV DNA in the anal canal versus 30% of other patients with inflammatory bowel disease.

Women were more likely to have anal canal high-risk HPV (23%) infection than were men (13%; P = .004). In a multivariable analysis of self-reported data and medical data, significant risk factors for high-risk HPV infection included female sex, a history of sexually transmitted infections, having more than 10 sexual partners over the life course, having at least one sexual partner during the past year, current smoking, and immunosuppressive therapy. The multivariable analysis also linked Crohn’s disease with anal canal high-risk HPV16 infection (odds ratio, 3.8), but the association did not reach statistical significance (95% confidence interval, 0.9-16.9).

Most patients with Crohn’s disease were on immunosuppressive therapy, “which markedly affected statistical power,” the researchers commented. Nonetheless, their findings support HPV vaccination for patients with Crohn’s disease, as well as efforts to target high-risk patients who could benefit from anal cancer screening, they said.

The work was funded by the APICHU research grant from Besançon (France) University Hospital and by the Région de Franche-Comté. Dr. Vuitton disclosed ties to AbbVie, Ferring, MSD, Hospira, Janssen, and Takeda. Three coinvestigators disclosed relationships with AbbVie, MSD, Hospira, Mayoli, and Roche.

SOURCE: Vuitton L et al. Clin Gastroenterol Hepatol. 2018 Nov. doi: 10.1016/j.cgh.2018.03.008.

Crohn’s disease was significantly associated with anal canal high-risk human papillomavirus (HPV) infection in a prospective, single-center study of patients undergoing colonoscopy for various indications.

xrender/Thinkstock

High-risk HPV and HPV strain 16 were detected in 30% of patients with Crohn’s disease and 18% of patients without Crohn’s disease (P = .005), said Lucine Vuitton, MD, of University Hospital of Besançon (France) and her associates. “Increasing our knowledge of HPV infection of anal tissues could help physicians identify populations at risk and promote prophylaxis with vaccination and adequate screening,” the investigators wrote in the November issue of Clinical Gastroenterology and Hepatology.

Most anal cancers are squamous cell carcinomas, for which infection with high-risk HPV (especially high-risk HPV16) is a driving risk factor. Case studies and literature reviews have linked Crohn’s disease to increased rates of anal canal cancers, but population-based data were lacking, the researchers wrote. Therefore, they prospectively analyzed anal tissue samples from 467 consecutive patients undergoing colonoscopy at a tertiary care center in France. Median age was 54 years (interquartile range, 18-86 years), and 52% of patients were women. No patient had detectable macroscopic neoplastic lesions at the anal margin at baseline.

The researchers used the QIAamp DNA Blood minikit (Qiagen) for DNA extraction and the INNO-LiPA HPV Genotyping Extra kit (Fujirebio Diagnostics) for HPV DNA detection and genotyping. These methods identified HPV DNA in anal tissue samples from 34% of the patients and high-risk HPV DNA in 18% of patients. The most prevalent genotype was HPV16 (detected in 7% of samples), followed by HPV51, HPV52, and HPV39.

A total of 112 patients were receiving at least one immunosuppressive treatment for inflammatory bowel disease or another condition. Seventy patients had Crohn’s disease, and 29 patients had ulcerative colitis. The prevalence of anal canal high-risk HPV and HPV16 infection in patients with ulcerative colitis was similar to that seen in those without inflammatory bowel disease. However, patients with Crohn’s disease were more likely to have anal canal high-risk HPV infection (30%) and HPV16 infection (14%), compared with patients without Crohn’s disease (18% and 7%, respectively). Additionally, among 22 patients with Crohn’s disease and perianal involvement, 11 had HPV DNA in the anal canal versus 30% of other patients with inflammatory bowel disease.

Women were more likely to have anal canal high-risk HPV (23%) infection than were men (13%; P = .004). In a multivariable analysis of self-reported data and medical data, significant risk factors for high-risk HPV infection included female sex, a history of sexually transmitted infections, having more than 10 sexual partners over the life course, having at least one sexual partner during the past year, current smoking, and immunosuppressive therapy. The multivariable analysis also linked Crohn’s disease with anal canal high-risk HPV16 infection (odds ratio, 3.8), but the association did not reach statistical significance (95% confidence interval, 0.9-16.9).

Most patients with Crohn’s disease were on immunosuppressive therapy, “which markedly affected statistical power,” the researchers commented. Nonetheless, their findings support HPV vaccination for patients with Crohn’s disease, as well as efforts to target high-risk patients who could benefit from anal cancer screening, they said.

The work was funded by the APICHU research grant from Besançon (France) University Hospital and by the Région de Franche-Comté. Dr. Vuitton disclosed ties to AbbVie, Ferring, MSD, Hospira, Janssen, and Takeda. Three coinvestigators disclosed relationships with AbbVie, MSD, Hospira, Mayoli, and Roche.

SOURCE: Vuitton L et al. Clin Gastroenterol Hepatol. 2018 Nov. doi: 10.1016/j.cgh.2018.03.008.

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Short-term NSAIDs appear safe for high-risk patients

To take the posttest, go to: https://bit.ly/2PgXKGx
Expires October 8, 2019

2. Chronic liver disease raises death risk in pneumonia patients

To take the posttest, go to: https://bit.ly/2NPSXXA
Expires October 8, 2019

3. Half of outpatient antibiotics prescribed with no infectious disease code

To take the posttest, go to: https://bit.ly/2pWEWxU
Expires October 6, 2019

4. Secondary fractures in older men spike soon after first, but exercise may help

To take the posttest, go to: https://bit.ly/2OCNl8A
Expires October 3, 2019

5. Consider ART for younger endometriosis patients

To take the posttest, go to: https://bit.ly/2NO1Sc4
Expires October 5, 2019

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Short-term NSAIDs appear safe for high-risk patients

To take the posttest, go to: https://bit.ly/2PgXKGx
Expires October 8, 2019

2. Chronic liver disease raises death risk in pneumonia patients

To take the posttest, go to: https://bit.ly/2NPSXXA
Expires October 8, 2019

3. Half of outpatient antibiotics prescribed with no infectious disease code

To take the posttest, go to: https://bit.ly/2pWEWxU
Expires October 6, 2019

4. Secondary fractures in older men spike soon after first, but exercise may help

To take the posttest, go to: https://bit.ly/2OCNl8A
Expires October 3, 2019

5. Consider ART for younger endometriosis patients

To take the posttest, go to: https://bit.ly/2NO1Sc4
Expires October 5, 2019

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Short-term NSAIDs appear safe for high-risk patients

To take the posttest, go to: https://bit.ly/2PgXKGx
Expires October 8, 2019

2. Chronic liver disease raises death risk in pneumonia patients

To take the posttest, go to: https://bit.ly/2NPSXXA
Expires October 8, 2019

3. Half of outpatient antibiotics prescribed with no infectious disease code

To take the posttest, go to: https://bit.ly/2pWEWxU
Expires October 6, 2019

4. Secondary fractures in older men spike soon after first, but exercise may help

To take the posttest, go to: https://bit.ly/2OCNl8A
Expires October 3, 2019

5. Consider ART for younger endometriosis patients

To take the posttest, go to: https://bit.ly/2NO1Sc4
Expires October 5, 2019

From the University of Arizona College of Medicine, Tucson, AZ (Dr. Beatty), and the Baylor College of Medicine, Houston, TX (Dr. Mohajer).

Abstract

• Objective: To review management issues regarding health care–associated urinary tract infections (UTIs) commonly encountered by practicing clinicians.
• Methods: Review of the literature.
• Results: Because urinary catheter (UC) placement plays a major role in the development of catheter-associated UTIs (CA-UTI), clinicians should be aware of the appropriate and inappropriate uses of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key to preventing CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. Percutaneous nephrostomy and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected. Candiduria rarely leads to symptoms unless it is related to an ascending process. Proper urine collection is crucial in determining whether contamination, colonization, or infection is present. Fluconazole is recommended in most cases of Candida UTI, while intravenous amphotericin B is recommended for fluconazole-resistant Candida species.
• Conclusion: Continued use of evidence-based strategies for preventing and managing health care–associated UTI should lead to further improvements in patient outcomes and overall decreased rates of infection.

Keywords: bacteriuria; catheter-associated UTI; catheterization; percutaneous nephrostomy; candiduria.

Health care–associated urinary tract infections (UTIs) are estimated to be the most common adverse infectious event in U.S. hospitals, occurring in 1 of 10 admitted patients.^1-3 Approximately 32% of all health care–associated infections are UTIs.¹ Furthermore, urinary catheters (UCs) are associated with 8% to 21% of health care–associated infections that occur in the intensive care unit.⁴ The most important predisposing factor for nosocomial UTI is urinary catheterization.⁵ Genitourinary manipulation and/or implementation also play a major role in the development of nosocomial UTIs.

In 2008, the U.S. Centers for Medicare & Medicaid Services instituted a new policy that reduced reimbursement rates for hospitalizations linked to health care–associated infections.⁶ Indwelling UCs are among the most overused health care devices in the hospital setting. They are placed in an estimated 15% to 25% of all hospitalized patients,^7,8 and are often inserted in the emergency department (ED) without a physician order or appropriate indication.⁹ Intermittent straight catheterization, male or female condom catheterization, and/or placement of an indwelling UC are the most common causes of catheter-associated asymptomatic bacteriuria (CA-ASB) and catheter-associated UTIs (CA-UTI).⁵ Prevention and management of CA-ASB and CA-UTI can be challenging and require an evidence-based approach. Furthermore, guidelines for the management of UTIs in the setting of active percutaneous nephrostomy (PCN) drainage and/or ureteral stenting are not established.⁵ This may leave clinicians with little mainstream data to aid in management decisions.

In 2009 the Centers for Disease Control and Prevention provided a guideline for the appropriate and inappropriate use of indwelling UCs to help promote their proper use.¹⁰ In the time since the guideline’s initiatives were instituted around the United States, published data have shown some improvement in the use of UCs,^11,12 but other recent reports indicate that rates of UC use have remained unchanged.¹³ This review discusses management issues regarding health care–associated UTIs that are commonly encountered by practicing clinicians, with a focus on current guidelines and evidence.

Catheter-Associated UTI

CA-UTI is defined as the presence of signs or symptoms of UTI with no other explainable infectious source along with ≥ 1000 colony-forming units (cfu) of ≥ 1 bacterial species per milliliter in a urine specimen from a catheter that has been changed within 48 hours of collection of the urine specimen.⁵ Signs and symptoms of CA-UTI include, but are not limited to: new-onset or worsening fever, chills, altered sensorium from baseline, lethargy, malaise, flank pain, pelvic pain, costovertebral angle tenderness, and acute hematuria.⁵ New-onset “foul-smelling” (odorous)urine and “cloudy” urine are neither sensitive nor specific when assessing for CA-UTI, and do not have significant clinical relevance when found alone.^14,15 Patients who have removed or exchanged the UC during this event and then experience dysuria, increased frequency, urgency, or suprapubic pain are likely having symptoms of CA-UTI.⁵

What is the recommended method for collecting urine samples when CA-UTI is suspected?

In a patient with an indwelling catheter that has been in place for more than 2 weeks at the onset of a suspected CA-UTI, the catheter should be replaced (if still indicated) or removed to accelerate resolution of symptoms and to reduce the risk of subsequent catheter-associated bacteriuria and CA-UTI. The urine culture should be acquired from the freshly placed UC.⁵

When should a patient be empirically treated?

A patient presenting with evidence of sepsis should be empirically treated with antimicrobials. Empiric coverage should be based on risk factors for multidrug-resistant organisms and data pertaining to local antimicrobial resistance patterns. A urine specimen for urinalysis and possible culture should be sent prior to administering empiric antibiotics (if possible) in a symptomatic patient.⁵

What bacteria are commonly associated with CA-UTI?

The bacteria most commonly associated with CA-UTI are found in or around the gastrointestinal and genitourinary tracts and also are part of the normal skin flora. The introduction and/or facilitated ascension of these microorganisms is believed to occur during UC insertion.^16,17 Two-thirds of all isolated uropathogens in those with indwelling UCs are extraluminally acquired (via ascension along the catheter-urethral mucosa interface), and one-third are believed to be intraluminally acquired.¹⁸

The most commonly isolated bacteria in CA-UTI are Enterobacteriaceae, which include Escherichia coli (most common), Klebsiella species (K. oxytoca, K. pneumoniae), Serratia species (S. marcescens), Citrobacter species (C. koseri), Enterobacter species (E. cloacae), and Proteus species; non-Enterobacteriaceae such as Pseudomonas species; and gram-positive cocci, which include coagulase-negative staphylococci (S. saprophyticus), Staphylococcus aureus, group B streptococci, and Enterococcus species (E. faecalis, E. faecium).^19-21 Coagulase-negative staphylococci and Enterococcus species can lead to CA-UTI but are usually avirulent and more commonly isolated from asymptomatic individuals.¹⁹ Also, coagulase-negative staphylococci such as S. epidermidis and S. lugdunensis are usually the manifestation of contamination during the collection process and their presence should prompt a repeat sample collection under sterile techniques. Monomicrobial infection is usually seen in those with short-term catheter use and CA-UTI. In contrast, polymicrobial infection is more common in those with long-term indwelling UCs and CA-UTI.¹⁹ Providencia stuartii, Proteus mirabilis, S. aureus, and Morganella morganii have all been associated with CA-UTI in those with long-term indwelling UCs.

Growth of S. aureus in the urine should prompt further investigation with blood cultures to explore the possibility of hematogenous dissemination to the urinary tract. Organisms leading to bacteremia due to CA-UTI are most commonly gram-negative bacilli (E. coli, Klebsiella species, Pseudomonas aeruginosa) and E. faecalis.²¹

What is the difference between CA-ASB and CA-UTI?

CA-ASB is defined as the presence of ≥ 1 bacteria species growing on urine culture at ≥ 100,000 cfu/mL in a patient with a history of urinary catheterization and/or indwelling UC who lacks signs or symptoms of UTI. In a man with a condom catheter, CA-ASB is defined using the same criteria, but the urine sample is collected after a fresh condom catheter is applied.⁵ The difference between CA-ASB and CA-UTI is simply the presence or absence of signs and symptoms related to UTI. Currently, there is no standard definition for significant bacteriuria in a catheterized patient.⁵ Pyuria found on urinalysis is indicative of genitourinary inflammation and can be present in both CA-ASB and CA-UTI. The absence, presence, and/or degree of pyuria in catheterized patients does not accurately differentiate between CA-ASB and CA-UTI.^5,22,23 On the other hand, the absence of pyuria in a symptomatic catheterized patient suggests an etiology other than CA-UTI.⁵

How can CA-UTI be prevented in patients with a short-term indwelling urinary catheter?

If a short-term UC is essential, the most important approach to preventing CA-UTI is limiting the duration of time it will be used. Strategies such as computer-based order entry and care maps with automated discontinuation of UCs have been shown to decrease catheter usage.¹⁹ Using closed-systems for UC collection with ports in the distal catheter for needle aspiration of urine has also been shown to decrease the incidence of CA-UTI.⁵ Securing the UC to avoid urethral trauma, aseptic techniques for insertion and repositioning, and placement of the tubing and collection bag below the level of the bladder to prevent reflux will likely also prevent CA-UTI, but these strategies have not been evaluated thoroughly.¹⁹

When should you screen for and treat CA-ASB?

The 2009 Infectious Diseases Society of America (IDSA) guidelines recommend that the only patients who should be screened and treated for CA-ASB are pregnant women and those who will undergo a potentially traumatic urologic procedure for which mucosal breaching may occur, causing bleeding. Routinely screening or treating patients for CA-ASB in not recommended in any other group of patients and will lead to unnecessary antibiotic use and antibiotic resistance.⁵

UTI Associated with Percutaneous Nephrostomy and Ureteral Stenting

Similar systemic symptoms of infection (fever, rigors, malaise, shock) are present in patients with and without percutaneous nephrostomy (PCN) and/or ureteral stent placement. Dysuria is not commonly present in those with PCN. The first signs of CA-UTI may be decreased urine output and pericatheter leakage due to an obstructive process resulting from the encrustation.^24-27 The most common complaint among patients with either acute or chronic ureteral stenting is discomfort, which has been described as “urinary symptoms” and “body pain.”²⁸ This discomfort can be related to ureteral hyperperistalsis after placement of the stent and is usually self-limiting. Ureteral stent migration, usually at the distal end, can also lead to discomfort, but is easily rectified with cystoscopy.²⁵ Body pain and/or urinary symptoms in the setting of ureteral stenting are not indicative of infection alone.

What is urinary catheter and/or ureteral stent encrustation?

Encrustation is the formation of a conditioning film that develops on the surface of the UC or ureteral stent. The exact mechanism is not well understood, but it is believed to involve electrostatic interactions of urinary proteins that stimulate binding onto the stent or UC surface.²⁵ Encrustation increases exponentially with the dwell time. Among patients with ureteral stents placed due to urolithiasis, encrustation occurred in 9.2% of stents removed prior to 6 weeks, 47.5% of stents removed at 6 weeks, and 76.3% of stents removed at 12 weeks.²⁶ Encrustation is most common at the proximal and distal ends (pigtails) of the ureteral stent and usually spares or presents last within the lumen.²⁹ Attempts have been made to prevent ureteral stent encrustation through the development of biodegradable, drug-eluting, and tissue-engineered substrates. These developments are promising, but currently there is limited observational data from large randomized trials to suggest that these new modalities decrease rates of encrustation.²⁵ Encrustation is highly associated with certain microorganisms, especially those that create biofilms.³⁰ Urease-producing bacteria, most commonly P. mirabilis, play a role in encrustation formation.³¹ Bacteria most commonly associated with encrustation include Proteus species (P. mirabilis is most common), P. aeruginosa, K. pneumoniae, Providencia species (P. stuartii is most common), and M. morganii.

Does ureteral stent bacterial colonization correlate with UTI?

