Infectious Diseases

“Health care spending and health care waste is a huge problem in the U.S., including for children,” Vivian Lee, MD, of Children’s Hospital, Los Angeles, said in a presentation at the 2021 virtual Pediatric Hospital Medicine conference.

Data from a 2019 study suggested that approximately 25% of health care spending in the United States qualifies as “wasteful spending,” in categories such as overtesting, and unnecessary hospitalization, Dr. Lee said. “It is essential for physicians in hospitals to be stewards of high-value care,” she emphasized.

To combat wasteful spending and control health care costs, the Choosing Wisely campaign was created in 2012 as an initiative from the American Board of Internal Medicine Foundation. An ongoing goal of the campaign is to raise awareness among physicians and patients about potential areas of low-value services and overuse. The overall campaign includes clinician-driven recommendations from multiple medical organizations.

The PHM produced its first set of five recommendations in 2012, Dr. Lee said. These recommendations, titled “Five Things Physicians and Patients Should Question,” have been updated for 2021. The updated recommendations were created as a partnership among the Academic Pediatric Association, the American Academy of Pediatrics, and the Society of Hospital Medicine. A joint committee reviewed the latest evidence, and the updates were approved by the societies and published by the ABIM in January 2021.

“We think these recommendations truly reflect an exciting and evolving landscape for pediatric hospitalists,” Dr. Lee said. “There is a greater focus on opportunities to transition out of the hospital sooner, or avoid hospitalization altogether. There is an emphasis on antibiotic stewardship and a growing recognition of the impact that overuse may have on our vulnerable neonatal population,” she said. Several members of the Choosing Wisely panel presented the recommendations during the virtual presentation.
 

Revised recommendations

The new “Five Things Physicians and Patients Should Question” are as follows:

1. Do not prescribe IV antibiotics for predetermined durations for patients hospitalized with infections such as pyelonephritis, osteomyelitis, and complicated pneumonia. Consider early transition to oral antibiotics.

Many antibiotic doses used in clinical practice are preset durations that are not based on high-quality evidence, said Mike Tchou, MD, of Children’s Hospital of Colorado in Aurora. However, studies now show that earlier transition to enteral antibiotics can improve a range of outcomes including neonatal UTIs, osteomyelitis, and complicated pneumonia, he said. Considering early transition based on a patient’s response can decrease adverse events, pain, length of stay, and health care costs, he explained.

2. Do not continue hospitalization in well-appearing febrile infants once bacterial cultures (i.e., blood, cerebrospinal, and/or urine) have been confirmed negative for 24-36 hours, if adequate outpatient follow-up can be assured.

Recent data indicate that continuing hospitalization beyond 24-36 hours of confirmed negative bacterial cultures does not improve clinical outcomes for well-appearing infants admitted for concern of serious bacterial infection, said Paula Soung, MD, of Children’s Wisconsin in Milwaukee. In fact, “blood culture yield is highest in the first 12-36 hours after incubation with multiple studies demonstrating > 90% of pathogen cultures being positive by 24 hours,” Dr. Soung said. “If adequate outpatient follow-up can be assured, discharging well-appearing febrile infants at 24-36 hours after confirming cultures are negative has many positive outcomes,” she said.

3. Do not initiate phototherapy in term or late preterm well-appearing infants with neonatal hyperbilirubinemia if their bilirubin is below levels at which the AAP guidelines recommend treatment.

In making this recommendation, “we considered that the risk of kernicterus and cerebral palsy is extremely low in otherwise healthy term and late preterm newborns,” said Allison Holmes, MD, of Children’s Hospital at Dartmouth-Hitchcock, Manchester, N.H. “Subthreshold phototherapy leads to unnecessary hospitalization and its associated costs and harms,” and data show that kernicterus generally occurs close to 40 mg/dL and occurs most often in infants with hemolysis, she added.

The evidence for the recommendations included data showing that, among other factors, 8.6 of 100,000 babies have a bilirubin greater than 30 mg/dL, said Dr. Holmes. Risks of using subthreshold phototherapy include increased length of stay, increased readmissions, and increased costs, as well as decreased breastfeeding, bonding with parents, and increased parental anxiety. “Adding prolonged hospitalization for an intervention that might not be necessary can be stressful for parents,” she said.

4. Do not use broad-spectrum antibiotics such as ceftriaxone for children hospitalized with uncomplicated community-acquired pneumonia. Use narrow-spectrum antibiotics such as penicillin, ampicillin, or amoxicillin.

Michelle Lossius, MD, of the Shands Hospital for Children at the University of Florida, Gainesville, noted that the recommendations reflect IDSA guidelines from 2011 advising the use of ampicillin or penicillin for this population of children. More recent studies with large populations support the ability of narrow-spectrum antibiotics to limit the development of resistant organisms while achieving the same or better outcomes for children hospitalized with CAP, she said.

5. Do not start IV antibiotic therapy on well-appearing newborn infants with isolated risk factors for sepsis such as maternal chorioamnionitis, prolonged rupture of membranes, or untreated group-B streptococcal colonization. Use clinical tools such as an evidence-based sepsis risk calculator to guide management.

“This recommendation combines other recommendations,” said Prabi Rajbhandari, MD, of Akron (Ohio) Children’s Hospital. The evidence is ample, as the Centers for Disease Control and Prevention recommends the use of sepsis calculators to guide clinical management in sepsis patients, she said.

Data comparing periods before and after the adoption of a sepsis risk calculator showed a significant reduction in the use of blood cultures and antibiotics, she noted. Other risks of jumping to IV antibiotics include increased hospital stay, increased parental anxiety, and decreased parental bonding, Dr. Rajbhandari added.

Next steps include how to prioritize implementation, as well as deimplementation of outdated practices, said Francisco Alvarez, MD, of Lucile Packard Children’s Hospital, Palo Alto, Calif. “A lot of our practices were started without good evidence for why they should be done,” he said. Other steps include value improvement research; use of dashboards and benchmarking; involving other stakeholders including patients, families, and other health care providers; and addressing racial disparities, he concluded.

The presenters had no financial conflicts to disclose. The conference was sponsored by the Academic Pediatric Association, the American Academy of Pediatrics, and the Society of Hospital Medicine.

“Health care spending and health care waste is a huge problem in the U.S., including for children,” Vivian Lee, MD, of Children’s Hospital, Los Angeles, said in a presentation at the 2021 virtual Pediatric Hospital Medicine conference.

Data from a 2019 study suggested that approximately 25% of health care spending in the United States qualifies as “wasteful spending,” in categories such as overtesting, and unnecessary hospitalization, Dr. Lee said. “It is essential for physicians in hospitals to be stewards of high-value care,” she emphasized.

To combat wasteful spending and control health care costs, the Choosing Wisely campaign was created in 2012 as an initiative from the American Board of Internal Medicine Foundation. An ongoing goal of the campaign is to raise awareness among physicians and patients about potential areas of low-value services and overuse. The overall campaign includes clinician-driven recommendations from multiple medical organizations.

The PHM produced its first set of five recommendations in 2012, Dr. Lee said. These recommendations, titled “Five Things Physicians and Patients Should Question,” have been updated for 2021. The updated recommendations were created as a partnership among the Academic Pediatric Association, the American Academy of Pediatrics, and the Society of Hospital Medicine. A joint committee reviewed the latest evidence, and the updates were approved by the societies and published by the ABIM in January 2021.

“We think these recommendations truly reflect an exciting and evolving landscape for pediatric hospitalists,” Dr. Lee said. “There is a greater focus on opportunities to transition out of the hospital sooner, or avoid hospitalization altogether. There is an emphasis on antibiotic stewardship and a growing recognition of the impact that overuse may have on our vulnerable neonatal population,” she said. Several members of the Choosing Wisely panel presented the recommendations during the virtual presentation.
 

Revised recommendations

The new “Five Things Physicians and Patients Should Question” are as follows:

1. Do not prescribe IV antibiotics for predetermined durations for patients hospitalized with infections such as pyelonephritis, osteomyelitis, and complicated pneumonia. Consider early transition to oral antibiotics.

Many antibiotic doses used in clinical practice are preset durations that are not based on high-quality evidence, said Mike Tchou, MD, of Children’s Hospital of Colorado in Aurora. However, studies now show that earlier transition to enteral antibiotics can improve a range of outcomes including neonatal UTIs, osteomyelitis, and complicated pneumonia, he said. Considering early transition based on a patient’s response can decrease adverse events, pain, length of stay, and health care costs, he explained.

2. Do not continue hospitalization in well-appearing febrile infants once bacterial cultures (i.e., blood, cerebrospinal, and/or urine) have been confirmed negative for 24-36 hours, if adequate outpatient follow-up can be assured.

Recent data indicate that continuing hospitalization beyond 24-36 hours of confirmed negative bacterial cultures does not improve clinical outcomes for well-appearing infants admitted for concern of serious bacterial infection, said Paula Soung, MD, of Children’s Wisconsin in Milwaukee. In fact, “blood culture yield is highest in the first 12-36 hours after incubation with multiple studies demonstrating > 90% of pathogen cultures being positive by 24 hours,” Dr. Soung said. “If adequate outpatient follow-up can be assured, discharging well-appearing febrile infants at 24-36 hours after confirming cultures are negative has many positive outcomes,” she said.

3. Do not initiate phototherapy in term or late preterm well-appearing infants with neonatal hyperbilirubinemia if their bilirubin is below levels at which the AAP guidelines recommend treatment.

In making this recommendation, “we considered that the risk of kernicterus and cerebral palsy is extremely low in otherwise healthy term and late preterm newborns,” said Allison Holmes, MD, of Children’s Hospital at Dartmouth-Hitchcock, Manchester, N.H. “Subthreshold phototherapy leads to unnecessary hospitalization and its associated costs and harms,” and data show that kernicterus generally occurs close to 40 mg/dL and occurs most often in infants with hemolysis, she added.

