Infectious Diseases

SEATTLE – Point-of-care viral load testing improves HIV viral suppression and retention in care, according to a randomized trial of 390 subjects in South Africa.

M. Alexander Otto/MDedge News

Point-of-care (POC) testing delivers viral load results in about 2-3 hours, as opposed to the month or so patients wait to get results from a laboratory. The nearly instant turnaround gives clinicians the ability to identify patients who aren’t doing well – as indicated by high viral loads despite antiretroviral therapy (ART) – before they walk out the door, so immediate steps can be taken to address adherence or resistance problems.

However, POC viral load testing hasn’t really caught on in the United States, at least not yet, according to study leader Paul Drain, MD, assistant professor of global health at the University of Washington, Seattle.

To see if it would help, the team turned to a large public clinic in the city of Durban, and focused on adults who had been on ART for 6 months following HIV diagnosis. They randomized 195 to standard laboratory testing at study entrance, with a repeat at 6 months, at which point subjects had been on ART for 12 months; 195 others were randomized to POC testing with the Xpert HIV-1 Viral Load machine, from Cepheid, on the same schedule and with same-day counseling for those with high loads.

Treatment was otherwise similar between the groups, with clinic visits every 2 months and other measures as per South African HIV treatment guidelines.

POC testing made a difference. At study month 12,175 participants (89.7%) in the POC arm, but only 148 (75.9%) in the laboratory testing group, had reached the study’s primary endpoint: viral suppression with less than 200 copies/mL plus retention in care, meaning that subjects were still picking up their ART prescriptions.

Overall, POC testing increased viral load suppression by 10.3%, from 83.1% to 93.3% (P = .003) and retention by 7.7% from 84.6% to 92.3% (P = .03).

The investigators would like to evaluate the approach in the United States. Potentially, “POC testing will have a very important role in U.S. health care,” Dr. Drain said at the Conference on Retroviruses and Opportunistic Infections.

It “helps us identify those who are having problems right away, before they leave the clinic, because whether it’s in South Africa or Seattle, as soon as they leave, it’s very hard to get them back. The more you can do POC testing, the better we can intervene and help these people,” he said.

“You don’t need POC testing for everybody; a lot of people do just fine. They take their medications reliably. They don’t need to get their results back right away ... But there are people who have challenges and would benefit from additional adherence counseling” or who might need help overcoming drug resistance. “We want to identify” them quickly; POC testing may be the answer, he said.

The mean age in the study was 33 years, and 60% of the subjects were women. The median CD4 count at baseline was 468 cells/mm³. POC was $22 per test, versus $25 for lab testing.

The National Institutes of Health funded the work. Dr. Drain had no disclosures. Cepheid donated the POC testing machines.

[email protected]

SOURCE: Drain PK et al. CROI 2019, Abstract 53LB.

SEATTLE – Point-of-care viral load testing improves HIV viral suppression and retention in care, according to a randomized trial of 390 subjects in South Africa.

M. Alexander Otto/MDedge News

Point-of-care (POC) testing delivers viral load results in about 2-3 hours, as opposed to the month or so patients wait to get results from a laboratory. The nearly instant turnaround gives clinicians the ability to identify patients who aren’t doing well – as indicated by high viral loads despite antiretroviral therapy (ART) – before they walk out the door, so immediate steps can be taken to address adherence or resistance problems.

However, POC viral load testing hasn’t really caught on in the United States, at least not yet, according to study leader Paul Drain, MD, assistant professor of global health at the University of Washington, Seattle.

To see if it would help, the team turned to a large public clinic in the city of Durban, and focused on adults who had been on ART for 6 months following HIV diagnosis. They randomized 195 to standard laboratory testing at study entrance, with a repeat at 6 months, at which point subjects had been on ART for 12 months; 195 others were randomized to POC testing with the Xpert HIV-1 Viral Load machine, from Cepheid, on the same schedule and with same-day counseling for those with high loads.

Treatment was otherwise similar between the groups, with clinic visits every 2 months and other measures as per South African HIV treatment guidelines.

POC testing made a difference. At study month 12,175 participants (89.7%) in the POC arm, but only 148 (75.9%) in the laboratory testing group, had reached the study’s primary endpoint: viral suppression with less than 200 copies/mL plus retention in care, meaning that subjects were still picking up their ART prescriptions.

Overall, POC testing increased viral load suppression by 10.3%, from 83.1% to 93.3% (P = .003) and retention by 7.7% from 84.6% to 92.3% (P = .03).

The investigators would like to evaluate the approach in the United States. Potentially, “POC testing will have a very important role in U.S. health care,” Dr. Drain said at the Conference on Retroviruses and Opportunistic Infections.

It “helps us identify those who are having problems right away, before they leave the clinic, because whether it’s in South Africa or Seattle, as soon as they leave, it’s very hard to get them back. The more you can do POC testing, the better we can intervene and help these people,” he said.

“You don’t need POC testing for everybody; a lot of people do just fine. They take their medications reliably. They don’t need to get their results back right away ... But there are people who have challenges and would benefit from additional adherence counseling” or who might need help overcoming drug resistance. “We want to identify” them quickly; POC testing may be the answer, he said.

The mean age in the study was 33 years, and 60% of the subjects were women. The median CD4 count at baseline was 468 cells/mm³. POC was $22 per test, versus $25 for lab testing.

The National Institutes of Health funded the work. Dr. Drain had no disclosures. Cepheid donated the POC testing machines.

[email protected]

SOURCE: Drain PK et al. CROI 2019, Abstract 53LB.

SEATTLE – Point-of-care viral load testing improves HIV viral suppression and retention in care, according to a randomized trial of 390 subjects in South Africa.

M. Alexander Otto/MDedge News

Point-of-care (POC) testing delivers viral load results in about 2-3 hours, as opposed to the month or so patients wait to get results from a laboratory. The nearly instant turnaround gives clinicians the ability to identify patients who aren’t doing well – as indicated by high viral loads despite antiretroviral therapy (ART) – before they walk out the door, so immediate steps can be taken to address adherence or resistance problems.

However, POC viral load testing hasn’t really caught on in the United States, at least not yet, according to study leader Paul Drain, MD, assistant professor of global health at the University of Washington, Seattle.

To see if it would help, the team turned to a large public clinic in the city of Durban, and focused on adults who had been on ART for 6 months following HIV diagnosis. They randomized 195 to standard laboratory testing at study entrance, with a repeat at 6 months, at which point subjects had been on ART for 12 months; 195 others were randomized to POC testing with the Xpert HIV-1 Viral Load machine, from Cepheid, on the same schedule and with same-day counseling for those with high loads.

Treatment was otherwise similar between the groups, with clinic visits every 2 months and other measures as per South African HIV treatment guidelines.

POC testing made a difference. At study month 12,175 participants (89.7%) in the POC arm, but only 148 (75.9%) in the laboratory testing group, had reached the study’s primary endpoint: viral suppression with less than 200 copies/mL plus retention in care, meaning that subjects were still picking up their ART prescriptions.

Overall, POC testing increased viral load suppression by 10.3%, from 83.1% to 93.3% (P = .003) and retention by 7.7% from 84.6% to 92.3% (P = .03).

The investigators would like to evaluate the approach in the United States. Potentially, “POC testing will have a very important role in U.S. health care,” Dr. Drain said at the Conference on Retroviruses and Opportunistic Infections.

It “helps us identify those who are having problems right away, before they leave the clinic, because whether it’s in South Africa or Seattle, as soon as they leave, it’s very hard to get them back. The more you can do POC testing, the better we can intervene and help these people,” he said.

“You don’t need POC testing for everybody; a lot of people do just fine. They take their medications reliably. They don’t need to get their results back right away ... But there are people who have challenges and would benefit from additional adherence counseling” or who might need help overcoming drug resistance. “We want to identify” them quickly; POC testing may be the answer, he said.

The mean age in the study was 33 years, and 60% of the subjects were women. The median CD4 count at baseline was 468 cells/mm³. POC was $22 per test, versus $25 for lab testing.

The National Institutes of Health funded the work. Dr. Drain had no disclosures. Cepheid donated the POC testing machines.

[email protected]

SOURCE: Drain PK et al. CROI 2019, Abstract 53LB.

Incidence and Characteristics

Stingrays are the most common cause of fish-related stings worldwide.¹ The Urolophidae and Dasyatidae stingray families are responsible for most marine stingray injuries, including approximately 1500 reported injuries in the United States annually.^1,2 Saltwater stingrays from these families commonly are encountered in shallow temperate and tropical coastal waters across the globe and possess dorsally and distally located spines capable of injuring humans that step on them (Figure 1).^1,3 Freshwater stingrays (Potamotrygonidae family)(Figure 2) are not present in North America but rather inhabit lakes and river systems in South America, Africa, Laos, and Vietnam.⁴ Although recent incidence is unknown, Marinkelle⁵ estimated that thousands of stingray injuries occurred annually in the freshwater of Columbia during the 1960s. Unfortunately, the annual worldwide incidence of stingray injuries is generally unknown and is difficult to estimate, in part because injuries often go unreported.

Stingrays are dorsoventrally flattened, diamond-shaped fish with light-colored ventral and dark-colored dorsal surfaces. They have strong pectoral wings that allow them to swim forward and backward and even launch off waves.³ Stingrays range in size from the palm of a human hand to 6.5 ft in width. They possess 1 or more spines (2.5 to >30 cm in length) that are disguised by much longer tails.^6,7 They often are encountered accidentally because they bury themselves in the sand or mud of shallow coastal waters or rivers with only their eyes and tails exposed to fool prey and avoid predators.

Injury Clinical Presentation

Stingray injuries typically involve the lower legs, ankles, or feet after stepping on a stingray.⁸ Fishermen can present with injuries of the upper extremities after handling fish with their hands.⁹ Other rarer injuries occur when individuals are swimming alongside stingrays or when stingrays catapult off waves into moving boats.^10,11 Stingrays impale victims by using their tails to direct a retroserrate barb composed of a strong cartilaginous material called vasodentin. The barb releases venom by breaking through the venom-containing integumentary sheath that encapsulates it. Stingray venom contains phosphodiesterase, serotonin, and 5′-nucleotidase. It causes severe pain, vasoconstriction, ischemia, and poor wound healing, along with systemic effects such as disorientation, syncope, seizures, salivation, nausea, vomiting, abdominal pain, diarrhea, muscle cramps or fasciculations, pruritus, allergic reaction, hypotension, cardiac arrhythmias, dyspnea, paralysis, and possibly death.^1,8,12,13

Management

Pain Relief
As with many marine envenomations, immersion in hot but not scalding water can inactivate venom and reduce symptoms.^8,9 In one retrospective review, 52 of 75 (69%) patients reporting to a California poison center with stingray injuries had improvement in pain within 1 hour of hot water immersion before any analgesics were instituted.⁸ In another review, 65 of 74 (88%) patients presenting to a California emergency department within 24 hours of sustaining a stingray injury had complete relief of pain within 30 minutes of hot water immersion. Patients who received analgesics in addition to hot water immersion did not require a second dose.⁹ In concordance with these studies, we suggest immersing areas affected by stingray injuries in hot water (temperature, 43.3°C to 46.1°C [110°F–115°F]; or as close to this range as tolerated) until pain subsides.^8,9,14 Ice packs are an alternative to hot water immersion that may be more readily available to patients. If pain does not resolve following hot water immersion or application of an ice pack, additional analgesics and xylocaine without epinephrine may be helpful.^9,15

Infection
One major complication of stingray injuries is infection.^8,9 Many bacterial species reside in stingray mucus, the marine environment, or on human skin that may be introduced during a single injury. Marine envenomations can involve organisms such as Vibrio, Aeromonas, and Mycobacterium species, which often are resistant to antibiotic prophylaxis covering common causes of soft-tissue infection such as Staphylococcus and Streptococcus species.^8,9,16,17 Additionally, physicians should cover for Clostridium species and ensure patients are up-to-date on vaccinations because severe cases of tetanus following stingray injuries have been reported.¹⁸ Lastly, fungal infections including fusariosis have been reported following stingray injuries and should be considered if a patient develops an infection.¹⁹

Several authors support the use of prophylactic broad-spectrum antibiotics in all but mild stingray injuries.^8,9,20,21 Although no standardized definition exists, mild injuries generally represent patients with superficial lacerations or less, while deeper lacerations and puncture wounds require prophylaxis. Several authors agree on the use of fluoroquinolone antibiotics (eg, ciprofloxacin 500 mg twice daily) for 5 to 7 days following severe stingray injuries.^1,9,13,22 Other proposed antibiotic regimens include trimethoprim-sulfamethoxazole (160/800 mg twice daily) or tetracycline (500 mg 4 times daily) for 7 days.¹³ Failure of ciprofloxacin therapy after 7 days has been reported, with resolution of infection after treatment with an intravenous cephalosporin for 7 days.²⁰ Failure of trimethoprim-sulfamethoxazole therapy also has been reported, with one case requiring levofloxacin for a much longer course.²¹ Clinical follow-up remains essential after prescribing prophylactic antibiotics, as resistance is common.

Foreign Bodies
Stingray injuries also are often complicated by foreign bodies or retained spines.^3,8 Although these complications are less severe than infection, all wounds should be explored for material under local anesthesia. Furthermore, there has been support for thorough debridement of necrotic tissue with referral to a hand specialist for deeper injuries to the hands as well as referral to a foot and ankle specialist for deeper injuries of the lower extremities.^23,24 More serious injuries with penetration of vital structures, such as through the chest or abdomen, require immediate exploration in an operating room.^1,24

Imaging
Routine imaging of stingray injuries remains controversial. In a case series of 119 patients presenting to a California emergency department with stingray injuries, Clark et al⁹ found that radiographs were not helpful. This finding likely is due in part to an inability to detect hypodense material such as integumentary or glandular tissue via radiography.³ However, radiographs have been used to identify retained stingray barbs in select cases in which retained barbs are suspected.^2,25 Lastly, ultrasonography potentially may offer a better first choice when a barb is not readily apparent; magnetic resonance imaging may be indicated for more involved areas and for further visualization of suspected hypodense material, though at a higher expense.^2,9

Biopsy
Biopsies of stingray injuries are rarely performed, and the findings are not well characterized. One case biopsied 2 months after injury showed a large zone of paucicellular necrosis with superficial ulceration and granulomatous inflammation. The stingray venom was most likely responsible for the pattern of necrosis noted in the biopsy.²¹

Avoidance and Prevention

Patients traveling to areas of the world inhabited by stingrays should receive counseling on how to avoid injury. Prior to entry, individuals can throw stones or use a long stick to clear their walking or swimming areas of venomous fish.²⁶ Polarized sunglasses may help spot stingrays in shallow water. Furthermore, wading through water with a shuffling gait can help individuals avoid stepping directly on a stingray and also warns stingrays that someone is in the area. Individuals who spend more time in coastal waters or river systems inhabited by stingrays may invest in protective stingray gear such as leg guards or specialized wading boots.²⁶ Lastly, fishermen should be advised to avoid handling stingrays with their hands and instead cut their fishing line to release the fish.

Incidence and Characteristics

Stingrays are the most common cause of fish-related stings worldwide.¹ The Urolophidae and Dasyatidae stingray families are responsible for most marine stingray injuries, including approximately 1500 reported injuries in the United States annually.^1,2 Saltwater stingrays from these families commonly are encountered in shallow temperate and tropical coastal waters across the globe and possess dorsally and distally located spines capable of injuring humans that step on them (Figure 1).^1,3 Freshwater stingrays (Potamotrygonidae family)(Figure 2) are not present in North America but rather inhabit lakes and river systems in South America, Africa, Laos, and Vietnam.⁴ Although recent incidence is unknown, Marinkelle⁵ estimated that thousands of stingray injuries occurred annually in the freshwater of Columbia during the 1960s. Unfortunately, the annual worldwide incidence of stingray injuries is generally unknown and is difficult to estimate, in part because injuries often go unreported.

Stingrays are dorsoventrally flattened, diamond-shaped fish with light-colored ventral and dark-colored dorsal surfaces. They have strong pectoral wings that allow them to swim forward and backward and even launch off waves.³ Stingrays range in size from the palm of a human hand to 6.5 ft in width. They possess 1 or more spines (2.5 to >30 cm in length) that are disguised by much longer tails.^6,7 They often are encountered accidentally because they bury themselves in the sand or mud of shallow coastal waters or rivers with only their eyes and tails exposed to fool prey and avoid predators.