Ureteral stent colonization with bacteria increases with dwell time and is found in 40% to 98.5% of stents placed.^32-35 If UTI is suspected in a patient with an active indwelling ureteral stent, a sample of urine should be cultured while the stent is in place.²⁵ Typically, genitourinary and normal skin flora pathogens are found when the ureteral stent is cultured. The top 3 organisms cultured from ureteral stents are S. aureus, P. aeruginosa, and E. faecalis.³⁴ Urine culture usually does not correlate with stent culture results, which has brought up the debate of how bacterial colonization occurs. It has been postulated that colonization is actually a manifestation of contamination during the insertion procedure, but this has yet to be validated.²⁵ In patients with symptoms of UTI in the setting of an indwelling ureteral stent, a positive culture has low sensitivity, with estimates between 21% and 40%.³⁵ Therefore, a negative urine culture does not rule out UTI alone in a symptomatic patient. Multiple studies have suggested that colonization of the ureteral stent does not correlate strongly with developing a UTI.^25,32-34

How can UTI be prevented in those receiving PCN or ureteral stent placement?

Antibiotic prophylaxis has been recommended to prevent UTI in patients who will undergo PCN or ureteral stent placement. The American Urological Association recommends empiric treatment even in the absence of signs and symptoms of UTI,³⁶ but substantial evidence is lacking that this approach prevents infection.³⁷ Ciprofloxacin or trimethoprim/sulfamethoxazole has been recommended by some for empiric coverage for enteric gram-negative bacilli and enterococcus in those undergoing genitourinary manipulation or instrumentation.^32,38 Most patients who develop CA-UTI and pyelonephritis do so within the first 2 to 6 weeks after placement.^37,39 Bacteriuria, candiduria, and/or pyuria are present in all patients approximately within 9 weeks even when sterile urine is confirmed prior to PCN placement.³⁹ Data on the effectiveness of antibiotic prophylaxis to prevent CA-UTI in those with PCN or ureteral stenting is limited. Currently, there are no recommendations from the IDSA on how to prevent infection in these situations.⁵ Early or frequent stent removal or exchanges has been proven to reduce UTI in those with ureteral stenting.³³ Patients with diabetes mellitus and chronic renal failure are at high-risk for UTI when ureteral stents are in place. This population should undergo close monitoring for UTI development and may warrant more frequent stent exchanges.^27,40

What is the treatment of CA-UTI associated with PCN and/or ureteral stenting?

The IDSA guidelines do not apply to patients with PCN and/or ureteral stenting.⁵ There is no treatment protocol for UTI related to these processes. Generally speaking, they are considered “complicated UTI” by most experts. Broad-spectrum, empiric antibiotic administration along with prompt removal of the PCN and/or ureteral stent is the gold standard of therapy.²⁷ The recommended duration of targeted antibiotic therapy is generally between 5 and 14 days.¹⁹ Most clinicians will treat this complicated UTI for at least 10 to 14 days. Antibiotic administration should be continued even after removal of the catheter and/or stent to complete the full course. Repeat urinalysis and culture is not indicated at the end of therapy if the patient is clinically improving or has remission of symptoms.

What is the exchange rate for those who require chronic PCN and/or ureteral stent use?

On average a PCN or ureteral stent should be exchanged every 2 to 3 months in patients who require chronic usage.^24,27 Some patients with persistent complications may require more frequent exchanges (< 10 weeks).²⁷ Encrustation and bacterial colonization become more prevalent the longer the devices are in place. This process is estimated to begin within the first 2 weeks after placement.^27,33,34 A “forgotten stent” is one that has been left in place after the patient is lost to follow-up. This unfortunate event can lead to massive encrustation, UTI, stent fracturing, and complete ureteral obstruction.²⁴ As noted, patients with diabetes mellitus, chronic renal failure, and frequent UTI may warrant more frequent exchanges, but this should be determined on a case-by-case basis.

Spinal cord injury (SCI) at any level can cause neurogenic bladder. This process ultimately leads to urinary stasis and colonization of the bladder with bacteria. According to the IDSA, the acceptable indications for UC insertion are: clinically significant urinary retention (if medical therapy is not effective), urinary incontinence, accurate urine output monitoring required, and patient is unable and/or unwilling to collect urine (Table 1).⁵ Recently, further guidelines were published regarding appropriate and inappropriate indwelling UC placement in hospitalized medical patients (Table 2 and Table 3), expanding upon the earlier acceptable criteria provided by the IDSA.⁴¹ According to the IDSA and Ann Arbor Criteria for Appropriate Urinary Catheter Use, patients with SCI and subsequent neurogenic bladder without obstruction where intermittent bladder straight catheterization for the drainage of urine is not feasible will likely need an indwelling UC.⁴¹ SCI patients often experience decubitus ulcers, and an indwelling UC can be used if needed to help with wound healing if other urinary management alternatives have been attempted. Other such situations in which an indwelling UC can used before attempting alternative approaches would be in a patient who is actively dying and is pursuing comfort care and/or hospice.⁴¹

Which indwelling UCs should be used in patients with SCI?

Efforts to reduce the likelihood of infection in patients with SCI have led to several advances in the design and manufacturing of UCs. UCs are made of either latex, plastic, silicone, or polytetrafluoroethylene (Teflon). None of these substrates is free of complications, but of them latex UCs have been studied the most in regards to their associated complications. Aside from being allergenic in nature, latex UCs have an increased propensity to allow bacteria to adhere to their surface due to microscopic planes of unevenness.⁴² Silicone UCs are less frequently associated with infection but are more rigid, leading to increased discomfort.^43,44 Hydrophilic and silver-hydrogel coatings are innovative methods that have been developed to increase comfort and reduce the likelihood of infection. Hydrophilic-coated UCs are associated with reduced microbial adherence, decreased encrustation, and better patient satisfaction.^45,46 In SCI patients, these UCs have demonstrated lower complication rates, including UTI; fewer episodes of post-, intra-, and inter-catheterization bleeding; and decreased rates of antibiotic-resistant bacteria.^45,46 Silver-hydrogel-coated UCs are less well studied but have also demonstrated reduced UTI rates in SCI patients; however, their efficacy over the long term has yet to be determined. Antibiotic-impregnated UCs are not currently recommended for either short- or long-term indwelling UC use.⁵

How can CA-UTI be prevented in a patient who will require a long-term indwelling catheter?

At this time, the data is insufficient to make a recommendation on routine UC exchange (eg, every 2 to 4 weeks) in patients who require long-term indwelling urethral or suprapubic catheters in an attempt to reduce the risk of CA-ASB or CA-UTI. This is also true for those who experience even repeated early catheter blockage from encrustation.⁵ Thus, the rate at which these exchanges occur can be controversial, but typically around every 4 weeks is a common approach. Some would argue that if the patient has repeated CA-UTI, an exchange rate of every 2 weeks might be needed, but data is currently lacking to support this practice.⁵ If intermittent urinary catheterization is feasible, it should be done at least every 6 hours and before bedtime. In general, when the volume of urine in the bladder reaches approximately 400 mL, the patient should undergo bladder catheterization to prevent stasis and infection.⁴⁷ A closed drainage system is recommended in all patients who require long-term indwelling UC use.^48,49 Placement of the collection bag above the catheter or above the level of the bladder and a breach in the closed drainage system have been shown to result in higher rates of catheter-associated bacteriuria.^48,50 Proper hand hygiene and sterile and/or clean techniques should be used when placing or exchanging a UC. However, in one study there was no difference in bacteremia or UTIs when using sterile versus clean techniques.⁵¹

Asymptomatic bacteriuria should not be treated in patients with long-term indwelling UCs, and prophylactic antibiotics have led to the emergence of resistance.⁵² At this time it is not clear whether prophylactic weekly oral cyclic antibiotic administration can effectively reduce the frequency of CA-UTI in patients with SCI and chronic indwelling UC use.

What are the signs and symptoms of CA-UTI in a patient with SCI?

Subjective and objective findings may be limited when a patient with SCI presents with CA-UTI. These patients often lack the usual symptoms of UTI (dysuria, suprapubic discomfort, urgency, increased frequency) and pyelonephritis (flank pain, costovertebral angle tenderness). Caregivers and health care providers should be aware that nonspecific symptoms such as foul-smelling urine, pyuria, increased residual volume of urine in the bladder, change in voiding habits, worsening detrusor spasticity, and aggravation of autonomic dysreflexia can be the only initial presenting symptoms.⁵³

Antibiotic therapy is indicated for a duration of 7 days if there is prompt resolution of symptoms, or for a total of 10 to 14 days if the response is delayed, regardless of whether the patient remains with a UC.⁵ Antibiotic stewardship is very important to reduce the risk for developing drug resistance in this high-risk population. Methods such as prescriber education practices, institution protocols, guideline implementation, auditing and feedback, restriction and reauthorization practices, computer-assisted programs, de-escalation or streamlining, and antibiotic cycling or dosage optimization have all been shown to assist in antibiotic stewardship in UTIs.⁵⁴

Candida UTI

What is the initial evaluation for a patient with candiduria?

The workup for candiduria hinges on determining whether the candiduria likely represents contamination, colonization, or infection; certain predisposing risk factors are associated with Candida UTI (Table 4).^55-57 The most important aspect to candiduria is the patient’s clinical status and comorbid conditions.⁵⁸ Among funguria, Candida species are the most common and represent 95% of organisms isolated on urine cultures (Table 5).⁵⁹ Candiduria is usually present in those with significant comorbidities and rarely is associated with healthy individuals.^59,60 Candiduria is increasing in prevalence among hospitalized patients, representing 22% to 40% of all nosocomial UTIs.^59,60 Markers in the urine (leukocyte esterase, colony count of culture growth, presence or absence of Candida casts and pseudohyphae) cannot alone differentiate colonization from infection.⁵⁵ When candiduria is discovered in a patient with symptoms related to UTI in the setting of predisposing risk factors, it should be considered a real infection until proven otherwise.

In a situation where an asymptomatic patient without an indwelling UC has Candida species isolated from a urine culture, a repeat culture (clean-catch midstream sample) should be performed to assess for a likely contaminated collection.⁵⁵ If the patient has an indwelling UC then it should be exchanged and urine collected from the fresh catheter.⁶¹ When candiduria is found in healthy asymptomatic adults, it is most commonly associated with poor collection techniques or postcollection contamination.⁵⁹ If candiduria persists in an asymptomatic patient, the patient should be assessed for predisposing factors. This includes checking hemoglobin A1C for developing diabetes and renal ultrasound looking for urolithiasis, renal abscess, hydronephrosis, and fungus ball. Postvoid residual urinary retention should also be ruled out with bladder ultrasound. Treatment of predisposing factors can lead to resolution of candiduria without antifungal treatment, and a urine culture should be repeated (1 to 2 weeks later).⁶¹ Asymptomatic patients lacking any predisposing factors can be observed with repeat urine cultures in 1 to 3 months.⁶¹

Candiduria may actually represent candidemia in those patients who have a predisposing risk factor for disseminated candidiasis. These risk factors include central venous catheters, administration of total parental nutrition, antibiotic use (especially broad spectrum), critical illness, recent surgical intervention (especially intra-abdominal), acute renal failure, nasogastric tube use, and active gastric acid suppression (ie, proton pump inhibitors).^62,63 The hematogenous spread of Candida can lead to the detection of candiduria in 46% to 80% of persons who are experiencing candidemia.⁵⁹ If the patient is at risk for candidemia, then blood fungal cultures should be drawn. It is not unreasonable to also order a serum-D-glucan assay if suspicions are high. A thorough skin assessment should be completed and ophthalmology consulted for a detailed eye exam in the event that the patient has candidemia. Candiduria is highly prevalent among those who are candidemic, but overall candidemia is encountered in less than 5% of patients in most intensive care units.⁵⁹ Thus, most patients with candiduria do not have disseminated candidiasis.

Candiduria rarely leads to symptoms of UTI,⁵⁸ unless the pathogenesis is related to an ascending process.⁵⁶ Symptoms of Candida UTI are no different from those experienced from a bacterial etiology. Some patients may complain of pneumaturia and/or endorse seeing particulate matter in their urine.⁵⁵ Patients showing signs of sepsis (fever, chills, flank pain) should be investigated for possible Candida pyelonephritis in the setting of candiduria.⁶⁴

When should asymptomatic candiduria be treated?

In adult patients with asymptomatic candiduria, there are 2 situations in which antifungal therapy is recommended. A patient undergoing a traumatic urologic procedure would be treated to avoid the risk for candidemia caused by the procedure. Also, in neutropenic patients empiric antifungal therapy should be administered because there is a high likelihood that this candiduria may actually represent hematogenous spread from candidemia.^61,65

What is the treatment for symptomatic Candida cystitis?

Empiric treatment with oral fluconazole 200 to 400 mg daily for a total of 2 weeks is recommended in patients with persisting candiduria and symptoms of cystitis.⁶⁵ Identifying the species is a crucial step in the treatment of Candida UTI. Several species (C. glabrata, C. krusei) are known to be resistant to fluconazole. Species identification and antifungal sensitivities should be done and therapy directed after obtaining these results.⁵⁵

What is the recommended treatment for Candida pyelonephritis?

Treatment for pyelonephritis caused by fluconazole-susceptible Candida species is oral fluconazole 200 to 400 mg (3-6 mg/kg) for a total of 2 weeks.⁶⁵ A fluconazole-resistant organism should be suspected when a non-albicans Candida species is isolated, such as C. krusei or C. glabrata. In this circumstance, in vitro antifungal susceptibility testing should be done. Echinocandins are not a good option in this situation because they do not reach adequate urine concentration and treatment failure is well documented.^66-68 Amphotericin B deoxycholate (AmB) 0.3 to 0.6 mg/kg daily for 1 to 7 days, with or without oral flucytosine (25 mg/kg) 4 times daily, is recommended by the IDSA for the treatment of fluconazole-resistant isolates of C. glabrata and C. krusei.⁶⁵ Further imaging with ultrasound, CT, or magnetic resonance should be done to rule out urinary tract obstruction and/or “fungus ball” formation. Emphysematous pyelonephritis and necrosis can occur and usually require nephrectomy. Perinephric abscess will need drainage, which can be accomplished through interventional radiological techniques.⁵⁵

If a “fungus ball” is suspected in the kidney, how does the management change in a patient with Candida pyelonephritis?

A fungus ball must be treated with both antifungals and surgical intervention. Antifungal therapy should be continued during the surgical removal process to avoid fungemia. Interventional radiology should be consulted and is usually the best option for removal. Fungus ball(s) can and often do cause urinary obstruction. Temporary nephrostomy tube placement may be warranted in these situations to relieve the obstruction.^55,65 AmB can be infused through the nephrostomy tube to increase local concentrations. This route of administration is not known to be nephrotoxic.⁵⁵ Fluconazole infusion through a nephrostomy tube has also been used in the successful treatment of a fungus ball.⁶⁹

Summary

Health care–associated UTIs are the most common nosocomial infection in the United States. UC placement and genitourinary manipulation or instrumentation play a major role in the development of CA-UTI. Clinicians should be aware of the appropriate and inappropriate use of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key in prevention of CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. A multidisciplinary approach is essential when managing chronic indwelling UCs in SCI. PCN and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected.

Candiduria is an emerging nosocomial source of UTI but rarely leads to symptoms unless related to an ascending process. Proper urine collection is crucial in determining whether you are dealing with contamination, colonization, or infection. If candiduria persists in an asymptomatic individual, then further investigations should be done in regards to possible predisposing risks factors. Fluconazole is recommended for treatment of most patients with Candida UTI, while intravenous AmB is the treatment of choice for fluconazole-resistant Candida species. As we continue to take an evidence-based approach to the prevention and management of health care-associated UTI, we will likely see continued improvement in patient outcomes and overall decreased rates of infection.

Corresponding author: Norman Beatty, MD, 1501 N. Campbell Ave., Tucson, AZ 85724; [email protected].

Financial disclosures: None.

From the University of Arizona College of Medicine, Tucson, AZ (Dr. Beatty), and the Baylor College of Medicine, Houston, TX (Dr. Mohajer).

Abstract

• Objective: To review management issues regarding health care–associated urinary tract infections (UTIs) commonly encountered by practicing clinicians.
• Methods: Review of the literature.
• Results: Because urinary catheter (UC) placement plays a major role in the development of catheter-associated UTIs (CA-UTI), clinicians should be aware of the appropriate and inappropriate uses of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key to preventing CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. Percutaneous nephrostomy and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected. Candiduria rarely leads to symptoms unless it is related to an ascending process. Proper urine collection is crucial in determining whether contamination, colonization, or infection is present. Fluconazole is recommended in most cases of Candida UTI, while intravenous amphotericin B is recommended for fluconazole-resistant Candida species.
• Conclusion: Continued use of evidence-based strategies for preventing and managing health care–associated UTI should lead to further improvements in patient outcomes and overall decreased rates of infection.

Keywords: bacteriuria; catheter-associated UTI; catheterization; percutaneous nephrostomy; candiduria.

Health care–associated urinary tract infections (UTIs) are estimated to be the most common adverse infectious event in U.S. hospitals, occurring in 1 of 10 admitted patients.^1-3 Approximately 32% of all health care–associated infections are UTIs.¹ Furthermore, urinary catheters (UCs) are associated with 8% to 21% of health care–associated infections that occur in the intensive care unit.⁴ The most important predisposing factor for nosocomial UTI is urinary catheterization.⁵ Genitourinary manipulation and/or implementation also play a major role in the development of nosocomial UTIs.

In 2008, the U.S. Centers for Medicare & Medicaid Services instituted a new policy that reduced reimbursement rates for hospitalizations linked to health care–associated infections.⁶ Indwelling UCs are among the most overused health care devices in the hospital setting. They are placed in an estimated 15% to 25% of all hospitalized patients,^7,8 and are often inserted in the emergency department (ED) without a physician order or appropriate indication.⁹ Intermittent straight catheterization, male or female condom catheterization, and/or placement of an indwelling UC are the most common causes of catheter-associated asymptomatic bacteriuria (CA-ASB) and catheter-associated UTIs (CA-UTI).⁵ Prevention and management of CA-ASB and CA-UTI can be challenging and require an evidence-based approach. Furthermore, guidelines for the management of UTIs in the setting of active percutaneous nephrostomy (PCN) drainage and/or ureteral stenting are not established.⁵ This may leave clinicians with little mainstream data to aid in management decisions.

In 2009 the Centers for Disease Control and Prevention provided a guideline for the appropriate and inappropriate use of indwelling UCs to help promote their proper use.¹⁰ In the time since the guideline’s initiatives were instituted around the United States, published data have shown some improvement in the use of UCs,^11,12 but other recent reports indicate that rates of UC use have remained unchanged.¹³ This review discusses management issues regarding health care–associated UTIs that are commonly encountered by practicing clinicians, with a focus on current guidelines and evidence.