The evidence for the recommendations included data showing that, among other factors, 8.6 of 100,000 babies have a bilirubin greater than 30 mg/dL, said Dr. Holmes. Risks of using subthreshold phototherapy include increased length of stay, increased readmissions, and increased costs, as well as decreased breastfeeding, bonding with parents, and increased parental anxiety. “Adding prolonged hospitalization for an intervention that might not be necessary can be stressful for parents,” she said.

4. Do not use broad-spectrum antibiotics such as ceftriaxone for children hospitalized with uncomplicated community-acquired pneumonia. Use narrow-spectrum antibiotics such as penicillin, ampicillin, or amoxicillin.

Michelle Lossius, MD, of the Shands Hospital for Children at the University of Florida, Gainesville, noted that the recommendations reflect IDSA guidelines from 2011 advising the use of ampicillin or penicillin for this population of children. More recent studies with large populations support the ability of narrow-spectrum antibiotics to limit the development of resistant organisms while achieving the same or better outcomes for children hospitalized with CAP, she said.

5. Do not start IV antibiotic therapy on well-appearing newborn infants with isolated risk factors for sepsis such as maternal chorioamnionitis, prolonged rupture of membranes, or untreated group-B streptococcal colonization. Use clinical tools such as an evidence-based sepsis risk calculator to guide management.

“This recommendation combines other recommendations,” said Prabi Rajbhandari, MD, of Akron (Ohio) Children’s Hospital. The evidence is ample, as the Centers for Disease Control and Prevention recommends the use of sepsis calculators to guide clinical management in sepsis patients, she said.

Data comparing periods before and after the adoption of a sepsis risk calculator showed a significant reduction in the use of blood cultures and antibiotics, she noted. Other risks of jumping to IV antibiotics include increased hospital stay, increased parental anxiety, and decreased parental bonding, Dr. Rajbhandari added.

Next steps include how to prioritize implementation, as well as deimplementation of outdated practices, said Francisco Alvarez, MD, of Lucile Packard Children’s Hospital, Palo Alto, Calif. “A lot of our practices were started without good evidence for why they should be done,” he said. Other steps include value improvement research; use of dashboards and benchmarking; involving other stakeholders including patients, families, and other health care providers; and addressing racial disparities, he concluded.

The presenters had no financial conflicts to disclose. The conference was sponsored by the Academic Pediatric Association, the American Academy of Pediatrics, and the Society of Hospital Medicine.

“Health care spending and health care waste is a huge problem in the U.S., including for children,” Vivian Lee, MD, of Children’s Hospital, Los Angeles, said in a presentation at the 2021 virtual Pediatric Hospital Medicine conference.

Data from a 2019 study suggested that approximately 25% of health care spending in the United States qualifies as “wasteful spending,” in categories such as overtesting, and unnecessary hospitalization, Dr. Lee said. “It is essential for physicians in hospitals to be stewards of high-value care,” she emphasized.

To combat wasteful spending and control health care costs, the Choosing Wisely campaign was created in 2012 as an initiative from the American Board of Internal Medicine Foundation. An ongoing goal of the campaign is to raise awareness among physicians and patients about potential areas of low-value services and overuse. The overall campaign includes clinician-driven recommendations from multiple medical organizations.

The PHM produced its first set of five recommendations in 2012, Dr. Lee said. These recommendations, titled “Five Things Physicians and Patients Should Question,” have been updated for 2021. The updated recommendations were created as a partnership among the Academic Pediatric Association, the American Academy of Pediatrics, and the Society of Hospital Medicine. A joint committee reviewed the latest evidence, and the updates were approved by the societies and published by the ABIM in January 2021.

“We think these recommendations truly reflect an exciting and evolving landscape for pediatric hospitalists,” Dr. Lee said. “There is a greater focus on opportunities to transition out of the hospital sooner, or avoid hospitalization altogether. There is an emphasis on antibiotic stewardship and a growing recognition of the impact that overuse may have on our vulnerable neonatal population,” she said. Several members of the Choosing Wisely panel presented the recommendations during the virtual presentation.
 

Revised recommendations

The new “Five Things Physicians and Patients Should Question” are as follows:

1. Do not prescribe IV antibiotics for predetermined durations for patients hospitalized with infections such as pyelonephritis, osteomyelitis, and complicated pneumonia. Consider early transition to oral antibiotics.

Many antibiotic doses used in clinical practice are preset durations that are not based on high-quality evidence, said Mike Tchou, MD, of Children’s Hospital of Colorado in Aurora. However, studies now show that earlier transition to enteral antibiotics can improve a range of outcomes including neonatal UTIs, osteomyelitis, and complicated pneumonia, he said. Considering early transition based on a patient’s response can decrease adverse events, pain, length of stay, and health care costs, he explained.

2. Do not continue hospitalization in well-appearing febrile infants once bacterial cultures (i.e., blood, cerebrospinal, and/or urine) have been confirmed negative for 24-36 hours, if adequate outpatient follow-up can be assured.

Recent data indicate that continuing hospitalization beyond 24-36 hours of confirmed negative bacterial cultures does not improve clinical outcomes for well-appearing infants admitted for concern of serious bacterial infection, said Paula Soung, MD, of Children’s Wisconsin in Milwaukee. In fact, “blood culture yield is highest in the first 12-36 hours after incubation with multiple studies demonstrating > 90% of pathogen cultures being positive by 24 hours,” Dr. Soung said. “If adequate outpatient follow-up can be assured, discharging well-appearing febrile infants at 24-36 hours after confirming cultures are negative has many positive outcomes,” she said.

3. Do not initiate phototherapy in term or late preterm well-appearing infants with neonatal hyperbilirubinemia if their bilirubin is below levels at which the AAP guidelines recommend treatment.

In making this recommendation, “we considered that the risk of kernicterus and cerebral palsy is extremely low in otherwise healthy term and late preterm newborns,” said Allison Holmes, MD, of Children’s Hospital at Dartmouth-Hitchcock, Manchester, N.H. “Subthreshold phototherapy leads to unnecessary hospitalization and its associated costs and harms,” and data show that kernicterus generally occurs close to 40 mg/dL and occurs most often in infants with hemolysis, she added.

The evidence for the recommendations included data showing that, among other factors, 8.6 of 100,000 babies have a bilirubin greater than 30 mg/dL, said Dr. Holmes. Risks of using subthreshold phototherapy include increased length of stay, increased readmissions, and increased costs, as well as decreased breastfeeding, bonding with parents, and increased parental anxiety. “Adding prolonged hospitalization for an intervention that might not be necessary can be stressful for parents,” she said.

4. Do not use broad-spectrum antibiotics such as ceftriaxone for children hospitalized with uncomplicated community-acquired pneumonia. Use narrow-spectrum antibiotics such as penicillin, ampicillin, or amoxicillin.

Michelle Lossius, MD, of the Shands Hospital for Children at the University of Florida, Gainesville, noted that the recommendations reflect IDSA guidelines from 2011 advising the use of ampicillin or penicillin for this population of children. More recent studies with large populations support the ability of narrow-spectrum antibiotics to limit the development of resistant organisms while achieving the same or better outcomes for children hospitalized with CAP, she said.

5. Do not start IV antibiotic therapy on well-appearing newborn infants with isolated risk factors for sepsis such as maternal chorioamnionitis, prolonged rupture of membranes, or untreated group-B streptococcal colonization. Use clinical tools such as an evidence-based sepsis risk calculator to guide management.

“This recommendation combines other recommendations,” said Prabi Rajbhandari, MD, of Akron (Ohio) Children’s Hospital. The evidence is ample, as the Centers for Disease Control and Prevention recommends the use of sepsis calculators to guide clinical management in sepsis patients, she said.

Data comparing periods before and after the adoption of a sepsis risk calculator showed a significant reduction in the use of blood cultures and antibiotics, she noted. Other risks of jumping to IV antibiotics include increased hospital stay, increased parental anxiety, and decreased parental bonding, Dr. Rajbhandari added.

Next steps include how to prioritize implementation, as well as deimplementation of outdated practices, said Francisco Alvarez, MD, of Lucile Packard Children’s Hospital, Palo Alto, Calif. “A lot of our practices were started without good evidence for why they should be done,” he said. Other steps include value improvement research; use of dashboards and benchmarking; involving other stakeholders including patients, families, and other health care providers; and addressing racial disparities, he concluded.

The presenters had no financial conflicts to disclose. The conference was sponsored by the Academic Pediatric Association, the American Academy of Pediatrics, and the Society of Hospital Medicine.

Cases of child COVID-19 set a new 1-week record and the total number of children infected during the pandemic passed 5 million, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

The nearly 282,000 new cases reported in the United States during the week ending Sept. 2 broke the record of 211,000 set in mid-January and brought the cumulative count to 5,049,465 children with COVID-19 since the pandemic began, the AAP and the CHA said in their weekly COVID report.

Hospitalizations in children aged 0-17 years have also reached record levels in recent days. The highest daily admission rate since the pandemic began, 0.51 per 100,000 population, was recorded on Sept. 2, less than 2 months after the nation saw its lowest child COVID admission rate for 1 day: 0.07 per 100,000 on July 4. That’s an increase of 629%, according to data from the Centers for Disease Control and Prevention.

Vaccinations in children, however, did not follow suit. New vaccinations in children aged 12-17 years dropped by 4.5% for the week ending Sept. 6, compared with the week before. Initiations were actually up almost 12% for children aged 16-17, but that was not enough to overcome the continued decline among 12- to 15-year-olds, the CDC said on its COVID Data Tracker.

Despite the decline in new vaccinations, those younger children passed a noteworthy group milestone: 50.9% of all 12- to 15-year-olds now have received at least one dose, with 38.6% having completed the regimen. The 16- to 17-year-olds got an earlier start and have reached 58.9% coverage for one dose and 47.6% for two, the CDC said.

A total of 12.2 million children aged 12-17 years had received at least one dose of COVID vaccine as of Sept. 6, of whom almost 9.5 million are fully vaccinated, based on the CDC data.