Injury Clinical Presentation

Stingray injuries typically involve the lower legs, ankles, or feet after stepping on a stingray.⁸ Fishermen can present with injuries of the upper extremities after handling fish with their hands.⁹ Other rarer injuries occur when individuals are swimming alongside stingrays or when stingrays catapult off waves into moving boats.^10,11 Stingrays impale victims by using their tails to direct a retroserrate barb composed of a strong cartilaginous material called vasodentin. The barb releases venom by breaking through the venom-containing integumentary sheath that encapsulates it. Stingray venom contains phosphodiesterase, serotonin, and 5′-nucleotidase. It causes severe pain, vasoconstriction, ischemia, and poor wound healing, along with systemic effects such as disorientation, syncope, seizures, salivation, nausea, vomiting, abdominal pain, diarrhea, muscle cramps or fasciculations, pruritus, allergic reaction, hypotension, cardiac arrhythmias, dyspnea, paralysis, and possibly death.^1,8,12,13

Management

Pain Relief
As with many marine envenomations, immersion in hot but not scalding water can inactivate venom and reduce symptoms.^8,9 In one retrospective review, 52 of 75 (69%) patients reporting to a California poison center with stingray injuries had improvement in pain within 1 hour of hot water immersion before any analgesics were instituted.⁸ In another review, 65 of 74 (88%) patients presenting to a California emergency department within 24 hours of sustaining a stingray injury had complete relief of pain within 30 minutes of hot water immersion. Patients who received analgesics in addition to hot water immersion did not require a second dose.⁹ In concordance with these studies, we suggest immersing areas affected by stingray injuries in hot water (temperature, 43.3°C to 46.1°C [110°F–115°F]; or as close to this range as tolerated) until pain subsides.^8,9,14 Ice packs are an alternative to hot water immersion that may be more readily available to patients. If pain does not resolve following hot water immersion or application of an ice pack, additional analgesics and xylocaine without epinephrine may be helpful.^9,15

Infection
One major complication of stingray injuries is infection.^8,9 Many bacterial species reside in stingray mucus, the marine environment, or on human skin that may be introduced during a single injury. Marine envenomations can involve organisms such as Vibrio, Aeromonas, and Mycobacterium species, which often are resistant to antibiotic prophylaxis covering common causes of soft-tissue infection such as Staphylococcus and Streptococcus species.^8,9,16,17 Additionally, physicians should cover for Clostridium species and ensure patients are up-to-date on vaccinations because severe cases of tetanus following stingray injuries have been reported.¹⁸ Lastly, fungal infections including fusariosis have been reported following stingray injuries and should be considered if a patient develops an infection.¹⁹

Several authors support the use of prophylactic broad-spectrum antibiotics in all but mild stingray injuries.^8,9,20,21 Although no standardized definition exists, mild injuries generally represent patients with superficial lacerations or less, while deeper lacerations and puncture wounds require prophylaxis. Several authors agree on the use of fluoroquinolone antibiotics (eg, ciprofloxacin 500 mg twice daily) for 5 to 7 days following severe stingray injuries.^1,9,13,22 Other proposed antibiotic regimens include trimethoprim-sulfamethoxazole (160/800 mg twice daily) or tetracycline (500 mg 4 times daily) for 7 days.¹³ Failure of ciprofloxacin therapy after 7 days has been reported, with resolution of infection after treatment with an intravenous cephalosporin for 7 days.²⁰ Failure of trimethoprim-sulfamethoxazole therapy also has been reported, with one case requiring levofloxacin for a much longer course.²¹ Clinical follow-up remains essential after prescribing prophylactic antibiotics, as resistance is common.

Foreign Bodies
Stingray injuries also are often complicated by foreign bodies or retained spines.^3,8 Although these complications are less severe than infection, all wounds should be explored for material under local anesthesia. Furthermore, there has been support for thorough debridement of necrotic tissue with referral to a hand specialist for deeper injuries to the hands as well as referral to a foot and ankle specialist for deeper injuries of the lower extremities.^23,24 More serious injuries with penetration of vital structures, such as through the chest or abdomen, require immediate exploration in an operating room.^1,24

Imaging
Routine imaging of stingray injuries remains controversial. In a case series of 119 patients presenting to a California emergency department with stingray injuries, Clark et al⁹ found that radiographs were not helpful. This finding likely is due in part to an inability to detect hypodense material such as integumentary or glandular tissue via radiography.³ However, radiographs have been used to identify retained stingray barbs in select cases in which retained barbs are suspected.^2,25 Lastly, ultrasonography potentially may offer a better first choice when a barb is not readily apparent; magnetic resonance imaging may be indicated for more involved areas and for further visualization of suspected hypodense material, though at a higher expense.^2,9

Biopsy
Biopsies of stingray injuries are rarely performed, and the findings are not well characterized. One case biopsied 2 months after injury showed a large zone of paucicellular necrosis with superficial ulceration and granulomatous inflammation. The stingray venom was most likely responsible for the pattern of necrosis noted in the biopsy.²¹

Avoidance and Prevention

Patients traveling to areas of the world inhabited by stingrays should receive counseling on how to avoid injury. Prior to entry, individuals can throw stones or use a long stick to clear their walking or swimming areas of venomous fish.²⁶ Polarized sunglasses may help spot stingrays in shallow water. Furthermore, wading through water with a shuffling gait can help individuals avoid stepping directly on a stingray and also warns stingrays that someone is in the area. Individuals who spend more time in coastal waters or river systems inhabited by stingrays may invest in protective stingray gear such as leg guards or specialized wading boots.²⁶ Lastly, fishermen should be advised to avoid handling stingrays with their hands and instead cut their fishing line to release the fish.

Incidence and Characteristics

Stingrays are the most common cause of fish-related stings worldwide.¹ The Urolophidae and Dasyatidae stingray families are responsible for most marine stingray injuries, including approximately 1500 reported injuries in the United States annually.^1,2 Saltwater stingrays from these families commonly are encountered in shallow temperate and tropical coastal waters across the globe and possess dorsally and distally located spines capable of injuring humans that step on them (Figure 1).^1,3 Freshwater stingrays (Potamotrygonidae family)(Figure 2) are not present in North America but rather inhabit lakes and river systems in South America, Africa, Laos, and Vietnam.⁴ Although recent incidence is unknown, Marinkelle⁵ estimated that thousands of stingray injuries occurred annually in the freshwater of Columbia during the 1960s. Unfortunately, the annual worldwide incidence of stingray injuries is generally unknown and is difficult to estimate, in part because injuries often go unreported.

Stingrays are dorsoventrally flattened, diamond-shaped fish with light-colored ventral and dark-colored dorsal surfaces. They have strong pectoral wings that allow them to swim forward and backward and even launch off waves.³ Stingrays range in size from the palm of a human hand to 6.5 ft in width. They possess 1 or more spines (2.5 to >30 cm in length) that are disguised by much longer tails.^6,7 They often are encountered accidentally because they bury themselves in the sand or mud of shallow coastal waters or rivers with only their eyes and tails exposed to fool prey and avoid predators.

Injury Clinical Presentation

Stingray injuries typically involve the lower legs, ankles, or feet after stepping on a stingray.⁸ Fishermen can present with injuries of the upper extremities after handling fish with their hands.⁹ Other rarer injuries occur when individuals are swimming alongside stingrays or when stingrays catapult off waves into moving boats.^10,11 Stingrays impale victims by using their tails to direct a retroserrate barb composed of a strong cartilaginous material called vasodentin. The barb releases venom by breaking through the venom-containing integumentary sheath that encapsulates it. Stingray venom contains phosphodiesterase, serotonin, and 5′-nucleotidase. It causes severe pain, vasoconstriction, ischemia, and poor wound healing, along with systemic effects such as disorientation, syncope, seizures, salivation, nausea, vomiting, abdominal pain, diarrhea, muscle cramps or fasciculations, pruritus, allergic reaction, hypotension, cardiac arrhythmias, dyspnea, paralysis, and possibly death.^1,8,12,13

Management

Pain Relief
As with many marine envenomations, immersion in hot but not scalding water can inactivate venom and reduce symptoms.^8,9 In one retrospective review, 52 of 75 (69%) patients reporting to a California poison center with stingray injuries had improvement in pain within 1 hour of hot water immersion before any analgesics were instituted.⁸ In another review, 65 of 74 (88%) patients presenting to a California emergency department within 24 hours of sustaining a stingray injury had complete relief of pain within 30 minutes of hot water immersion. Patients who received analgesics in addition to hot water immersion did not require a second dose.⁹ In concordance with these studies, we suggest immersing areas affected by stingray injuries in hot water (temperature, 43.3°C to 46.1°C [110°F–115°F]; or as close to this range as tolerated) until pain subsides.^8,9,14 Ice packs are an alternative to hot water immersion that may be more readily available to patients. If pain does not resolve following hot water immersion or application of an ice pack, additional analgesics and xylocaine without epinephrine may be helpful.^9,15

Infection
One major complication of stingray injuries is infection.^8,9 Many bacterial species reside in stingray mucus, the marine environment, or on human skin that may be introduced during a single injury. Marine envenomations can involve organisms such as Vibrio, Aeromonas, and Mycobacterium species, which often are resistant to antibiotic prophylaxis covering common causes of soft-tissue infection such as Staphylococcus and Streptococcus species.^8,9,16,17 Additionally, physicians should cover for Clostridium species and ensure patients are up-to-date on vaccinations because severe cases of tetanus following stingray injuries have been reported.¹⁸ Lastly, fungal infections including fusariosis have been reported following stingray injuries and should be considered if a patient develops an infection.¹⁹

Several authors support the use of prophylactic broad-spectrum antibiotics in all but mild stingray injuries.^8,9,20,21 Although no standardized definition exists, mild injuries generally represent patients with superficial lacerations or less, while deeper lacerations and puncture wounds require prophylaxis. Several authors agree on the use of fluoroquinolone antibiotics (eg, ciprofloxacin 500 mg twice daily) for 5 to 7 days following severe stingray injuries.^1,9,13,22 Other proposed antibiotic regimens include trimethoprim-sulfamethoxazole (160/800 mg twice daily) or tetracycline (500 mg 4 times daily) for 7 days.¹³ Failure of ciprofloxacin therapy after 7 days has been reported, with resolution of infection after treatment with an intravenous cephalosporin for 7 days.²⁰ Failure of trimethoprim-sulfamethoxazole therapy also has been reported, with one case requiring levofloxacin for a much longer course.²¹ Clinical follow-up remains essential after prescribing prophylactic antibiotics, as resistance is common.

Foreign Bodies
Stingray injuries also are often complicated by foreign bodies or retained spines.^3,8 Although these complications are less severe than infection, all wounds should be explored for material under local anesthesia. Furthermore, there has been support for thorough debridement of necrotic tissue with referral to a hand specialist for deeper injuries to the hands as well as referral to a foot and ankle specialist for deeper injuries of the lower extremities.^23,24 More serious injuries with penetration of vital structures, such as through the chest or abdomen, require immediate exploration in an operating room.^1,24

Imaging
Routine imaging of stingray injuries remains controversial. In a case series of 119 patients presenting to a California emergency department with stingray injuries, Clark et al⁹ found that radiographs were not helpful. This finding likely is due in part to an inability to detect hypodense material such as integumentary or glandular tissue via radiography.³ However, radiographs have been used to identify retained stingray barbs in select cases in which retained barbs are suspected.^2,25 Lastly, ultrasonography potentially may offer a better first choice when a barb is not readily apparent; magnetic resonance imaging may be indicated for more involved areas and for further visualization of suspected hypodense material, though at a higher expense.^2,9

Biopsy
Biopsies of stingray injuries are rarely performed, and the findings are not well characterized. One case biopsied 2 months after injury showed a large zone of paucicellular necrosis with superficial ulceration and granulomatous inflammation. The stingray venom was most likely responsible for the pattern of necrosis noted in the biopsy.²¹

Avoidance and Prevention

Patients traveling to areas of the world inhabited by stingrays should receive counseling on how to avoid injury. Prior to entry, individuals can throw stones or use a long stick to clear their walking or swimming areas of venomous fish.²⁶ Polarized sunglasses may help spot stingrays in shallow water. Furthermore, wading through water with a shuffling gait can help individuals avoid stepping directly on a stingray and also warns stingrays that someone is in the area. Individuals who spend more time in coastal waters or river systems inhabited by stingrays may invest in protective stingray gear such as leg guards or specialized wading boots.²⁶ Lastly, fishermen should be advised to avoid handling stingrays with their hands and instead cut their fishing line to release the fish.

The 2018-2019 flu season may have peaked as the major nationwide measure of influenza activity held steady for the week ending Feb. 23, according to the Centers for Disease Control and Prevention. The proportion of outpatient visits for influenza-like illness (ILI) was 5.0% for the most recent reporting week, the CDC’s influenza division said in its March 1 report. The previous week’s outpatient visit rate, originally reported as 5.1%, was revised this week to 5.0% as well, suggesting that flu activity is no longer increasing.

Activity at the state level was more mixed. The number of states at level 10 on the CDC’s 1-10 scale of ILI activity stayed at 24 as Indiana and North Dakota replaced Tennessee and Wyoming, but the number of states in the high range (8-10) of the activity scale increased from 30 to 33, CDC data show.

The signs of plateauing ILI activity did not, however, extend to flu-related deaths, with 15 reported among children – the highest weekly number for the 2018-2019 season, although 11 actually occurred in previous weeks – during the week ending Feb. 23 and 289 deaths among all ages for the week ending Feb. 16, which is already more than the 268 listed the week before despite less complete reporting (82% vs. 97%), the CDC reported. Total flu-related deaths in children are now up to 56, compared with 138 at the corresponding point in the 2017-2018 season.

[email protected]

The 2018-2019 flu season may have peaked as the major nationwide measure of influenza activity held steady for the week ending Feb. 23, according to the Centers for Disease Control and Prevention. The proportion of outpatient visits for influenza-like illness (ILI) was 5.0% for the most recent reporting week, the CDC’s influenza division said in its March 1 report. The previous week’s outpatient visit rate, originally reported as 5.1%, was revised this week to 5.0% as well, suggesting that flu activity is no longer increasing.

Activity at the state level was more mixed. The number of states at level 10 on the CDC’s 1-10 scale of ILI activity stayed at 24 as Indiana and North Dakota replaced Tennessee and Wyoming, but the number of states in the high range (8-10) of the activity scale increased from 30 to 33, CDC data show.

The signs of plateauing ILI activity did not, however, extend to flu-related deaths, with 15 reported among children – the highest weekly number for the 2018-2019 season, although 11 actually occurred in previous weeks – during the week ending Feb. 23 and 289 deaths among all ages for the week ending Feb. 16, which is already more than the 268 listed the week before despite less complete reporting (82% vs. 97%), the CDC reported. Total flu-related deaths in children are now up to 56, compared with 138 at the corresponding point in the 2017-2018 season.

[email protected]

The 2018-2019 flu season may have peaked as the major nationwide measure of influenza activity held steady for the week ending Feb. 23, according to the Centers for Disease Control and Prevention. The proportion of outpatient visits for influenza-like illness (ILI) was 5.0% for the most recent reporting week, the CDC’s influenza division said in its March 1 report. The previous week’s outpatient visit rate, originally reported as 5.1%, was revised this week to 5.0% as well, suggesting that flu activity is no longer increasing.

Activity at the state level was more mixed. The number of states at level 10 on the CDC’s 1-10 scale of ILI activity stayed at 24 as Indiana and North Dakota replaced Tennessee and Wyoming, but the number of states in the high range (8-10) of the activity scale increased from 30 to 33, CDC data show.

The signs of plateauing ILI activity did not, however, extend to flu-related deaths, with 15 reported among children – the highest weekly number for the 2018-2019 season, although 11 actually occurred in previous weeks – during the week ending Feb. 23 and 289 deaths among all ages for the week ending Feb. 16, which is already more than the 268 listed the week before despite less complete reporting (82% vs. 97%), the CDC reported. Total flu-related deaths in children are now up to 56, compared with 138 at the corresponding point in the 2017-2018 season.

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About 12% of women worldwide are infected with human papillomavirus (HPV).¹ Persistent HPV infection with high-risk strains such as HPV 6, 11, 16, and 18 cause nearly all cases of cervical cancer and some anal, vaginal, penile, and oropharyngeal cancers.² An estimated 13,000 cases of invasive cervical cancer will be diagnosed this year in the United States alone.³

Up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. A number of changes have been made to the vaccination schedule within the past few years—patients younger than 15 need only 2 rather than 3 doses, and the vaccine itself can be used in adults up to age 45.

Vaccination and routine cervical cancer screening are both necessary to prevent this disease³ along with effective family and patient counseling. Here, we discuss the most up-to-date HPV vaccination recommendations, current cervical cancer screening guidelines, counseling techniques that increase vaccination acceptance rates, and follow-up protocols for abnormal cervical cancer screening results.

TYPES OF HPV VACCINES

HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts.⁴ The US Food and Drug Administration (FDA) has approved 3 HPV vaccines:

• Gardasil 9 targets HPV types 6, 11, 16, and 18 along with 31, 33, 45, 52, 58—these cause 90% of cervical cancer cases and most cases of genital warts⁵—making it the most effective vaccine available; Gardasil 9 is the only HPV vaccine currently available in the United States
• The bivalent vaccine (Cervarix) targeted HPV 16 and 18 only, and was discontinued in the United States in 2016
• The quadrivalent HPV vaccine (Gardasil) targeted HPV 16 and 18 as well as 6 and 11, which cause most cases of genital warts; the last available doses in the United States expired in May 2017; it has been replaced by Gardasil 9.