Catheter-Associated UTI

CA-UTI is defined as the presence of signs or symptoms of UTI with no other explainable infectious source along with ≥ 1000 colony-forming units (cfu) of ≥ 1 bacterial species per milliliter in a urine specimen from a catheter that has been changed within 48 hours of collection of the urine specimen.⁵ Signs and symptoms of CA-UTI include, but are not limited to: new-onset or worsening fever, chills, altered sensorium from baseline, lethargy, malaise, flank pain, pelvic pain, costovertebral angle tenderness, and acute hematuria.⁵ New-onset “foul-smelling” (odorous)urine and “cloudy” urine are neither sensitive nor specific when assessing for CA-UTI, and do not have significant clinical relevance when found alone.^14,15 Patients who have removed or exchanged the UC during this event and then experience dysuria, increased frequency, urgency, or suprapubic pain are likely having symptoms of CA-UTI.⁵

What is the recommended method for collecting urine samples when CA-UTI is suspected?

In a patient with an indwelling catheter that has been in place for more than 2 weeks at the onset of a suspected CA-UTI, the catheter should be replaced (if still indicated) or removed to accelerate resolution of symptoms and to reduce the risk of subsequent catheter-associated bacteriuria and CA-UTI. The urine culture should be acquired from the freshly placed UC.⁵

When should a patient be empirically treated?

A patient presenting with evidence of sepsis should be empirically treated with antimicrobials. Empiric coverage should be based on risk factors for multidrug-resistant organisms and data pertaining to local antimicrobial resistance patterns. A urine specimen for urinalysis and possible culture should be sent prior to administering empiric antibiotics (if possible) in a symptomatic patient.⁵

What bacteria are commonly associated with CA-UTI?

The bacteria most commonly associated with CA-UTI are found in or around the gastrointestinal and genitourinary tracts and also are part of the normal skin flora. The introduction and/or facilitated ascension of these microorganisms is believed to occur during UC insertion.^16,17 Two-thirds of all isolated uropathogens in those with indwelling UCs are extraluminally acquired (via ascension along the catheter-urethral mucosa interface), and one-third are believed to be intraluminally acquired.¹⁸

The most commonly isolated bacteria in CA-UTI are Enterobacteriaceae, which include Escherichia coli (most common), Klebsiella species (K. oxytoca, K. pneumoniae), Serratia species (S. marcescens), Citrobacter species (C. koseri), Enterobacter species (E. cloacae), and Proteus species; non-Enterobacteriaceae such as Pseudomonas species; and gram-positive cocci, which include coagulase-negative staphylococci (S. saprophyticus), Staphylococcus aureus, group B streptococci, and Enterococcus species (E. faecalis, E. faecium).^19-21 Coagulase-negative staphylococci and Enterococcus species can lead to CA-UTI but are usually avirulent and more commonly isolated from asymptomatic individuals.¹⁹ Also, coagulase-negative staphylococci such as S. epidermidis and S. lugdunensis are usually the manifestation of contamination during the collection process and their presence should prompt a repeat sample collection under sterile techniques. Monomicrobial infection is usually seen in those with short-term catheter use and CA-UTI. In contrast, polymicrobial infection is more common in those with long-term indwelling UCs and CA-UTI.¹⁹ Providencia stuartii, Proteus mirabilis, S. aureus, and Morganella morganii have all been associated with CA-UTI in those with long-term indwelling UCs.

Growth of S. aureus in the urine should prompt further investigation with blood cultures to explore the possibility of hematogenous dissemination to the urinary tract. Organisms leading to bacteremia due to CA-UTI are most commonly gram-negative bacilli (E. coli, Klebsiella species, Pseudomonas aeruginosa) and E. faecalis.²¹

What is the difference between CA-ASB and CA-UTI?

CA-ASB is defined as the presence of ≥ 1 bacteria species growing on urine culture at ≥ 100,000 cfu/mL in a patient with a history of urinary catheterization and/or indwelling UC who lacks signs or symptoms of UTI. In a man with a condom catheter, CA-ASB is defined using the same criteria, but the urine sample is collected after a fresh condom catheter is applied.⁵ The difference between CA-ASB and CA-UTI is simply the presence or absence of signs and symptoms related to UTI. Currently, there is no standard definition for significant bacteriuria in a catheterized patient.⁵ Pyuria found on urinalysis is indicative of genitourinary inflammation and can be present in both CA-ASB and CA-UTI. The absence, presence, and/or degree of pyuria in catheterized patients does not accurately differentiate between CA-ASB and CA-UTI.^5,22,23 On the other hand, the absence of pyuria in a symptomatic catheterized patient suggests an etiology other than CA-UTI.⁵

How can CA-UTI be prevented in patients with a short-term indwelling urinary catheter?

If a short-term UC is essential, the most important approach to preventing CA-UTI is limiting the duration of time it will be used. Strategies such as computer-based order entry and care maps with automated discontinuation of UCs have been shown to decrease catheter usage.¹⁹ Using closed-systems for UC collection with ports in the distal catheter for needle aspiration of urine has also been shown to decrease the incidence of CA-UTI.⁵ Securing the UC to avoid urethral trauma, aseptic techniques for insertion and repositioning, and placement of the tubing and collection bag below the level of the bladder to prevent reflux will likely also prevent CA-UTI, but these strategies have not been evaluated thoroughly.¹⁹

When should you screen for and treat CA-ASB?

The 2009 Infectious Diseases Society of America (IDSA) guidelines recommend that the only patients who should be screened and treated for CA-ASB are pregnant women and those who will undergo a potentially traumatic urologic procedure for which mucosal breaching may occur, causing bleeding. Routinely screening or treating patients for CA-ASB in not recommended in any other group of patients and will lead to unnecessary antibiotic use and antibiotic resistance.⁵

UTI Associated with Percutaneous Nephrostomy and Ureteral Stenting

Similar systemic symptoms of infection (fever, rigors, malaise, shock) are present in patients with and without percutaneous nephrostomy (PCN) and/or ureteral stent placement. Dysuria is not commonly present in those with PCN. The first signs of CA-UTI may be decreased urine output and pericatheter leakage due to an obstructive process resulting from the encrustation.^24-27 The most common complaint among patients with either acute or chronic ureteral stenting is discomfort, which has been described as “urinary symptoms” and “body pain.”²⁸ This discomfort can be related to ureteral hyperperistalsis after placement of the stent and is usually self-limiting. Ureteral stent migration, usually at the distal end, can also lead to discomfort, but is easily rectified with cystoscopy.²⁵ Body pain and/or urinary symptoms in the setting of ureteral stenting are not indicative of infection alone.

What is urinary catheter and/or ureteral stent encrustation?

Encrustation is the formation of a conditioning film that develops on the surface of the UC or ureteral stent. The exact mechanism is not well understood, but it is believed to involve electrostatic interactions of urinary proteins that stimulate binding onto the stent or UC surface.²⁵ Encrustation increases exponentially with the dwell time. Among patients with ureteral stents placed due to urolithiasis, encrustation occurred in 9.2% of stents removed prior to 6 weeks, 47.5% of stents removed at 6 weeks, and 76.3% of stents removed at 12 weeks.²⁶ Encrustation is most common at the proximal and distal ends (pigtails) of the ureteral stent and usually spares or presents last within the lumen.²⁹ Attempts have been made to prevent ureteral stent encrustation through the development of biodegradable, drug-eluting, and tissue-engineered substrates. These developments are promising, but currently there is limited observational data from large randomized trials to suggest that these new modalities decrease rates of encrustation.²⁵ Encrustation is highly associated with certain microorganisms, especially those that create biofilms.³⁰ Urease-producing bacteria, most commonly P. mirabilis, play a role in encrustation formation.³¹ Bacteria most commonly associated with encrustation include Proteus species (P. mirabilis is most common), P. aeruginosa, K. pneumoniae, Providencia species (P. stuartii is most common), and M. morganii.

Does ureteral stent bacterial colonization correlate with UTI?

Ureteral stent colonization with bacteria increases with dwell time and is found in 40% to 98.5% of stents placed.^32-35 If UTI is suspected in a patient with an active indwelling ureteral stent, a sample of urine should be cultured while the stent is in place.²⁵ Typically, genitourinary and normal skin flora pathogens are found when the ureteral stent is cultured. The top 3 organisms cultured from ureteral stents are S. aureus, P. aeruginosa, and E. faecalis.³⁴ Urine culture usually does not correlate with stent culture results, which has brought up the debate of how bacterial colonization occurs. It has been postulated that colonization is actually a manifestation of contamination during the insertion procedure, but this has yet to be validated.²⁵ In patients with symptoms of UTI in the setting of an indwelling ureteral stent, a positive culture has low sensitivity, with estimates between 21% and 40%.³⁵ Therefore, a negative urine culture does not rule out UTI alone in a symptomatic patient. Multiple studies have suggested that colonization of the ureteral stent does not correlate strongly with developing a UTI.^25,32-34

How can UTI be prevented in those receiving PCN or ureteral stent placement?

Antibiotic prophylaxis has been recommended to prevent UTI in patients who will undergo PCN or ureteral stent placement. The American Urological Association recommends empiric treatment even in the absence of signs and symptoms of UTI,³⁶ but substantial evidence is lacking that this approach prevents infection.³⁷ Ciprofloxacin or trimethoprim/sulfamethoxazole has been recommended by some for empiric coverage for enteric gram-negative bacilli and enterococcus in those undergoing genitourinary manipulation or instrumentation.^32,38 Most patients who develop CA-UTI and pyelonephritis do so within the first 2 to 6 weeks after placement.^37,39 Bacteriuria, candiduria, and/or pyuria are present in all patients approximately within 9 weeks even when sterile urine is confirmed prior to PCN placement.³⁹ Data on the effectiveness of antibiotic prophylaxis to prevent CA-UTI in those with PCN or ureteral stenting is limited. Currently, there are no recommendations from the IDSA on how to prevent infection in these situations.⁵ Early or frequent stent removal or exchanges has been proven to reduce UTI in those with ureteral stenting.³³ Patients with diabetes mellitus and chronic renal failure are at high-risk for UTI when ureteral stents are in place. This population should undergo close monitoring for UTI development and may warrant more frequent stent exchanges.^27,40

What is the treatment of CA-UTI associated with PCN and/or ureteral stenting?

The IDSA guidelines do not apply to patients with PCN and/or ureteral stenting.⁵ There is no treatment protocol for UTI related to these processes. Generally speaking, they are considered “complicated UTI” by most experts. Broad-spectrum, empiric antibiotic administration along with prompt removal of the PCN and/or ureteral stent is the gold standard of therapy.²⁷ The recommended duration of targeted antibiotic therapy is generally between 5 and 14 days.¹⁹ Most clinicians will treat this complicated UTI for at least 10 to 14 days. Antibiotic administration should be continued even after removal of the catheter and/or stent to complete the full course. Repeat urinalysis and culture is not indicated at the end of therapy if the patient is clinically improving or has remission of symptoms.

What is the exchange rate for those who require chronic PCN and/or ureteral stent use?

On average a PCN or ureteral stent should be exchanged every 2 to 3 months in patients who require chronic usage.^24,27 Some patients with persistent complications may require more frequent exchanges (< 10 weeks).²⁷ Encrustation and bacterial colonization become more prevalent the longer the devices are in place. This process is estimated to begin within the first 2 weeks after placement.^27,33,34 A “forgotten stent” is one that has been left in place after the patient is lost to follow-up. This unfortunate event can lead to massive encrustation, UTI, stent fracturing, and complete ureteral obstruction.²⁴ As noted, patients with diabetes mellitus, chronic renal failure, and frequent UTI may warrant more frequent exchanges, but this should be determined on a case-by-case basis.

Spinal cord injury (SCI) at any level can cause neurogenic bladder. This process ultimately leads to urinary stasis and colonization of the bladder with bacteria. According to the IDSA, the acceptable indications for UC insertion are: clinically significant urinary retention (if medical therapy is not effective), urinary incontinence, accurate urine output monitoring required, and patient is unable and/or unwilling to collect urine (Table 1).⁵ Recently, further guidelines were published regarding appropriate and inappropriate indwelling UC placement in hospitalized medical patients (Table 2 and Table 3), expanding upon the earlier acceptable criteria provided by the IDSA.⁴¹ According to the IDSA and Ann Arbor Criteria for Appropriate Urinary Catheter Use, patients with SCI and subsequent neurogenic bladder without obstruction where intermittent bladder straight catheterization for the drainage of urine is not feasible will likely need an indwelling UC.⁴¹ SCI patients often experience decubitus ulcers, and an indwelling UC can be used if needed to help with wound healing if other urinary management alternatives have been attempted. Other such situations in which an indwelling UC can used before attempting alternative approaches would be in a patient who is actively dying and is pursuing comfort care and/or hospice.⁴¹

Which indwelling UCs should be used in patients with SCI?

Efforts to reduce the likelihood of infection in patients with SCI have led to several advances in the design and manufacturing of UCs. UCs are made of either latex, plastic, silicone, or polytetrafluoroethylene (Teflon). None of these substrates is free of complications, but of them latex UCs have been studied the most in regards to their associated complications. Aside from being allergenic in nature, latex UCs have an increased propensity to allow bacteria to adhere to their surface due to microscopic planes of unevenness.⁴² Silicone UCs are less frequently associated with infection but are more rigid, leading to increased discomfort.^43,44 Hydrophilic and silver-hydrogel coatings are innovative methods that have been developed to increase comfort and reduce the likelihood of infection. Hydrophilic-coated UCs are associated with reduced microbial adherence, decreased encrustation, and better patient satisfaction.^45,46 In SCI patients, these UCs have demonstrated lower complication rates, including UTI; fewer episodes of post-, intra-, and inter-catheterization bleeding; and decreased rates of antibiotic-resistant bacteria.^45,46 Silver-hydrogel-coated UCs are less well studied but have also demonstrated reduced UTI rates in SCI patients; however, their efficacy over the long term has yet to be determined. Antibiotic-impregnated UCs are not currently recommended for either short- or long-term indwelling UC use.⁵

How can CA-UTI be prevented in a patient who will require a long-term indwelling catheter?

At this time, the data is insufficient to make a recommendation on routine UC exchange (eg, every 2 to 4 weeks) in patients who require long-term indwelling urethral or suprapubic catheters in an attempt to reduce the risk of CA-ASB or CA-UTI. This is also true for those who experience even repeated early catheter blockage from encrustation.⁵ Thus, the rate at which these exchanges occur can be controversial, but typically around every 4 weeks is a common approach. Some would argue that if the patient has repeated CA-UTI, an exchange rate of every 2 weeks might be needed, but data is currently lacking to support this practice.⁵ If intermittent urinary catheterization is feasible, it should be done at least every 6 hours and before bedtime. In general, when the volume of urine in the bladder reaches approximately 400 mL, the patient should undergo bladder catheterization to prevent stasis and infection.⁴⁷ A closed drainage system is recommended in all patients who require long-term indwelling UC use.^48,49 Placement of the collection bag above the catheter or above the level of the bladder and a breach in the closed drainage system have been shown to result in higher rates of catheter-associated bacteriuria.^48,50 Proper hand hygiene and sterile and/or clean techniques should be used when placing or exchanging a UC. However, in one study there was no difference in bacteremia or UTIs when using sterile versus clean techniques.⁵¹

Asymptomatic bacteriuria should not be treated in patients with long-term indwelling UCs, and prophylactic antibiotics have led to the emergence of resistance.⁵² At this time it is not clear whether prophylactic weekly oral cyclic antibiotic administration can effectively reduce the frequency of CA-UTI in patients with SCI and chronic indwelling UC use.

What are the signs and symptoms of CA-UTI in a patient with SCI?

Subjective and objective findings may be limited when a patient with SCI presents with CA-UTI. These patients often lack the usual symptoms of UTI (dysuria, suprapubic discomfort, urgency, increased frequency) and pyelonephritis (flank pain, costovertebral angle tenderness). Caregivers and health care providers should be aware that nonspecific symptoms such as foul-smelling urine, pyuria, increased residual volume of urine in the bladder, change in voiding habits, worsening detrusor spasticity, and aggravation of autonomic dysreflexia can be the only initial presenting symptoms.⁵³

Antibiotic therapy is indicated for a duration of 7 days if there is prompt resolution of symptoms, or for a total of 10 to 14 days if the response is delayed, regardless of whether the patient remains with a UC.⁵ Antibiotic stewardship is very important to reduce the risk for developing drug resistance in this high-risk population. Methods such as prescriber education practices, institution protocols, guideline implementation, auditing and feedback, restriction and reauthorization practices, computer-assisted programs, de-escalation or streamlining, and antibiotic cycling or dosage optimization have all been shown to assist in antibiotic stewardship in UTIs.⁵⁴

Candida UTI

What is the initial evaluation for a patient with candiduria?

The workup for candiduria hinges on determining whether the candiduria likely represents contamination, colonization, or infection; certain predisposing risk factors are associated with Candida UTI (Table 4).^55-57 The most important aspect to candiduria is the patient’s clinical status and comorbid conditions.⁵⁸ Among funguria, Candida species are the most common and represent 95% of organisms isolated on urine cultures (Table 5).⁵⁹ Candiduria is usually present in those with significant comorbidities and rarely is associated with healthy individuals.^59,60 Candiduria is increasing in prevalence among hospitalized patients, representing 22% to 40% of all nosocomial UTIs.^59,60 Markers in the urine (leukocyte esterase, colony count of culture growth, presence or absence of Candida casts and pseudohyphae) cannot alone differentiate colonization from infection.⁵⁵ When candiduria is discovered in a patient with symptoms related to UTI in the setting of predisposing risk factors, it should be considered a real infection until proven otherwise.