At the state level, Vermont has the highest rates for vaccine initiation (75%) and full vaccination (65%), with Massachusetts (75%/62%) and Connecticut (73%/59%) just behind. The other end of the scale is occupied by Wyoming (28% initiation/19% full vaccination), Alabama (32%/19%), and North Dakota (32%/23%), the AAP said in a separate report.

In a recent letter to the Food and Drug Administration, AAP President Lee Savio Beers, MD, said that the “Delta variant is surging at extremely alarming rates in every region of America. This surge is seriously impacting all populations, including children.” Dr. Beers urged the FDA to work “aggressively toward authorizing safe and effective COVID-19 vaccines for children under age 12 as soon as possible.”

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Cases of child COVID-19 set a new 1-week record and the total number of children infected during the pandemic passed 5 million, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

The nearly 282,000 new cases reported in the United States during the week ending Sept. 2 broke the record of 211,000 set in mid-January and brought the cumulative count to 5,049,465 children with COVID-19 since the pandemic began, the AAP and the CHA said in their weekly COVID report.

Hospitalizations in children aged 0-17 years have also reached record levels in recent days. The highest daily admission rate since the pandemic began, 0.51 per 100,000 population, was recorded on Sept. 2, less than 2 months after the nation saw its lowest child COVID admission rate for 1 day: 0.07 per 100,000 on July 4. That’s an increase of 629%, according to data from the Centers for Disease Control and Prevention.

Vaccinations in children, however, did not follow suit. New vaccinations in children aged 12-17 years dropped by 4.5% for the week ending Sept. 6, compared with the week before. Initiations were actually up almost 12% for children aged 16-17, but that was not enough to overcome the continued decline among 12- to 15-year-olds, the CDC said on its COVID Data Tracker.

Despite the decline in new vaccinations, those younger children passed a noteworthy group milestone: 50.9% of all 12- to 15-year-olds now have received at least one dose, with 38.6% having completed the regimen. The 16- to 17-year-olds got an earlier start and have reached 58.9% coverage for one dose and 47.6% for two, the CDC said.

A total of 12.2 million children aged 12-17 years had received at least one dose of COVID vaccine as of Sept. 6, of whom almost 9.5 million are fully vaccinated, based on the CDC data.

At the state level, Vermont has the highest rates for vaccine initiation (75%) and full vaccination (65%), with Massachusetts (75%/62%) and Connecticut (73%/59%) just behind. The other end of the scale is occupied by Wyoming (28% initiation/19% full vaccination), Alabama (32%/19%), and North Dakota (32%/23%), the AAP said in a separate report.

In a recent letter to the Food and Drug Administration, AAP President Lee Savio Beers, MD, said that the “Delta variant is surging at extremely alarming rates in every region of America. This surge is seriously impacting all populations, including children.” Dr. Beers urged the FDA to work “aggressively toward authorizing safe and effective COVID-19 vaccines for children under age 12 as soon as possible.”

[email protected]

Cases of child COVID-19 set a new 1-week record and the total number of children infected during the pandemic passed 5 million, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

The nearly 282,000 new cases reported in the United States during the week ending Sept. 2 broke the record of 211,000 set in mid-January and brought the cumulative count to 5,049,465 children with COVID-19 since the pandemic began, the AAP and the CHA said in their weekly COVID report.

Hospitalizations in children aged 0-17 years have also reached record levels in recent days. The highest daily admission rate since the pandemic began, 0.51 per 100,000 population, was recorded on Sept. 2, less than 2 months after the nation saw its lowest child COVID admission rate for 1 day: 0.07 per 100,000 on July 4. That’s an increase of 629%, according to data from the Centers for Disease Control and Prevention.

Vaccinations in children, however, did not follow suit. New vaccinations in children aged 12-17 years dropped by 4.5% for the week ending Sept. 6, compared with the week before. Initiations were actually up almost 12% for children aged 16-17, but that was not enough to overcome the continued decline among 12- to 15-year-olds, the CDC said on its COVID Data Tracker.

Despite the decline in new vaccinations, those younger children passed a noteworthy group milestone: 50.9% of all 12- to 15-year-olds now have received at least one dose, with 38.6% having completed the regimen. The 16- to 17-year-olds got an earlier start and have reached 58.9% coverage for one dose and 47.6% for two, the CDC said.

A total of 12.2 million children aged 12-17 years had received at least one dose of COVID vaccine as of Sept. 6, of whom almost 9.5 million are fully vaccinated, based on the CDC data.

At the state level, Vermont has the highest rates for vaccine initiation (75%) and full vaccination (65%), with Massachusetts (75%/62%) and Connecticut (73%/59%) just behind. The other end of the scale is occupied by Wyoming (28% initiation/19% full vaccination), Alabama (32%/19%), and North Dakota (32%/23%), the AAP said in a separate report.

In a recent letter to the Food and Drug Administration, AAP President Lee Savio Beers, MD, said that the “Delta variant is surging at extremely alarming rates in every region of America. This surge is seriously impacting all populations, including children.” Dr. Beers urged the FDA to work “aggressively toward authorizing safe and effective COVID-19 vaccines for children under age 12 as soon as possible.”

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Autoeczematization (AE), or id reaction, is a disseminated eczematous reaction that occurs days or weeks after exposure to a primary stimulus, resulting from a release of antigen(s). Whitfield¹ first described AE in 1921, when he postulated that the id reaction was due to sensitization of the skin after a primary stimulus. He called it “a form of auto-intoxication derived from changes in the patient’s own tissues.”¹ The exact prevalence of id reactions is unknown; one study showed that 17% of patients with dermatophyte infections developed an id reaction, typically tinea pedis linked with vesicles on the palms.² Tinea capitis is one of the most common causes of AE in children, which is frequently misdiagnosed as a drug reaction. Approximately 37% of patients diagnosed with stasis dermatitis develop an id reaction (Figure 1). A history of contact dermatitis is common in patients presenting with AE.^2-6

Pathophysiology of Id Reactions

An abnormal immune response against autologous skin antigens may be responsible for the development of AE. Shelley⁵ postulated that hair follicles play an important role in id reactions, as Sharquie et al⁶ recently emphasized for many skin disorders. The pathogenesis of AE is uncertain, but circulating T lymphocytes play a role in this reaction. Normally, T cells are activated by a release of antigens after a primary exposure to a stimulus. However, overactivation of these T cells induces autoimmune reactions such as AE.⁷ Activated T lymphocytes express HLA-DR and IL-2 receptor, markers elevated in the peripheral blood of patients undergoing id reactions. After treatment, the levels of activated T lymphocytes decline. An increase in the number of CD25⁺ T cells and a decrease in the number of suppressor T cells in the blood may occur during an id reaction.^7-9 Keratinocytes produce proinflammatory cytokines, such as thymic stromal erythropoietin, IL-25, and IL-33, that activate T cells.^10-12 Therefore, the most likely pathogenesis of an id reaction is that T lymphocytes are activated at the primary reaction site due to proinflammatory cytokines released by keratinocytes. These activated T cells then travel systemically via hematogenous dissemination. The spread of activated T lymphocytes produces an eczematous reaction at secondary locations distant to the primary site.⁹

Clinical and Histopathological Features of Id Reactions

Clinically, AE is first evident as a vesicular dissemination that groups to form papules or nummular patches and usually is present on the legs, feet, arms, and/or trunk (Figure 2). The primary dermatitis is localized to the area that was the site of contact to the offending stimuli. This localized eczematous eruption begins with an acute or subacute onset. It has the appearance of small crusted vesicles with erythema (Figure 1). The first sign of AE is vesicles presenting near the primary site on flexural surfaces or on the hands and feet. A classic example is tinea pedis linked with vesicles on the palms and sides of the fingers, resembling dyshidrotic eczema. Sites of prior cutaneous trauma, such as dermatoses, scars, and burns, are common locations for early AE. In later stages, vesicles disseminate to the legs, arms, and trunk, where they group to form papules and nummular patches in a symmetrical pattern.^5,13-15 These lesions may be extremely pruritic. The pruritus may be so intense that it interrupts daily activities and disrupts the ability to fall or stay asleep.¹⁶

Histologically, biopsy specimens show psoriasiform spongiotic dermatitis with mononuclear cells contained in the vesicles. Interstitial edema and perivascular lymphohistiocytic infiltrates are evident. Eosinophils also may be present. This pattern is not unique toid reactions.^17-19 Although AE is a reaction pattern that may be due to a fungal or bacterial infection, the etiologic agent is not evident microscopically within the eczema itself.