The incidence of cervical cancer in the United States dropped 29% among 15- to 24-year-olds from 2003–2006 when HPV vaccination first started to 2011–2014.⁶

VACCINE DOSING RECOMMENDATIONS FOR PRIMARY PREVENTION

The Advisory Committee on Immunization Practices (ACIP) revised its HPV vaccine schedule in 2016, when it decreased the necessary doses from 3 to 2 for patients under age 15 and addressed the needs of special patient populations.⁷ In late 2018, the FDA approved the use of the vaccine in men and women up to age 45. However, no change in guidelines have yet been made (Table 1).

In females, the ACIP recommends starting HPV vaccination at age 11 or 12, but it can be given as early as age 9. A 2-dose schedule is recommended for the 9-valent vaccine before the patient’s 15th birthday (the second dose 6 to 12 months after the first).⁷ For females who initiate HPV vaccination between ages 15 and 45, a 3-dose schedule is necessary (at 0, 1 to 2, and 6 months).^7,8

The change to a 2-dose schedule was prompted by an evaluation of girls ages 9 to 13 randomized to receive either a 2- or 3-dose schedule. Antibody responses with a 2-dose schedule were not inferior to those of young women (ages 16 to 26) who received all 3 doses.⁹ The geometric mean titer ratios remained noninferior throughout the study period of 36 months.

However, a loss of noninferiority was noted for HPV-18 by 24 months and for HPV-6 by 36 months.⁹ Thus, further studies are needed to understand the duration of protection with a 2-dose schedule. Nevertheless, decreasing the number of doses makes it a more convenient and cost-effective option for many families.

The recommendations are the same for males except for one notable difference: in males ages 21 to 26, vaccination is not routinely recommended by the ACIP, but rather it is considered a “permissive use” recommendation: ie, the vaccine should be offered and final decisions on administration be made after individualized discussion with the patient.¹⁰ Permissive-use status also means the vaccine may not be covered by health insurance. Even though the vaccine is now available to men and women until age 45, many insurance plans do not cover it after age 26.

Children of either sex with a history of sexual abuse should receive their first vaccine dose beginning at age 9.⁷

Immunocompromised patients should follow the 3-dose schedule regardless of their sex or the age when vaccination was initiated.¹⁰

For transgender patients and for men not previously vaccinated who have sex with men, the 3-dose schedule vaccine should be given by the age of 26 (this is a routine recommendation, not a permissive one).⁸

Effective patient and family counseling is important. Even though the first HPV vaccine was approved in 2006, only 34.9% of US adolescents were fully vaccinated by 2015. This was in part because providers did not recommend it, were unfamiliar with it, or had concerns about its safety,^11,12 and in part because some parents refused it.

The physician must address any myths regarding HPV vaccination and ensure that parents and patients understand that HPV vaccine is safe and effective. Studies have shown that with high-quality recommendations (ie, the care provider strongly endorses the HPV vaccine, encourages same-day vaccination, and discusses cancer prevention), patients are 9 times more likely to start the HPV vaccination schedule and 3 times more likely to follow through with subsequent doses.¹³

Providing good family and patient education does not necessarily require spending more counseling time. A recent study showed that spending less time discussing the HPV vaccine can lead to better vaccine coverage.¹⁴ The study compared parent HPV vaccine counseling techniques and found that simply informing patients and their families that the HPV vaccine was due was associated with a higher vaccine acceptance rate than inviting conversations about it.¹⁴ When providers announced that the vaccine was due, assuming the parents were ready to vaccinate, there was a 5.4% increase in HPV vaccination coverage.¹⁴

Conversely, physicians who engaged parents in open-ended discussions about the HPV vaccine did not improve HPV vaccination coverage.¹⁴ The authors suggested that providers approach HPV vaccination as if they were counseling patients and families about the need to avoid second-hand smoke or the need to use car seats. If parents or patients resist the presumptive announcement approach, expanded counseling and shared decision-making are appropriate. This includes addressing misconceptions that parents and patients may have about the HPV vaccine. The American Cancer Society lists 8 facts to reference (Table 2).¹⁵

SECONDARY PREVENTION: CERVICAL CANCER SCREENING

Since the introduction of the Papanicolaou (Pap) test, US cervical cancer incidence rates have decreased by more than 60%.¹⁶ Because almost all cervical cancer is preventable with proper screening, all women ages 21 to 65 should be screened.

Currently, there are 3 options available for cervical cancer screening: the Pap-only test, the Pap-HPV cotest, and the high-risk HPV-only test (Table 3). The latter 2 options detect high-risk HPV genotypes.

Several organizations have screening algorithms that recommend when to use these tests, but the 3 that shape today’s standard of care in cervical cancer screening come from the American College of Obstetricians and Gynecologists (ACOG), the American Society for Colposcopy and Cervical Pathology (ASCCP), and US Preventive Services Task Force (USPSTF).^17–19

Pap-only testing is performed every 3 years to screen for cervical neoplasia that might indicate premalignancy.

Pap-HPV cotesting is performed every 5 years in women older than 30 with past normal screening. Until 2018, all 3 organizations recommended cotesting as the preferred screening algorithm for women ages 30 to 65.^17–19 Patients with a history of abnormal test results require more frequent testing as recommended by the ASCCP.¹⁸

The high-risk HPV-only test utilizes real-time polymerase chain reaction to detect HPV 16, HPV 18, and 12 other HPV genotypes. Only 2 tests are approved by the FDA as stand-alone cervical cancer screening tests—the Roche Cobas HPV test approved in 2014 and the Becton Dickinson Onclarity HPV assay approved in 2018. Other HPV tests that are used in a cotesting strategy should not be used for high-risk HPV-only testing because their performance characteristics may differ.

In 2015, the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study showed that 1 round of high-risk HPV-only screening for women older than 25 was more sensitive than Pap-only or cotesting for stage 3 cervical intraepithelial neoplasia or more severe disease (after 3 years of follow-up).²⁰ Current guidelines from ASCCP¹⁸ and ACOG¹⁷ state that the high-risk HPV test can be repeated every 3 years (when used to screen by itself) if the woman is older than 25 and has had a normal test result.

If the HPV test result is positive for high-risk HPV 16 or 18 genotypes, then immediate colposcopy is indicated; women who test positive for one of the other 12 high-risk subtypes will need to undergo a Pap test to determine the appropriate follow-up (Figure 1).^18,21

In 2018, the USPSTF updated its recommendations, noting that for women age 30 to 65, Pap-only testing every 3 years, cotesting every 5 years, or high-risk HPV-only testing every 5 years are all appropriate screening strategies, with the Pap-only or high-risk HPV-only screenings being preferred.¹⁹ This is in contrast to ACOG and ASCCP recommendations for cotesting every 5 years, with alternative options of Pap-only or HPV-only testing being done every 3 years.^17,18

The USPSTF reviewed large randomized and observational studies to summarize the effectiveness of the 3 screening strategies and commissioned a decision analysis model to compare the risks, benefits, and costs of the 3 screening algorithms. The guideline statement notes both cotesting and high-risk HPV testing offer similar cancer detection rates: each prevents 1 additional cancer per 1,000 women screened as opposed to Pap-only testing.¹⁹

Also, tests that incorporate high-risk HPV screening may offer better detection of cervical adenocarcinoma (which has a worse prognosis than the more common squamous cell carcinoma type). However, both HPV-based screening strategies are more likely to require additional colposcopies for follow-up than Pap-only screening (1,630 colposcopies required for each cancer prevented with high-risk HPV alone, 1,635 with cotesting). Colposcopy is a simple office procedure that causes minimal discomfort to the patient.

The USPSTF guideline also differs in the recommended frequency of high-risk HPV-only testing; a high-risk HPV result should be repeated every 5 years if normal (as opposed to every 3 years as recommended by ACOG and ASCCP).¹⁹ The 5-year recommendation is based on analysis modeling, which suggests that performing high-risk HPV-only testing more frequently is unlikely to improve detection rates but will increase the number of screening tests and colposcopies.¹⁹

No trial has directly compared cotesting with high-risk HPV testing for more than 2 rounds of screening. The updated USPSTF recommendations are based on modeling estimates and expert opinion, which assesses cost and benefit vs harm in the long term. Also, no high-risk HPV test is currently FDA-approved for every-5-year screening when used by itself.

All 3 cervical cancer screening methods provide highly effective cancer prevention, so it is important for providers to choose the strategy that best fits their practice. The most critical aspect of screening is getting all women screened, no matter which method is used.

It is critical to remember that the screening intervals are intended for patients without symptoms. Those who have new concerns such as bleeding should have a diagnostic Pap done to evaluate their symptoms.

Follow-up of abnormal results

Regardless of the pathway chosen, appropriate follow-up of any abnormal test result is critical to the early detection of cancer. Established follow-up guidelines exist,^22,23 but accessing this information can be difficult for the busy clinician. The ASCCP has a mobile phone application that outlines the action steps corresponding to the patient’s age and results of any combination of Pap or HPV testing. The app also includes the best screening algorithms for a particular patient.²⁴

All guidelines agree that cervical cancer screening should start at age 21, regardless of HPV vaccination status or age of sexual initiation.^17,18,25 Screening can be discontinued at age 65 for women with normal screening results in the prior decade (3 consecutive negative Pap results or 2 consecutive negative cotest results).²³

For women who have had a total hysterectomy and no history of cervical neoplasia, screening should be stopped immediately after the procedure. However, several high-risk groups of women will need continued screening past the age of 65, or after a hysterectomy.

For a woman with a history of stage 2 cervical intraepithelial neoplasia or higher grade lesions, routine screening is continued for an additional 20 years, even if she is over age 65. Pap-only testing every 3 years is acceptable, because the role of HPV testing is unclear after hysterectomy.²³ Prior guidelines suggested annual screening in these patients, so the change to every 3 years is notable. Many gynecologic oncologists will recommend that women with a history of cervical cancer continue annual screening indefinitely.

Within the first 2 to 3 years after treatment for high-grade dysplastic changes, annual follow-up is done by the gynecologic oncology team. Providers who offer follow-up during this time frame should keep in communication with the oncology team to ensure appropriate, individualized care. These recommendations are based on expert opinion, so variations in clinical practice may be seen.

Women infected with the human immunodeficiency virus can have Pap-only testing every 3 years, after a series of 3 normal annual Pap results.²⁶ But screening does not stop at age 65.^23,26 For patients who are immunosuppressed or have a history of diethylstilbestrol exposure, screening should be done annually indefinitely.²³

About 12% of women worldwide are infected with human papillomavirus (HPV).¹ Persistent HPV infection with high-risk strains such as HPV 6, 11, 16, and 18 cause nearly all cases of cervical cancer and some anal, vaginal, penile, and oropharyngeal cancers.² An estimated 13,000 cases of invasive cervical cancer will be diagnosed this year in the United States alone.³

Up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. A number of changes have been made to the vaccination schedule within the past few years—patients younger than 15 need only 2 rather than 3 doses, and the vaccine itself can be used in adults up to age 45.

Vaccination and routine cervical cancer screening are both necessary to prevent this disease³ along with effective family and patient counseling. Here, we discuss the most up-to-date HPV vaccination recommendations, current cervical cancer screening guidelines, counseling techniques that increase vaccination acceptance rates, and follow-up protocols for abnormal cervical cancer screening results.

TYPES OF HPV VACCINES

HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts.⁴ The US Food and Drug Administration (FDA) has approved 3 HPV vaccines:

• Gardasil 9 targets HPV types 6, 11, 16, and 18 along with 31, 33, 45, 52, 58—these cause 90% of cervical cancer cases and most cases of genital warts⁵—making it the most effective vaccine available; Gardasil 9 is the only HPV vaccine currently available in the United States
• The bivalent vaccine (Cervarix) targeted HPV 16 and 18 only, and was discontinued in the United States in 2016
• The quadrivalent HPV vaccine (Gardasil) targeted HPV 16 and 18 as well as 6 and 11, which cause most cases of genital warts; the last available doses in the United States expired in May 2017; it has been replaced by Gardasil 9.

The incidence of cervical cancer in the United States dropped 29% among 15- to 24-year-olds from 2003–2006 when HPV vaccination first started to 2011–2014.⁶

VACCINE DOSING RECOMMENDATIONS FOR PRIMARY PREVENTION

The Advisory Committee on Immunization Practices (ACIP) revised its HPV vaccine schedule in 2016, when it decreased the necessary doses from 3 to 2 for patients under age 15 and addressed the needs of special patient populations.⁷ In late 2018, the FDA approved the use of the vaccine in men and women up to age 45. However, no change in guidelines have yet been made (Table 1).

In females, the ACIP recommends starting HPV vaccination at age 11 or 12, but it can be given as early as age 9. A 2-dose schedule is recommended for the 9-valent vaccine before the patient’s 15th birthday (the second dose 6 to 12 months after the first).⁷ For females who initiate HPV vaccination between ages 15 and 45, a 3-dose schedule is necessary (at 0, 1 to 2, and 6 months).^7,8

The change to a 2-dose schedule was prompted by an evaluation of girls ages 9 to 13 randomized to receive either a 2- or 3-dose schedule. Antibody responses with a 2-dose schedule were not inferior to those of young women (ages 16 to 26) who received all 3 doses.⁹ The geometric mean titer ratios remained noninferior throughout the study period of 36 months.

However, a loss of noninferiority was noted for HPV-18 by 24 months and for HPV-6 by 36 months.⁹ Thus, further studies are needed to understand the duration of protection with a 2-dose schedule. Nevertheless, decreasing the number of doses makes it a more convenient and cost-effective option for many families.

The recommendations are the same for males except for one notable difference: in males ages 21 to 26, vaccination is not routinely recommended by the ACIP, but rather it is considered a “permissive use” recommendation: ie, the vaccine should be offered and final decisions on administration be made after individualized discussion with the patient.¹⁰ Permissive-use status also means the vaccine may not be covered by health insurance. Even though the vaccine is now available to men and women until age 45, many insurance plans do not cover it after age 26.

Children of either sex with a history of sexual abuse should receive their first vaccine dose beginning at age 9.⁷

Immunocompromised patients should follow the 3-dose schedule regardless of their sex or the age when vaccination was initiated.¹⁰

For transgender patients and for men not previously vaccinated who have sex with men, the 3-dose schedule vaccine should be given by the age of 26 (this is a routine recommendation, not a permissive one).⁸

Effective patient and family counseling is important. Even though the first HPV vaccine was approved in 2006, only 34.9% of US adolescents were fully vaccinated by 2015. This was in part because providers did not recommend it, were unfamiliar with it, or had concerns about its safety,^11,12 and in part because some parents refused it.

The physician must address any myths regarding HPV vaccination and ensure that parents and patients understand that HPV vaccine is safe and effective. Studies have shown that with high-quality recommendations (ie, the care provider strongly endorses the HPV vaccine, encourages same-day vaccination, and discusses cancer prevention), patients are 9 times more likely to start the HPV vaccination schedule and 3 times more likely to follow through with subsequent doses.¹³

Providing good family and patient education does not necessarily require spending more counseling time. A recent study showed that spending less time discussing the HPV vaccine can lead to better vaccine coverage.¹⁴ The study compared parent HPV vaccine counseling techniques and found that simply informing patients and their families that the HPV vaccine was due was associated with a higher vaccine acceptance rate than inviting conversations about it.¹⁴ When providers announced that the vaccine was due, assuming the parents were ready to vaccinate, there was a 5.4% increase in HPV vaccination coverage.¹⁴

Conversely, physicians who engaged parents in open-ended discussions about the HPV vaccine did not improve HPV vaccination coverage.¹⁴ The authors suggested that providers approach HPV vaccination as if they were counseling patients and families about the need to avoid second-hand smoke or the need to use car seats. If parents or patients resist the presumptive announcement approach, expanded counseling and shared decision-making are appropriate. This includes addressing misconceptions that parents and patients may have about the HPV vaccine. The American Cancer Society lists 8 facts to reference (Table 2).¹⁵

SECONDARY PREVENTION: CERVICAL CANCER SCREENING

Since the introduction of the Papanicolaou (Pap) test, US cervical cancer incidence rates have decreased by more than 60%.¹⁶ Because almost all cervical cancer is preventable with proper screening, all women ages 21 to 65 should be screened.

Currently, there are 3 options available for cervical cancer screening: the Pap-only test, the Pap-HPV cotest, and the high-risk HPV-only test (Table 3). The latter 2 options detect high-risk HPV genotypes.

Several organizations have screening algorithms that recommend when to use these tests, but the 3 that shape today’s standard of care in cervical cancer screening come from the American College of Obstetricians and Gynecologists (ACOG), the American Society for Colposcopy and Cervical Pathology (ASCCP), and US Preventive Services Task Force (USPSTF).^17–19

Pap-only testing is performed every 3 years to screen for cervical neoplasia that might indicate premalignancy.