In a situation where an asymptomatic patient without an indwelling UC has Candida species isolated from a urine culture, a repeat culture (clean-catch midstream sample) should be performed to assess for a likely contaminated collection.⁵⁵ If the patient has an indwelling UC then it should be exchanged and urine collected from the fresh catheter.⁶¹ When candiduria is found in healthy asymptomatic adults, it is most commonly associated with poor collection techniques or postcollection contamination.⁵⁹ If candiduria persists in an asymptomatic patient, the patient should be assessed for predisposing factors. This includes checking hemoglobin A1C for developing diabetes and renal ultrasound looking for urolithiasis, renal abscess, hydronephrosis, and fungus ball. Postvoid residual urinary retention should also be ruled out with bladder ultrasound. Treatment of predisposing factors can lead to resolution of candiduria without antifungal treatment, and a urine culture should be repeated (1 to 2 weeks later).⁶¹ Asymptomatic patients lacking any predisposing factors can be observed with repeat urine cultures in 1 to 3 months.⁶¹

Candiduria may actually represent candidemia in those patients who have a predisposing risk factor for disseminated candidiasis. These risk factors include central venous catheters, administration of total parental nutrition, antibiotic use (especially broad spectrum), critical illness, recent surgical intervention (especially intra-abdominal), acute renal failure, nasogastric tube use, and active gastric acid suppression (ie, proton pump inhibitors).^62,63 The hematogenous spread of Candida can lead to the detection of candiduria in 46% to 80% of persons who are experiencing candidemia.⁵⁹ If the patient is at risk for candidemia, then blood fungal cultures should be drawn. It is not unreasonable to also order a serum-D-glucan assay if suspicions are high. A thorough skin assessment should be completed and ophthalmology consulted for a detailed eye exam in the event that the patient has candidemia. Candiduria is highly prevalent among those who are candidemic, but overall candidemia is encountered in less than 5% of patients in most intensive care units.⁵⁹ Thus, most patients with candiduria do not have disseminated candidiasis.

Candiduria rarely leads to symptoms of UTI,⁵⁸ unless the pathogenesis is related to an ascending process.⁵⁶ Symptoms of Candida UTI are no different from those experienced from a bacterial etiology. Some patients may complain of pneumaturia and/or endorse seeing particulate matter in their urine.⁵⁵ Patients showing signs of sepsis (fever, chills, flank pain) should be investigated for possible Candida pyelonephritis in the setting of candiduria.⁶⁴

When should asymptomatic candiduria be treated?

In adult patients with asymptomatic candiduria, there are 2 situations in which antifungal therapy is recommended. A patient undergoing a traumatic urologic procedure would be treated to avoid the risk for candidemia caused by the procedure. Also, in neutropenic patients empiric antifungal therapy should be administered because there is a high likelihood that this candiduria may actually represent hematogenous spread from candidemia.^61,65

What is the treatment for symptomatic Candida cystitis?

Empiric treatment with oral fluconazole 200 to 400 mg daily for a total of 2 weeks is recommended in patients with persisting candiduria and symptoms of cystitis.⁶⁵ Identifying the species is a crucial step in the treatment of Candida UTI. Several species (C. glabrata, C. krusei) are known to be resistant to fluconazole. Species identification and antifungal sensitivities should be done and therapy directed after obtaining these results.⁵⁵

What is the recommended treatment for Candida pyelonephritis?

Treatment for pyelonephritis caused by fluconazole-susceptible Candida species is oral fluconazole 200 to 400 mg (3-6 mg/kg) for a total of 2 weeks.⁶⁵ A fluconazole-resistant organism should be suspected when a non-albicans Candida species is isolated, such as C. krusei or C. glabrata. In this circumstance, in vitro antifungal susceptibility testing should be done. Echinocandins are not a good option in this situation because they do not reach adequate urine concentration and treatment failure is well documented.^66-68 Amphotericin B deoxycholate (AmB) 0.3 to 0.6 mg/kg daily for 1 to 7 days, with or without oral flucytosine (25 mg/kg) 4 times daily, is recommended by the IDSA for the treatment of fluconazole-resistant isolates of C. glabrata and C. krusei.⁶⁵ Further imaging with ultrasound, CT, or magnetic resonance should be done to rule out urinary tract obstruction and/or “fungus ball” formation. Emphysematous pyelonephritis and necrosis can occur and usually require nephrectomy. Perinephric abscess will need drainage, which can be accomplished through interventional radiological techniques.⁵⁵

If a “fungus ball” is suspected in the kidney, how does the management change in a patient with Candida pyelonephritis?

A fungus ball must be treated with both antifungals and surgical intervention. Antifungal therapy should be continued during the surgical removal process to avoid fungemia. Interventional radiology should be consulted and is usually the best option for removal. Fungus ball(s) can and often do cause urinary obstruction. Temporary nephrostomy tube placement may be warranted in these situations to relieve the obstruction.^55,65 AmB can be infused through the nephrostomy tube to increase local concentrations. This route of administration is not known to be nephrotoxic.⁵⁵ Fluconazole infusion through a nephrostomy tube has also been used in the successful treatment of a fungus ball.⁶⁹

Summary

Health care–associated UTIs are the most common nosocomial infection in the United States. UC placement and genitourinary manipulation or instrumentation play a major role in the development of CA-UTI. Clinicians should be aware of the appropriate and inappropriate use of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key in prevention of CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. A multidisciplinary approach is essential when managing chronic indwelling UCs in SCI. PCN and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected.

Candiduria is an emerging nosocomial source of UTI but rarely leads to symptoms unless related to an ascending process. Proper urine collection is crucial in determining whether you are dealing with contamination, colonization, or infection. If candiduria persists in an asymptomatic individual, then further investigations should be done in regards to possible predisposing risks factors. Fluconazole is recommended for treatment of most patients with Candida UTI, while intravenous AmB is the treatment of choice for fluconazole-resistant Candida species. As we continue to take an evidence-based approach to the prevention and management of health care-associated UTI, we will likely see continued improvement in patient outcomes and overall decreased rates of infection.

Corresponding author: Norman Beatty, MD, 1501 N. Campbell Ave., Tucson, AZ 85724; [email protected].

Financial disclosures: None.

From the University of Arizona College of Medicine, Tucson, AZ (Dr. Beatty), and the Baylor College of Medicine, Houston, TX (Dr. Mohajer).

Abstract

• Objective: To review management issues regarding health care–associated urinary tract infections (UTIs) commonly encountered by practicing clinicians.
• Methods: Review of the literature.
• Results: Because urinary catheter (UC) placement plays a major role in the development of catheter-associated UTIs (CA-UTI), clinicians should be aware of the appropriate and inappropriate uses of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key to preventing CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. Percutaneous nephrostomy and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected. Candiduria rarely leads to symptoms unless it is related to an ascending process. Proper urine collection is crucial in determining whether contamination, colonization, or infection is present. Fluconazole is recommended in most cases of Candida UTI, while intravenous amphotericin B is recommended for fluconazole-resistant Candida species.
• Conclusion: Continued use of evidence-based strategies for preventing and managing health care–associated UTI should lead to further improvements in patient outcomes and overall decreased rates of infection.

Keywords: bacteriuria; catheter-associated UTI; catheterization; percutaneous nephrostomy; candiduria.

Health care–associated urinary tract infections (UTIs) are estimated to be the most common adverse infectious event in U.S. hospitals, occurring in 1 of 10 admitted patients.^1-3 Approximately 32% of all health care–associated infections are UTIs.¹ Furthermore, urinary catheters (UCs) are associated with 8% to 21% of health care–associated infections that occur in the intensive care unit.⁴ The most important predisposing factor for nosocomial UTI is urinary catheterization.⁵ Genitourinary manipulation and/or implementation also play a major role in the development of nosocomial UTIs.

In 2008, the U.S. Centers for Medicare & Medicaid Services instituted a new policy that reduced reimbursement rates for hospitalizations linked to health care–associated infections.⁶ Indwelling UCs are among the most overused health care devices in the hospital setting. They are placed in an estimated 15% to 25% of all hospitalized patients,^7,8 and are often inserted in the emergency department (ED) without a physician order or appropriate indication.⁹ Intermittent straight catheterization, male or female condom catheterization, and/or placement of an indwelling UC are the most common causes of catheter-associated asymptomatic bacteriuria (CA-ASB) and catheter-associated UTIs (CA-UTI).⁵ Prevention and management of CA-ASB and CA-UTI can be challenging and require an evidence-based approach. Furthermore, guidelines for the management of UTIs in the setting of active percutaneous nephrostomy (PCN) drainage and/or ureteral stenting are not established.⁵ This may leave clinicians with little mainstream data to aid in management decisions.

In 2009 the Centers for Disease Control and Prevention provided a guideline for the appropriate and inappropriate use of indwelling UCs to help promote their proper use.¹⁰ In the time since the guideline’s initiatives were instituted around the United States, published data have shown some improvement in the use of UCs,^11,12 but other recent reports indicate that rates of UC use have remained unchanged.¹³ This review discusses management issues regarding health care–associated UTIs that are commonly encountered by practicing clinicians, with a focus on current guidelines and evidence.

Catheter-Associated UTI

CA-UTI is defined as the presence of signs or symptoms of UTI with no other explainable infectious source along with ≥ 1000 colony-forming units (cfu) of ≥ 1 bacterial species per milliliter in a urine specimen from a catheter that has been changed within 48 hours of collection of the urine specimen.⁵ Signs and symptoms of CA-UTI include, but are not limited to: new-onset or worsening fever, chills, altered sensorium from baseline, lethargy, malaise, flank pain, pelvic pain, costovertebral angle tenderness, and acute hematuria.⁵ New-onset “foul-smelling” (odorous)urine and “cloudy” urine are neither sensitive nor specific when assessing for CA-UTI, and do not have significant clinical relevance when found alone.^14,15 Patients who have removed or exchanged the UC during this event and then experience dysuria, increased frequency, urgency, or suprapubic pain are likely having symptoms of CA-UTI.⁵

What is the recommended method for collecting urine samples when CA-UTI is suspected?

In a patient with an indwelling catheter that has been in place for more than 2 weeks at the onset of a suspected CA-UTI, the catheter should be replaced (if still indicated) or removed to accelerate resolution of symptoms and to reduce the risk of subsequent catheter-associated bacteriuria and CA-UTI. The urine culture should be acquired from the freshly placed UC.⁵

When should a patient be empirically treated?

A patient presenting with evidence of sepsis should be empirically treated with antimicrobials. Empiric coverage should be based on risk factors for multidrug-resistant organisms and data pertaining to local antimicrobial resistance patterns. A urine specimen for urinalysis and possible culture should be sent prior to administering empiric antibiotics (if possible) in a symptomatic patient.⁵

What bacteria are commonly associated with CA-UTI?

The bacteria most commonly associated with CA-UTI are found in or around the gastrointestinal and genitourinary tracts and also are part of the normal skin flora. The introduction and/or facilitated ascension of these microorganisms is believed to occur during UC insertion.^16,17 Two-thirds of all isolated uropathogens in those with indwelling UCs are extraluminally acquired (via ascension along the catheter-urethral mucosa interface), and one-third are believed to be intraluminally acquired.¹⁸

The most commonly isolated bacteria in CA-UTI are Enterobacteriaceae, which include Escherichia coli (most common), Klebsiella species (K. oxytoca, K. pneumoniae), Serratia species (S. marcescens), Citrobacter species (C. koseri), Enterobacter species (E. cloacae), and Proteus species; non-Enterobacteriaceae such as Pseudomonas species; and gram-positive cocci, which include coagulase-negative staphylococci (S. saprophyticus), Staphylococcus aureus, group B streptococci, and Enterococcus species (E. faecalis, E. faecium).^19-21 Coagulase-negative staphylococci and Enterococcus species can lead to CA-UTI but are usually avirulent and more commonly isolated from asymptomatic individuals.¹⁹ Also, coagulase-negative staphylococci such as S. epidermidis and S. lugdunensis are usually the manifestation of contamination during the collection process and their presence should prompt a repeat sample collection under sterile techniques. Monomicrobial infection is usually seen in those with short-term catheter use and CA-UTI. In contrast, polymicrobial infection is more common in those with long-term indwelling UCs and CA-UTI.¹⁹ Providencia stuartii, Proteus mirabilis, S. aureus, and Morganella morganii have all been associated with CA-UTI in those with long-term indwelling UCs.

Growth of S. aureus in the urine should prompt further investigation with blood cultures to explore the possibility of hematogenous dissemination to the urinary tract. Organisms leading to bacteremia due to CA-UTI are most commonly gram-negative bacilli (E. coli, Klebsiella species, Pseudomonas aeruginosa) and E. faecalis.²¹

What is the difference between CA-ASB and CA-UTI?

CA-ASB is defined as the presence of ≥ 1 bacteria species growing on urine culture at ≥ 100,000 cfu/mL in a patient with a history of urinary catheterization and/or indwelling UC who lacks signs or symptoms of UTI. In a man with a condom catheter, CA-ASB is defined using the same criteria, but the urine sample is collected after a fresh condom catheter is applied.⁵ The difference between CA-ASB and CA-UTI is simply the presence or absence of signs and symptoms related to UTI. Currently, there is no standard definition for significant bacteriuria in a catheterized patient.⁵ Pyuria found on urinalysis is indicative of genitourinary inflammation and can be present in both CA-ASB and CA-UTI. The absence, presence, and/or degree of pyuria in catheterized patients does not accurately differentiate between CA-ASB and CA-UTI.^5,22,23 On the other hand, the absence of pyuria in a symptomatic catheterized patient suggests an etiology other than CA-UTI.⁵

How can CA-UTI be prevented in patients with a short-term indwelling urinary catheter?

If a short-term UC is essential, the most important approach to preventing CA-UTI is limiting the duration of time it will be used. Strategies such as computer-based order entry and care maps with automated discontinuation of UCs have been shown to decrease catheter usage.¹⁹ Using closed-systems for UC collection with ports in the distal catheter for needle aspiration of urine has also been shown to decrease the incidence of CA-UTI.⁵ Securing the UC to avoid urethral trauma, aseptic techniques for insertion and repositioning, and placement of the tubing and collection bag below the level of the bladder to prevent reflux will likely also prevent CA-UTI, but these strategies have not been evaluated thoroughly.¹⁹

When should you screen for and treat CA-ASB?

The 2009 Infectious Diseases Society of America (IDSA) guidelines recommend that the only patients who should be screened and treated for CA-ASB are pregnant women and those who will undergo a potentially traumatic urologic procedure for which mucosal breaching may occur, causing bleeding. Routinely screening or treating patients for CA-ASB in not recommended in any other group of patients and will lead to unnecessary antibiotic use and antibiotic resistance.⁵

UTI Associated with Percutaneous Nephrostomy and Ureteral Stenting

Similar systemic symptoms of infection (fever, rigors, malaise, shock) are present in patients with and without percutaneous nephrostomy (PCN) and/or ureteral stent placement. Dysuria is not commonly present in those with PCN. The first signs of CA-UTI may be decreased urine output and pericatheter leakage due to an obstructive process resulting from the encrustation.^24-27 The most common complaint among patients with either acute or chronic ureteral stenting is discomfort, which has been described as “urinary symptoms” and “body pain.”²⁸ This discomfort can be related to ureteral hyperperistalsis after placement of the stent and is usually self-limiting. Ureteral stent migration, usually at the distal end, can also lead to discomfort, but is easily rectified with cystoscopy.²⁵ Body pain and/or urinary symptoms in the setting of ureteral stenting are not indicative of infection alone.

What is urinary catheter and/or ureteral stent encrustation?

Encrustation is the formation of a conditioning film that develops on the surface of the UC or ureteral stent. The exact mechanism is not well understood, but it is believed to involve electrostatic interactions of urinary proteins that stimulate binding onto the stent or UC surface.²⁵ Encrustation increases exponentially with the dwell time. Among patients with ureteral stents placed due to urolithiasis, encrustation occurred in 9.2% of stents removed prior to 6 weeks, 47.5% of stents removed at 6 weeks, and 76.3% of stents removed at 12 weeks.²⁶ Encrustation is most common at the proximal and distal ends (pigtails) of the ureteral stent and usually spares or presents last within the lumen.²⁹ Attempts have been made to prevent ureteral stent encrustation through the development of biodegradable, drug-eluting, and tissue-engineered substrates. These developments are promising, but currently there is limited observational data from large randomized trials to suggest that these new modalities decrease rates of encrustation.²⁵ Encrustation is highly associated with certain microorganisms, especially those that create biofilms.³⁰ Urease-producing bacteria, most commonly P. mirabilis, play a role in encrustation formation.³¹ Bacteria most commonly associated with encrustation include Proteus species (P. mirabilis is most common), P. aeruginosa, K. pneumoniae, Providencia species (P. stuartii is most common), and M. morganii.

Does ureteral stent bacterial colonization correlate with UTI?

Ureteral stent colonization with bacteria increases with dwell time and is found in 40% to 98.5% of stents placed.^32-35 If UTI is suspected in a patient with an active indwelling ureteral stent, a sample of urine should be cultured while the stent is in place.²⁵ Typically, genitourinary and normal skin flora pathogens are found when the ureteral stent is cultured. The top 3 organisms cultured from ureteral stents are S. aureus, P. aeruginosa, and E. faecalis.³⁴ Urine culture usually does not correlate with stent culture results, which has brought up the debate of how bacterial colonization occurs. It has been postulated that colonization is actually a manifestation of contamination during the insertion procedure, but this has yet to be validated.²⁵ In patients with symptoms of UTI in the setting of an indwelling ureteral stent, a positive culture has low sensitivity, with estimates between 21% and 40%.³⁵ Therefore, a negative urine culture does not rule out UTI alone in a symptomatic patient. Multiple studies have suggested that colonization of the ureteral stent does not correlate strongly with developing a UTI.^25,32-34

How can UTI be prevented in those receiving PCN or ureteral stent placement?

Antibiotic prophylaxis has been recommended to prevent UTI in patients who will undergo PCN or ureteral stent placement. The American Urological Association recommends empiric treatment even in the absence of signs and symptoms of UTI,³⁶ but substantial evidence is lacking that this approach prevents infection.³⁷ Ciprofloxacin or trimethoprim/sulfamethoxazole has been recommended by some for empiric coverage for enteric gram-negative bacilli and enterococcus in those undergoing genitourinary manipulation or instrumentation.^32,38 Most patients who develop CA-UTI and pyelonephritis do so within the first 2 to 6 weeks after placement.^37,39 Bacteriuria, candiduria, and/or pyuria are present in all patients approximately within 9 weeks even when sterile urine is confirmed prior to PCN placement.³⁹ Data on the effectiveness of antibiotic prophylaxis to prevent CA-UTI in those with PCN or ureteral stenting is limited. Currently, there are no recommendations from the IDSA on how to prevent infection in these situations.⁵ Early or frequent stent removal or exchanges has been proven to reduce UTI in those with ureteral stenting.³³ Patients with diabetes mellitus and chronic renal failure are at high-risk for UTI when ureteral stents are in place. This population should undergo close monitoring for UTI development and may warrant more frequent stent exchanges.^27,40

What is the treatment of CA-UTI associated with PCN and/or ureteral stenting?