Etiology of Id Reactions

Id reactions most commonly occur from either stasis dermatitis or tinea pedis, although a wide variety of other causes should be considered. Evaluation of the primary site rather than the id reaction may identify an infectious or parasitic agent. Sometimes the AE reaction is specifically named: dermatophytid with dermatophytosis, bacterid with a bacterial infectious process, and tuberculid with tuberculosis. Similarly, there may be reactions to underlying candidiasis, sporotrichosis, histoplasmosis, and other fungal infections that can cause a cutaneous id reaction.^18,20-22Mycobacterium species, Pseudomonas, Staphylococcus, and Streptococcus are bacterial causes of AE.^15,23-26 Viral infections that can cause an id reaction are herpes simplex virus and molluscum contagiosum.^27-29 Scabies, leishmaniasis, and pediculosis capitis are parasitic infections that may be etiologic.^14,30,31 In addition, noninfectious stimuli besides stasis dermatitis that can produce id reactions include medications, topical creams, tattoo ink, sutures, radiotherapy, and dyshidrotic eczema. The primary reaction to these agents is a localized dermatitis followed by the immunological response that induces a secondary reaction distant from the primary site.^17,18,32-38

Differential Diagnoses

Differential diagnoses include other types of eczema and some vesicular eruptions. Irritant contact dermatitis is another dermatosis that presents as a widespread vesicular eruption due to repetitive exposure to toxic irritants. The rash is erythematous with pustules, blisters, and crusts. It is only found in areas directly exposed to irritants, as opposed to AE, which spreads to areas distant to the primary reaction site. Irritant contact dermatitis presents with more of a burning sensation, whereas AE is more pruritic.^39,40 Allergic contact dermatitis presents with erythematous vesicles and papules and sometimes with bullae. There is edema and crust formation, which often can spread past the point of contact in later stages. Similar to AE, there is intense pruritus. However, allergic contact dermatitis most commonly is caused by exposure to metals, cosmetics, and fragrances, whereas infectious agents and stasis dermatitis are the most common causes of AE.^40,41 It may be challenging to distinguish AE from other causes of widespread eczematous dissemination. Vesicular eruptions sometimes require distinction from AE, including herpetic infections, insect bite reactions, and drug eruptions.^18,42

Treatment

The underlying condition should be treated to mitigate the inflammatory response causing the id reaction. If not skillfully orchestrated, the id reaction can reoccur. For infectious causes of AE, an antifungal, antibacterial, antiviral, or antiparasitic should be given. If stasis dermatitis is responsible for the id reaction, compression stockings and leg elevation are indicated. The id reaction itself is treated with systemic or topical corticosteroids and wet compresses if acute. The goal of these treatments is to reduce patient discomfort caused by the inflammation and pruritus.^18,43

Conclusion

Id reactions are an unusual phenomenon that commonly occurs after fungal skin infections and stasis dermatitis. T lymphocytes and keratinocytes may play a key role in this reaction, with newer research further delineating the process and possibly providing enhanced treatment options. Therapy focuses on treating the underlying condition, supplemented with corticosteroids for the autoeczema.

Autoeczematization (AE), or id reaction, is a disseminated eczematous reaction that occurs days or weeks after exposure to a primary stimulus, resulting from a release of antigen(s). Whitfield¹ first described AE in 1921, when he postulated that the id reaction was due to sensitization of the skin after a primary stimulus. He called it “a form of auto-intoxication derived from changes in the patient’s own tissues.”¹ The exact prevalence of id reactions is unknown; one study showed that 17% of patients with dermatophyte infections developed an id reaction, typically tinea pedis linked with vesicles on the palms.² Tinea capitis is one of the most common causes of AE in children, which is frequently misdiagnosed as a drug reaction. Approximately 37% of patients diagnosed with stasis dermatitis develop an id reaction (Figure 1). A history of contact dermatitis is common in patients presenting with AE.^2-6

Pathophysiology of Id Reactions

An abnormal immune response against autologous skin antigens may be responsible for the development of AE. Shelley⁵ postulated that hair follicles play an important role in id reactions, as Sharquie et al⁶ recently emphasized for many skin disorders. The pathogenesis of AE is uncertain, but circulating T lymphocytes play a role in this reaction. Normally, T cells are activated by a release of antigens after a primary exposure to a stimulus. However, overactivation of these T cells induces autoimmune reactions such as AE.⁷ Activated T lymphocytes express HLA-DR and IL-2 receptor, markers elevated in the peripheral blood of patients undergoing id reactions. After treatment, the levels of activated T lymphocytes decline. An increase in the number of CD25⁺ T cells and a decrease in the number of suppressor T cells in the blood may occur during an id reaction.^7-9 Keratinocytes produce proinflammatory cytokines, such as thymic stromal erythropoietin, IL-25, and IL-33, that activate T cells.^10-12 Therefore, the most likely pathogenesis of an id reaction is that T lymphocytes are activated at the primary reaction site due to proinflammatory cytokines released by keratinocytes. These activated T cells then travel systemically via hematogenous dissemination. The spread of activated T lymphocytes produces an eczematous reaction at secondary locations distant to the primary site.⁹

Clinical and Histopathological Features of Id Reactions

Clinically, AE is first evident as a vesicular dissemination that groups to form papules or nummular patches and usually is present on the legs, feet, arms, and/or trunk (Figure 2). The primary dermatitis is localized to the area that was the site of contact to the offending stimuli. This localized eczematous eruption begins with an acute or subacute onset. It has the appearance of small crusted vesicles with erythema (Figure 1). The first sign of AE is vesicles presenting near the primary site on flexural surfaces or on the hands and feet. A classic example is tinea pedis linked with vesicles on the palms and sides of the fingers, resembling dyshidrotic eczema. Sites of prior cutaneous trauma, such as dermatoses, scars, and burns, are common locations for early AE. In later stages, vesicles disseminate to the legs, arms, and trunk, where they group to form papules and nummular patches in a symmetrical pattern.^5,13-15 These lesions may be extremely pruritic. The pruritus may be so intense that it interrupts daily activities and disrupts the ability to fall or stay asleep.¹⁶

Histologically, biopsy specimens show psoriasiform spongiotic dermatitis with mononuclear cells contained in the vesicles. Interstitial edema and perivascular lymphohistiocytic infiltrates are evident. Eosinophils also may be present. This pattern is not unique toid reactions.^17-19 Although AE is a reaction pattern that may be due to a fungal or bacterial infection, the etiologic agent is not evident microscopically within the eczema itself.

Etiology of Id Reactions

Id reactions most commonly occur from either stasis dermatitis or tinea pedis, although a wide variety of other causes should be considered. Evaluation of the primary site rather than the id reaction may identify an infectious or parasitic agent. Sometimes the AE reaction is specifically named: dermatophytid with dermatophytosis, bacterid with a bacterial infectious process, and tuberculid with tuberculosis. Similarly, there may be reactions to underlying candidiasis, sporotrichosis, histoplasmosis, and other fungal infections that can cause a cutaneous id reaction.^18,20-22Mycobacterium species, Pseudomonas, Staphylococcus, and Streptococcus are bacterial causes of AE.^15,23-26 Viral infections that can cause an id reaction are herpes simplex virus and molluscum contagiosum.^27-29 Scabies, leishmaniasis, and pediculosis capitis are parasitic infections that may be etiologic.^14,30,31 In addition, noninfectious stimuli besides stasis dermatitis that can produce id reactions include medications, topical creams, tattoo ink, sutures, radiotherapy, and dyshidrotic eczema. The primary reaction to these agents is a localized dermatitis followed by the immunological response that induces a secondary reaction distant from the primary site.^17,18,32-38

Differential Diagnoses

Differential diagnoses include other types of eczema and some vesicular eruptions. Irritant contact dermatitis is another dermatosis that presents as a widespread vesicular eruption due to repetitive exposure to toxic irritants. The rash is erythematous with pustules, blisters, and crusts. It is only found in areas directly exposed to irritants, as opposed to AE, which spreads to areas distant to the primary reaction site. Irritant contact dermatitis presents with more of a burning sensation, whereas AE is more pruritic.^39,40 Allergic contact dermatitis presents with erythematous vesicles and papules and sometimes with bullae. There is edema and crust formation, which often can spread past the point of contact in later stages. Similar to AE, there is intense pruritus. However, allergic contact dermatitis most commonly is caused by exposure to metals, cosmetics, and fragrances, whereas infectious agents and stasis dermatitis are the most common causes of AE.^40,41 It may be challenging to distinguish AE from other causes of widespread eczematous dissemination. Vesicular eruptions sometimes require distinction from AE, including herpetic infections, insect bite reactions, and drug eruptions.^18,42

Treatment

The underlying condition should be treated to mitigate the inflammatory response causing the id reaction. If not skillfully orchestrated, the id reaction can reoccur. For infectious causes of AE, an antifungal, antibacterial, antiviral, or antiparasitic should be given. If stasis dermatitis is responsible for the id reaction, compression stockings and leg elevation are indicated. The id reaction itself is treated with systemic or topical corticosteroids and wet compresses if acute. The goal of these treatments is to reduce patient discomfort caused by the inflammation and pruritus.^18,43

Conclusion

Id reactions are an unusual phenomenon that commonly occurs after fungal skin infections and stasis dermatitis. T lymphocytes and keratinocytes may play a key role in this reaction, with newer research further delineating the process and possibly providing enhanced treatment options. Therapy focuses on treating the underlying condition, supplemented with corticosteroids for the autoeczema.

Autoeczematization (AE), or id reaction, is a disseminated eczematous reaction that occurs days or weeks after exposure to a primary stimulus, resulting from a release of antigen(s). Whitfield¹ first described AE in 1921, when he postulated that the id reaction was due to sensitization of the skin after a primary stimulus. He called it “a form of auto-intoxication derived from changes in the patient’s own tissues.”¹ The exact prevalence of id reactions is unknown; one study showed that 17% of patients with dermatophyte infections developed an id reaction, typically tinea pedis linked with vesicles on the palms.² Tinea capitis is one of the most common causes of AE in children, which is frequently misdiagnosed as a drug reaction. Approximately 37% of patients diagnosed with stasis dermatitis develop an id reaction (Figure 1). A history of contact dermatitis is common in patients presenting with AE.^2-6

Pathophysiology of Id Reactions

An abnormal immune response against autologous skin antigens may be responsible for the development of AE. Shelley⁵ postulated that hair follicles play an important role in id reactions, as Sharquie et al⁶ recently emphasized for many skin disorders. The pathogenesis of AE is uncertain, but circulating T lymphocytes play a role in this reaction. Normally, T cells are activated by a release of antigens after a primary exposure to a stimulus. However, overactivation of these T cells induces autoimmune reactions such as AE.⁷ Activated T lymphocytes express HLA-DR and IL-2 receptor, markers elevated in the peripheral blood of patients undergoing id reactions. After treatment, the levels of activated T lymphocytes decline. An increase in the number of CD25⁺ T cells and a decrease in the number of suppressor T cells in the blood may occur during an id reaction.^7-9 Keratinocytes produce proinflammatory cytokines, such as thymic stromal erythropoietin, IL-25, and IL-33, that activate T cells.^10-12 Therefore, the most likely pathogenesis of an id reaction is that T lymphocytes are activated at the primary reaction site due to proinflammatory cytokines released by keratinocytes. These activated T cells then travel systemically via hematogenous dissemination. The spread of activated T lymphocytes produces an eczematous reaction at secondary locations distant to the primary site.⁹