Pap-HPV cotesting is performed every 5 years in women older than 30 with past normal screening. Until 2018, all 3 organizations recommended cotesting as the preferred screening algorithm for women ages 30 to 65.^17–19 Patients with a history of abnormal test results require more frequent testing as recommended by the ASCCP.¹⁸

The high-risk HPV-only test utilizes real-time polymerase chain reaction to detect HPV 16, HPV 18, and 12 other HPV genotypes. Only 2 tests are approved by the FDA as stand-alone cervical cancer screening tests—the Roche Cobas HPV test approved in 2014 and the Becton Dickinson Onclarity HPV assay approved in 2018. Other HPV tests that are used in a cotesting strategy should not be used for high-risk HPV-only testing because their performance characteristics may differ.

In 2015, the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study showed that 1 round of high-risk HPV-only screening for women older than 25 was more sensitive than Pap-only or cotesting for stage 3 cervical intraepithelial neoplasia or more severe disease (after 3 years of follow-up).²⁰ Current guidelines from ASCCP¹⁸ and ACOG¹⁷ state that the high-risk HPV test can be repeated every 3 years (when used to screen by itself) if the woman is older than 25 and has had a normal test result.

If the HPV test result is positive for high-risk HPV 16 or 18 genotypes, then immediate colposcopy is indicated; women who test positive for one of the other 12 high-risk subtypes will need to undergo a Pap test to determine the appropriate follow-up (Figure 1).^18,21

In 2018, the USPSTF updated its recommendations, noting that for women age 30 to 65, Pap-only testing every 3 years, cotesting every 5 years, or high-risk HPV-only testing every 5 years are all appropriate screening strategies, with the Pap-only or high-risk HPV-only screenings being preferred.¹⁹ This is in contrast to ACOG and ASCCP recommendations for cotesting every 5 years, with alternative options of Pap-only or HPV-only testing being done every 3 years.^17,18

The USPSTF reviewed large randomized and observational studies to summarize the effectiveness of the 3 screening strategies and commissioned a decision analysis model to compare the risks, benefits, and costs of the 3 screening algorithms. The guideline statement notes both cotesting and high-risk HPV testing offer similar cancer detection rates: each prevents 1 additional cancer per 1,000 women screened as opposed to Pap-only testing.¹⁹

Also, tests that incorporate high-risk HPV screening may offer better detection of cervical adenocarcinoma (which has a worse prognosis than the more common squamous cell carcinoma type). However, both HPV-based screening strategies are more likely to require additional colposcopies for follow-up than Pap-only screening (1,630 colposcopies required for each cancer prevented with high-risk HPV alone, 1,635 with cotesting). Colposcopy is a simple office procedure that causes minimal discomfort to the patient.

The USPSTF guideline also differs in the recommended frequency of high-risk HPV-only testing; a high-risk HPV result should be repeated every 5 years if normal (as opposed to every 3 years as recommended by ACOG and ASCCP).¹⁹ The 5-year recommendation is based on analysis modeling, which suggests that performing high-risk HPV-only testing more frequently is unlikely to improve detection rates but will increase the number of screening tests and colposcopies.¹⁹

No trial has directly compared cotesting with high-risk HPV testing for more than 2 rounds of screening. The updated USPSTF recommendations are based on modeling estimates and expert opinion, which assesses cost and benefit vs harm in the long term. Also, no high-risk HPV test is currently FDA-approved for every-5-year screening when used by itself.

All 3 cervical cancer screening methods provide highly effective cancer prevention, so it is important for providers to choose the strategy that best fits their practice. The most critical aspect of screening is getting all women screened, no matter which method is used.

It is critical to remember that the screening intervals are intended for patients without symptoms. Those who have new concerns such as bleeding should have a diagnostic Pap done to evaluate their symptoms.

Follow-up of abnormal results

Regardless of the pathway chosen, appropriate follow-up of any abnormal test result is critical to the early detection of cancer. Established follow-up guidelines exist,^22,23 but accessing this information can be difficult for the busy clinician. The ASCCP has a mobile phone application that outlines the action steps corresponding to the patient’s age and results of any combination of Pap or HPV testing. The app also includes the best screening algorithms for a particular patient.²⁴

All guidelines agree that cervical cancer screening should start at age 21, regardless of HPV vaccination status or age of sexual initiation.^17,18,25 Screening can be discontinued at age 65 for women with normal screening results in the prior decade (3 consecutive negative Pap results or 2 consecutive negative cotest results).²³

For women who have had a total hysterectomy and no history of cervical neoplasia, screening should be stopped immediately after the procedure. However, several high-risk groups of women will need continued screening past the age of 65, or after a hysterectomy.

For a woman with a history of stage 2 cervical intraepithelial neoplasia or higher grade lesions, routine screening is continued for an additional 20 years, even if she is over age 65. Pap-only testing every 3 years is acceptable, because the role of HPV testing is unclear after hysterectomy.²³ Prior guidelines suggested annual screening in these patients, so the change to every 3 years is notable. Many gynecologic oncologists will recommend that women with a history of cervical cancer continue annual screening indefinitely.

Within the first 2 to 3 years after treatment for high-grade dysplastic changes, annual follow-up is done by the gynecologic oncology team. Providers who offer follow-up during this time frame should keep in communication with the oncology team to ensure appropriate, individualized care. These recommendations are based on expert opinion, so variations in clinical practice may be seen.

Women infected with the human immunodeficiency virus can have Pap-only testing every 3 years, after a series of 3 normal annual Pap results.²⁶ But screening does not stop at age 65.^23,26 For patients who are immunosuppressed or have a history of diethylstilbestrol exposure, screening should be done annually indefinitely.²³

About 12% of women worldwide are infected with human papillomavirus (HPV).¹ Persistent HPV infection with high-risk strains such as HPV 6, 11, 16, and 18 cause nearly all cases of cervical cancer and some anal, vaginal, penile, and oropharyngeal cancers.² An estimated 13,000 cases of invasive cervical cancer will be diagnosed this year in the United States alone.³

Up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. A number of changes have been made to the vaccination schedule within the past few years—patients younger than 15 need only 2 rather than 3 doses, and the vaccine itself can be used in adults up to age 45.

Vaccination and routine cervical cancer screening are both necessary to prevent this disease³ along with effective family and patient counseling. Here, we discuss the most up-to-date HPV vaccination recommendations, current cervical cancer screening guidelines, counseling techniques that increase vaccination acceptance rates, and follow-up protocols for abnormal cervical cancer screening results.

TYPES OF HPV VACCINES

HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts.⁴ The US Food and Drug Administration (FDA) has approved 3 HPV vaccines:

• Gardasil 9 targets HPV types 6, 11, 16, and 18 along with 31, 33, 45, 52, 58—these cause 90% of cervical cancer cases and most cases of genital warts⁵—making it the most effective vaccine available; Gardasil 9 is the only HPV vaccine currently available in the United States
• The bivalent vaccine (Cervarix) targeted HPV 16 and 18 only, and was discontinued in the United States in 2016
• The quadrivalent HPV vaccine (Gardasil) targeted HPV 16 and 18 as well as 6 and 11, which cause most cases of genital warts; the last available doses in the United States expired in May 2017; it has been replaced by Gardasil 9.

The incidence of cervical cancer in the United States dropped 29% among 15- to 24-year-olds from 2003–2006 when HPV vaccination first started to 2011–2014.⁶

VACCINE DOSING RECOMMENDATIONS FOR PRIMARY PREVENTION

The Advisory Committee on Immunization Practices (ACIP) revised its HPV vaccine schedule in 2016, when it decreased the necessary doses from 3 to 2 for patients under age 15 and addressed the needs of special patient populations.⁷ In late 2018, the FDA approved the use of the vaccine in men and women up to age 45. However, no change in guidelines have yet been made (Table 1).

In females, the ACIP recommends starting HPV vaccination at age 11 or 12, but it can be given as early as age 9. A 2-dose schedule is recommended for the 9-valent vaccine before the patient’s 15th birthday (the second dose 6 to 12 months after the first).⁷ For females who initiate HPV vaccination between ages 15 and 45, a 3-dose schedule is necessary (at 0, 1 to 2, and 6 months).^7,8

The change to a 2-dose schedule was prompted by an evaluation of girls ages 9 to 13 randomized to receive either a 2- or 3-dose schedule. Antibody responses with a 2-dose schedule were not inferior to those of young women (ages 16 to 26) who received all 3 doses.⁹ The geometric mean titer ratios remained noninferior throughout the study period of 36 months.

However, a loss of noninferiority was noted for HPV-18 by 24 months and for HPV-6 by 36 months.⁹ Thus, further studies are needed to understand the duration of protection with a 2-dose schedule. Nevertheless, decreasing the number of doses makes it a more convenient and cost-effective option for many families.

The recommendations are the same for males except for one notable difference: in males ages 21 to 26, vaccination is not routinely recommended by the ACIP, but rather it is considered a “permissive use” recommendation: ie, the vaccine should be offered and final decisions on administration be made after individualized discussion with the patient.¹⁰ Permissive-use status also means the vaccine may not be covered by health insurance. Even though the vaccine is now available to men and women until age 45, many insurance plans do not cover it after age 26.

Children of either sex with a history of sexual abuse should receive their first vaccine dose beginning at age 9.⁷

Immunocompromised patients should follow the 3-dose schedule regardless of their sex or the age when vaccination was initiated.¹⁰

For transgender patients and for men not previously vaccinated who have sex with men, the 3-dose schedule vaccine should be given by the age of 26 (this is a routine recommendation, not a permissive one).⁸

Effective patient and family counseling is important. Even though the first HPV vaccine was approved in 2006, only 34.9% of US adolescents were fully vaccinated by 2015. This was in part because providers did not recommend it, were unfamiliar with it, or had concerns about its safety,^11,12 and in part because some parents refused it.

The physician must address any myths regarding HPV vaccination and ensure that parents and patients understand that HPV vaccine is safe and effective. Studies have shown that with high-quality recommendations (ie, the care provider strongly endorses the HPV vaccine, encourages same-day vaccination, and discusses cancer prevention), patients are 9 times more likely to start the HPV vaccination schedule and 3 times more likely to follow through with subsequent doses.¹³

Providing good family and patient education does not necessarily require spending more counseling time. A recent study showed that spending less time discussing the HPV vaccine can lead to better vaccine coverage.¹⁴ The study compared parent HPV vaccine counseling techniques and found that simply informing patients and their families that the HPV vaccine was due was associated with a higher vaccine acceptance rate than inviting conversations about it.¹⁴ When providers announced that the vaccine was due, assuming the parents were ready to vaccinate, there was a 5.4% increase in HPV vaccination coverage.¹⁴

Conversely, physicians who engaged parents in open-ended discussions about the HPV vaccine did not improve HPV vaccination coverage.¹⁴ The authors suggested that providers approach HPV vaccination as if they were counseling patients and families about the need to avoid second-hand smoke or the need to use car seats. If parents or patients resist the presumptive announcement approach, expanded counseling and shared decision-making are appropriate. This includes addressing misconceptions that parents and patients may have about the HPV vaccine. The American Cancer Society lists 8 facts to reference (Table 2).¹⁵

SECONDARY PREVENTION: CERVICAL CANCER SCREENING

Since the introduction of the Papanicolaou (Pap) test, US cervical cancer incidence rates have decreased by more than 60%.¹⁶ Because almost all cervical cancer is preventable with proper screening, all women ages 21 to 65 should be screened.

Currently, there are 3 options available for cervical cancer screening: the Pap-only test, the Pap-HPV cotest, and the high-risk HPV-only test (Table 3). The latter 2 options detect high-risk HPV genotypes.

Several organizations have screening algorithms that recommend when to use these tests, but the 3 that shape today’s standard of care in cervical cancer screening come from the American College of Obstetricians and Gynecologists (ACOG), the American Society for Colposcopy and Cervical Pathology (ASCCP), and US Preventive Services Task Force (USPSTF).^17–19

Pap-only testing is performed every 3 years to screen for cervical neoplasia that might indicate premalignancy.

Pap-HPV cotesting is performed every 5 years in women older than 30 with past normal screening. Until 2018, all 3 organizations recommended cotesting as the preferred screening algorithm for women ages 30 to 65.^17–19 Patients with a history of abnormal test results require more frequent testing as recommended by the ASCCP.¹⁸

The high-risk HPV-only test utilizes real-time polymerase chain reaction to detect HPV 16, HPV 18, and 12 other HPV genotypes. Only 2 tests are approved by the FDA as stand-alone cervical cancer screening tests—the Roche Cobas HPV test approved in 2014 and the Becton Dickinson Onclarity HPV assay approved in 2018. Other HPV tests that are used in a cotesting strategy should not be used for high-risk HPV-only testing because their performance characteristics may differ.

In 2015, the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study showed that 1 round of high-risk HPV-only screening for women older than 25 was more sensitive than Pap-only or cotesting for stage 3 cervical intraepithelial neoplasia or more severe disease (after 3 years of follow-up).²⁰ Current guidelines from ASCCP¹⁸ and ACOG¹⁷ state that the high-risk HPV test can be repeated every 3 years (when used to screen by itself) if the woman is older than 25 and has had a normal test result.

If the HPV test result is positive for high-risk HPV 16 or 18 genotypes, then immediate colposcopy is indicated; women who test positive for one of the other 12 high-risk subtypes will need to undergo a Pap test to determine the appropriate follow-up (Figure 1).^18,21

In 2018, the USPSTF updated its recommendations, noting that for women age 30 to 65, Pap-only testing every 3 years, cotesting every 5 years, or high-risk HPV-only testing every 5 years are all appropriate screening strategies, with the Pap-only or high-risk HPV-only screenings being preferred.¹⁹ This is in contrast to ACOG and ASCCP recommendations for cotesting every 5 years, with alternative options of Pap-only or HPV-only testing being done every 3 years.^17,18

The USPSTF reviewed large randomized and observational studies to summarize the effectiveness of the 3 screening strategies and commissioned a decision analysis model to compare the risks, benefits, and costs of the 3 screening algorithms. The guideline statement notes both cotesting and high-risk HPV testing offer similar cancer detection rates: each prevents 1 additional cancer per 1,000 women screened as opposed to Pap-only testing.¹⁹

Also, tests that incorporate high-risk HPV screening may offer better detection of cervical adenocarcinoma (which has a worse prognosis than the more common squamous cell carcinoma type). However, both HPV-based screening strategies are more likely to require additional colposcopies for follow-up than Pap-only screening (1,630 colposcopies required for each cancer prevented with high-risk HPV alone, 1,635 with cotesting). Colposcopy is a simple office procedure that causes minimal discomfort to the patient.

The USPSTF guideline also differs in the recommended frequency of high-risk HPV-only testing; a high-risk HPV result should be repeated every 5 years if normal (as opposed to every 3 years as recommended by ACOG and ASCCP).¹⁹ The 5-year recommendation is based on analysis modeling, which suggests that performing high-risk HPV-only testing more frequently is unlikely to improve detection rates but will increase the number of screening tests and colposcopies.¹⁹

No trial has directly compared cotesting with high-risk HPV testing for more than 2 rounds of screening. The updated USPSTF recommendations are based on modeling estimates and expert opinion, which assesses cost and benefit vs harm in the long term. Also, no high-risk HPV test is currently FDA-approved for every-5-year screening when used by itself.

All 3 cervical cancer screening methods provide highly effective cancer prevention, so it is important for providers to choose the strategy that best fits their practice. The most critical aspect of screening is getting all women screened, no matter which method is used.

It is critical to remember that the screening intervals are intended for patients without symptoms. Those who have new concerns such as bleeding should have a diagnostic Pap done to evaluate their symptoms.

Follow-up of abnormal results

Regardless of the pathway chosen, appropriate follow-up of any abnormal test result is critical to the early detection of cancer. Established follow-up guidelines exist,^22,23 but accessing this information can be difficult for the busy clinician. The ASCCP has a mobile phone application that outlines the action steps corresponding to the patient’s age and results of any combination of Pap or HPV testing. The app also includes the best screening algorithms for a particular patient.²⁴

All guidelines agree that cervical cancer screening should start at age 21, regardless of HPV vaccination status or age of sexual initiation.^17,18,25 Screening can be discontinued at age 65 for women with normal screening results in the prior decade (3 consecutive negative Pap results or 2 consecutive negative cotest results).²³

For women who have had a total hysterectomy and no history of cervical neoplasia, screening should be stopped immediately after the procedure. However, several high-risk groups of women will need continued screening past the age of 65, or after a hysterectomy.

For a woman with a history of stage 2 cervical intraepithelial neoplasia or higher grade lesions, routine screening is continued for an additional 20 years, even if she is over age 65. Pap-only testing every 3 years is acceptable, because the role of HPV testing is unclear after hysterectomy.²³ Prior guidelines suggested annual screening in these patients, so the change to every 3 years is notable. Many gynecologic oncologists will recommend that women with a history of cervical cancer continue annual screening indefinitely.

Within the first 2 to 3 years after treatment for high-grade dysplastic changes, annual follow-up is done by the gynecologic oncology team. Providers who offer follow-up during this time frame should keep in communication with the oncology team to ensure appropriate, individualized care. These recommendations are based on expert opinion, so variations in clinical practice may be seen.