The IDSA guidelines do not apply to patients with PCN and/or ureteral stenting.⁵ There is no treatment protocol for UTI related to these processes. Generally speaking, they are considered “complicated UTI” by most experts. Broad-spectrum, empiric antibiotic administration along with prompt removal of the PCN and/or ureteral stent is the gold standard of therapy.²⁷ The recommended duration of targeted antibiotic therapy is generally between 5 and 14 days.¹⁹ Most clinicians will treat this complicated UTI for at least 10 to 14 days. Antibiotic administration should be continued even after removal of the catheter and/or stent to complete the full course. Repeat urinalysis and culture is not indicated at the end of therapy if the patient is clinically improving or has remission of symptoms.

What is the exchange rate for those who require chronic PCN and/or ureteral stent use?

On average a PCN or ureteral stent should be exchanged every 2 to 3 months in patients who require chronic usage.^24,27 Some patients with persistent complications may require more frequent exchanges (< 10 weeks).²⁷ Encrustation and bacterial colonization become more prevalent the longer the devices are in place. This process is estimated to begin within the first 2 weeks after placement.^27,33,34 A “forgotten stent” is one that has been left in place after the patient is lost to follow-up. This unfortunate event can lead to massive encrustation, UTI, stent fracturing, and complete ureteral obstruction.²⁴ As noted, patients with diabetes mellitus, chronic renal failure, and frequent UTI may warrant more frequent exchanges, but this should be determined on a case-by-case basis.

Spinal cord injury (SCI) at any level can cause neurogenic bladder. This process ultimately leads to urinary stasis and colonization of the bladder with bacteria. According to the IDSA, the acceptable indications for UC insertion are: clinically significant urinary retention (if medical therapy is not effective), urinary incontinence, accurate urine output monitoring required, and patient is unable and/or unwilling to collect urine (Table 1).⁵ Recently, further guidelines were published regarding appropriate and inappropriate indwelling UC placement in hospitalized medical patients (Table 2 and Table 3), expanding upon the earlier acceptable criteria provided by the IDSA.⁴¹ According to the IDSA and Ann Arbor Criteria for Appropriate Urinary Catheter Use, patients with SCI and subsequent neurogenic bladder without obstruction where intermittent bladder straight catheterization for the drainage of urine is not feasible will likely need an indwelling UC.⁴¹ SCI patients often experience decubitus ulcers, and an indwelling UC can be used if needed to help with wound healing if other urinary management alternatives have been attempted. Other such situations in which an indwelling UC can used before attempting alternative approaches would be in a patient who is actively dying and is pursuing comfort care and/or hospice.⁴¹

Which indwelling UCs should be used in patients with SCI?

Efforts to reduce the likelihood of infection in patients with SCI have led to several advances in the design and manufacturing of UCs. UCs are made of either latex, plastic, silicone, or polytetrafluoroethylene (Teflon). None of these substrates is free of complications, but of them latex UCs have been studied the most in regards to their associated complications. Aside from being allergenic in nature, latex UCs have an increased propensity to allow bacteria to adhere to their surface due to microscopic planes of unevenness.⁴² Silicone UCs are less frequently associated with infection but are more rigid, leading to increased discomfort.^43,44 Hydrophilic and silver-hydrogel coatings are innovative methods that have been developed to increase comfort and reduce the likelihood of infection. Hydrophilic-coated UCs are associated with reduced microbial adherence, decreased encrustation, and better patient satisfaction.^45,46 In SCI patients, these UCs have demonstrated lower complication rates, including UTI; fewer episodes of post-, intra-, and inter-catheterization bleeding; and decreased rates of antibiotic-resistant bacteria.^45,46 Silver-hydrogel-coated UCs are less well studied but have also demonstrated reduced UTI rates in SCI patients; however, their efficacy over the long term has yet to be determined. Antibiotic-impregnated UCs are not currently recommended for either short- or long-term indwelling UC use.⁵

How can CA-UTI be prevented in a patient who will require a long-term indwelling catheter?

At this time, the data is insufficient to make a recommendation on routine UC exchange (eg, every 2 to 4 weeks) in patients who require long-term indwelling urethral or suprapubic catheters in an attempt to reduce the risk of CA-ASB or CA-UTI. This is also true for those who experience even repeated early catheter blockage from encrustation.⁵ Thus, the rate at which these exchanges occur can be controversial, but typically around every 4 weeks is a common approach. Some would argue that if the patient has repeated CA-UTI, an exchange rate of every 2 weeks might be needed, but data is currently lacking to support this practice.⁵ If intermittent urinary catheterization is feasible, it should be done at least every 6 hours and before bedtime. In general, when the volume of urine in the bladder reaches approximately 400 mL, the patient should undergo bladder catheterization to prevent stasis and infection.⁴⁷ A closed drainage system is recommended in all patients who require long-term indwelling UC use.^48,49 Placement of the collection bag above the catheter or above the level of the bladder and a breach in the closed drainage system have been shown to result in higher rates of catheter-associated bacteriuria.^48,50 Proper hand hygiene and sterile and/or clean techniques should be used when placing or exchanging a UC. However, in one study there was no difference in bacteremia or UTIs when using sterile versus clean techniques.⁵¹

Asymptomatic bacteriuria should not be treated in patients with long-term indwelling UCs, and prophylactic antibiotics have led to the emergence of resistance.⁵² At this time it is not clear whether prophylactic weekly oral cyclic antibiotic administration can effectively reduce the frequency of CA-UTI in patients with SCI and chronic indwelling UC use.

What are the signs and symptoms of CA-UTI in a patient with SCI?

Subjective and objective findings may be limited when a patient with SCI presents with CA-UTI. These patients often lack the usual symptoms of UTI (dysuria, suprapubic discomfort, urgency, increased frequency) and pyelonephritis (flank pain, costovertebral angle tenderness). Caregivers and health care providers should be aware that nonspecific symptoms such as foul-smelling urine, pyuria, increased residual volume of urine in the bladder, change in voiding habits, worsening detrusor spasticity, and aggravation of autonomic dysreflexia can be the only initial presenting symptoms.⁵³

Antibiotic therapy is indicated for a duration of 7 days if there is prompt resolution of symptoms, or for a total of 10 to 14 days if the response is delayed, regardless of whether the patient remains with a UC.⁵ Antibiotic stewardship is very important to reduce the risk for developing drug resistance in this high-risk population. Methods such as prescriber education practices, institution protocols, guideline implementation, auditing and feedback, restriction and reauthorization practices, computer-assisted programs, de-escalation or streamlining, and antibiotic cycling or dosage optimization have all been shown to assist in antibiotic stewardship in UTIs.⁵⁴

Candida UTI

What is the initial evaluation for a patient with candiduria?

The workup for candiduria hinges on determining whether the candiduria likely represents contamination, colonization, or infection; certain predisposing risk factors are associated with Candida UTI (Table 4).^55-57 The most important aspect to candiduria is the patient’s clinical status and comorbid conditions.⁵⁸ Among funguria, Candida species are the most common and represent 95% of organisms isolated on urine cultures (Table 5).⁵⁹ Candiduria is usually present in those with significant comorbidities and rarely is associated with healthy individuals.^59,60 Candiduria is increasing in prevalence among hospitalized patients, representing 22% to 40% of all nosocomial UTIs.^59,60 Markers in the urine (leukocyte esterase, colony count of culture growth, presence or absence of Candida casts and pseudohyphae) cannot alone differentiate colonization from infection.⁵⁵ When candiduria is discovered in a patient with symptoms related to UTI in the setting of predisposing risk factors, it should be considered a real infection until proven otherwise.

In a situation where an asymptomatic patient without an indwelling UC has Candida species isolated from a urine culture, a repeat culture (clean-catch midstream sample) should be performed to assess for a likely contaminated collection.⁵⁵ If the patient has an indwelling UC then it should be exchanged and urine collected from the fresh catheter.⁶¹ When candiduria is found in healthy asymptomatic adults, it is most commonly associated with poor collection techniques or postcollection contamination.⁵⁹ If candiduria persists in an asymptomatic patient, the patient should be assessed for predisposing factors. This includes checking hemoglobin A1C for developing diabetes and renal ultrasound looking for urolithiasis, renal abscess, hydronephrosis, and fungus ball. Postvoid residual urinary retention should also be ruled out with bladder ultrasound. Treatment of predisposing factors can lead to resolution of candiduria without antifungal treatment, and a urine culture should be repeated (1 to 2 weeks later).⁶¹ Asymptomatic patients lacking any predisposing factors can be observed with repeat urine cultures in 1 to 3 months.⁶¹

Candiduria may actually represent candidemia in those patients who have a predisposing risk factor for disseminated candidiasis. These risk factors include central venous catheters, administration of total parental nutrition, antibiotic use (especially broad spectrum), critical illness, recent surgical intervention (especially intra-abdominal), acute renal failure, nasogastric tube use, and active gastric acid suppression (ie, proton pump inhibitors).^62,63 The hematogenous spread of Candida can lead to the detection of candiduria in 46% to 80% of persons who are experiencing candidemia.⁵⁹ If the patient is at risk for candidemia, then blood fungal cultures should be drawn. It is not unreasonable to also order a serum-D-glucan assay if suspicions are high. A thorough skin assessment should be completed and ophthalmology consulted for a detailed eye exam in the event that the patient has candidemia. Candiduria is highly prevalent among those who are candidemic, but overall candidemia is encountered in less than 5% of patients in most intensive care units.⁵⁹ Thus, most patients with candiduria do not have disseminated candidiasis.

Candiduria rarely leads to symptoms of UTI,⁵⁸ unless the pathogenesis is related to an ascending process.⁵⁶ Symptoms of Candida UTI are no different from those experienced from a bacterial etiology. Some patients may complain of pneumaturia and/or endorse seeing particulate matter in their urine.⁵⁵ Patients showing signs of sepsis (fever, chills, flank pain) should be investigated for possible Candida pyelonephritis in the setting of candiduria.⁶⁴

When should asymptomatic candiduria be treated?

In adult patients with asymptomatic candiduria, there are 2 situations in which antifungal therapy is recommended. A patient undergoing a traumatic urologic procedure would be treated to avoid the risk for candidemia caused by the procedure. Also, in neutropenic patients empiric antifungal therapy should be administered because there is a high likelihood that this candiduria may actually represent hematogenous spread from candidemia.^61,65

What is the treatment for symptomatic Candida cystitis?

Empiric treatment with oral fluconazole 200 to 400 mg daily for a total of 2 weeks is recommended in patients with persisting candiduria and symptoms of cystitis.⁶⁵ Identifying the species is a crucial step in the treatment of Candida UTI. Several species (C. glabrata, C. krusei) are known to be resistant to fluconazole. Species identification and antifungal sensitivities should be done and therapy directed after obtaining these results.⁵⁵

What is the recommended treatment for Candida pyelonephritis?

Treatment for pyelonephritis caused by fluconazole-susceptible Candida species is oral fluconazole 200 to 400 mg (3-6 mg/kg) for a total of 2 weeks.⁶⁵ A fluconazole-resistant organism should be suspected when a non-albicans Candida species is isolated, such as C. krusei or C. glabrata. In this circumstance, in vitro antifungal susceptibility testing should be done. Echinocandins are not a good option in this situation because they do not reach adequate urine concentration and treatment failure is well documented.^66-68 Amphotericin B deoxycholate (AmB) 0.3 to 0.6 mg/kg daily for 1 to 7 days, with or without oral flucytosine (25 mg/kg) 4 times daily, is recommended by the IDSA for the treatment of fluconazole-resistant isolates of C. glabrata and C. krusei.⁶⁵ Further imaging with ultrasound, CT, or magnetic resonance should be done to rule out urinary tract obstruction and/or “fungus ball” formation. Emphysematous pyelonephritis and necrosis can occur and usually require nephrectomy. Perinephric abscess will need drainage, which can be accomplished through interventional radiological techniques.⁵⁵

If a “fungus ball” is suspected in the kidney, how does the management change in a patient with Candida pyelonephritis?

A fungus ball must be treated with both antifungals and surgical intervention. Antifungal therapy should be continued during the surgical removal process to avoid fungemia. Interventional radiology should be consulted and is usually the best option for removal. Fungus ball(s) can and often do cause urinary obstruction. Temporary nephrostomy tube placement may be warranted in these situations to relieve the obstruction.^55,65 AmB can be infused through the nephrostomy tube to increase local concentrations. This route of administration is not known to be nephrotoxic.⁵⁵ Fluconazole infusion through a nephrostomy tube has also been used in the successful treatment of a fungus ball.⁶⁹

Summary

Health care–associated UTIs are the most common nosocomial infection in the United States. UC placement and genitourinary manipulation or instrumentation play a major role in the development of CA-UTI. Clinicians should be aware of the appropriate and inappropriate use of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key in prevention of CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. A multidisciplinary approach is essential when managing chronic indwelling UCs in SCI. PCN and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected.

Candiduria is an emerging nosocomial source of UTI but rarely leads to symptoms unless related to an ascending process. Proper urine collection is crucial in determining whether you are dealing with contamination, colonization, or infection. If candiduria persists in an asymptomatic individual, then further investigations should be done in regards to possible predisposing risks factors. Fluconazole is recommended for treatment of most patients with Candida UTI, while intravenous AmB is the treatment of choice for fluconazole-resistant Candida species. As we continue to take an evidence-based approach to the prevention and management of health care-associated UTI, we will likely see continued improvement in patient outcomes and overall decreased rates of infection.

Corresponding author: Norman Beatty, MD, 1501 N. Campbell Ave., Tucson, AZ 85724; [email protected].

Financial disclosures: None.

Over the past decade, Helicobacter pylori strains have reached “alarming levels” of antimicrobial resistance worldwide, investigators reported in the November issue of Gastroenterology.

In a large meta-analysis spanning 2007-2017, H. pylori isolates showed a 15% or higher pooled prevalence of primary and secondary resistance to clarithromycin, metronidazole, and levofloxacin in almost all World Health Organization (WHO) regions. “Local surveillance networks are required to select appropriate eradication regimens for each region,” concluded Alessia Savoldi, MD, of the University of Tübingen (Germany) and her associates.

Typically, the threshold of antimicrobial resistance for choosing empiric regimens is 15%, Dr. Savoldi and her associates noted. Their systematic review and meta-analysis included 178 studies comprising 66,142 isolates from 65 countries. They defined H. pylori infection as a positive histology, serology, stool antigen, urea breath test, or rapid urease test. They excluded studies of fewer than 50 isolates, studies that only reported resistance as a percentage with no denominator, studies that failed to specify time frames or clustered data over more than 3 years, and data reported in guidelines, conference presentations, or letters without formal publication.

Patho/Wikimedia Commons/CC BY-SA 3.0

SOURCE: Savoldi A et al. Gastroenterology. 2018 Nov. doi: 10.1053/j.gastro.2018.07.007.

Over the past decade, Helicobacter pylori strains have reached “alarming levels” of antimicrobial resistance worldwide, investigators reported in the November issue of Gastroenterology.

In a large meta-analysis spanning 2007-2017, H. pylori isolates showed a 15% or higher pooled prevalence of primary and secondary resistance to clarithromycin, metronidazole, and levofloxacin in almost all World Health Organization (WHO) regions. “Local surveillance networks are required to select appropriate eradication regimens for each region,” concluded Alessia Savoldi, MD, of the University of Tübingen (Germany) and her associates.

Typically, the threshold of antimicrobial resistance for choosing empiric regimens is 15%, Dr. Savoldi and her associates noted. Their systematic review and meta-analysis included 178 studies comprising 66,142 isolates from 65 countries. They defined H. pylori infection as a positive histology, serology, stool antigen, urea breath test, or rapid urease test. They excluded studies of fewer than 50 isolates, studies that only reported resistance as a percentage with no denominator, studies that failed to specify time frames or clustered data over more than 3 years, and data reported in guidelines, conference presentations, or letters without formal publication.

Patho/Wikimedia Commons/CC BY-SA 3.0

SOURCE: Savoldi A et al. Gastroenterology. 2018 Nov. doi: 10.1053/j.gastro.2018.07.007.

Over the past decade, Helicobacter pylori strains have reached “alarming levels” of antimicrobial resistance worldwide, investigators reported in the November issue of Gastroenterology.

In a large meta-analysis spanning 2007-2017, H. pylori isolates showed a 15% or higher pooled prevalence of primary and secondary resistance to clarithromycin, metronidazole, and levofloxacin in almost all World Health Organization (WHO) regions. “Local surveillance networks are required to select appropriate eradication regimens for each region,” concluded Alessia Savoldi, MD, of the University of Tübingen (Germany) and her associates.

Typically, the threshold of antimicrobial resistance for choosing empiric regimens is 15%, Dr. Savoldi and her associates noted. Their systematic review and meta-analysis included 178 studies comprising 66,142 isolates from 65 countries. They defined H. pylori infection as a positive histology, serology, stool antigen, urea breath test, or rapid urease test. They excluded studies of fewer than 50 isolates, studies that only reported resistance as a percentage with no denominator, studies that failed to specify time frames or clustered data over more than 3 years, and data reported in guidelines, conference presentations, or letters without formal publication.

Patho/Wikimedia Commons/CC BY-SA 3.0

SOURCE: Savoldi A et al. Gastroenterology. 2018 Nov. doi: 10.1053/j.gastro.2018.07.007.

For patients with inflammatory bowel disease (IBD), thiopurine exposure was associated with a significantly increased risk of herpes zoster, compared with 5-aminosalicylic acid (5-ASA) monotherapy, according to the results of two large retrospective cohort studies.

Joloei/Thinkstock

In the multivariable analysis, thiopurine monotherapy was linked to about a 47% increase in the risk of herpes zoster, compared with 5-ASA monotherapy (adjusted hazard ratio, 1.47; 95% confidence interval, 1.31-1.65; P less than .001). Combination therapy with thiopurines and tumor necrosis factor antagonists conferred about a 65% increase in zoster risk (aHR, 1.65; 95% CI, 1.22-2.23; P = .001). However, tumor necrosis factor–antagonist monotherapy did not appear to significantly increase the risk of zoster when compared with 5-ASA monotherapy, reported Nabeel Khan, MD, of the University of Pennsylvania in Philadelphia, and his associates.