Clinical and Histopathological Features of Id Reactions

Clinically, AE is first evident as a vesicular dissemination that groups to form papules or nummular patches and usually is present on the legs, feet, arms, and/or trunk (Figure 2). The primary dermatitis is localized to the area that was the site of contact to the offending stimuli. This localized eczematous eruption begins with an acute or subacute onset. It has the appearance of small crusted vesicles with erythema (Figure 1). The first sign of AE is vesicles presenting near the primary site on flexural surfaces or on the hands and feet. A classic example is tinea pedis linked with vesicles on the palms and sides of the fingers, resembling dyshidrotic eczema. Sites of prior cutaneous trauma, such as dermatoses, scars, and burns, are common locations for early AE. In later stages, vesicles disseminate to the legs, arms, and trunk, where they group to form papules and nummular patches in a symmetrical pattern.^5,13-15 These lesions may be extremely pruritic. The pruritus may be so intense that it interrupts daily activities and disrupts the ability to fall or stay asleep.¹⁶

Histologically, biopsy specimens show psoriasiform spongiotic dermatitis with mononuclear cells contained in the vesicles. Interstitial edema and perivascular lymphohistiocytic infiltrates are evident. Eosinophils also may be present. This pattern is not unique toid reactions.^17-19 Although AE is a reaction pattern that may be due to a fungal or bacterial infection, the etiologic agent is not evident microscopically within the eczema itself.

Etiology of Id Reactions

Id reactions most commonly occur from either stasis dermatitis or tinea pedis, although a wide variety of other causes should be considered. Evaluation of the primary site rather than the id reaction may identify an infectious or parasitic agent. Sometimes the AE reaction is specifically named: dermatophytid with dermatophytosis, bacterid with a bacterial infectious process, and tuberculid with tuberculosis. Similarly, there may be reactions to underlying candidiasis, sporotrichosis, histoplasmosis, and other fungal infections that can cause a cutaneous id reaction.^18,20-22Mycobacterium species, Pseudomonas, Staphylococcus, and Streptococcus are bacterial causes of AE.^15,23-26 Viral infections that can cause an id reaction are herpes simplex virus and molluscum contagiosum.^27-29 Scabies, leishmaniasis, and pediculosis capitis are parasitic infections that may be etiologic.^14,30,31 In addition, noninfectious stimuli besides stasis dermatitis that can produce id reactions include medications, topical creams, tattoo ink, sutures, radiotherapy, and dyshidrotic eczema. The primary reaction to these agents is a localized dermatitis followed by the immunological response that induces a secondary reaction distant from the primary site.^17,18,32-38

Differential Diagnoses

Differential diagnoses include other types of eczema and some vesicular eruptions. Irritant contact dermatitis is another dermatosis that presents as a widespread vesicular eruption due to repetitive exposure to toxic irritants. The rash is erythematous with pustules, blisters, and crusts. It is only found in areas directly exposed to irritants, as opposed to AE, which spreads to areas distant to the primary reaction site. Irritant contact dermatitis presents with more of a burning sensation, whereas AE is more pruritic.^39,40 Allergic contact dermatitis presents with erythematous vesicles and papules and sometimes with bullae. There is edema and crust formation, which often can spread past the point of contact in later stages. Similar to AE, there is intense pruritus. However, allergic contact dermatitis most commonly is caused by exposure to metals, cosmetics, and fragrances, whereas infectious agents and stasis dermatitis are the most common causes of AE.^40,41 It may be challenging to distinguish AE from other causes of widespread eczematous dissemination. Vesicular eruptions sometimes require distinction from AE, including herpetic infections, insect bite reactions, and drug eruptions.^18,42

Treatment

The underlying condition should be treated to mitigate the inflammatory response causing the id reaction. If not skillfully orchestrated, the id reaction can reoccur. For infectious causes of AE, an antifungal, antibacterial, antiviral, or antiparasitic should be given. If stasis dermatitis is responsible for the id reaction, compression stockings and leg elevation are indicated. The id reaction itself is treated with systemic or topical corticosteroids and wet compresses if acute. The goal of these treatments is to reduce patient discomfort caused by the inflammation and pruritus.^18,43

Conclusion

Id reactions are an unusual phenomenon that commonly occurs after fungal skin infections and stasis dermatitis. T lymphocytes and keratinocytes may play a key role in this reaction, with newer research further delineating the process and possibly providing enhanced treatment options. Therapy focuses on treating the underlying condition, supplemented with corticosteroids for the autoeczema.

Hospitalized COVID-19 patients at increased risk for respiratory failure showed significant improvement after treatment with anakinra, compared with placebo, based on data from a phase 3, randomized trial of nearly 600 patients who also received standard of care treatment.

Anakinra, a recombinant interleukin (IL)-1 receptor antagonist that blocks activity for both IL-1 alpha and beta, showed a 70% decrease in the risk of progression to severe respiratory failure in a prior open-label, phase 2, proof-of-concept study, wrote Evdoxia Kyriazopoulou, MD, PhD, of National and Kapodistrian University of Athens, and colleagues.

Previous research has shown that soluble urokinase plasminogen activator receptor (suPAR) serum levels can signal increased risk of progression to severe disease and respiratory failure in COVID-19 patients, they noted.

Supported by these early findings, “the SAVE-MORE study (suPAR-guided anakinra treatment for validation of the risk and early management of severe respiratory failure by COVID-19) is a pivotal, confirmatory, phase 3, double-blind, randomized controlled trial that evaluated the efficacy and safety of early initiation of anakinra treatment in hospitalized patients with moderate or severe COVID-19,” the researchers said.

In the SAVE-MORE study published Sept. 3 in Nature Medicine, the researchers identified 594 adults with COVID-19 who were hospitalized at 37 centers in Greece and Italy and at risk of progressing to respiratory failure based on plasma suPAR levels of at least 6 ng/mL.

The primary objective was to assess the impact of early anakinra treatment on the clinical status of COVID-19 patients at risk for severe disease according to the 11-point, ordinal World Health Organization Clinical Progression Scale (WHO-CPS) at 28 days after starting treatment. All patients received standard of care, which consisted of regular monitoring of physical signs, oximetry, and anticoagulation. Patients with severe disease by the WHO definition were also received 6 mg of dexamethasone intravenously daily for 10 days. A total of 405 were randomized to anakinra and 189 to placebo. Approximately 92% of the study participants had severe pneumonia according to the WHO classification for COVID-19. The average age of the patients was 62 years, 58% were male, and the average body mass index was 29.5 kg/m².

At 28 days, 204 (50.4%) of the anakinra-treated patients had fully recovered, with no detectable viral RNA, compared with 50 (26.5%) of the placebo-treated patients (P < .0001). In addition, significantly fewer patients in the anakinra group had died by 28 days (13 patients, 3.2%), compared with patients in the placebo group (13 patients, 6.9%).

The median decrease in WHO-CPS scores from baseline to 28 days was 4 points in the anakinra group and 3 points in the placebo group, a statistically significant difference (P < .0001).

“Overall, the unadjusted proportional odds of having a worse score on the 11-point WHO-CPS at day 28 with anakinra was 0.36 versus placebo,” and this number remained the same in adjusted analysis, the researchers wrote.

All five secondary endpoints on the WHO-CPS showed significant benefits of anakinra, compared with placebo. These included an absolute decrease of WHO-CPS at day 28 and day 14 from baseline; an absolute decrease of Sequential Organ Failure Assessment scores at day 7 from baseline; and a significantly shorter mean time to both hospital and ICU discharge (1 day and 4 days, respectively) with anakinra versus placebo.

Follow-up laboratory data showed a significant increase in absolute lymphocyte count at 7 days, a significant decrease in circulating IL-6 levels at 4 and 7 days, and significantly decreased plasma C-reactive protein (CRP) levels at 7 days.

Serious treatment-emergent adverse events were reported in 16% with anakinra and in 21.7% with placebo; the most common of these events were infections (8.4% with anakinra and 15.9% with placebo). The next most common serious treatment-emergent adverse events were ventilator-associated pneumonia, septic shock and multiple organ dysfunction, bloodstream infections, and pulmonary embolism. The most common nonserious treatment-emergent adverse events were an increase of liver function tests and hyperglycemia (similar in anakinra and placebo groups) and nonserious anemia (lower in the anakinra group).

The study findings were limited by several factors, including the lack of patients with critical COVID-19 disease and the challenge of application of suPAR in all hospital settings, the researchers noted. However, “the results validate the findings of the previous SAVE open-label phase 2 trial,” they said. The results suggest “that suPAR should be measured upon admission of all patients with COVID-19 who do not need oxygen or who need nasal or mask oxygen, and that, if suPAR levels are 6 ng/mL or higher, anakinra treatment might be a suitable therapy,” they concluded.
 

Cytokine storm syndrome remains a treatment challenge

“Many who die from COVID-19 suffer hyperinflammation with features of cytokine storm syndrome (CSS) and associated acute respiratory distress syndrome,” wrote Randy Q. Cron, MD, and W. Winn Chatham, MD, of the University of Alabama at Birmingham, and Roberto Caricchio, MD, of Temple University, Philadelphia, in an accompanying editorial. They noted that the SAVE-MORE trial results contrast with another recent randomized trial of canakinumab, which failed to show notable benefits, compared with placebo, in treating hospitalized patients with COVID-19 pneumonia.

“There are some key differences between these trials, one being that anakinra blocks signaling of both IL-1 alpha and IL-1 beta, whereas canakinumab binds only IL-1 beta,” the editorialists explained. “SARS-CoV-2–infected endothelium may be a particularly important source of IL-1 alpha that is not targeted by canakinumab,” they noted.