Women infected with the human immunodeficiency virus can have Pap-only testing every 3 years, after a series of 3 normal annual Pap results.²⁶ But screening does not stop at age 65.^23,26 For patients who are immunosuppressed or have a history of diethylstilbestrol exposure, screening should be done annually indefinitely.²³

Staging of liver fibrosis, important for determining prognosis in patients with chronic liver disease and for the need to start screening for complications of cirrhosis, was traditionally done only by liver biopsy. While biopsy is still the gold standard method to stage fibrosis, noninvasive methods have been developed that can also assess disease severity.

This article briefly reviews the epidemiology and physiology of chronic liver disease and the traditional role of liver biopsy. Pros and cons of alternative fibrosis assessment methods are discussed, with a focus on their utility for patients with nonalcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV) infection.

CHRONIC LIVER DISEASE: A HUGE HEALTH BURDEN

Chronic liver disease is associated with enormous health and financial costs in the United States. Its prevalence is about 15%,¹ and it is the 12th leading cause of death.² Hospital costs are estimated at about $4 billion annually.³

The most common causes of chronic liver disease are NAFLD (which may be present in up to one-third of the US population and is increasing with the epidemic of obesity), its aggressive variant, nonalcoholic steatohepatitis (NASH) (present in about 3% of the population), and HCV infection (1%).^4,5

Since direct-acting antiviral agents were introduced, HCV infection dropped from being the leading cause of liver transplant to third place.⁶ But at the same time, the number of patients on the transplant waiting list who have NASH has risen faster than for any other cause of chronic liver disease.⁷

FIBROSIS: A KEY INDICATOR OF DISEASE SEVERITY

In HCV infection, advanced fibrosis is defined as either stage 4 to 6 using the Ishak system¹⁰ or stage 3 to 4 using the Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) system.¹¹

In NAFLD, advanced fibrosis is defined as stage 3 to 4 using the NASH Clinical Research Network system.¹²

Staging fibrosis is also important so that patients with cirrhosis can be identified early to begin screening for hepatocellular carcinoma and esophageal varices to reduce the risks of illness and death. In addition, insurance companies often require documentation of fibrosis stage before treating HCV with the new direct-acting antiviral agents.

LIVER BIOPSY IS STILL THE GOLD STANDARD

Although invasive, liver biopsy remains the gold standard for determining fibrosis stage. Liver biopsies were performed “blindly” (without imaging) until the 1990s, but imaging-guided biopsy using ultrasonography was then developed, which entailed less pain and lower complication and hospitalization rates. Slightly more hepatic tissue is obtained with guided liver biopsy, but the difference was deemed clinically insignificant.¹³ Concern initially arose about the added cost involved with imaging, but imaging-guided biopsy was actually found to be more cost-effective.¹⁴

In the 2000s, transjugular liver biopsy via the right internal jugular vein became available. This method was originally used primarily in patients with ascites or significant coagulopathy. At first, there were concerns about the adequacy of specimens obtained to make an accurate diagnosis or establish fibrosis stage, but this limitation was overcome with improved techniques.^15,16 Transjugular liver biopsy has the additional advantage of enabling one to measure the hepatic venous pressure gradient, which also has prognostic significance; a gradient greater than 10 mm Hg is associated with worse prognosis.¹⁷

Disadvantages of biopsy: Complications, sampling errors

Liver biopsy has disadvantages. Reported rates of complications necessitating hospitalization using the blind method were as high as 6% in the 1970s,¹⁸ dropping to 3.2% in a 1993 study.¹⁹ Bleeding remains the most worrisome complication. With the transjugular method, major and minor complication rates are less than 1% and 7%, respectively.^15,16 Complication rates with imaging-guided biopsy are also low.

Liver biopsy is also prone to sampling error. The number of portal tracts obtained in the biopsy correlates with the accuracy of fibrosis staging, and smaller samples may lead to underestimating fibrosis stage. In patients with HCV, samples more than 15 mm long led to accurate staging diagnosis in 65% of patients, and those longer than 25 mm conferred 75% accuracy.²⁰ Also, different stages can be diagnosed from samples obtained from separate locations in the liver, although rarely is the difference more than a single stage.²¹

Histologic evaluation of liver biopsies is operator-dependent. Although significant interobserver variation has been reported for degree of inflammation, there tends to be good concordance for fibrosis staging.^22,23

Several scores based on patient characteristics and laboratory values have been developed for assessing liver fibrosis and have been specifically validated for HCV infection, NAFLD, or both. They can serve as inexpensive initial screening tests for the presence or absence of advanced fibrosis.

FIB-4 index for HCV, NAFLD

The FIB-4 index predicts the presence of advanced fibrosis using, as its name indicates, a combination of 4 factors in fibrosis: age, platelet count, and the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), according to the formula:

FIB-4 index = (age × AST [U/L]) /
(platelet count [× 10⁹/L] × √ALT [U/L]).

The index was derived from data from 832 patients co-infected with HCV and human immunodeficiency virus.²⁴ The Ishak staging system¹⁰ for fibrosis on liver biopsy was used for confirmation, with stage 4 to 6 defined as advanced fibrosis. A cutoff value of more than 3.25 had a positive predictive value of 65% for advanced fibrosis, and to exclude advanced fibrosis, a cutoff value of less than 1.45 had a negative predictive value of 90%.

The FIB-4 index has since been validated in patients with HCV infection²⁵ and NAFLD.²⁶ In a subsequent study in 142 patients with NAFLD, the FIB-4 index was more accurate in diagnosing advanced fibrosis than the other noninvasive prediction models discussed below.²⁷

NAFLD fibrosis score

The NAFLD fibrosis score, constructed and validated only in patients with biopsy-confirmed NAFLD, incorporates age, body mass index, presence of diabetes or prediabetes, albumin level, platelet count, and AST and ALT levels.

A group of 480 patients was used to construct the score, and 253 patients were used to validate it. Using the high cutoff value of 0.676, the presence of advanced fibrosis was diagnosed with a positive predictive value of 90% in the group used to construct the model (82% in the validation group). Using the low cutoff score of –1.455, advanced fibrosis could be excluded with a negative predictive value of 93% in the construction group and 88% in the validation group.²⁸ A score between the cutoff values merits liver biopsy to determine fibrosis stage. The score is more accurate in patients with diabetes.²⁹ When used by primary care physicians, the NAFLD fibrosis score is more cost-effective than transient elastography and liver biopsy for accurately predicting advanced fibrosis.³⁰

AST-to-platelet ratio index score for HCV, NAFLD

The AST-to-platelet ratio index (APRI) score was developed in 2003 using a cohort of 270 patients with HCV and liver biopsy as the standard. A cutoff value of less than or equal to 0.5 had a negative predictive value of 86% for the absence of significant fibrosis, while a score of more than 1.5 detected the presence of significant fibrosis with a positive predictive value of 88%.³¹ The APRI score was subsequently validated for NAFLD.^27,32

FibroSure uses a patented formula

FibroSure (LabCorp; labcorp.com) uses a patented mathematical formula that takes into account age, sex, and levels of gamma-glutamyl transferase, total bilirubin, haptoglobin, apolipoprotein-A, and alpha-2 macroglobulin to assess fibrosis. Developed in 2001 for use in patients with HCV infection, it was reported to have a positive predictive value of greater than 90% and a negative predictive value of 100% for clinically significant fibrosis, defined as stage 2 to 4 based on the METAVIR staging system in the prediction model.³³ The use of FibroSure in patients with HCV was subsequently validated in various meta-analyses and systematic reviews.^34,35 It is less accurate in patients with normal ALT levels.³⁶

FibroSure also has good accuracy for predicting fibrosis stage in chronic liver disease due to other causes, including NAFLD.³⁷

The prediction models discussed above use routine laboratory tests for chronic liver disease and thus are inexpensive. The high cost of additional testing needed for FibroSure, coupled with the risk of misdiagnosis, makes its cost-effectiveness questionable.³⁸

Conventional ultrasonography (with or without vascular imaging) and computed tomography can detect cirrhosis on the basis of certain imaging characteristics,^39,40 including the nodular contour of the liver, caudate lobe hypertrophy, ascites, reversal of blood flow in the portal vein, and splenomegaly. However, they cannot detect fibrosis in its early stages.

The 3 methods discussed below provide more accurate fibrosis staging by measuring the velocity of shear waves sent across hepatic tissue. Because shear-wave velocity increases with liver stiffness, the fibrosis stage can be estimated from this information.⁴¹

Transient elastography

Transient elastography uses a special ultrasound transducer. It is highly accurate for predicting advanced fibrosis for almost all causes of chronic liver disease, including HCV infection^42,43 and NAFLD.⁴⁴ The cutoff values of wave velocity to estimate fibrosis stage differ by liver disease etiology.

Transient elastography should not be used to evaluate fibrosis in patients with acute hepatitis, which transiently increases liver stiffness, resulting in a falsely high fibrosis stage diagnosis.⁴⁵ It is also not a good method for evaluating fibrosis in patients with biliary obstruction or extrahepatic venous congestion. Because liver stiffness can increase after eating,⁴⁶ the test should be done under fasting conditions.

A significant limitation of transient elastography has been its poor accuracy in patients with obesity.⁴⁷ This has been largely overcome with the use of a more powerful (XL) probe but is still a limitation for those with morbid obesity.⁴⁸ Because many patients with NAFLD are obese, this limitation can be significant.

Transient elastography has gained popularity for evaluating fibrosis in patients with chronic liver disease for multiple reasons: it is cost-effective and results are highly reproducible, with low variation in results among different observers and in individual observers.⁴⁹ Combined with a platelet count, it can also be used to detect the development of clinically significant portal hypertension in patients with cirrhosis, thus determining the need to screen for esophageal varices using endoscopy.⁵⁰ Screening endoscopy can be avoided in patients whose liver stiffness remains below 20 kPa or whose platelet count is above 150 × 10⁹/L.

Acoustic radiation force imaging

Unlike transient elastography, which requires a separate transducer probe to assess shear- wave velocity, acoustic radiation force imaging uses the same transducer for both this function and imaging. Different image modes are available when testing for liver stiffness, so a region of interest that is optimal for avoiding vascular structures or masses can be selected, increasing accuracy.⁵¹

Acoustic radiation force imaging has been tested in different causes of chronic liver disease, including HCV and NAFLD,⁵² with accuracy similar to that of transient elastography.⁵³ For overweight and obese patients, acoustic radiation force imaging is more accurate than transient elastography using the XL probe.⁵⁴ However, this method is still new, and we need more data to support using one method over the other.

Magnetic resonance elastography

Magnetic resonance elastography uses a special transducer placed under the rib cage to transmit shear waves concurrently with magnetic resonance imaging. It has been tested in patients with HCV and NAFLD and has been found to have better diagnostic accuracy than transient elastography and acoustic radiation force imaging.^55,56 Patients must be fasting for better diagnostic accuracy⁵⁷ and must hold their breath while elastography is performed. The need for breath-holding and the high cost limit the use of this method for assessing fibrosis.

BOTTOM LINE FOR ASSESSING FIBROSIS

Staging of liver fibrosis, important for determining prognosis in patients with chronic liver disease and for the need to start screening for complications of cirrhosis, was traditionally done only by liver biopsy. While biopsy is still the gold standard method to stage fibrosis, noninvasive methods have been developed that can also assess disease severity.

This article briefly reviews the epidemiology and physiology of chronic liver disease and the traditional role of liver biopsy. Pros and cons of alternative fibrosis assessment methods are discussed, with a focus on their utility for patients with nonalcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV) infection.

CHRONIC LIVER DISEASE: A HUGE HEALTH BURDEN

Chronic liver disease is associated with enormous health and financial costs in the United States. Its prevalence is about 15%,¹ and it is the 12th leading cause of death.² Hospital costs are estimated at about $4 billion annually.³

The most common causes of chronic liver disease are NAFLD (which may be present in up to one-third of the US population and is increasing with the epidemic of obesity), its aggressive variant, nonalcoholic steatohepatitis (NASH) (present in about 3% of the population), and HCV infection (1%).^4,5

Since direct-acting antiviral agents were introduced, HCV infection dropped from being the leading cause of liver transplant to third place.⁶ But at the same time, the number of patients on the transplant waiting list who have NASH has risen faster than for any other cause of chronic liver disease.⁷

FIBROSIS: A KEY INDICATOR OF DISEASE SEVERITY

In HCV infection, advanced fibrosis is defined as either stage 4 to 6 using the Ishak system¹⁰ or stage 3 to 4 using the Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) system.¹¹

In NAFLD, advanced fibrosis is defined as stage 3 to 4 using the NASH Clinical Research Network system.¹²

Staging fibrosis is also important so that patients with cirrhosis can be identified early to begin screening for hepatocellular carcinoma and esophageal varices to reduce the risks of illness and death. In addition, insurance companies often require documentation of fibrosis stage before treating HCV with the new direct-acting antiviral agents.

LIVER BIOPSY IS STILL THE GOLD STANDARD

Although invasive, liver biopsy remains the gold standard for determining fibrosis stage. Liver biopsies were performed “blindly” (without imaging) until the 1990s, but imaging-guided biopsy using ultrasonography was then developed, which entailed less pain and lower complication and hospitalization rates. Slightly more hepatic tissue is obtained with guided liver biopsy, but the difference was deemed clinically insignificant.¹³ Concern initially arose about the added cost involved with imaging, but imaging-guided biopsy was actually found to be more cost-effective.¹⁴

In the 2000s, transjugular liver biopsy via the right internal jugular vein became available. This method was originally used primarily in patients with ascites or significant coagulopathy. At first, there were concerns about the adequacy of specimens obtained to make an accurate diagnosis or establish fibrosis stage, but this limitation was overcome with improved techniques.^15,16 Transjugular liver biopsy has the additional advantage of enabling one to measure the hepatic venous pressure gradient, which also has prognostic significance; a gradient greater than 10 mm Hg is associated with worse prognosis.¹⁷

Disadvantages of biopsy: Complications, sampling errors

Liver biopsy has disadvantages. Reported rates of complications necessitating hospitalization using the blind method were as high as 6% in the 1970s,¹⁸ dropping to 3.2% in a 1993 study.¹⁹ Bleeding remains the most worrisome complication. With the transjugular method, major and minor complication rates are less than 1% and 7%, respectively.^15,16 Complication rates with imaging-guided biopsy are also low.

Liver biopsy is also prone to sampling error. The number of portal tracts obtained in the biopsy correlates with the accuracy of fibrosis staging, and smaller samples may lead to underestimating fibrosis stage. In patients with HCV, samples more than 15 mm long led to accurate staging diagnosis in 65% of patients, and those longer than 25 mm conferred 75% accuracy.²⁰ Also, different stages can be diagnosed from samples obtained from separate locations in the liver, although rarely is the difference more than a single stage.²¹

Histologic evaluation of liver biopsies is operator-dependent. Although significant interobserver variation has been reported for degree of inflammation, there tends to be good concordance for fibrosis staging.^22,23

Several scores based on patient characteristics and laboratory values have been developed for assessing liver fibrosis and have been specifically validated for HCV infection, NAFLD, or both. They can serve as inexpensive initial screening tests for the presence or absence of advanced fibrosis.

FIB-4 index for HCV, NAFLD

The FIB-4 index predicts the presence of advanced fibrosis using, as its name indicates, a combination of 4 factors in fibrosis: age, platelet count, and the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), according to the formula:

FIB-4 index = (age × AST [U/L]) /
(platelet count [× 10⁹/L] × √ALT [U/L]).

The index was derived from data from 832 patients co-infected with HCV and human immunodeficiency virus.²⁴ The Ishak staging system¹⁰ for fibrosis on liver biopsy was used for confirmation, with stage 4 to 6 defined as advanced fibrosis. A cutoff value of more than 3.25 had a positive predictive value of 65% for advanced fibrosis, and to exclude advanced fibrosis, a cutoff value of less than 1.45 had a negative predictive value of 90%.

The FIB-4 index has since been validated in patients with HCV infection²⁵ and NAFLD.²⁶ In a subsequent study in 142 patients with NAFLD, the FIB-4 index was more accurate in diagnosing advanced fibrosis than the other noninvasive prediction models discussed below.²⁷

NAFLD fibrosis score

The NAFLD fibrosis score, constructed and validated only in patients with biopsy-confirmed NAFLD, incorporates age, body mass index, presence of diabetes or prediabetes, albumin level, platelet count, and AST and ALT levels.