“Compared to [patients without] IBD, ulcerative colitis (UC) and Crohn’s disease (CD) each were associated with significantly increased risk of herpes zoster infection,” the researchers wrote online in Clinical Gastroenterology and Hepatology. “With the approval of a new and potentially safer vaccine for herpes zoster, the effects of immunization of patients with IBD should be investigated.”

Past studies have linked IBD with a 1.2- to 1.8-fold increase in the risk of zoster, but these studies date to the prebiologic era or excluded patients who were in their midsixties or older, the researchers wrote. “Additionally, these prior studies have not assessed the validity of the codes used to identify herpes zoster and also did not account for the impact of vaccination,” they added. “They also did not take into consideration the severity of the disease or degree of steroid exposure.”

Therefore, the researchers conducted two retrospective cohort studies of patients in the United States Department of Veterans Affairs between 2000 and 2016. The first cohort study compared the incidence of herpes zoster among patients with IBD who received 5-ASA alone with matched patients without IBD. The second cohort study measured the incidence of herpes zoster in patients with IBD who received various medications and combination regimen. “The VA has a predominantly older population, which makes it an ideal cohort to study herpes zoster incidence in a high-risk population,” the investigators noted. “Unlike insurance databases, the VA database can be validated internally and vaccination records are documented.”

After adjusting for age, race, sex, geographic region, disease flare, corticosteroid use, and baseline comorbidities, the estimated hazard of developing herpes zoster was 1.81 (95% confidence interval, 1.56-2.11) among patients with ulcerative colitis and 1.56 (95% CI, 1.28-1.91) among patients with Crohn’s disease, as compared with patients without IBD. Regardless of their age or the medications they were receiving, patients with IBD had a higher incidence of zoster than the oldest group of patients without IBD (older than 60 years), regardless of age or medication. “The highest risk of herpes zoster was observed in patients with IBD who were less than 60 years of age and on combination therapy,” the investigators wrote. “Patients with IBD younger than 50 years who were on combination therapy had higher risk of herpes zoster, compared with patients with IBD older than 60 years of age who were not on immunosuppressive therapy.” Based on the findings, they recommended studying the efficacy of widespread use of the new herpes zoster vaccine in patients with IBD.

Pfizer provided unrestricted research funding but was not otherwise involved in the study. One coinvestigator disclosed ties to Pfizer and several other pharmaceutical companies. The remaining investigators reported having no conflicts of interest.
 

SOURCE: Khan N et al. Clin Gastroenterol Hepatol. 2018 Jan 5. doi: 10.1016/j.cgh.2017.12.052.

For patients with inflammatory bowel disease (IBD), thiopurine exposure was associated with a significantly increased risk of herpes zoster, compared with 5-aminosalicylic acid (5-ASA) monotherapy, according to the results of two large retrospective cohort studies.

Joloei/Thinkstock

In the multivariable analysis, thiopurine monotherapy was linked to about a 47% increase in the risk of herpes zoster, compared with 5-ASA monotherapy (adjusted hazard ratio, 1.47; 95% confidence interval, 1.31-1.65; P less than .001). Combination therapy with thiopurines and tumor necrosis factor antagonists conferred about a 65% increase in zoster risk (aHR, 1.65; 95% CI, 1.22-2.23; P = .001). However, tumor necrosis factor–antagonist monotherapy did not appear to significantly increase the risk of zoster when compared with 5-ASA monotherapy, reported Nabeel Khan, MD, of the University of Pennsylvania in Philadelphia, and his associates.

“Compared to [patients without] IBD, ulcerative colitis (UC) and Crohn’s disease (CD) each were associated with significantly increased risk of herpes zoster infection,” the researchers wrote online in Clinical Gastroenterology and Hepatology. “With the approval of a new and potentially safer vaccine for herpes zoster, the effects of immunization of patients with IBD should be investigated.”

Past studies have linked IBD with a 1.2- to 1.8-fold increase in the risk of zoster, but these studies date to the prebiologic era or excluded patients who were in their midsixties or older, the researchers wrote. “Additionally, these prior studies have not assessed the validity of the codes used to identify herpes zoster and also did not account for the impact of vaccination,” they added. “They also did not take into consideration the severity of the disease or degree of steroid exposure.”

Therefore, the researchers conducted two retrospective cohort studies of patients in the United States Department of Veterans Affairs between 2000 and 2016. The first cohort study compared the incidence of herpes zoster among patients with IBD who received 5-ASA alone with matched patients without IBD. The second cohort study measured the incidence of herpes zoster in patients with IBD who received various medications and combination regimen. “The VA has a predominantly older population, which makes it an ideal cohort to study herpes zoster incidence in a high-risk population,” the investigators noted. “Unlike insurance databases, the VA database can be validated internally and vaccination records are documented.”

After adjusting for age, race, sex, geographic region, disease flare, corticosteroid use, and baseline comorbidities, the estimated hazard of developing herpes zoster was 1.81 (95% confidence interval, 1.56-2.11) among patients with ulcerative colitis and 1.56 (95% CI, 1.28-1.91) among patients with Crohn’s disease, as compared with patients without IBD. Regardless of their age or the medications they were receiving, patients with IBD had a higher incidence of zoster than the oldest group of patients without IBD (older than 60 years), regardless of age or medication. “The highest risk of herpes zoster was observed in patients with IBD who were less than 60 years of age and on combination therapy,” the investigators wrote. “Patients with IBD younger than 50 years who were on combination therapy had higher risk of herpes zoster, compared with patients with IBD older than 60 years of age who were not on immunosuppressive therapy.” Based on the findings, they recommended studying the efficacy of widespread use of the new herpes zoster vaccine in patients with IBD.

Pfizer provided unrestricted research funding but was not otherwise involved in the study. One coinvestigator disclosed ties to Pfizer and several other pharmaceutical companies. The remaining investigators reported having no conflicts of interest.
 

SOURCE: Khan N et al. Clin Gastroenterol Hepatol. 2018 Jan 5. doi: 10.1016/j.cgh.2017.12.052.

For patients with inflammatory bowel disease (IBD), thiopurine exposure was associated with a significantly increased risk of herpes zoster, compared with 5-aminosalicylic acid (5-ASA) monotherapy, according to the results of two large retrospective cohort studies.

Joloei/Thinkstock

In the multivariable analysis, thiopurine monotherapy was linked to about a 47% increase in the risk of herpes zoster, compared with 5-ASA monotherapy (adjusted hazard ratio, 1.47; 95% confidence interval, 1.31-1.65; P less than .001). Combination therapy with thiopurines and tumor necrosis factor antagonists conferred about a 65% increase in zoster risk (aHR, 1.65; 95% CI, 1.22-2.23; P = .001). However, tumor necrosis factor–antagonist monotherapy did not appear to significantly increase the risk of zoster when compared with 5-ASA monotherapy, reported Nabeel Khan, MD, of the University of Pennsylvania in Philadelphia, and his associates.

“Compared to [patients without] IBD, ulcerative colitis (UC) and Crohn’s disease (CD) each were associated with significantly increased risk of herpes zoster infection,” the researchers wrote online in Clinical Gastroenterology and Hepatology. “With the approval of a new and potentially safer vaccine for herpes zoster, the effects of immunization of patients with IBD should be investigated.”

Past studies have linked IBD with a 1.2- to 1.8-fold increase in the risk of zoster, but these studies date to the prebiologic era or excluded patients who were in their midsixties or older, the researchers wrote. “Additionally, these prior studies have not assessed the validity of the codes used to identify herpes zoster and also did not account for the impact of vaccination,” they added. “They also did not take into consideration the severity of the disease or degree of steroid exposure.”

Therefore, the researchers conducted two retrospective cohort studies of patients in the United States Department of Veterans Affairs between 2000 and 2016. The first cohort study compared the incidence of herpes zoster among patients with IBD who received 5-ASA alone with matched patients without IBD. The second cohort study measured the incidence of herpes zoster in patients with IBD who received various medications and combination regimen. “The VA has a predominantly older population, which makes it an ideal cohort to study herpes zoster incidence in a high-risk population,” the investigators noted. “Unlike insurance databases, the VA database can be validated internally and vaccination records are documented.”

After adjusting for age, race, sex, geographic region, disease flare, corticosteroid use, and baseline comorbidities, the estimated hazard of developing herpes zoster was 1.81 (95% confidence interval, 1.56-2.11) among patients with ulcerative colitis and 1.56 (95% CI, 1.28-1.91) among patients with Crohn’s disease, as compared with patients without IBD. Regardless of their age or the medications they were receiving, patients with IBD had a higher incidence of zoster than the oldest group of patients without IBD (older than 60 years), regardless of age or medication. “The highest risk of herpes zoster was observed in patients with IBD who were less than 60 years of age and on combination therapy,” the investigators wrote. “Patients with IBD younger than 50 years who were on combination therapy had higher risk of herpes zoster, compared with patients with IBD older than 60 years of age who were not on immunosuppressive therapy.” Based on the findings, they recommended studying the efficacy of widespread use of the new herpes zoster vaccine in patients with IBD.

Pfizer provided unrestricted research funding but was not otherwise involved in the study. One coinvestigator disclosed ties to Pfizer and several other pharmaceutical companies. The remaining investigators reported having no conflicts of interest.
 

SOURCE: Khan N et al. Clin Gastroenterol Hepatol. 2018 Jan 5. doi: 10.1016/j.cgh.2017.12.052.

The Diagnosis: Self-healing Langerhans Cell Histiocytosis

Histopathologic examination showed an infiltrate of mononuclear cells with indented nuclei admixed with a variable dermal inflammatory infiltrate. Immunohistochemistry demonstrated cells that were strongly positive for CD1a (Figure, A) and langerin (Figure, B) antigens as well as S-100 protein (Figure, C), which was consistent with Langerhans cell histiocytosis (LCH).

Histiocytoses are a heterogeneous group of disorders in which the infiltrating cells belong to the mononuclear phagocyte system.^1,2 Langerhans cell histiocytosis is the most common dendritic cell-related histiocytosis, occurring in approximately 5 per 1 million children annually, giving it an incidence comparable to pediatric Hodgkin lymphoma and acute myeloid leukemia.^1,2

Historically, there has been much debate about the pathogenesis of the disease.² Until recently it was unknown whether LCH was primarily a neoplastic or an inflammatory disorder. Although the condition initially was thought to have a reactive etiology,¹ more recent evidence suggests a clonal neoplastic process. Langerhans cell histiocytosis lesions are clonal and display malignancy-associated mechanisms such as immune evasion. Genome sequencing has revealed several mutations in precursor myeloid cells that result in the common downstream hyperactivation of the mitogen-activated protein kinase signaling pathway that regulates cell proliferation and differentiation.¹

Langerhans cell histiocytosis displays a wide spectrum of clinical phenotypes, which historically were subclassified as eosinophilic granulomas (localized lesions in bone), Hand-Schüller-Christian disease (multiple organ involvement with the classic triad of skull defects, diabetes insipidus, and exophthalmos), and Letterer-Siwe disease (visceral lesions involving multiple organs).³ However, in 1997 the Reclassification Working Group of the Histiocyte Society redefined LCH as single-system single site (SS-s) LCH, single-system multisite LCH, and multisystem LCH.⁴

In SS-s LCH, the most common site is bone (82%), followed by the skin (12%).⁵ Skin SS-s LCH classically presents as multiple skin lesions at birth without systemic manifestations; the lesions spontaneously involute within a few months.⁶ Less commonly, skin SS-s LCH can present as a single lesion. Berger et al⁷ described 4 neonates with unilesional skin SS-s LCH. Since then, more than 30 cases have been reported in the literature,⁸ and we report herein another unilesional self-healing LCH.

The morphology of skin lesions in self-healing LCH is highly variable, with the most common being multiple erythematous crusted papules (50%), followed by eczematous scaly lesions resembling seborrheic dermatitis in intertriginous areas (37.5%).^3,6 Unilesional self-healing LCH typically presents as an ulcerated or crusted nodule or papule on the trunk. This variability results in a large differential diagnosis. Self-healing LCH is easily mistaken for infectious processes including neonatal herpes simplex and varicella-zoster virus infection.⁹ Often, the dermatology department is consulted to rule out LCH when the asymptomatic neonate does not respond to parenteral acyclovir.

Less commonly, the magenta-colored papulonodules of self-healing LCH can mimic blueberry muffin rash and mandate a workup for intrauterine infections, especially cytomegalovirus, rubella, and blood dyscrasia.¹⁰ Other noninfectious processes in the differential of self-healing LCH include congenital infantile hemangioma, neonatal lupus erythematosus, seborrheic dermatitis (cradle cap), pyogenic granuloma, and psoriasis.^3,10 Definitive diagnosis requires histopathology.

Because unilesional self-healing LCH has an excellent prognosis and usually resolves on its own, therapy is unnecessary.^3,8 One large retrospective study (N=146) found that of all patients with skin lesions, 56% were managed with biopsy only.⁵ Other options include watchful waiting and topical corticosteroids. If the skin lesions are large, ulcerated, and/or painful, alkylating antitumor agents have been used. For extensive cutaneous disease, systemic corticosteroids combined with chemotherapy and psoralen plus UVA can be effective.⁶

The primary concern in the management of self-healing LCH is that the solitary skin lesion may be the harbinger of an aggressive disorder that can progress to systemic disease.⁵ Moreover, recurrent visceral or disseminated disease may occur months to years after resolution of solitary skin lesions.⁹ Studies have shown that localized and disseminated disease cannot be differentiated on the basis of clinical findings, histology, immunohistochemistry, or biomarkers.^3,11 As a result, an evaluation for systemic disease should be performed at the time of diagnosis for cutaneous LCH.^3,9 Minimum baseline studies recommended by the Writing Group of the Histiocyte Society include a complete blood cell count, liver function tests, coagulation studies, chest radiography, skeletal surveys, and urine osmolality testing.¹² Periodic clinical follow-up is recommended for all variants of LCH.⁹

Our case was diagnosed as self-healing LCH based on histologic findings. No treatment was required, and at 3-month follow-up the infant was asymptomatic without recurrence and was meeting all developmental milestones.

The Diagnosis: Self-healing Langerhans Cell Histiocytosis

Histopathologic examination showed an infiltrate of mononuclear cells with indented nuclei admixed with a variable dermal inflammatory infiltrate. Immunohistochemistry demonstrated cells that were strongly positive for CD1a (Figure, A) and langerin (Figure, B) antigens as well as S-100 protein (Figure, C), which was consistent with Langerhans cell histiocytosis (LCH).

Histiocytoses are a heterogeneous group of disorders in which the infiltrating cells belong to the mononuclear phagocyte system.^1,2 Langerhans cell histiocytosis is the most common dendritic cell-related histiocytosis, occurring in approximately 5 per 1 million children annually, giving it an incidence comparable to pediatric Hodgkin lymphoma and acute myeloid leukemia.^1,2

Historically, there has been much debate about the pathogenesis of the disease.² Until recently it was unknown whether LCH was primarily a neoplastic or an inflammatory disorder. Although the condition initially was thought to have a reactive etiology,¹ more recent evidence suggests a clonal neoplastic process. Langerhans cell histiocytosis lesions are clonal and display malignancy-associated mechanisms such as immune evasion. Genome sequencing has revealed several mutations in precursor myeloid cells that result in the common downstream hyperactivation of the mitogen-activated protein kinase signaling pathway that regulates cell proliferation and differentiation.¹

Langerhans cell histiocytosis displays a wide spectrum of clinical phenotypes, which historically were subclassified as eosinophilic granulomas (localized lesions in bone), Hand-Schüller-Christian disease (multiple organ involvement with the classic triad of skull defects, diabetes insipidus, and exophthalmos), and Letterer-Siwe disease (visceral lesions involving multiple organs).³ However, in 1997 the Reclassification Working Group of the Histiocyte Society redefined LCH as single-system single site (SS-s) LCH, single-system multisite LCH, and multisystem LCH.⁴

In SS-s LCH, the most common site is bone (82%), followed by the skin (12%).⁵ Skin SS-s LCH classically presents as multiple skin lesions at birth without systemic manifestations; the lesions spontaneously involute within a few months.⁶ Less commonly, skin SS-s LCH can present as a single lesion. Berger et al⁷ described 4 neonates with unilesional skin SS-s LCH. Since then, more than 30 cases have been reported in the literature,⁸ and we report herein another unilesional self-healing LCH.

The morphology of skin lesions in self-healing LCH is highly variable, with the most common being multiple erythematous crusted papules (50%), followed by eczematous scaly lesions resembling seborrheic dermatitis in intertriginous areas (37.5%).^3,6 Unilesional self-healing LCH typically presents as an ulcerated or crusted nodule or papule on the trunk. This variability results in a large differential diagnosis. Self-healing LCH is easily mistaken for infectious processes including neonatal herpes simplex and varicella-zoster virus infection.⁹ Often, the dermatology department is consulted to rule out LCH when the asymptomatic neonate does not respond to parenteral acyclovir.

Less commonly, the magenta-colored papulonodules of self-healing LCH can mimic blueberry muffin rash and mandate a workup for intrauterine infections, especially cytomegalovirus, rubella, and blood dyscrasia.¹⁰ Other noninfectious processes in the differential of self-healing LCH include congenital infantile hemangioma, neonatal lupus erythematosus, seborrheic dermatitis (cradle cap), pyogenic granuloma, and psoriasis.^3,10 Definitive diagnosis requires histopathology.

Because unilesional self-healing LCH has an excellent prognosis and usually resolves on its own, therapy is unnecessary.^3,8 One large retrospective study (N=146) found that of all patients with skin lesions, 56% were managed with biopsy only.⁵ Other options include watchful waiting and topical corticosteroids. If the skin lesions are large, ulcerated, and/or painful, alkylating antitumor agents have been used. For extensive cutaneous disease, systemic corticosteroids combined with chemotherapy and psoralen plus UVA can be effective.⁶

The primary concern in the management of self-healing LCH is that the solitary skin lesion may be the harbinger of an aggressive disorder that can progress to systemic disease.⁵ Moreover, recurrent visceral or disseminated disease may occur months to years after resolution of solitary skin lesions.⁹ Studies have shown that localized and disseminated disease cannot be differentiated on the basis of clinical findings, histology, immunohistochemistry, or biomarkers.^3,11 As a result, an evaluation for systemic disease should be performed at the time of diagnosis for cutaneous LCH.^3,9 Minimum baseline studies recommended by the Writing Group of the Histiocyte Society include a complete blood cell count, liver function tests, coagulation studies, chest radiography, skeletal surveys, and urine osmolality testing.¹² Periodic clinical follow-up is recommended for all variants of LCH.⁹

Our case was diagnosed as self-healing LCH based on histologic findings. No treatment was required, and at 3-month follow-up the infant was asymptomatic without recurrence and was meeting all developmental milestones.