Additional studies have examined IL-6 inhibition to treat COVID-19 patients, but data have been inconsistent, the editorialists said.

“One thing that is clearly emerging from this pandemic is that the CSS associated with COVID-19 is relatively unique, with only modestly elevated levels of IL-6, CRP, and ferritin, for example,” they noted. However, the SAVE-MORE study suggests that more targeted approaches, such as anakinra, “may allow earlier introduction of anticytokine treatment” and support the use of IL-1 blockade with anakinra for cases of severe COVID-19 pneumonia.
 

Predicting risk for severe disease

“One of the major challenges in the management of patients with COVID-19 is identifying patients at risk of severe disease who would warrant early intervention with anti-inflammatory therapy,” said Salim Hayek, MD, medical director of the University of Michigan’s Frankel Cardiovascular Center Clinics, in an interview. “We and others had found that soluble urokinase plasminogen activator receptor (suPAR) levels are the strongest predictor of severe disease amongst biomarkers of inflammation,” he said. “In this study, patients with high suPAR levels derived benefit from anakinra, compared to those with placebo. This study is a great example of how suPAR levels could be used to identify high-risk patients that would benefit from therapies targeting inflammation,” Dr. Hayek emphasized.

“The findings are in line with the hypothesis that patients with the highest degrees of inflammation would benefit the best from targeting the hyperinflammatory cascade using anakinra or other interleukin antagonists,” Dr. Hayek said. “Given suPAR levels are the best predictors of high-risk disease, it is not surprising to see that patients with high levels benefit from targeting inflammation,” he noted.

The take-home message for clinicians at this time is that anakinra effectively improves outcomes in COVID-19 patients with high suPAR levels, Dr. Hayek said. “SuPAR can be measured easily at the point of care. Thus, a targeted strategy using suPAR to identify patients who would benefit from anakinra appears to be viable,” he explained.

However, “Whether anakinra is effective in patients with lower suPAR levels (<6 ng/mL) is unclear and was not answered by this study,” he said. “We eagerly await results of other trials to make that determination. Whether suPAR levels can also help guide the use of other therapies for COVID-19 should be explored and would enhance the personalization of treatment for COVID-19 according to the underlying inflammatory state,” he added.

The SAVE-MORE study was funded by the Hellenic Institute for the Study of Sepsis and Sobi, which manufactures anakinra. Some of the study authors reported financial relationships with Sobi and other pharmaceutical companies.

Dr. Cron disclosed serving as a consultant to Sobi, Novartis, Pfizer, and Sironax. Dr. Cron and Dr. Chatham disclosed having received grant support from Sobi for investigator-initiated clinical trials, and Dr. Caricchio disclosed serving as a consultant to GlaxoSmithKline, Johnson & Johnson, Aurinia, and Bristol-Myers Squibb. Dr. Hayek had no relevant financial conflicts to disclose.

Hospitalized COVID-19 patients at increased risk for respiratory failure showed significant improvement after treatment with anakinra, compared with placebo, based on data from a phase 3, randomized trial of nearly 600 patients who also received standard of care treatment.

Anakinra, a recombinant interleukin (IL)-1 receptor antagonist that blocks activity for both IL-1 alpha and beta, showed a 70% decrease in the risk of progression to severe respiratory failure in a prior open-label, phase 2, proof-of-concept study, wrote Evdoxia Kyriazopoulou, MD, PhD, of National and Kapodistrian University of Athens, and colleagues.

Previous research has shown that soluble urokinase plasminogen activator receptor (suPAR) serum levels can signal increased risk of progression to severe disease and respiratory failure in COVID-19 patients, they noted.

Supported by these early findings, “the SAVE-MORE study (suPAR-guided anakinra treatment for validation of the risk and early management of severe respiratory failure by COVID-19) is a pivotal, confirmatory, phase 3, double-blind, randomized controlled trial that evaluated the efficacy and safety of early initiation of anakinra treatment in hospitalized patients with moderate or severe COVID-19,” the researchers said.

In the SAVE-MORE study published Sept. 3 in Nature Medicine, the researchers identified 594 adults with COVID-19 who were hospitalized at 37 centers in Greece and Italy and at risk of progressing to respiratory failure based on plasma suPAR levels of at least 6 ng/mL.

The primary objective was to assess the impact of early anakinra treatment on the clinical status of COVID-19 patients at risk for severe disease according to the 11-point, ordinal World Health Organization Clinical Progression Scale (WHO-CPS) at 28 days after starting treatment. All patients received standard of care, which consisted of regular monitoring of physical signs, oximetry, and anticoagulation. Patients with severe disease by the WHO definition were also received 6 mg of dexamethasone intravenously daily for 10 days. A total of 405 were randomized to anakinra and 189 to placebo. Approximately 92% of the study participants had severe pneumonia according to the WHO classification for COVID-19. The average age of the patients was 62 years, 58% were male, and the average body mass index was 29.5 kg/m².

At 28 days, 204 (50.4%) of the anakinra-treated patients had fully recovered, with no detectable viral RNA, compared with 50 (26.5%) of the placebo-treated patients (P < .0001). In addition, significantly fewer patients in the anakinra group had died by 28 days (13 patients, 3.2%), compared with patients in the placebo group (13 patients, 6.9%).

The median decrease in WHO-CPS scores from baseline to 28 days was 4 points in the anakinra group and 3 points in the placebo group, a statistically significant difference (P < .0001).

“Overall, the unadjusted proportional odds of having a worse score on the 11-point WHO-CPS at day 28 with anakinra was 0.36 versus placebo,” and this number remained the same in adjusted analysis, the researchers wrote.

All five secondary endpoints on the WHO-CPS showed significant benefits of anakinra, compared with placebo. These included an absolute decrease of WHO-CPS at day 28 and day 14 from baseline; an absolute decrease of Sequential Organ Failure Assessment scores at day 7 from baseline; and a significantly shorter mean time to both hospital and ICU discharge (1 day and 4 days, respectively) with anakinra versus placebo.

Follow-up laboratory data showed a significant increase in absolute lymphocyte count at 7 days, a significant decrease in circulating IL-6 levels at 4 and 7 days, and significantly decreased plasma C-reactive protein (CRP) levels at 7 days.

Serious treatment-emergent adverse events were reported in 16% with anakinra and in 21.7% with placebo; the most common of these events were infections (8.4% with anakinra and 15.9% with placebo). The next most common serious treatment-emergent adverse events were ventilator-associated pneumonia, septic shock and multiple organ dysfunction, bloodstream infections, and pulmonary embolism. The most common nonserious treatment-emergent adverse events were an increase of liver function tests and hyperglycemia (similar in anakinra and placebo groups) and nonserious anemia (lower in the anakinra group).

The study findings were limited by several factors, including the lack of patients with critical COVID-19 disease and the challenge of application of suPAR in all hospital settings, the researchers noted. However, “the results validate the findings of the previous SAVE open-label phase 2 trial,” they said. The results suggest “that suPAR should be measured upon admission of all patients with COVID-19 who do not need oxygen or who need nasal or mask oxygen, and that, if suPAR levels are 6 ng/mL or higher, anakinra treatment might be a suitable therapy,” they concluded.
 

Cytokine storm syndrome remains a treatment challenge

“Many who die from COVID-19 suffer hyperinflammation with features of cytokine storm syndrome (CSS) and associated acute respiratory distress syndrome,” wrote Randy Q. Cron, MD, and W. Winn Chatham, MD, of the University of Alabama at Birmingham, and Roberto Caricchio, MD, of Temple University, Philadelphia, in an accompanying editorial. They noted that the SAVE-MORE trial results contrast with another recent randomized trial of canakinumab, which failed to show notable benefits, compared with placebo, in treating hospitalized patients with COVID-19 pneumonia.

“There are some key differences between these trials, one being that anakinra blocks signaling of both IL-1 alpha and IL-1 beta, whereas canakinumab binds only IL-1 beta,” the editorialists explained. “SARS-CoV-2–infected endothelium may be a particularly important source of IL-1 alpha that is not targeted by canakinumab,” they noted.

Additional studies have examined IL-6 inhibition to treat COVID-19 patients, but data have been inconsistent, the editorialists said.

“One thing that is clearly emerging from this pandemic is that the CSS associated with COVID-19 is relatively unique, with only modestly elevated levels of IL-6, CRP, and ferritin, for example,” they noted. However, the SAVE-MORE study suggests that more targeted approaches, such as anakinra, “may allow earlier introduction of anticytokine treatment” and support the use of IL-1 blockade with anakinra for cases of severe COVID-19 pneumonia.
 

Predicting risk for severe disease

“One of the major challenges in the management of patients with COVID-19 is identifying patients at risk of severe disease who would warrant early intervention with anti-inflammatory therapy,” said Salim Hayek, MD, medical director of the University of Michigan’s Frankel Cardiovascular Center Clinics, in an interview. “We and others had found that soluble urokinase plasminogen activator receptor (suPAR) levels are the strongest predictor of severe disease amongst biomarkers of inflammation,” he said. “In this study, patients with high suPAR levels derived benefit from anakinra, compared to those with placebo. This study is a great example of how suPAR levels could be used to identify high-risk patients that would benefit from therapies targeting inflammation,” Dr. Hayek emphasized.

“The findings are in line with the hypothesis that patients with the highest degrees of inflammation would benefit the best from targeting the hyperinflammatory cascade using anakinra or other interleukin antagonists,” Dr. Hayek said. “Given suPAR levels are the best predictors of high-risk disease, it is not surprising to see that patients with high levels benefit from targeting inflammation,” he noted.

The take-home message for clinicians at this time is that anakinra effectively improves outcomes in COVID-19 patients with high suPAR levels, Dr. Hayek said. “SuPAR can be measured easily at the point of care. Thus, a targeted strategy using suPAR to identify patients who would benefit from anakinra appears to be viable,” he explained.