A group of 480 patients was used to construct the score, and 253 patients were used to validate it. Using the high cutoff value of 0.676, the presence of advanced fibrosis was diagnosed with a positive predictive value of 90% in the group used to construct the model (82% in the validation group). Using the low cutoff score of –1.455, advanced fibrosis could be excluded with a negative predictive value of 93% in the construction group and 88% in the validation group.²⁸ A score between the cutoff values merits liver biopsy to determine fibrosis stage. The score is more accurate in patients with diabetes.²⁹ When used by primary care physicians, the NAFLD fibrosis score is more cost-effective than transient elastography and liver biopsy for accurately predicting advanced fibrosis.³⁰

AST-to-platelet ratio index score for HCV, NAFLD

The AST-to-platelet ratio index (APRI) score was developed in 2003 using a cohort of 270 patients with HCV and liver biopsy as the standard. A cutoff value of less than or equal to 0.5 had a negative predictive value of 86% for the absence of significant fibrosis, while a score of more than 1.5 detected the presence of significant fibrosis with a positive predictive value of 88%.³¹ The APRI score was subsequently validated for NAFLD.^27,32

FibroSure uses a patented formula

FibroSure (LabCorp; labcorp.com) uses a patented mathematical formula that takes into account age, sex, and levels of gamma-glutamyl transferase, total bilirubin, haptoglobin, apolipoprotein-A, and alpha-2 macroglobulin to assess fibrosis. Developed in 2001 for use in patients with HCV infection, it was reported to have a positive predictive value of greater than 90% and a negative predictive value of 100% for clinically significant fibrosis, defined as stage 2 to 4 based on the METAVIR staging system in the prediction model.³³ The use of FibroSure in patients with HCV was subsequently validated in various meta-analyses and systematic reviews.^34,35 It is less accurate in patients with normal ALT levels.³⁶

FibroSure also has good accuracy for predicting fibrosis stage in chronic liver disease due to other causes, including NAFLD.³⁷

The prediction models discussed above use routine laboratory tests for chronic liver disease and thus are inexpensive. The high cost of additional testing needed for FibroSure, coupled with the risk of misdiagnosis, makes its cost-effectiveness questionable.³⁸

Conventional ultrasonography (with or without vascular imaging) and computed tomography can detect cirrhosis on the basis of certain imaging characteristics,^39,40 including the nodular contour of the liver, caudate lobe hypertrophy, ascites, reversal of blood flow in the portal vein, and splenomegaly. However, they cannot detect fibrosis in its early stages.

The 3 methods discussed below provide more accurate fibrosis staging by measuring the velocity of shear waves sent across hepatic tissue. Because shear-wave velocity increases with liver stiffness, the fibrosis stage can be estimated from this information.⁴¹

Transient elastography

Transient elastography uses a special ultrasound transducer. It is highly accurate for predicting advanced fibrosis for almost all causes of chronic liver disease, including HCV infection^42,43 and NAFLD.⁴⁴ The cutoff values of wave velocity to estimate fibrosis stage differ by liver disease etiology.

Transient elastography should not be used to evaluate fibrosis in patients with acute hepatitis, which transiently increases liver stiffness, resulting in a falsely high fibrosis stage diagnosis.⁴⁵ It is also not a good method for evaluating fibrosis in patients with biliary obstruction or extrahepatic venous congestion. Because liver stiffness can increase after eating,⁴⁶ the test should be done under fasting conditions.

A significant limitation of transient elastography has been its poor accuracy in patients with obesity.⁴⁷ This has been largely overcome with the use of a more powerful (XL) probe but is still a limitation for those with morbid obesity.⁴⁸ Because many patients with NAFLD are obese, this limitation can be significant.

Transient elastography has gained popularity for evaluating fibrosis in patients with chronic liver disease for multiple reasons: it is cost-effective and results are highly reproducible, with low variation in results among different observers and in individual observers.⁴⁹ Combined with a platelet count, it can also be used to detect the development of clinically significant portal hypertension in patients with cirrhosis, thus determining the need to screen for esophageal varices using endoscopy.⁵⁰ Screening endoscopy can be avoided in patients whose liver stiffness remains below 20 kPa or whose platelet count is above 150 × 10⁹/L.

Acoustic radiation force imaging

Unlike transient elastography, which requires a separate transducer probe to assess shear- wave velocity, acoustic radiation force imaging uses the same transducer for both this function and imaging. Different image modes are available when testing for liver stiffness, so a region of interest that is optimal for avoiding vascular structures or masses can be selected, increasing accuracy.⁵¹

Acoustic radiation force imaging has been tested in different causes of chronic liver disease, including HCV and NAFLD,⁵² with accuracy similar to that of transient elastography.⁵³ For overweight and obese patients, acoustic radiation force imaging is more accurate than transient elastography using the XL probe.⁵⁴ However, this method is still new, and we need more data to support using one method over the other.

Magnetic resonance elastography

Magnetic resonance elastography uses a special transducer placed under the rib cage to transmit shear waves concurrently with magnetic resonance imaging. It has been tested in patients with HCV and NAFLD and has been found to have better diagnostic accuracy than transient elastography and acoustic radiation force imaging.^55,56 Patients must be fasting for better diagnostic accuracy⁵⁷ and must hold their breath while elastography is performed. The need for breath-holding and the high cost limit the use of this method for assessing fibrosis.

BOTTOM LINE FOR ASSESSING FIBROSIS

Staging of liver fibrosis, important for determining prognosis in patients with chronic liver disease and for the need to start screening for complications of cirrhosis, was traditionally done only by liver biopsy. While biopsy is still the gold standard method to stage fibrosis, noninvasive methods have been developed that can also assess disease severity.

This article briefly reviews the epidemiology and physiology of chronic liver disease and the traditional role of liver biopsy. Pros and cons of alternative fibrosis assessment methods are discussed, with a focus on their utility for patients with nonalcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV) infection.

CHRONIC LIVER DISEASE: A HUGE HEALTH BURDEN

Chronic liver disease is associated with enormous health and financial costs in the United States. Its prevalence is about 15%,¹ and it is the 12th leading cause of death.² Hospital costs are estimated at about $4 billion annually.³

The most common causes of chronic liver disease are NAFLD (which may be present in up to one-third of the US population and is increasing with the epidemic of obesity), its aggressive variant, nonalcoholic steatohepatitis (NASH) (present in about 3% of the population), and HCV infection (1%).^4,5

Since direct-acting antiviral agents were introduced, HCV infection dropped from being the leading cause of liver transplant to third place.⁶ But at the same time, the number of patients on the transplant waiting list who have NASH has risen faster than for any other cause of chronic liver disease.⁷

FIBROSIS: A KEY INDICATOR OF DISEASE SEVERITY

In HCV infection, advanced fibrosis is defined as either stage 4 to 6 using the Ishak system¹⁰ or stage 3 to 4 using the Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) system.¹¹

In NAFLD, advanced fibrosis is defined as stage 3 to 4 using the NASH Clinical Research Network system.¹²

Staging fibrosis is also important so that patients with cirrhosis can be identified early to begin screening for hepatocellular carcinoma and esophageal varices to reduce the risks of illness and death. In addition, insurance companies often require documentation of fibrosis stage before treating HCV with the new direct-acting antiviral agents.

LIVER BIOPSY IS STILL THE GOLD STANDARD

Although invasive, liver biopsy remains the gold standard for determining fibrosis stage. Liver biopsies were performed “blindly” (without imaging) until the 1990s, but imaging-guided biopsy using ultrasonography was then developed, which entailed less pain and lower complication and hospitalization rates. Slightly more hepatic tissue is obtained with guided liver biopsy, but the difference was deemed clinically insignificant.¹³ Concern initially arose about the added cost involved with imaging, but imaging-guided biopsy was actually found to be more cost-effective.¹⁴

In the 2000s, transjugular liver biopsy via the right internal jugular vein became available. This method was originally used primarily in patients with ascites or significant coagulopathy. At first, there were concerns about the adequacy of specimens obtained to make an accurate diagnosis or establish fibrosis stage, but this limitation was overcome with improved techniques.^15,16 Transjugular liver biopsy has the additional advantage of enabling one to measure the hepatic venous pressure gradient, which also has prognostic significance; a gradient greater than 10 mm Hg is associated with worse prognosis.¹⁷

Disadvantages of biopsy: Complications, sampling errors

Liver biopsy has disadvantages. Reported rates of complications necessitating hospitalization using the blind method were as high as 6% in the 1970s,¹⁸ dropping to 3.2% in a 1993 study.¹⁹ Bleeding remains the most worrisome complication. With the transjugular method, major and minor complication rates are less than 1% and 7%, respectively.^15,16 Complication rates with imaging-guided biopsy are also low.

Liver biopsy is also prone to sampling error. The number of portal tracts obtained in the biopsy correlates with the accuracy of fibrosis staging, and smaller samples may lead to underestimating fibrosis stage. In patients with HCV, samples more than 15 mm long led to accurate staging diagnosis in 65% of patients, and those longer than 25 mm conferred 75% accuracy.²⁰ Also, different stages can be diagnosed from samples obtained from separate locations in the liver, although rarely is the difference more than a single stage.²¹

Histologic evaluation of liver biopsies is operator-dependent. Although significant interobserver variation has been reported for degree of inflammation, there tends to be good concordance for fibrosis staging.^22,23

Several scores based on patient characteristics and laboratory values have been developed for assessing liver fibrosis and have been specifically validated for HCV infection, NAFLD, or both. They can serve as inexpensive initial screening tests for the presence or absence of advanced fibrosis.

FIB-4 index for HCV, NAFLD

The FIB-4 index predicts the presence of advanced fibrosis using, as its name indicates, a combination of 4 factors in fibrosis: age, platelet count, and the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), according to the formula:

FIB-4 index = (age × AST [U/L]) /
(platelet count [× 10⁹/L] × √ALT [U/L]).

The index was derived from data from 832 patients co-infected with HCV and human immunodeficiency virus.²⁴ The Ishak staging system¹⁰ for fibrosis on liver biopsy was used for confirmation, with stage 4 to 6 defined as advanced fibrosis. A cutoff value of more than 3.25 had a positive predictive value of 65% for advanced fibrosis, and to exclude advanced fibrosis, a cutoff value of less than 1.45 had a negative predictive value of 90%.

The FIB-4 index has since been validated in patients with HCV infection²⁵ and NAFLD.²⁶ In a subsequent study in 142 patients with NAFLD, the FIB-4 index was more accurate in diagnosing advanced fibrosis than the other noninvasive prediction models discussed below.²⁷

NAFLD fibrosis score

The NAFLD fibrosis score, constructed and validated only in patients with biopsy-confirmed NAFLD, incorporates age, body mass index, presence of diabetes or prediabetes, albumin level, platelet count, and AST and ALT levels.

A group of 480 patients was used to construct the score, and 253 patients were used to validate it. Using the high cutoff value of 0.676, the presence of advanced fibrosis was diagnosed with a positive predictive value of 90% in the group used to construct the model (82% in the validation group). Using the low cutoff score of –1.455, advanced fibrosis could be excluded with a negative predictive value of 93% in the construction group and 88% in the validation group.²⁸ A score between the cutoff values merits liver biopsy to determine fibrosis stage. The score is more accurate in patients with diabetes.²⁹ When used by primary care physicians, the NAFLD fibrosis score is more cost-effective than transient elastography and liver biopsy for accurately predicting advanced fibrosis.³⁰

AST-to-platelet ratio index score for HCV, NAFLD

The AST-to-platelet ratio index (APRI) score was developed in 2003 using a cohort of 270 patients with HCV and liver biopsy as the standard. A cutoff value of less than or equal to 0.5 had a negative predictive value of 86% for the absence of significant fibrosis, while a score of more than 1.5 detected the presence of significant fibrosis with a positive predictive value of 88%.³¹ The APRI score was subsequently validated for NAFLD.^27,32

FibroSure uses a patented formula

FibroSure (LabCorp; labcorp.com) uses a patented mathematical formula that takes into account age, sex, and levels of gamma-glutamyl transferase, total bilirubin, haptoglobin, apolipoprotein-A, and alpha-2 macroglobulin to assess fibrosis. Developed in 2001 for use in patients with HCV infection, it was reported to have a positive predictive value of greater than 90% and a negative predictive value of 100% for clinically significant fibrosis, defined as stage 2 to 4 based on the METAVIR staging system in the prediction model.³³ The use of FibroSure in patients with HCV was subsequently validated in various meta-analyses and systematic reviews.^34,35 It is less accurate in patients with normal ALT levels.³⁶

FibroSure also has good accuracy for predicting fibrosis stage in chronic liver disease due to other causes, including NAFLD.³⁷

The prediction models discussed above use routine laboratory tests for chronic liver disease and thus are inexpensive. The high cost of additional testing needed for FibroSure, coupled with the risk of misdiagnosis, makes its cost-effectiveness questionable.³⁸

Conventional ultrasonography (with or without vascular imaging) and computed tomography can detect cirrhosis on the basis of certain imaging characteristics,^39,40 including the nodular contour of the liver, caudate lobe hypertrophy, ascites, reversal of blood flow in the portal vein, and splenomegaly. However, they cannot detect fibrosis in its early stages.

The 3 methods discussed below provide more accurate fibrosis staging by measuring the velocity of shear waves sent across hepatic tissue. Because shear-wave velocity increases with liver stiffness, the fibrosis stage can be estimated from this information.⁴¹

Transient elastography

Transient elastography uses a special ultrasound transducer. It is highly accurate for predicting advanced fibrosis for almost all causes of chronic liver disease, including HCV infection^42,43 and NAFLD.⁴⁴ The cutoff values of wave velocity to estimate fibrosis stage differ by liver disease etiology.

Transient elastography should not be used to evaluate fibrosis in patients with acute hepatitis, which transiently increases liver stiffness, resulting in a falsely high fibrosis stage diagnosis.⁴⁵ It is also not a good method for evaluating fibrosis in patients with biliary obstruction or extrahepatic venous congestion. Because liver stiffness can increase after eating,⁴⁶ the test should be done under fasting conditions.

A significant limitation of transient elastography has been its poor accuracy in patients with obesity.⁴⁷ This has been largely overcome with the use of a more powerful (XL) probe but is still a limitation for those with morbid obesity.⁴⁸ Because many patients with NAFLD are obese, this limitation can be significant.

Transient elastography has gained popularity for evaluating fibrosis in patients with chronic liver disease for multiple reasons: it is cost-effective and results are highly reproducible, with low variation in results among different observers and in individual observers.⁴⁹ Combined with a platelet count, it can also be used to detect the development of clinically significant portal hypertension in patients with cirrhosis, thus determining the need to screen for esophageal varices using endoscopy.⁵⁰ Screening endoscopy can be avoided in patients whose liver stiffness remains below 20 kPa or whose platelet count is above 150 × 10⁹/L.

Acoustic radiation force imaging

Unlike transient elastography, which requires a separate transducer probe to assess shear- wave velocity, acoustic radiation force imaging uses the same transducer for both this function and imaging. Different image modes are available when testing for liver stiffness, so a region of interest that is optimal for avoiding vascular structures or masses can be selected, increasing accuracy.⁵¹

Acoustic radiation force imaging has been tested in different causes of chronic liver disease, including HCV and NAFLD,⁵² with accuracy similar to that of transient elastography.⁵³ For overweight and obese patients, acoustic radiation force imaging is more accurate than transient elastography using the XL probe.⁵⁴ However, this method is still new, and we need more data to support using one method over the other.

Magnetic resonance elastography

Magnetic resonance elastography uses a special transducer placed under the rib cage to transmit shear waves concurrently with magnetic resonance imaging. It has been tested in patients with HCV and NAFLD and has been found to have better diagnostic accuracy than transient elastography and acoustic radiation force imaging.^55,56 Patients must be fasting for better diagnostic accuracy⁵⁷ and must hold their breath while elastography is performed. The need for breath-holding and the high cost limit the use of this method for assessing fibrosis.

BOTTOM LINE FOR ASSESSING FIBROSIS

A 62-year-old woman presented to our emergency department with fever, chills, hoarseness, pain on swallowing, and a painful neck. Her symptoms had begun 1 day earlier. Because acetaminophen brought no improvement, she went to an urgent care facility, where a nasal swab polymerase chain reaction test was positive for influenza A, and a throat swab rapid test was positive for group A streptococci. She was then referred to our emergency department.

She reported no pre-existing conditions predisposing her to infection. Her temperature was 99.9°F (37.7°C), pulse 112 beats per minute, and respiratory rate 24 breaths per minute. The physical examination was unremarkable except for bilateral anterior cervical adenopathy and bilateral anterior neck tenderness. Her pharynx was not injected, and no exudate, palatal edema, or petechiae were noted.

Results of initial laboratory testing were as follows:

• White blood cell count 20.5 × 10⁹/L (reference range 3.9–11)
• Neutrophils 76% (42%–75%)
• Bands 15% (0%–5%)
• Lymphocytes 3% (21%–51%)
• Erythrocyte sedimentation rate 75 mm/h (< 20 mm/h)
• C-reactive protein 247.14 mg/L (≤ 3 mg/L)
• Serum aminotransferase levels were normal.
• Polymerase chain reaction testing of a nasal swab was negative for viral infection.

Throat swabs and blood samples were sent for culture.

She was started on ceftriaxone 1 g intravenously every 24 hours, with close observation in the medical intensive care unit, where she was admitted because of epiglottitis. On hospital day 3, the throat culture was reported as negative, but the blood culture was reported as positive for Haemophilus influenzae. Thus, the clinical diagnosis was acute epiglottitis due to H influenzae, not group A streptococci.

The patient completed 10 days of ceftriaxone therapy; her recovery was uneventful, and she was discharged on hospital day 10.