The Diagnosis: Self-healing Langerhans Cell Histiocytosis

Histopathologic examination showed an infiltrate of mononuclear cells with indented nuclei admixed with a variable dermal inflammatory infiltrate. Immunohistochemistry demonstrated cells that were strongly positive for CD1a (Figure, A) and langerin (Figure, B) antigens as well as S-100 protein (Figure, C), which was consistent with Langerhans cell histiocytosis (LCH).

Histiocytoses are a heterogeneous group of disorders in which the infiltrating cells belong to the mononuclear phagocyte system.^1,2 Langerhans cell histiocytosis is the most common dendritic cell-related histiocytosis, occurring in approximately 5 per 1 million children annually, giving it an incidence comparable to pediatric Hodgkin lymphoma and acute myeloid leukemia.^1,2

Historically, there has been much debate about the pathogenesis of the disease.² Until recently it was unknown whether LCH was primarily a neoplastic or an inflammatory disorder. Although the condition initially was thought to have a reactive etiology,¹ more recent evidence suggests a clonal neoplastic process. Langerhans cell histiocytosis lesions are clonal and display malignancy-associated mechanisms such as immune evasion. Genome sequencing has revealed several mutations in precursor myeloid cells that result in the common downstream hyperactivation of the mitogen-activated protein kinase signaling pathway that regulates cell proliferation and differentiation.¹

Langerhans cell histiocytosis displays a wide spectrum of clinical phenotypes, which historically were subclassified as eosinophilic granulomas (localized lesions in bone), Hand-Schüller-Christian disease (multiple organ involvement with the classic triad of skull defects, diabetes insipidus, and exophthalmos), and Letterer-Siwe disease (visceral lesions involving multiple organs).³ However, in 1997 the Reclassification Working Group of the Histiocyte Society redefined LCH as single-system single site (SS-s) LCH, single-system multisite LCH, and multisystem LCH.⁴

In SS-s LCH, the most common site is bone (82%), followed by the skin (12%).⁵ Skin SS-s LCH classically presents as multiple skin lesions at birth without systemic manifestations; the lesions spontaneously involute within a few months.⁶ Less commonly, skin SS-s LCH can present as a single lesion. Berger et al⁷ described 4 neonates with unilesional skin SS-s LCH. Since then, more than 30 cases have been reported in the literature,⁸ and we report herein another unilesional self-healing LCH.

The morphology of skin lesions in self-healing LCH is highly variable, with the most common being multiple erythematous crusted papules (50%), followed by eczematous scaly lesions resembling seborrheic dermatitis in intertriginous areas (37.5%).^3,6 Unilesional self-healing LCH typically presents as an ulcerated or crusted nodule or papule on the trunk. This variability results in a large differential diagnosis. Self-healing LCH is easily mistaken for infectious processes including neonatal herpes simplex and varicella-zoster virus infection.⁹ Often, the dermatology department is consulted to rule out LCH when the asymptomatic neonate does not respond to parenteral acyclovir.

Less commonly, the magenta-colored papulonodules of self-healing LCH can mimic blueberry muffin rash and mandate a workup for intrauterine infections, especially cytomegalovirus, rubella, and blood dyscrasia.¹⁰ Other noninfectious processes in the differential of self-healing LCH include congenital infantile hemangioma, neonatal lupus erythematosus, seborrheic dermatitis (cradle cap), pyogenic granuloma, and psoriasis.^3,10 Definitive diagnosis requires histopathology.

Because unilesional self-healing LCH has an excellent prognosis and usually resolves on its own, therapy is unnecessary.^3,8 One large retrospective study (N=146) found that of all patients with skin lesions, 56% were managed with biopsy only.⁵ Other options include watchful waiting and topical corticosteroids. If the skin lesions are large, ulcerated, and/or painful, alkylating antitumor agents have been used. For extensive cutaneous disease, systemic corticosteroids combined with chemotherapy and psoralen plus UVA can be effective.⁶

The primary concern in the management of self-healing LCH is that the solitary skin lesion may be the harbinger of an aggressive disorder that can progress to systemic disease.⁵ Moreover, recurrent visceral or disseminated disease may occur months to years after resolution of solitary skin lesions.⁹ Studies have shown that localized and disseminated disease cannot be differentiated on the basis of clinical findings, histology, immunohistochemistry, or biomarkers.^3,11 As a result, an evaluation for systemic disease should be performed at the time of diagnosis for cutaneous LCH.^3,9 Minimum baseline studies recommended by the Writing Group of the Histiocyte Society include a complete blood cell count, liver function tests, coagulation studies, chest radiography, skeletal surveys, and urine osmolality testing.¹² Periodic clinical follow-up is recommended for all variants of LCH.⁹

Our case was diagnosed as self-healing LCH based on histologic findings. No treatment was required, and at 3-month follow-up the infant was asymptomatic without recurrence and was meeting all developmental milestones.

The change in policy eliminating nonmedical vaccine exemptions in California (Senate Bill 277) led to a 250% increase in requests for medical exemptions, according to data from interviews with health officials and immunization staff after implementation of the policy.

©LeventKonuk/Thinkstock.com

In a study published in Pediatrics, Salini Mohanty, DrPH, of the University of Pennsylvania School of Nursing, Philadelphia, and her colleagues conducted semistructured phone interviews with 40 health officers and immunization staff who represented 35 of 61 California heath jurisdictions. The interviews occurred between August 2017 and September 2017, and participants discussed their experiences with medical exemption requests after the policy change.

Although the percentage of fully vaccinated kindergarten students in California increased from 93% in 2015-2016 to 95% in 2017-2018, and the rate of personal belief exemptions declined, overall medical exemption requests rose 250% from 0.2% in 2015-2016 to 0.7% 2017-2018, the researchers noted.

They identified four main issues based on participant responses: the role of stakeholders, the review of medical exemptions received by schools, the medical exemptions perceived as problematic, and the general frustration and concern over medical exemptions.

Based on the interviews, one concerning subtheme involved reports that some physicians wrote medical exemptions for vaccine-hesitant parents based on conditions such as allergies and autoimmune diseases.

“The Internet provides access to physicians who are willing to sign off on exemptions and to websites used to instruct parents on how to get physicians to approve medical exemptions,” the researchers said.

“Understanding how physicians interpret the law is important because they are writing the medical exemptions,” Dr. Mohanty and her associates noted, and they proposed increased outreach and education of physicians about the law to reduce problematic medical exemptions.

Many health officials expressed frustration with their inability to review medical exemptions submitted directly to schools. In fact, interviewees cited one California jurisdiction that was named in a lawsuit for attempting to track medical exemptions, “which had an impact on other jurisdictions decision to track,” they said.

Officials also expressed concern that parents’ use of medical exemptions to replace personal belief exemptions would reduce herd immunity. Overall, regions with high levels of personal belief exemptions showed the largest increases in medical exemptions after SB277, which could put these regions at increased risk for vaccine-preventable outbreaks, the researchers noted.

There also were reports of physicians “who advertised medical exemptions online for a fee.” Officials also reported “receiving medical exemptions signed by physicians who do not typically treat children (cardiologists, dermatologists, surgeons, and physicians at medical marijuana dispensaries) and by unauthorized nonphysician providers, including nurse practitioners,” Dr. Mohanty and her associates said.

The study findings were limited by several factors including small sample size and potential recall bias, the researchers noted. However, the study is the first to include perspectives of local health officials after a change in vaccine exemption policy.

The National Institutes of Health supported the study. Dr. Mohanty had no financial conflicts to disclose; one coauthor disclosed relationships with Merck, Pfizer, and Walgreens.

SOURCE: Mohanty S et al. Pediatrics. 2018. doi: 10.1542/peds.2018-1051.

The change in policy eliminating nonmedical vaccine exemptions in California (Senate Bill 277) led to a 250% increase in requests for medical exemptions, according to data from interviews with health officials and immunization staff after implementation of the policy.

©LeventKonuk/Thinkstock.com

In a study published in Pediatrics, Salini Mohanty, DrPH, of the University of Pennsylvania School of Nursing, Philadelphia, and her colleagues conducted semistructured phone interviews with 40 health officers and immunization staff who represented 35 of 61 California heath jurisdictions. The interviews occurred between August 2017 and September 2017, and participants discussed their experiences with medical exemption requests after the policy change.

Although the percentage of fully vaccinated kindergarten students in California increased from 93% in 2015-2016 to 95% in 2017-2018, and the rate of personal belief exemptions declined, overall medical exemption requests rose 250% from 0.2% in 2015-2016 to 0.7% 2017-2018, the researchers noted.

They identified four main issues based on participant responses: the role of stakeholders, the review of medical exemptions received by schools, the medical exemptions perceived as problematic, and the general frustration and concern over medical exemptions.

Based on the interviews, one concerning subtheme involved reports that some physicians wrote medical exemptions for vaccine-hesitant parents based on conditions such as allergies and autoimmune diseases.

“The Internet provides access to physicians who are willing to sign off on exemptions and to websites used to instruct parents on how to get physicians to approve medical exemptions,” the researchers said.

“Understanding how physicians interpret the law is important because they are writing the medical exemptions,” Dr. Mohanty and her associates noted, and they proposed increased outreach and education of physicians about the law to reduce problematic medical exemptions.

Many health officials expressed frustration with their inability to review medical exemptions submitted directly to schools. In fact, interviewees cited one California jurisdiction that was named in a lawsuit for attempting to track medical exemptions, “which had an impact on other jurisdictions decision to track,” they said.

Officials also expressed concern that parents’ use of medical exemptions to replace personal belief exemptions would reduce herd immunity. Overall, regions with high levels of personal belief exemptions showed the largest increases in medical exemptions after SB277, which could put these regions at increased risk for vaccine-preventable outbreaks, the researchers noted.

There also were reports of physicians “who advertised medical exemptions online for a fee.” Officials also reported “receiving medical exemptions signed by physicians who do not typically treat children (cardiologists, dermatologists, surgeons, and physicians at medical marijuana dispensaries) and by unauthorized nonphysician providers, including nurse practitioners,” Dr. Mohanty and her associates said.

The study findings were limited by several factors including small sample size and potential recall bias, the researchers noted. However, the study is the first to include perspectives of local health officials after a change in vaccine exemption policy.

The National Institutes of Health supported the study. Dr. Mohanty had no financial conflicts to disclose; one coauthor disclosed relationships with Merck, Pfizer, and Walgreens.

SOURCE: Mohanty S et al. Pediatrics. 2018. doi: 10.1542/peds.2018-1051.

The change in policy eliminating nonmedical vaccine exemptions in California (Senate Bill 277) led to a 250% increase in requests for medical exemptions, according to data from interviews with health officials and immunization staff after implementation of the policy.

©LeventKonuk/Thinkstock.com

In a study published in Pediatrics, Salini Mohanty, DrPH, of the University of Pennsylvania School of Nursing, Philadelphia, and her colleagues conducted semistructured phone interviews with 40 health officers and immunization staff who represented 35 of 61 California heath jurisdictions. The interviews occurred between August 2017 and September 2017, and participants discussed their experiences with medical exemption requests after the policy change.

Although the percentage of fully vaccinated kindergarten students in California increased from 93% in 2015-2016 to 95% in 2017-2018, and the rate of personal belief exemptions declined, overall medical exemption requests rose 250% from 0.2% in 2015-2016 to 0.7% 2017-2018, the researchers noted.

They identified four main issues based on participant responses: the role of stakeholders, the review of medical exemptions received by schools, the medical exemptions perceived as problematic, and the general frustration and concern over medical exemptions.

Based on the interviews, one concerning subtheme involved reports that some physicians wrote medical exemptions for vaccine-hesitant parents based on conditions such as allergies and autoimmune diseases.

“The Internet provides access to physicians who are willing to sign off on exemptions and to websites used to instruct parents on how to get physicians to approve medical exemptions,” the researchers said.

“Understanding how physicians interpret the law is important because they are writing the medical exemptions,” Dr. Mohanty and her associates noted, and they proposed increased outreach and education of physicians about the law to reduce problematic medical exemptions.

Many health officials expressed frustration with their inability to review medical exemptions submitted directly to schools. In fact, interviewees cited one California jurisdiction that was named in a lawsuit for attempting to track medical exemptions, “which had an impact on other jurisdictions decision to track,” they said.

Officials also expressed concern that parents’ use of medical exemptions to replace personal belief exemptions would reduce herd immunity. Overall, regions with high levels of personal belief exemptions showed the largest increases in medical exemptions after SB277, which could put these regions at increased risk for vaccine-preventable outbreaks, the researchers noted.

There also were reports of physicians “who advertised medical exemptions online for a fee.” Officials also reported “receiving medical exemptions signed by physicians who do not typically treat children (cardiologists, dermatologists, surgeons, and physicians at medical marijuana dispensaries) and by unauthorized nonphysician providers, including nurse practitioners,” Dr. Mohanty and her associates said.

The study findings were limited by several factors including small sample size and potential recall bias, the researchers noted. However, the study is the first to include perspectives of local health officials after a change in vaccine exemption policy.

The National Institutes of Health supported the study. Dr. Mohanty had no financial conflicts to disclose; one coauthor disclosed relationships with Merck, Pfizer, and Walgreens.

SOURCE: Mohanty S et al. Pediatrics. 2018. doi: 10.1542/peds.2018-1051.

Clinicians and even the general public are aware of the dangers of sepsis, the life-threatening illness caused by a body’s response to an infection. Irrespective of one’s perception of pharmaceutical marketing materials or the evidence-based medicine used, awareness about sepsis has led to earlier diagnosis and interventions that have likely saved countless patients’ lives.

Moreover, hospitalists have played a key role in sepsis prevention. In their research, “Improving Survival from Sepsis in Noncritical Units: Role of Hospitalists and Sepsis Team in Early Detection and Initial Treatment of Septic Patients,” Adriana Ducci, MD, and her colleagues showed that a hospitalist-managed sepsis protocol improved sepsis case notifications and patient outcomes.

Although sepsis and respiratory compromise are clearly very different conditions, I believe that greater awareness about respiratory compromise will lead to earlier diagnosis and interventions, which will theoretically improve patient outcomes. Moreover, as with the sepsis awareness campaign, hospitalists can play a key role in recognizing respiratory compromise and in the implementation of appropriate interventions.

As defined by the Respiratory Compromise Institute, “respiratory compromise” is defined as a state in which there is a high likelihood of decompensation into respiratory failure and/or death, but, in which specific interventions – be it therapeutic and/or monitoring – might prevent or mitigate this decompensation.

A significant segment of patients who may be at risk for respiratory compromise are those receiving opioids. The cost of opioid-related adverse events, in terms of both human life and hospital expenses, remains at the forefront of the public eye. It has been estimated that yearly costs in the United States associated with opioid-related postoperative respiratory failure were estimated at $2 billion.

Thomas W. Frederickson MD, FACP, SFHM, MBA, the lead author of the Society of Hospital Medicine guide for Reducing Adverse Drug Events Related to Opioids (RADEO), emphasized in a podcast with the Physician-Patient Alliance for Health & Safety the need to identify patient conditions that pose a greater risk of respiratory compromise.

In particular, Dr. Frederickson pointed out the need to screen for obstructive sleep apnea (OSA): “Patients with obstructive sleep apnea are dependent upon their arousal mechanism in order to avoid respiratory depression and eventual respiratory failure. When these patients receive opioid medication, it decreases this ability for arousal. That puts them at risk for a sudden spiral that includes respiratory insufficiency and respiratory arrest. This can happen very quickly and part of the risk is that the traditional monitoring for sedation that we use in the hospital – that is on a periodic basis and depends upon nursing interventions and questioning – really becomes much less effective in this patient population that can have a respiratory arrest, because of failure to arouse, very quickly. So, a monitoring regimen that takes place every 60 minutes is likely to be ineffective.”

Patient conditions such as OSA should be considered, along with other comorbidities. As the RADEO Guide states: “Before starting opioid therapy, either in surgical or non-surgical settings, it is important to identify any real or potential risks of respiratory depression or other opioid-related adverse effects. Patient comorbidities such as OSA, neurologic disorders, organ impairment, substance abuse history, and other medication use are important aspects to consider.”

Although we have clearly recognized a significant increase in respiratory complications associated with opioid administration, there are other areas, which are non–opioid related, that can create respiratory compromise. We view many patients with stable or underlying respiratory conditions, whether it be COPD, sleep apnea, or preexisting pathophysiology, where either due to sedative agents, or an acute illness – like pneumonia – they can go from a stable condition to respiratory compromise and become at risk for respiratory failure.

A classic example of that in my world of anesthesia has been the well-recognized area of non–operating room anesthesia – in particular, in endoscopy suites where numerous endoscopy procedures are performed under the administration of propofol or other anxiolytic-like drugs. There has been a well-recognized incidence of sentinel events related to oxygenation and ventilation, including death.

Many clinicians see sedation as a benign introduction of relatively limited-effect drugs, which isn’t always true. So, therefore, it is essential that clinicians understand three things:

1. The drugs we employ as sedative agents can have variable effects on individuals depending on their tolerance and their underlying medical condition.

2. The dosages and particular combination of drugs employed may cause an adverse event – for example, the combination of opioids and benzodiazepines.

3. There are factors that can distract from the clinical assessment of routine vital signs, such as respiratory rate, heart rate, and blood pressure. For example, when pulse oximetry is administered with oxygen therapy, there can often be a delay in the recognition of hypoventilation. Consequently, that’s why more and more clinicians are beginning to utilize capnography, or CO₂ monitoring, in the expired gas to earlier detect depressed respiratory rate and/or apnea, as well as signs of hypoventilation or inadequate ventilation.