However, “Whether anakinra is effective in patients with lower suPAR levels (<6 ng/mL) is unclear and was not answered by this study,” he said. “We eagerly await results of other trials to make that determination. Whether suPAR levels can also help guide the use of other therapies for COVID-19 should be explored and would enhance the personalization of treatment for COVID-19 according to the underlying inflammatory state,” he added.

The SAVE-MORE study was funded by the Hellenic Institute for the Study of Sepsis and Sobi, which manufactures anakinra. Some of the study authors reported financial relationships with Sobi and other pharmaceutical companies.

Dr. Cron disclosed serving as a consultant to Sobi, Novartis, Pfizer, and Sironax. Dr. Cron and Dr. Chatham disclosed having received grant support from Sobi for investigator-initiated clinical trials, and Dr. Caricchio disclosed serving as a consultant to GlaxoSmithKline, Johnson & Johnson, Aurinia, and Bristol-Myers Squibb. Dr. Hayek had no relevant financial conflicts to disclose.

Hospitalized COVID-19 patients at increased risk for respiratory failure showed significant improvement after treatment with anakinra, compared with placebo, based on data from a phase 3, randomized trial of nearly 600 patients who also received standard of care treatment.

Anakinra, a recombinant interleukin (IL)-1 receptor antagonist that blocks activity for both IL-1 alpha and beta, showed a 70% decrease in the risk of progression to severe respiratory failure in a prior open-label, phase 2, proof-of-concept study, wrote Evdoxia Kyriazopoulou, MD, PhD, of National and Kapodistrian University of Athens, and colleagues.

Previous research has shown that soluble urokinase plasminogen activator receptor (suPAR) serum levels can signal increased risk of progression to severe disease and respiratory failure in COVID-19 patients, they noted.

Supported by these early findings, “the SAVE-MORE study (suPAR-guided anakinra treatment for validation of the risk and early management of severe respiratory failure by COVID-19) is a pivotal, confirmatory, phase 3, double-blind, randomized controlled trial that evaluated the efficacy and safety of early initiation of anakinra treatment in hospitalized patients with moderate or severe COVID-19,” the researchers said.

In the SAVE-MORE study published Sept. 3 in Nature Medicine, the researchers identified 594 adults with COVID-19 who were hospitalized at 37 centers in Greece and Italy and at risk of progressing to respiratory failure based on plasma suPAR levels of at least 6 ng/mL.

The primary objective was to assess the impact of early anakinra treatment on the clinical status of COVID-19 patients at risk for severe disease according to the 11-point, ordinal World Health Organization Clinical Progression Scale (WHO-CPS) at 28 days after starting treatment. All patients received standard of care, which consisted of regular monitoring of physical signs, oximetry, and anticoagulation. Patients with severe disease by the WHO definition were also received 6 mg of dexamethasone intravenously daily for 10 days. A total of 405 were randomized to anakinra and 189 to placebo. Approximately 92% of the study participants had severe pneumonia according to the WHO classification for COVID-19. The average age of the patients was 62 years, 58% were male, and the average body mass index was 29.5 kg/m².

At 28 days, 204 (50.4%) of the anakinra-treated patients had fully recovered, with no detectable viral RNA, compared with 50 (26.5%) of the placebo-treated patients (P < .0001). In addition, significantly fewer patients in the anakinra group had died by 28 days (13 patients, 3.2%), compared with patients in the placebo group (13 patients, 6.9%).

The median decrease in WHO-CPS scores from baseline to 28 days was 4 points in the anakinra group and 3 points in the placebo group, a statistically significant difference (P < .0001).

“Overall, the unadjusted proportional odds of having a worse score on the 11-point WHO-CPS at day 28 with anakinra was 0.36 versus placebo,” and this number remained the same in adjusted analysis, the researchers wrote.

All five secondary endpoints on the WHO-CPS showed significant benefits of anakinra, compared with placebo. These included an absolute decrease of WHO-CPS at day 28 and day 14 from baseline; an absolute decrease of Sequential Organ Failure Assessment scores at day 7 from baseline; and a significantly shorter mean time to both hospital and ICU discharge (1 day and 4 days, respectively) with anakinra versus placebo.

Follow-up laboratory data showed a significant increase in absolute lymphocyte count at 7 days, a significant decrease in circulating IL-6 levels at 4 and 7 days, and significantly decreased plasma C-reactive protein (CRP) levels at 7 days.

Serious treatment-emergent adverse events were reported in 16% with anakinra and in 21.7% with placebo; the most common of these events were infections (8.4% with anakinra and 15.9% with placebo). The next most common serious treatment-emergent adverse events were ventilator-associated pneumonia, septic shock and multiple organ dysfunction, bloodstream infections, and pulmonary embolism. The most common nonserious treatment-emergent adverse events were an increase of liver function tests and hyperglycemia (similar in anakinra and placebo groups) and nonserious anemia (lower in the anakinra group).

The study findings were limited by several factors, including the lack of patients with critical COVID-19 disease and the challenge of application of suPAR in all hospital settings, the researchers noted. However, “the results validate the findings of the previous SAVE open-label phase 2 trial,” they said. The results suggest “that suPAR should be measured upon admission of all patients with COVID-19 who do not need oxygen or who need nasal or mask oxygen, and that, if suPAR levels are 6 ng/mL or higher, anakinra treatment might be a suitable therapy,” they concluded.
 

Cytokine storm syndrome remains a treatment challenge

“Many who die from COVID-19 suffer hyperinflammation with features of cytokine storm syndrome (CSS) and associated acute respiratory distress syndrome,” wrote Randy Q. Cron, MD, and W. Winn Chatham, MD, of the University of Alabama at Birmingham, and Roberto Caricchio, MD, of Temple University, Philadelphia, in an accompanying editorial. They noted that the SAVE-MORE trial results contrast with another recent randomized trial of canakinumab, which failed to show notable benefits, compared with placebo, in treating hospitalized patients with COVID-19 pneumonia.

“There are some key differences between these trials, one being that anakinra blocks signaling of both IL-1 alpha and IL-1 beta, whereas canakinumab binds only IL-1 beta,” the editorialists explained. “SARS-CoV-2–infected endothelium may be a particularly important source of IL-1 alpha that is not targeted by canakinumab,” they noted.

Additional studies have examined IL-6 inhibition to treat COVID-19 patients, but data have been inconsistent, the editorialists said.

“One thing that is clearly emerging from this pandemic is that the CSS associated with COVID-19 is relatively unique, with only modestly elevated levels of IL-6, CRP, and ferritin, for example,” they noted. However, the SAVE-MORE study suggests that more targeted approaches, such as anakinra, “may allow earlier introduction of anticytokine treatment” and support the use of IL-1 blockade with anakinra for cases of severe COVID-19 pneumonia.
 

Predicting risk for severe disease

“One of the major challenges in the management of patients with COVID-19 is identifying patients at risk of severe disease who would warrant early intervention with anti-inflammatory therapy,” said Salim Hayek, MD, medical director of the University of Michigan’s Frankel Cardiovascular Center Clinics, in an interview. “We and others had found that soluble urokinase plasminogen activator receptor (suPAR) levels are the strongest predictor of severe disease amongst biomarkers of inflammation,” he said. “In this study, patients with high suPAR levels derived benefit from anakinra, compared to those with placebo. This study is a great example of how suPAR levels could be used to identify high-risk patients that would benefit from therapies targeting inflammation,” Dr. Hayek emphasized.

“The findings are in line with the hypothesis that patients with the highest degrees of inflammation would benefit the best from targeting the hyperinflammatory cascade using anakinra or other interleukin antagonists,” Dr. Hayek said. “Given suPAR levels are the best predictors of high-risk disease, it is not surprising to see that patients with high levels benefit from targeting inflammation,” he noted.

The take-home message for clinicians at this time is that anakinra effectively improves outcomes in COVID-19 patients with high suPAR levels, Dr. Hayek said. “SuPAR can be measured easily at the point of care. Thus, a targeted strategy using suPAR to identify patients who would benefit from anakinra appears to be viable,” he explained.

However, “Whether anakinra is effective in patients with lower suPAR levels (<6 ng/mL) is unclear and was not answered by this study,” he said. “We eagerly await results of other trials to make that determination. Whether suPAR levels can also help guide the use of other therapies for COVID-19 should be explored and would enhance the personalization of treatment for COVID-19 according to the underlying inflammatory state,” he added.

The SAVE-MORE study was funded by the Hellenic Institute for the Study of Sepsis and Sobi, which manufactures anakinra. Some of the study authors reported financial relationships with Sobi and other pharmaceutical companies.

Dr. Cron disclosed serving as a consultant to Sobi, Novartis, Pfizer, and Sironax. Dr. Cron and Dr. Chatham disclosed having received grant support from Sobi for investigator-initiated clinical trials, and Dr. Caricchio disclosed serving as a consultant to GlaxoSmithKline, Johnson & Johnson, Aurinia, and Bristol-Myers Squibb. Dr. Hayek had no relevant financial conflicts to disclose.

A large, real-world test of face masks in Bangladesh shows that masks work to reduce community spread of COVID-19. It also shows that surgical masks are more effective than cloth face coverings.

OsakaWayne Studios/Moment

The study, which was published ahead of peer review, demonstrates the power of careful investigation and offers a host of lessons about mask wearing that will be important worldwide. One key finding of the study, for example, is that wearing a mask doesn’t lead people to abandon social distancing, something public health officials had feared might happen if masks gave people a false sense of security.

“What we really were able to achieve is to demonstrate that masks are effective against COVID-19, even under a rigorous and systematic evaluation that was done in the throes of the pandemic,” said Ashley Styczynski, MD, who was an infectious disease fellow at Stanford (Calif.) University when she collaborated on the study with other colleagues at Stanford, Yale, and Innovations for Poverty Action, a large research and policy nonprofit organization that currently works in 22 countries.

“And so, I think people who have been holding out on wearing masks because [they] felt like there wasn’t enough evidence for it, we’re hoping this will really help bridge that gap for them,” she said.