INFLUENZA: CHALLENGES TO PROMPT, ACCURATE DIAGNOSIS

During influenza season, emergency departments are inundated with adults with influenza A and other viral respiratory infections. This makes prompt, accurate diagnosis a challenge,¹ given the broad differential diagnosis.^2,3 Adults with influenza and its complications as well as unrelated conditions can present a special challenge.⁴

Our patient presented with acute-onset influenza A and was then found to have acute epiglottitis, an unexpected complication of influenza A.⁵ A positive rapid test for group A streptococci done at an urgent care facility led emergency department physicians to assume that the acute epiglottitis was due to group A streptococci. Unless correlated with clinical findings, results of rapid diagnostic tests may mislead the unwary practitioner. Accurate diagnosis should be based mainly on the history and physical findings. Results of rapid diagnostic tests can be helpful if interpreted in the clinical context.^6–8

The rapid test for streptococci is appropriate for the diagnosis of pharyngitis due to group A streptococci in people under age 30 with acute-onset sore throat, fever, and bilateral acute cervical adenopathy, without fatigue or myalgias. However, the rapid test does not differentiate colonization from infection. Group A streptococci are common colonizers with viral pharyngitis. In 30% of cases of Epstein-Barr virus pharyngitis, there is colonization with group A streptococci. A positive rapid test in such cases can result in the wrong diagnosis, ie, pharyngitis due to group A streptococci rather than Epstein-Barr virus.

A 62-year-old woman presented to our emergency department with fever, chills, hoarseness, pain on swallowing, and a painful neck. Her symptoms had begun 1 day earlier. Because acetaminophen brought no improvement, she went to an urgent care facility, where a nasal swab polymerase chain reaction test was positive for influenza A, and a throat swab rapid test was positive for group A streptococci. She was then referred to our emergency department.

She reported no pre-existing conditions predisposing her to infection. Her temperature was 99.9°F (37.7°C), pulse 112 beats per minute, and respiratory rate 24 breaths per minute. The physical examination was unremarkable except for bilateral anterior cervical adenopathy and bilateral anterior neck tenderness. Her pharynx was not injected, and no exudate, palatal edema, or petechiae were noted.

Results of initial laboratory testing were as follows:

• White blood cell count 20.5 × 10⁹/L (reference range 3.9–11)
• Neutrophils 76% (42%–75%)
• Bands 15% (0%–5%)
• Lymphocytes 3% (21%–51%)
• Erythrocyte sedimentation rate 75 mm/h (< 20 mm/h)
• C-reactive protein 247.14 mg/L (≤ 3 mg/L)
• Serum aminotransferase levels were normal.
• Polymerase chain reaction testing of a nasal swab was negative for viral infection.

Throat swabs and blood samples were sent for culture.

She was started on ceftriaxone 1 g intravenously every 24 hours, with close observation in the medical intensive care unit, where she was admitted because of epiglottitis. On hospital day 3, the throat culture was reported as negative, but the blood culture was reported as positive for Haemophilus influenzae. Thus, the clinical diagnosis was acute epiglottitis due to H influenzae, not group A streptococci.

The patient completed 10 days of ceftriaxone therapy; her recovery was uneventful, and she was discharged on hospital day 10.

INFLUENZA: CHALLENGES TO PROMPT, ACCURATE DIAGNOSIS

During influenza season, emergency departments are inundated with adults with influenza A and other viral respiratory infections. This makes prompt, accurate diagnosis a challenge,¹ given the broad differential diagnosis.^2,3 Adults with influenza and its complications as well as unrelated conditions can present a special challenge.⁴

Our patient presented with acute-onset influenza A and was then found to have acute epiglottitis, an unexpected complication of influenza A.⁵ A positive rapid test for group A streptococci done at an urgent care facility led emergency department physicians to assume that the acute epiglottitis was due to group A streptococci. Unless correlated with clinical findings, results of rapid diagnostic tests may mislead the unwary practitioner. Accurate diagnosis should be based mainly on the history and physical findings. Results of rapid diagnostic tests can be helpful if interpreted in the clinical context.^6–8

The rapid test for streptococci is appropriate for the diagnosis of pharyngitis due to group A streptococci in people under age 30 with acute-onset sore throat, fever, and bilateral acute cervical adenopathy, without fatigue or myalgias. However, the rapid test does not differentiate colonization from infection. Group A streptococci are common colonizers with viral pharyngitis. In 30% of cases of Epstein-Barr virus pharyngitis, there is colonization with group A streptococci. A positive rapid test in such cases can result in the wrong diagnosis, ie, pharyngitis due to group A streptococci rather than Epstein-Barr virus.

A 62-year-old woman presented to our emergency department with fever, chills, hoarseness, pain on swallowing, and a painful neck. Her symptoms had begun 1 day earlier. Because acetaminophen brought no improvement, she went to an urgent care facility, where a nasal swab polymerase chain reaction test was positive for influenza A, and a throat swab rapid test was positive for group A streptococci. She was then referred to our emergency department.

She reported no pre-existing conditions predisposing her to infection. Her temperature was 99.9°F (37.7°C), pulse 112 beats per minute, and respiratory rate 24 breaths per minute. The physical examination was unremarkable except for bilateral anterior cervical adenopathy and bilateral anterior neck tenderness. Her pharynx was not injected, and no exudate, palatal edema, or petechiae were noted.

Results of initial laboratory testing were as follows:

• White blood cell count 20.5 × 10⁹/L (reference range 3.9–11)
• Neutrophils 76% (42%–75%)
• Bands 15% (0%–5%)
• Lymphocytes 3% (21%–51%)
• Erythrocyte sedimentation rate 75 mm/h (< 20 mm/h)
• C-reactive protein 247.14 mg/L (≤ 3 mg/L)
• Serum aminotransferase levels were normal.
• Polymerase chain reaction testing of a nasal swab was negative for viral infection.

Throat swabs and blood samples were sent for culture.

She was started on ceftriaxone 1 g intravenously every 24 hours, with close observation in the medical intensive care unit, where she was admitted because of epiglottitis. On hospital day 3, the throat culture was reported as negative, but the blood culture was reported as positive for Haemophilus influenzae. Thus, the clinical diagnosis was acute epiglottitis due to H influenzae, not group A streptococci.

The patient completed 10 days of ceftriaxone therapy; her recovery was uneventful, and she was discharged on hospital day 10.

INFLUENZA: CHALLENGES TO PROMPT, ACCURATE DIAGNOSIS

During influenza season, emergency departments are inundated with adults with influenza A and other viral respiratory infections. This makes prompt, accurate diagnosis a challenge,¹ given the broad differential diagnosis.^2,3 Adults with influenza and its complications as well as unrelated conditions can present a special challenge.⁴

Our patient presented with acute-onset influenza A and was then found to have acute epiglottitis, an unexpected complication of influenza A.⁵ A positive rapid test for group A streptococci done at an urgent care facility led emergency department physicians to assume that the acute epiglottitis was due to group A streptococci. Unless correlated with clinical findings, results of rapid diagnostic tests may mislead the unwary practitioner. Accurate diagnosis should be based mainly on the history and physical findings. Results of rapid diagnostic tests can be helpful if interpreted in the clinical context.^6–8

The rapid test for streptococci is appropriate for the diagnosis of pharyngitis due to group A streptococci in people under age 30 with acute-onset sore throat, fever, and bilateral acute cervical adenopathy, without fatigue or myalgias. However, the rapid test does not differentiate colonization from infection. Group A streptococci are common colonizers with viral pharyngitis. In 30% of cases of Epstein-Barr virus pharyngitis, there is colonization with group A streptococci. A positive rapid test in such cases can result in the wrong diagnosis, ie, pharyngitis due to group A streptococci rather than Epstein-Barr virus.

DIAGNOSIS, TREATMENT, CONTROL

The differential diagnosis of Norwegian scabies includes psoriasis, eczema, contact dermatitis, insect bites, seborrheic dermatitis, lichen planus, systemic infection, palmoplantar keratoderma, and cutaneous lymphoma.²

Treatment involves eradicating the infestation with a topical ointment consisting of permethrin, crotamiton, lindane, benzyl benzoate, and sulfur, applied directly to the skin. However, topical treatments often cannot penetrate the crusted and thickened skin, leading to treatment failure. A dose of oral ivermectin 200 µg/kg on days 1, 2, and 8 is a safe, effective, first-line treatment for Norwegian scabies, rapidly reducing scabies symptoms.³ Adverse effects of oral ivermectin are rare and usually minor.

Norwegian scabies is extremely contagious, spread by close physical contact and sharing of contaminated items such as clothing, bedding, towels, and furniture. Scabies mites can survive off the skin for 48 to 72 hours at room temperature.⁴ Potentially contaminated items should be decontaminated by washing in hot water and drying in a drying machine or by dry cleaning. Body contact with other contaminated items should be avoided for at least 72 hours.

Outbreaks can spread among patients, visitors, and medical staff in institutions such as nursing homes, day care centers, long-term-care facilities, and hospitals.⁵ Early identification facilitates appropriate management and treatment, thereby preventing infection and community-wide scabies outbreaks.          

Acknowledgment: The authors would like to sincerely thank Paul Williams for his editing of the article.

DIAGNOSIS, TREATMENT, CONTROL

The differential diagnosis of Norwegian scabies includes psoriasis, eczema, contact dermatitis, insect bites, seborrheic dermatitis, lichen planus, systemic infection, palmoplantar keratoderma, and cutaneous lymphoma.²

Treatment involves eradicating the infestation with a topical ointment consisting of permethrin, crotamiton, lindane, benzyl benzoate, and sulfur, applied directly to the skin. However, topical treatments often cannot penetrate the crusted and thickened skin, leading to treatment failure. A dose of oral ivermectin 200 µg/kg on days 1, 2, and 8 is a safe, effective, first-line treatment for Norwegian scabies, rapidly reducing scabies symptoms.³ Adverse effects of oral ivermectin are rare and usually minor.

Norwegian scabies is extremely contagious, spread by close physical contact and sharing of contaminated items such as clothing, bedding, towels, and furniture. Scabies mites can survive off the skin for 48 to 72 hours at room temperature.⁴ Potentially contaminated items should be decontaminated by washing in hot water and drying in a drying machine or by dry cleaning. Body contact with other contaminated items should be avoided for at least 72 hours.

Outbreaks can spread among patients, visitors, and medical staff in institutions such as nursing homes, day care centers, long-term-care facilities, and hospitals.⁵ Early identification facilitates appropriate management and treatment, thereby preventing infection and community-wide scabies outbreaks.          

Acknowledgment: The authors would like to sincerely thank Paul Williams for his editing of the article.

DIAGNOSIS, TREATMENT, CONTROL

The differential diagnosis of Norwegian scabies includes psoriasis, eczema, contact dermatitis, insect bites, seborrheic dermatitis, lichen planus, systemic infection, palmoplantar keratoderma, and cutaneous lymphoma.²

Treatment involves eradicating the infestation with a topical ointment consisting of permethrin, crotamiton, lindane, benzyl benzoate, and sulfur, applied directly to the skin. However, topical treatments often cannot penetrate the crusted and thickened skin, leading to treatment failure. A dose of oral ivermectin 200 µg/kg on days 1, 2, and 8 is a safe, effective, first-line treatment for Norwegian scabies, rapidly reducing scabies symptoms.³ Adverse effects of oral ivermectin are rare and usually minor.

Norwegian scabies is extremely contagious, spread by close physical contact and sharing of contaminated items such as clothing, bedding, towels, and furniture. Scabies mites can survive off the skin for 48 to 72 hours at room temperature.⁴ Potentially contaminated items should be decontaminated by washing in hot water and drying in a drying machine or by dry cleaning. Body contact with other contaminated items should be avoided for at least 72 hours.

Outbreaks can spread among patients, visitors, and medical staff in institutions such as nursing homes, day care centers, long-term-care facilities, and hospitals.⁵ Early identification facilitates appropriate management and treatment, thereby preventing infection and community-wide scabies outbreaks.          

Acknowledgment: The authors would like to sincerely thank Paul Williams for his editing of the article.

Delaying or withholding antibiotics in elderly patients with a urinary tract infection (UTI) increases the risk of sepsis and death, results of a large, population-based study suggest.

andresr/Getty Images

The risk of bloodstream infection was more than seven times greater in patients who did not receive antibiotics immediately after seeing a general practitioner for a UTI versus those who did, according to results of the study based on primary care records and other data for nearly 160,000 U.K. patients aged 65 years or older. Death rates and hospital admissions were significantly higher for these patients, according to the study published in The BMJ by Myriam Gharbi, PharmD, Phd, Imperial College London, and her colleagues.

The publication of these findings coincides with an increase in Escherichia coli bloodstream infections in England.

“Our study suggests the early initiation of antibiotics for UTI in older high risk adult populations (especially men aged [older than] 85 years) should be recommended to prevent serious complications,” Dr. Gharbi and her coauthors said in their report.

The population-based cohort study comprised 157,264 adult primary care patients at least 65 years of age who had one or more suspected or confirmed lower UTIs from November 2007 to May 2015. The researchers found that health care providers had diagnosed a total of 312,896 UTI episodes in these patients during the period they studied. In 7.2% (22,534) of the UTI episodes, the researchers were unable to find records of the patients having been prescribed antibiotics by a general practitioner within 7 days of the UTI diagnosis. These 22,534 episodes included those that occurred in patients who had a complication before an antibiotic was prescribed. An additional 6.2% (19,292) of the episodes occurred in patients who were prescribed antibiotics, but not during their first UTI-related visit to a general practitioner or on the same day of such a visit. The researchers classified this group of patients as having been prescribed antibiotics on a deferred or delayed basis, as they were not prescribed such drugs within 7 days of their visit.

Overall, there were 1,539 cases (0.5% of the total number of UTIs) of bloodstream infection within 60 days of the initial urinary tract infection diagnosis, the researchers reported.

The bloodstream infection rate was 2.9% for patients who were not prescribed antibiotics ever or prior to an infection occurring, 2.2% in those who were prescribed antibiotics on a deferred basis, and 0.2% in those who were prescribed antibiotics immediately, meaning during their first visit to a general practitioner for a UTI or on the same day of such a visit (P less than .001). After adjustment for potential confounding variables such as age, sex, and region, the patients classified as having not been prescribed antibiotics or having been prescribed antibiotics on a deferred basis were significantly more likely to have a bloodstream infection within 60 days of their visit to a health care provider, compared with those who received antibiotics immediately, with odds ratios of 8.08 (95% confidence interval, 7.12-9.16) and 7.12 (95% CI, 6.22-8.14), respectively.

Hospital admissions after a UTI episode were nearly twice as high in the no- or deferred-antibiotics groups (27.0% and 26.8%, respectively), compared with the group that received antibiotics right away (14.8%), the investigators reported. The lengths of hospital stays were 12.1 days for the group classified as having not been prescribed antibiotics, 7.7 days for the group subject to delayed antibiotic prescribing, and 6.3 days for the group who received antibiotics immediately.

Deaths within 60 days of experiencing a urinary tract infection occurred in 5.4% of patients in the no-antibiotics group, 2.8% of the deferred-antibiotics group, and 1.6% of the immediate-antibiotics group. After adjustment for covariates, a regression analysis showed the risks for all-cause mortality were 1.16 and 2.18 times higher in the deferred-antibiotics group and the no-antibiotics group, respectively, according to the paper.

In the immediate-antibiotics group, those patients who received nitrofurantoin had a “small but significant increase” in 60-day survival versus those who received trimethoprim, the investigators noted in the discussion section of their report.

“This increase could reflect either higher levels of resistance to trimethoprim or a healthier population treated with nitrofurantoin, the latest being not recommended for patients with poor kidney function,” the researchers wrote.

This study was supported by the National Institute for Health Research and other U.K. sources. One study coauthor reported working as an epidemiologist with GSK in areas not related to the study.

SOURCE: Gharbi M et al. BMJ. 2019 Feb 27. doi: 10.1136/bmj.l525.

Delaying or withholding antibiotics in elderly patients with a urinary tract infection (UTI) increases the risk of sepsis and death, results of a large, population-based study suggest.

andresr/Getty Images

The risk of bloodstream infection was more than seven times greater in patients who did not receive antibiotics immediately after seeing a general practitioner for a UTI versus those who did, according to results of the study based on primary care records and other data for nearly 160,000 U.K. patients aged 65 years or older. Death rates and hospital admissions were significantly higher for these patients, according to the study published in The BMJ by Myriam Gharbi, PharmD, Phd, Imperial College London, and her colleagues.

The publication of these findings coincides with an increase in Escherichia coli bloodstream infections in England.

“Our study suggests the early initiation of antibiotics for UTI in older high risk adult populations (especially men aged [older than] 85 years) should be recommended to prevent serious complications,” Dr. Gharbi and her coauthors said in their report.