There clearly are obstacles to continuous patient monitoring, such as the associated cost, familiarity with the utilization, the benefit, as well as the limitations of specific monitors in different clinical situations, which mandates an educational process to employ these. However, currently, patient monitoring provides the best early indicator of a patient’s deterioration and the possibility of respiratory compromise.

In my field, we have become very comfortable with capnography and patient monitoring, because for decades it’s been a standard of care for monitoring in the operating room. The role for utilization of capnography for patients who are receiving an opioid or sedative agent outside of the operating room needs to be further assessed. However, technology is not a silver bullet and should be used as an adjunct to clinical judgment in at-risk populations.

Simple recognition and greater awareness of respiratory compromise, just as with sepsis awareness campaigns, will mean more patients are diagnosed earlier, more appropriate interventions are made, and hopefully more adverse events and patient deaths are averted.

Dr. Vender is the emeritus Harris Family Foundation chairman of the department of anesthesiology at NorthShore University Health System in Evanston, Ill. He is clinical professor at the University of Chicago Pritzker School of Medicine and chairman, Clinical Advisory Committee, Respiratory Compromise Institute. Dr. Vender has consulted with Medtronic.

Clinicians and even the general public are aware of the dangers of sepsis, the life-threatening illness caused by a body’s response to an infection. Irrespective of one’s perception of pharmaceutical marketing materials or the evidence-based medicine used, awareness about sepsis has led to earlier diagnosis and interventions that have likely saved countless patients’ lives.

Moreover, hospitalists have played a key role in sepsis prevention. In their research, “Improving Survival from Sepsis in Noncritical Units: Role of Hospitalists and Sepsis Team in Early Detection and Initial Treatment of Septic Patients,” Adriana Ducci, MD, and her colleagues showed that a hospitalist-managed sepsis protocol improved sepsis case notifications and patient outcomes.

Although sepsis and respiratory compromise are clearly very different conditions, I believe that greater awareness about respiratory compromise will lead to earlier diagnosis and interventions, which will theoretically improve patient outcomes. Moreover, as with the sepsis awareness campaign, hospitalists can play a key role in recognizing respiratory compromise and in the implementation of appropriate interventions.

As defined by the Respiratory Compromise Institute, “respiratory compromise” is defined as a state in which there is a high likelihood of decompensation into respiratory failure and/or death, but, in which specific interventions – be it therapeutic and/or monitoring – might prevent or mitigate this decompensation.

A significant segment of patients who may be at risk for respiratory compromise are those receiving opioids. The cost of opioid-related adverse events, in terms of both human life and hospital expenses, remains at the forefront of the public eye. It has been estimated that yearly costs in the United States associated with opioid-related postoperative respiratory failure were estimated at $2 billion.

Thomas W. Frederickson MD, FACP, SFHM, MBA, the lead author of the Society of Hospital Medicine guide for Reducing Adverse Drug Events Related to Opioids (RADEO), emphasized in a podcast with the Physician-Patient Alliance for Health & Safety the need to identify patient conditions that pose a greater risk of respiratory compromise.

In particular, Dr. Frederickson pointed out the need to screen for obstructive sleep apnea (OSA): “Patients with obstructive sleep apnea are dependent upon their arousal mechanism in order to avoid respiratory depression and eventual respiratory failure. When these patients receive opioid medication, it decreases this ability for arousal. That puts them at risk for a sudden spiral that includes respiratory insufficiency and respiratory arrest. This can happen very quickly and part of the risk is that the traditional monitoring for sedation that we use in the hospital – that is on a periodic basis and depends upon nursing interventions and questioning – really becomes much less effective in this patient population that can have a respiratory arrest, because of failure to arouse, very quickly. So, a monitoring regimen that takes place every 60 minutes is likely to be ineffective.”

Patient conditions such as OSA should be considered, along with other comorbidities. As the RADEO Guide states: “Before starting opioid therapy, either in surgical or non-surgical settings, it is important to identify any real or potential risks of respiratory depression or other opioid-related adverse effects. Patient comorbidities such as OSA, neurologic disorders, organ impairment, substance abuse history, and other medication use are important aspects to consider.”

Although we have clearly recognized a significant increase in respiratory complications associated with opioid administration, there are other areas, which are non–opioid related, that can create respiratory compromise. We view many patients with stable or underlying respiratory conditions, whether it be COPD, sleep apnea, or preexisting pathophysiology, where either due to sedative agents, or an acute illness – like pneumonia – they can go from a stable condition to respiratory compromise and become at risk for respiratory failure.

A classic example of that in my world of anesthesia has been the well-recognized area of non–operating room anesthesia – in particular, in endoscopy suites where numerous endoscopy procedures are performed under the administration of propofol or other anxiolytic-like drugs. There has been a well-recognized incidence of sentinel events related to oxygenation and ventilation, including death.

Many clinicians see sedation as a benign introduction of relatively limited-effect drugs, which isn’t always true. So, therefore, it is essential that clinicians understand three things:

1. The drugs we employ as sedative agents can have variable effects on individuals depending on their tolerance and their underlying medical condition.

2. The dosages and particular combination of drugs employed may cause an adverse event – for example, the combination of opioids and benzodiazepines.

3. There are factors that can distract from the clinical assessment of routine vital signs, such as respiratory rate, heart rate, and blood pressure. For example, when pulse oximetry is administered with oxygen therapy, there can often be a delay in the recognition of hypoventilation. Consequently, that’s why more and more clinicians are beginning to utilize capnography, or CO₂ monitoring, in the expired gas to earlier detect depressed respiratory rate and/or apnea, as well as signs of hypoventilation or inadequate ventilation.

There clearly are obstacles to continuous patient monitoring, such as the associated cost, familiarity with the utilization, the benefit, as well as the limitations of specific monitors in different clinical situations, which mandates an educational process to employ these. However, currently, patient monitoring provides the best early indicator of a patient’s deterioration and the possibility of respiratory compromise.

In my field, we have become very comfortable with capnography and patient monitoring, because for decades it’s been a standard of care for monitoring in the operating room. The role for utilization of capnography for patients who are receiving an opioid or sedative agent outside of the operating room needs to be further assessed. However, technology is not a silver bullet and should be used as an adjunct to clinical judgment in at-risk populations.

Simple recognition and greater awareness of respiratory compromise, just as with sepsis awareness campaigns, will mean more patients are diagnosed earlier, more appropriate interventions are made, and hopefully more adverse events and patient deaths are averted.

Dr. Vender is the emeritus Harris Family Foundation chairman of the department of anesthesiology at NorthShore University Health System in Evanston, Ill. He is clinical professor at the University of Chicago Pritzker School of Medicine and chairman, Clinical Advisory Committee, Respiratory Compromise Institute. Dr. Vender has consulted with Medtronic.

Clinicians and even the general public are aware of the dangers of sepsis, the life-threatening illness caused by a body’s response to an infection. Irrespective of one’s perception of pharmaceutical marketing materials or the evidence-based medicine used, awareness about sepsis has led to earlier diagnosis and interventions that have likely saved countless patients’ lives.

Moreover, hospitalists have played a key role in sepsis prevention. In their research, “Improving Survival from Sepsis in Noncritical Units: Role of Hospitalists and Sepsis Team in Early Detection and Initial Treatment of Septic Patients,” Adriana Ducci, MD, and her colleagues showed that a hospitalist-managed sepsis protocol improved sepsis case notifications and patient outcomes.

Although sepsis and respiratory compromise are clearly very different conditions, I believe that greater awareness about respiratory compromise will lead to earlier diagnosis and interventions, which will theoretically improve patient outcomes. Moreover, as with the sepsis awareness campaign, hospitalists can play a key role in recognizing respiratory compromise and in the implementation of appropriate interventions.

As defined by the Respiratory Compromise Institute, “respiratory compromise” is defined as a state in which there is a high likelihood of decompensation into respiratory failure and/or death, but, in which specific interventions – be it therapeutic and/or monitoring – might prevent or mitigate this decompensation.

A significant segment of patients who may be at risk for respiratory compromise are those receiving opioids. The cost of opioid-related adverse events, in terms of both human life and hospital expenses, remains at the forefront of the public eye. It has been estimated that yearly costs in the United States associated with opioid-related postoperative respiratory failure were estimated at $2 billion.

Thomas W. Frederickson MD, FACP, SFHM, MBA, the lead author of the Society of Hospital Medicine guide for Reducing Adverse Drug Events Related to Opioids (RADEO), emphasized in a podcast with the Physician-Patient Alliance for Health & Safety the need to identify patient conditions that pose a greater risk of respiratory compromise.

In particular, Dr. Frederickson pointed out the need to screen for obstructive sleep apnea (OSA): “Patients with obstructive sleep apnea are dependent upon their arousal mechanism in order to avoid respiratory depression and eventual respiratory failure. When these patients receive opioid medication, it decreases this ability for arousal. That puts them at risk for a sudden spiral that includes respiratory insufficiency and respiratory arrest. This can happen very quickly and part of the risk is that the traditional monitoring for sedation that we use in the hospital – that is on a periodic basis and depends upon nursing interventions and questioning – really becomes much less effective in this patient population that can have a respiratory arrest, because of failure to arouse, very quickly. So, a monitoring regimen that takes place every 60 minutes is likely to be ineffective.”

Patient conditions such as OSA should be considered, along with other comorbidities. As the RADEO Guide states: “Before starting opioid therapy, either in surgical or non-surgical settings, it is important to identify any real or potential risks of respiratory depression or other opioid-related adverse effects. Patient comorbidities such as OSA, neurologic disorders, organ impairment, substance abuse history, and other medication use are important aspects to consider.”

Although we have clearly recognized a significant increase in respiratory complications associated with opioid administration, there are other areas, which are non–opioid related, that can create respiratory compromise. We view many patients with stable or underlying respiratory conditions, whether it be COPD, sleep apnea, or preexisting pathophysiology, where either due to sedative agents, or an acute illness – like pneumonia – they can go from a stable condition to respiratory compromise and become at risk for respiratory failure.

A classic example of that in my world of anesthesia has been the well-recognized area of non–operating room anesthesia – in particular, in endoscopy suites where numerous endoscopy procedures are performed under the administration of propofol or other anxiolytic-like drugs. There has been a well-recognized incidence of sentinel events related to oxygenation and ventilation, including death.

Many clinicians see sedation as a benign introduction of relatively limited-effect drugs, which isn’t always true. So, therefore, it is essential that clinicians understand three things:

1. The drugs we employ as sedative agents can have variable effects on individuals depending on their tolerance and their underlying medical condition.

2. The dosages and particular combination of drugs employed may cause an adverse event – for example, the combination of opioids and benzodiazepines.

3. There are factors that can distract from the clinical assessment of routine vital signs, such as respiratory rate, heart rate, and blood pressure. For example, when pulse oximetry is administered with oxygen therapy, there can often be a delay in the recognition of hypoventilation. Consequently, that’s why more and more clinicians are beginning to utilize capnography, or CO₂ monitoring, in the expired gas to earlier detect depressed respiratory rate and/or apnea, as well as signs of hypoventilation or inadequate ventilation.

There clearly are obstacles to continuous patient monitoring, such as the associated cost, familiarity with the utilization, the benefit, as well as the limitations of specific monitors in different clinical situations, which mandates an educational process to employ these. However, currently, patient monitoring provides the best early indicator of a patient’s deterioration and the possibility of respiratory compromise.

In my field, we have become very comfortable with capnography and patient monitoring, because for decades it’s been a standard of care for monitoring in the operating room. The role for utilization of capnography for patients who are receiving an opioid or sedative agent outside of the operating room needs to be further assessed. However, technology is not a silver bullet and should be used as an adjunct to clinical judgment in at-risk populations.

Simple recognition and greater awareness of respiratory compromise, just as with sepsis awareness campaigns, will mean more patients are diagnosed earlier, more appropriate interventions are made, and hopefully more adverse events and patient deaths are averted.

Dr. Vender is the emeritus Harris Family Foundation chairman of the department of anesthesiology at NorthShore University Health System in Evanston, Ill. He is clinical professor at the University of Chicago Pritzker School of Medicine and chairman, Clinical Advisory Committee, Respiratory Compromise Institute. Dr. Vender has consulted with Medtronic.

A full 0.5-mL dose of inactivated influenza vaccine was as safe and effective as a was a half dose of 0.25 mL, with slightly higher immunogenicity, according to data from a randomized trial of nearly 2,000 children aged 6-35 months.

KatarzynaBialasiewicz/Thinkstock

Data from previous studies have suggested that a full dose of vaccine may be more immunogenic in young children compared with a half dose, and Sanofi Pasteur has submitted a supplemental Biologics License Application to the Food and Drug Administration to allow use of the full 0.5-mL dose in children as young as 6 months, Monica Mercer, MD, of Sanofi Pasteur, said at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices in Atlanta.

Dr. Mercer presented findings from a phase IV randomized, observer-blinded study, in which the researchers assigned healthy children aged 6-35 months to receive Fluzone quadrivalent vaccine at a dose of 0.25 mL or 0.5 mL.

A total of 1,941 children (949 for the 0.25-mL dose and 992 for the 0.5-mL dose) were included in the safety analysis.

The most important safety outcome was to compare the rate of any fever, Dr. Mercer said at the meeting.

Overall, at 7 days after vaccination, the rate of fever was 11% for the half dose and 12% for the full dose, she said. The resulting difference of 0.84% met the criteria for noninferiority (less than 5%), she added.

In terms of safety, tenderness was the most frequently reported injection site reaction, noted in 47% of the half-dose group and 50% of the full-dose group. The rates of unsolicited adverse events were similar in both groups, the most common included diarrhea and cough, Dr. Mercer said.

No subjects in the full-dose group and three in the half-dose group discontinued the study because of adverse events. The only reported serious adverse event was one case of chronic urticaria in the half-dose group; no deaths were reported in either group.

As for efficacy, the full dose demonstrated noninferiority, compared with the half dose, against each of four strains: influenza A H1N1, influenza A H3N2, influenza B Victoria, and influenza B Yamagata. The geometric mean titers of the full and half doses for each of the four strains were, respectively, 310 and 214, 332 and 221, 348 and 261, and 349 and 243.

The potential action date for the supplemental Biologics License Application is January 2019, noted Dr. Mercer, who is employed by Sanofi Pasteur.

A full 0.5-mL dose of inactivated influenza vaccine was as safe and effective as a was a half dose of 0.25 mL, with slightly higher immunogenicity, according to data from a randomized trial of nearly 2,000 children aged 6-35 months.

KatarzynaBialasiewicz/Thinkstock

Data from previous studies have suggested that a full dose of vaccine may be more immunogenic in young children compared with a half dose, and Sanofi Pasteur has submitted a supplemental Biologics License Application to the Food and Drug Administration to allow use of the full 0.5-mL dose in children as young as 6 months, Monica Mercer, MD, of Sanofi Pasteur, said at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices in Atlanta.

Dr. Mercer presented findings from a phase IV randomized, observer-blinded study, in which the researchers assigned healthy children aged 6-35 months to receive Fluzone quadrivalent vaccine at a dose of 0.25 mL or 0.5 mL.

A total of 1,941 children (949 for the 0.25-mL dose and 992 for the 0.5-mL dose) were included in the safety analysis.

The most important safety outcome was to compare the rate of any fever, Dr. Mercer said at the meeting.

Overall, at 7 days after vaccination, the rate of fever was 11% for the half dose and 12% for the full dose, she said. The resulting difference of 0.84% met the criteria for noninferiority (less than 5%), she added.

In terms of safety, tenderness was the most frequently reported injection site reaction, noted in 47% of the half-dose group and 50% of the full-dose group. The rates of unsolicited adverse events were similar in both groups, the most common included diarrhea and cough, Dr. Mercer said.

No subjects in the full-dose group and three in the half-dose group discontinued the study because of adverse events. The only reported serious adverse event was one case of chronic urticaria in the half-dose group; no deaths were reported in either group.

As for efficacy, the full dose demonstrated noninferiority, compared with the half dose, against each of four strains: influenza A H1N1, influenza A H3N2, influenza B Victoria, and influenza B Yamagata. The geometric mean titers of the full and half doses for each of the four strains were, respectively, 310 and 214, 332 and 221, 348 and 261, and 349 and 243.

The potential action date for the supplemental Biologics License Application is January 2019, noted Dr. Mercer, who is employed by Sanofi Pasteur.

A full 0.5-mL dose of inactivated influenza vaccine was as safe and effective as a was a half dose of 0.25 mL, with slightly higher immunogenicity, according to data from a randomized trial of nearly 2,000 children aged 6-35 months.

KatarzynaBialasiewicz/Thinkstock

Data from previous studies have suggested that a full dose of vaccine may be more immunogenic in young children compared with a half dose, and Sanofi Pasteur has submitted a supplemental Biologics License Application to the Food and Drug Administration to allow use of the full 0.5-mL dose in children as young as 6 months, Monica Mercer, MD, of Sanofi Pasteur, said at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices in Atlanta.

Dr. Mercer presented findings from a phase IV randomized, observer-blinded study, in which the researchers assigned healthy children aged 6-35 months to receive Fluzone quadrivalent vaccine at a dose of 0.25 mL or 0.5 mL.

A total of 1,941 children (949 for the 0.25-mL dose and 992 for the 0.5-mL dose) were included in the safety analysis.

The most important safety outcome was to compare the rate of any fever, Dr. Mercer said at the meeting.

Overall, at 7 days after vaccination, the rate of fever was 11% for the half dose and 12% for the full dose, she said. The resulting difference of 0.84% met the criteria for noninferiority (less than 5%), she added.

In terms of safety, tenderness was the most frequently reported injection site reaction, noted in 47% of the half-dose group and 50% of the full-dose group. The rates of unsolicited adverse events were similar in both groups, the most common included diarrhea and cough, Dr. Mercer said.

No subjects in the full-dose group and three in the half-dose group discontinued the study because of adverse events. The only reported serious adverse event was one case of chronic urticaria in the half-dose group; no deaths were reported in either group.

As for efficacy, the full dose demonstrated noninferiority, compared with the half dose, against each of four strains: influenza A H1N1, influenza A H3N2, influenza B Victoria, and influenza B Yamagata. The geometric mean titers of the full and half doses for each of the four strains were, respectively, 310 and 214, 332 and 221, 348 and 261, and 349 and 243.

The potential action date for the supplemental Biologics License Application is January 2019, noted Dr. Mercer, who is employed by Sanofi Pasteur.