The population-based cohort study comprised 157,264 adult primary care patients at least 65 years of age who had one or more suspected or confirmed lower UTIs from November 2007 to May 2015. The researchers found that health care providers had diagnosed a total of 312,896 UTI episodes in these patients during the period they studied. In 7.2% (22,534) of the UTI episodes, the researchers were unable to find records of the patients having been prescribed antibiotics by a general practitioner within 7 days of the UTI diagnosis. These 22,534 episodes included those that occurred in patients who had a complication before an antibiotic was prescribed. An additional 6.2% (19,292) of the episodes occurred in patients who were prescribed antibiotics, but not during their first UTI-related visit to a general practitioner or on the same day of such a visit. The researchers classified this group of patients as having been prescribed antibiotics on a deferred or delayed basis, as they were not prescribed such drugs within 7 days of their visit.

Overall, there were 1,539 cases (0.5% of the total number of UTIs) of bloodstream infection within 60 days of the initial urinary tract infection diagnosis, the researchers reported.

The bloodstream infection rate was 2.9% for patients who were not prescribed antibiotics ever or prior to an infection occurring, 2.2% in those who were prescribed antibiotics on a deferred basis, and 0.2% in those who were prescribed antibiotics immediately, meaning during their first visit to a general practitioner for a UTI or on the same day of such a visit (P less than .001). After adjustment for potential confounding variables such as age, sex, and region, the patients classified as having not been prescribed antibiotics or having been prescribed antibiotics on a deferred basis were significantly more likely to have a bloodstream infection within 60 days of their visit to a health care provider, compared with those who received antibiotics immediately, with odds ratios of 8.08 (95% confidence interval, 7.12-9.16) and 7.12 (95% CI, 6.22-8.14), respectively.

Hospital admissions after a UTI episode were nearly twice as high in the no- or deferred-antibiotics groups (27.0% and 26.8%, respectively), compared with the group that received antibiotics right away (14.8%), the investigators reported. The lengths of hospital stays were 12.1 days for the group classified as having not been prescribed antibiotics, 7.7 days for the group subject to delayed antibiotic prescribing, and 6.3 days for the group who received antibiotics immediately.

Deaths within 60 days of experiencing a urinary tract infection occurred in 5.4% of patients in the no-antibiotics group, 2.8% of the deferred-antibiotics group, and 1.6% of the immediate-antibiotics group. After adjustment for covariates, a regression analysis showed the risks for all-cause mortality were 1.16 and 2.18 times higher in the deferred-antibiotics group and the no-antibiotics group, respectively, according to the paper.

In the immediate-antibiotics group, those patients who received nitrofurantoin had a “small but significant increase” in 60-day survival versus those who received trimethoprim, the investigators noted in the discussion section of their report.

“This increase could reflect either higher levels of resistance to trimethoprim or a healthier population treated with nitrofurantoin, the latest being not recommended for patients with poor kidney function,” the researchers wrote.

This study was supported by the National Institute for Health Research and other U.K. sources. One study coauthor reported working as an epidemiologist with GSK in areas not related to the study.

SOURCE: Gharbi M et al. BMJ. 2019 Feb 27. doi: 10.1136/bmj.l525.

Delaying or withholding antibiotics in elderly patients with a urinary tract infection (UTI) increases the risk of sepsis and death, results of a large, population-based study suggest.

andresr/Getty Images

The risk of bloodstream infection was more than seven times greater in patients who did not receive antibiotics immediately after seeing a general practitioner for a UTI versus those who did, according to results of the study based on primary care records and other data for nearly 160,000 U.K. patients aged 65 years or older. Death rates and hospital admissions were significantly higher for these patients, according to the study published in The BMJ by Myriam Gharbi, PharmD, Phd, Imperial College London, and her colleagues.

The publication of these findings coincides with an increase in Escherichia coli bloodstream infections in England.

“Our study suggests the early initiation of antibiotics for UTI in older high risk adult populations (especially men aged [older than] 85 years) should be recommended to prevent serious complications,” Dr. Gharbi and her coauthors said in their report.

The population-based cohort study comprised 157,264 adult primary care patients at least 65 years of age who had one or more suspected or confirmed lower UTIs from November 2007 to May 2015. The researchers found that health care providers had diagnosed a total of 312,896 UTI episodes in these patients during the period they studied. In 7.2% (22,534) of the UTI episodes, the researchers were unable to find records of the patients having been prescribed antibiotics by a general practitioner within 7 days of the UTI diagnosis. These 22,534 episodes included those that occurred in patients who had a complication before an antibiotic was prescribed. An additional 6.2% (19,292) of the episodes occurred in patients who were prescribed antibiotics, but not during their first UTI-related visit to a general practitioner or on the same day of such a visit. The researchers classified this group of patients as having been prescribed antibiotics on a deferred or delayed basis, as they were not prescribed such drugs within 7 days of their visit.

Overall, there were 1,539 cases (0.5% of the total number of UTIs) of bloodstream infection within 60 days of the initial urinary tract infection diagnosis, the researchers reported.

The bloodstream infection rate was 2.9% for patients who were not prescribed antibiotics ever or prior to an infection occurring, 2.2% in those who were prescribed antibiotics on a deferred basis, and 0.2% in those who were prescribed antibiotics immediately, meaning during their first visit to a general practitioner for a UTI or on the same day of such a visit (P less than .001). After adjustment for potential confounding variables such as age, sex, and region, the patients classified as having not been prescribed antibiotics or having been prescribed antibiotics on a deferred basis were significantly more likely to have a bloodstream infection within 60 days of their visit to a health care provider, compared with those who received antibiotics immediately, with odds ratios of 8.08 (95% confidence interval, 7.12-9.16) and 7.12 (95% CI, 6.22-8.14), respectively.

Hospital admissions after a UTI episode were nearly twice as high in the no- or deferred-antibiotics groups (27.0% and 26.8%, respectively), compared with the group that received antibiotics right away (14.8%), the investigators reported. The lengths of hospital stays were 12.1 days for the group classified as having not been prescribed antibiotics, 7.7 days for the group subject to delayed antibiotic prescribing, and 6.3 days for the group who received antibiotics immediately.

Deaths within 60 days of experiencing a urinary tract infection occurred in 5.4% of patients in the no-antibiotics group, 2.8% of the deferred-antibiotics group, and 1.6% of the immediate-antibiotics group. After adjustment for covariates, a regression analysis showed the risks for all-cause mortality were 1.16 and 2.18 times higher in the deferred-antibiotics group and the no-antibiotics group, respectively, according to the paper.

In the immediate-antibiotics group, those patients who received nitrofurantoin had a “small but significant increase” in 60-day survival versus those who received trimethoprim, the investigators noted in the discussion section of their report.

“This increase could reflect either higher levels of resistance to trimethoprim or a healthier population treated with nitrofurantoin, the latest being not recommended for patients with poor kidney function,” the researchers wrote.

This study was supported by the National Institute for Health Research and other U.K. sources. One study coauthor reported working as an epidemiologist with GSK in areas not related to the study.

SOURCE: Gharbi M et al. BMJ. 2019 Feb 27. doi: 10.1136/bmj.l525.

A booster dose for pre-exposure prophylaxis with an anthrax vaccine may be given at 3 years after an initial series for individuals not currently at risk who wish to maintain protection, according to the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

Carolina K. Smith, MD/Fotolia.com

In a unanimous 15-0 vote at the February meeting, ACIP committee members agreed on the recommendation after adjusting the wording to reflect a permissive, rather than mandated, guidance.

William Bower, MD, of the CDC’s National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), presented data on Anthrax Vaccine Adsorbed (AVA) to support its protective effects over a longer booster dose interval.

The recommendations apply to persons aged 18 years or older who are not currently at high risk of exposure to Bacillus anthracis, but who might need to deploy to a high-risk area quickly, such as military personnel, Dr. Bower said.

In addition, data suggest that adults who have started, but not completed the pre-exposure priming series, can transition to the postexposure schedule prior to entering a high-risk area, he noted.

The previous pre-exposure anthrax vaccination schedule was a three-dose priming series at 0, 1, and 3 months, followed by a booster at 12 months and 18 months, then annually.

Data from several human immunogenicity studies showed a robust immune response following a delayed anthrax booster dose, with “sustained immunological memory to at least month 42,” and suggested that even longer intervals between boosters may be possible, Dr. Bower said.

A dosing schedule of intramuscular injections at 0 and at 1 month and 6 months, with a booster at 42 months yielded survival estimates of approximately 84%-93%.

Dr. Bower noted that a new vaccine, AV7909, has demonstrated safety and effectiveness similar to AVA and could be used for pre-exposure prophylaxis if AVA is not available. AVA remains the preferred option, but ultimately will be replaced by AV7909, when the current AVA stockpile is exhausted.

Additional safety data on AV7909 will be reviewed by ACIP as they become available, and future guidance from the CDC will include statements on dosing for special populations including pregnant and breastfeeding women, said Dr. Bower.

“We anticipate that this [anthrax vaccine] work group will reconvene in 2021 to review data from pending studies” of AV7909, he said.

The ACIP members had no financial conflicts to disclose.

A booster dose for pre-exposure prophylaxis with an anthrax vaccine may be given at 3 years after an initial series for individuals not currently at risk who wish to maintain protection, according to the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

Carolina K. Smith, MD/Fotolia.com

In a unanimous 15-0 vote at the February meeting, ACIP committee members agreed on the recommendation after adjusting the wording to reflect a permissive, rather than mandated, guidance.

William Bower, MD, of the CDC’s National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), presented data on Anthrax Vaccine Adsorbed (AVA) to support its protective effects over a longer booster dose interval.

The recommendations apply to persons aged 18 years or older who are not currently at high risk of exposure to Bacillus anthracis, but who might need to deploy to a high-risk area quickly, such as military personnel, Dr. Bower said.

In addition, data suggest that adults who have started, but not completed the pre-exposure priming series, can transition to the postexposure schedule prior to entering a high-risk area, he noted.

The previous pre-exposure anthrax vaccination schedule was a three-dose priming series at 0, 1, and 3 months, followed by a booster at 12 months and 18 months, then annually.

Data from several human immunogenicity studies showed a robust immune response following a delayed anthrax booster dose, with “sustained immunological memory to at least month 42,” and suggested that even longer intervals between boosters may be possible, Dr. Bower said.

A dosing schedule of intramuscular injections at 0 and at 1 month and 6 months, with a booster at 42 months yielded survival estimates of approximately 84%-93%.

Dr. Bower noted that a new vaccine, AV7909, has demonstrated safety and effectiveness similar to AVA and could be used for pre-exposure prophylaxis if AVA is not available. AVA remains the preferred option, but ultimately will be replaced by AV7909, when the current AVA stockpile is exhausted.

Additional safety data on AV7909 will be reviewed by ACIP as they become available, and future guidance from the CDC will include statements on dosing for special populations including pregnant and breastfeeding women, said Dr. Bower.

“We anticipate that this [anthrax vaccine] work group will reconvene in 2021 to review data from pending studies” of AV7909, he said.

The ACIP members had no financial conflicts to disclose.

A booster dose for pre-exposure prophylaxis with an anthrax vaccine may be given at 3 years after an initial series for individuals not currently at risk who wish to maintain protection, according to the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

Carolina K. Smith, MD/Fotolia.com

In a unanimous 15-0 vote at the February meeting, ACIP committee members agreed on the recommendation after adjusting the wording to reflect a permissive, rather than mandated, guidance.

William Bower, MD, of the CDC’s National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), presented data on Anthrax Vaccine Adsorbed (AVA) to support its protective effects over a longer booster dose interval.

The recommendations apply to persons aged 18 years or older who are not currently at high risk of exposure to Bacillus anthracis, but who might need to deploy to a high-risk area quickly, such as military personnel, Dr. Bower said.

In addition, data suggest that adults who have started, but not completed the pre-exposure priming series, can transition to the postexposure schedule prior to entering a high-risk area, he noted.

The previous pre-exposure anthrax vaccination schedule was a three-dose priming series at 0, 1, and 3 months, followed by a booster at 12 months and 18 months, then annually.

Data from several human immunogenicity studies showed a robust immune response following a delayed anthrax booster dose, with “sustained immunological memory to at least month 42,” and suggested that even longer intervals between boosters may be possible, Dr. Bower said.

A dosing schedule of intramuscular injections at 0 and at 1 month and 6 months, with a booster at 42 months yielded survival estimates of approximately 84%-93%.

Dr. Bower noted that a new vaccine, AV7909, has demonstrated safety and effectiveness similar to AVA and could be used for pre-exposure prophylaxis if AVA is not available. AVA remains the preferred option, but ultimately will be replaced by AV7909, when the current AVA stockpile is exhausted.

Additional safety data on AV7909 will be reviewed by ACIP as they become available, and future guidance from the CDC will include statements on dosing for special populations including pregnant and breastfeeding women, said Dr. Bower.

“We anticipate that this [anthrax vaccine] work group will reconvene in 2021 to review data from pending studies” of AV7909, he said.

The ACIP members had no financial conflicts to disclose.

Vaccination against Japanese encephalitis is recommended for persons moving to endemic areas, or who travel to these areas frequently or for long-term visits, according to a vote at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

Japanese encephalitis (JE) virus is a mosquito-borne flavivirus and those at risk for infection include travelers to countries where JE is endemic, as well as laboratory personnel who work with the virus.

The committee voted unanimously 15-0 in favor of the recommendations, which also advised vaccination for those whose travels in endemic areas are uncertain, but not for travelers with low-risk itineraries “such as shorter term travel limited to urban areas or travel that occurs outside of a well-defined JE virus transmission season.”

Susan Hills, MD, of the of the CDC’s National Center for Emerging and Zoonotic Infectious Diseases, presented data in support of the recommendations.

A second unanimous vote confirmed recommendations for a primary series schedule for JE vaccination for adults aged 18-65 years as “two doses of vaccine administered on days 0 and 7-28.”

The third vote, also a unanimous 15-0, updated recommendations for a JE booster dose. The new recommendation is that adults and children receive a booster dose (a third dose) at least a year after completion of the primary JE vaccine series “if ongoing exposure or re-exposure to JE virus is expected.”

The currently available Japanese encephalitis vaccine in the United States is an inactivated Vero cell culture-derived vaccine marketed as IXIARO that was approved in March 2009 for individuals aged 17 years and older and approved in May 2013 for children aged 2 months through 16 years.

The ACIP members had no financial conflicts to disclose.
 

Vaccination against Japanese encephalitis is recommended for persons moving to endemic areas, or who travel to these areas frequently or for long-term visits, according to a vote at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

Japanese encephalitis (JE) virus is a mosquito-borne flavivirus and those at risk for infection include travelers to countries where JE is endemic, as well as laboratory personnel who work with the virus.

The committee voted unanimously 15-0 in favor of the recommendations, which also advised vaccination for those whose travels in endemic areas are uncertain, but not for travelers with low-risk itineraries “such as shorter term travel limited to urban areas or travel that occurs outside of a well-defined JE virus transmission season.”

Susan Hills, MD, of the of the CDC’s National Center for Emerging and Zoonotic Infectious Diseases, presented data in support of the recommendations.

A second unanimous vote confirmed recommendations for a primary series schedule for JE vaccination for adults aged 18-65 years as “two doses of vaccine administered on days 0 and 7-28.”

The third vote, also a unanimous 15-0, updated recommendations for a JE booster dose. The new recommendation is that adults and children receive a booster dose (a third dose) at least a year after completion of the primary JE vaccine series “if ongoing exposure or re-exposure to JE virus is expected.”

The currently available Japanese encephalitis vaccine in the United States is an inactivated Vero cell culture-derived vaccine marketed as IXIARO that was approved in March 2009 for individuals aged 17 years and older and approved in May 2013 for children aged 2 months through 16 years.

The ACIP members had no financial conflicts to disclose.
 

Vaccination against Japanese encephalitis is recommended for persons moving to endemic areas, or who travel to these areas frequently or for long-term visits, according to a vote at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

Japanese encephalitis (JE) virus is a mosquito-borne flavivirus and those at risk for infection include travelers to countries where JE is endemic, as well as laboratory personnel who work with the virus.

The committee voted unanimously 15-0 in favor of the recommendations, which also advised vaccination for those whose travels in endemic areas are uncertain, but not for travelers with low-risk itineraries “such as shorter term travel limited to urban areas or travel that occurs outside of a well-defined JE virus transmission season.”

Susan Hills, MD, of the of the CDC’s National Center for Emerging and Zoonotic Infectious Diseases, presented data in support of the recommendations.

A second unanimous vote confirmed recommendations for a primary series schedule for JE vaccination for adults aged 18-65 years as “two doses of vaccine administered on days 0 and 7-28.”

The third vote, also a unanimous 15-0, updated recommendations for a JE booster dose. The new recommendation is that adults and children receive a booster dose (a third dose) at least a year after completion of the primary JE vaccine series “if ongoing exposure or re-exposure to JE virus is expected.”

The currently available Japanese encephalitis vaccine in the United States is an inactivated Vero cell culture-derived vaccine marketed as IXIARO that was approved in March 2009 for individuals aged 17 years and older and approved in May 2013 for children aged 2 months through 16 years.

The ACIP members had no financial conflicts to disclose.