It included more than 600 unions – or local governmental districts in Bangladesh – and roughly 340,000 people.

Half of the districts were given cloth or surgical face masks along with continual reminders to wear them properly; the other half were tracked with no intervention. Blood tests of people who developed symptoms during the study verified their infections.

Compared to villages that didn’t mask, those in which masks of any type were worn had about 9% fewer symptomatic cases of COVID-19. The finding was statistically significant and was unlikely to have occurred by chance alone.

“Somebody could read this study and say, ‘OK, you reduced COVID-19 by 9%. Big deal.’ And what I would respond to that would be that, if anything, we think that that is a substantial underestimate,” Dr. Styczynski said.

One reason they think they underestimated the effectiveness of masks is that they tested only people who were having symptoms, so people who had only very mild or asymptomatic infections were missed.

Another reason is that, among people who had symptoms, only one-third agreed to undergo a blood test. The effect may have been bigger had participation been universal.

Local transmission may have played a role, too. Rates of COVID-19 in Bangladesh were relatively low during the study. Most infections were caused by the B.1.1.7, or Alpha, variant.

Since then, Delta has taken over. Delta is thought to be more transmissible, and some studies have suggested that people infected with Delta shed more viral particles. Masks may be more effective when more virus is circulating.

The investigators also found important differences by age and by the type of mask. Villages in which surgical masks were worn had 11% fewer COVID-19 cases than villages in which masks were not worn. In villages in which cloth masks were worn, on the other hand, infections were reduced by only 5%.

The cloth masks were substantial. Each had three layers – two layers of fabric with an outer layer of polypropylene. On testing, the filtration efficiency of the cloth masks was only about 37%, compared with 95% for the three-layer surgical masks, which were also made of polypropylene.

Masks were most effective for older individuals. People aged 50-60 years who wore surgical masks were 23% less likely to test positive for COVID, compared with their peers who didn’t wear masks. For people older than 60, the reduction in risk was greater – 35%.
 

Rigorous research

The study took place over a period of 8 weeks in each district. The interventions were rolled out in waves, with the first starting in November 2020 and the last in January 2021.

Investigators gave each household free cloth or surgical face masks and showed families a video about proper mask wearing with promotional messages from the prime minister, a head imam, and a national cricket star. They also handed out free masks.

Previous studies have shown that people aren’t always truthful about wearing masks in public. In Kenya, for example, 88% of people answering a phone survey said that they wore masks regularly, but researchers determined that only 10% of them actually did so.

Investigators in the Bangladesh study didn’t just ask people if they’d worn masks, they stationed themselves in public markets, mosques, tea stalls, and on roads that were the main entrances to the villages and took notes.

They also tested various ways to educate people and to remind them to wear masks. They found that four factors were effective at promoting the wearing of masks, and they gave them an acronym – NORM.

• N for no-cost masks.
• O for offering information through the video and local leaders.
• R for regular reminders to people by investigators who stand in public markets and offer masks or encourage anyone who wasn’t wearing one or wasn’t wearing it correctly.
• M for modeling, in which local leaders, such as imams, wear masks and remind their followers to wear them.

These four measures tripled the wearing of masks in the intervention communities, from a baseline level of 13% to 42%. People continued to wear their masks properly for about 2 weeks after the study ended, indicating that they’d gotten used to wearing them.

Dr. Styczynski said that nothing else – not text message reminders, or signs posted in public places, or local incentives – moved the needle on mask wearing.
 

Saved lives and money

The study found that the strategy was cost effective, too. Giving masks to a large population and getting people to use them costs about $10,000 per life saved from COVID, on par with the cost of deploying mosquito nets to save people from malaria, Dr. Styczynski said.

“I think that what we’ve been able to show is that this is a really important tool to be used globally, especially as countries have delays in getting access to vaccines and rolling them out,” she said.

Dr. Styczynski said masks will continue to be important even in countries such as the United States, where vaccines aren’t stopping transmission 100% and there are still large portions of the population who are unvaccinated, such as children.

“If we want to reduce COVID-19 here, it’s really important that we consider the ongoing utility of masks, in addition to vaccines, and not really thinking of them as one or the other,” she said.

The study was funded by a grant from GiveWell.org. The funder had no role in the study design, interpretation, or the decision to publish.

A version of this article first appeared on Medscape.com.

A large, real-world test of face masks in Bangladesh shows that masks work to reduce community spread of COVID-19. It also shows that surgical masks are more effective than cloth face coverings.

OsakaWayne Studios/Moment

The study, which was published ahead of peer review, demonstrates the power of careful investigation and offers a host of lessons about mask wearing that will be important worldwide. One key finding of the study, for example, is that wearing a mask doesn’t lead people to abandon social distancing, something public health officials had feared might happen if masks gave people a false sense of security.

“What we really were able to achieve is to demonstrate that masks are effective against COVID-19, even under a rigorous and systematic evaluation that was done in the throes of the pandemic,” said Ashley Styczynski, MD, who was an infectious disease fellow at Stanford (Calif.) University when she collaborated on the study with other colleagues at Stanford, Yale, and Innovations for Poverty Action, a large research and policy nonprofit organization that currently works in 22 countries.

“And so, I think people who have been holding out on wearing masks because [they] felt like there wasn’t enough evidence for it, we’re hoping this will really help bridge that gap for them,” she said.

It included more than 600 unions – or local governmental districts in Bangladesh – and roughly 340,000 people.

Half of the districts were given cloth or surgical face masks along with continual reminders to wear them properly; the other half were tracked with no intervention. Blood tests of people who developed symptoms during the study verified their infections.

Compared to villages that didn’t mask, those in which masks of any type were worn had about 9% fewer symptomatic cases of COVID-19. The finding was statistically significant and was unlikely to have occurred by chance alone.

“Somebody could read this study and say, ‘OK, you reduced COVID-19 by 9%. Big deal.’ And what I would respond to that would be that, if anything, we think that that is a substantial underestimate,” Dr. Styczynski said.

One reason they think they underestimated the effectiveness of masks is that they tested only people who were having symptoms, so people who had only very mild or asymptomatic infections were missed.

Another reason is that, among people who had symptoms, only one-third agreed to undergo a blood test. The effect may have been bigger had participation been universal.

Local transmission may have played a role, too. Rates of COVID-19 in Bangladesh were relatively low during the study. Most infections were caused by the B.1.1.7, or Alpha, variant.

Since then, Delta has taken over. Delta is thought to be more transmissible, and some studies have suggested that people infected with Delta shed more viral particles. Masks may be more effective when more virus is circulating.

The investigators also found important differences by age and by the type of mask. Villages in which surgical masks were worn had 11% fewer COVID-19 cases than villages in which masks were not worn. In villages in which cloth masks were worn, on the other hand, infections were reduced by only 5%.

The cloth masks were substantial. Each had three layers – two layers of fabric with an outer layer of polypropylene. On testing, the filtration efficiency of the cloth masks was only about 37%, compared with 95% for the three-layer surgical masks, which were also made of polypropylene.

Masks were most effective for older individuals. People aged 50-60 years who wore surgical masks were 23% less likely to test positive for COVID, compared with their peers who didn’t wear masks. For people older than 60, the reduction in risk was greater – 35%.
 

Rigorous research

The study took place over a period of 8 weeks in each district. The interventions were rolled out in waves, with the first starting in November 2020 and the last in January 2021.

Investigators gave each household free cloth or surgical face masks and showed families a video about proper mask wearing with promotional messages from the prime minister, a head imam, and a national cricket star. They also handed out free masks.

Previous studies have shown that people aren’t always truthful about wearing masks in public. In Kenya, for example, 88% of people answering a phone survey said that they wore masks regularly, but researchers determined that only 10% of them actually did so.

Investigators in the Bangladesh study didn’t just ask people if they’d worn masks, they stationed themselves in public markets, mosques, tea stalls, and on roads that were the main entrances to the villages and took notes.

They also tested various ways to educate people and to remind them to wear masks. They found that four factors were effective at promoting the wearing of masks, and they gave them an acronym – NORM.

• N for no-cost masks.
• O for offering information through the video and local leaders.
• R for regular reminders to people by investigators who stand in public markets and offer masks or encourage anyone who wasn’t wearing one or wasn’t wearing it correctly.
• M for modeling, in which local leaders, such as imams, wear masks and remind their followers to wear them.

These four measures tripled the wearing of masks in the intervention communities, from a baseline level of 13% to 42%. People continued to wear their masks properly for about 2 weeks after the study ended, indicating that they’d gotten used to wearing them.

Dr. Styczynski said that nothing else – not text message reminders, or signs posted in public places, or local incentives – moved the needle on mask wearing.
 

Saved lives and money

The study found that the strategy was cost effective, too. Giving masks to a large population and getting people to use them costs about $10,000 per life saved from COVID, on par with the cost of deploying mosquito nets to save people from malaria, Dr. Styczynski said.

“I think that what we’ve been able to show is that this is a really important tool to be used globally, especially as countries have delays in getting access to vaccines and rolling them out,” she said.

Dr. Styczynski said masks will continue to be important even in countries such as the United States, where vaccines aren’t stopping transmission 100% and there are still large portions of the population who are unvaccinated, such as children.

“If we want to reduce COVID-19 here, it’s really important that we consider the ongoing utility of masks, in addition to vaccines, and not really thinking of them as one or the other,” she said.

The study was funded by a grant from GiveWell.org. The funder had no role in the study design, interpretation, or the decision to publish.

A version of this article first appeared on Medscape.com.

A large, real-world test of face masks in Bangladesh shows that masks work to reduce community spread of COVID-19. It also shows that surgical masks are more effective than cloth face coverings.

OsakaWayne Studios/Moment

The study, which was published ahead of peer review, demonstrates the power of careful investigation and offers a host of lessons about mask wearing that will be important worldwide. One key finding of the study, for example, is that wearing a mask doesn’t lead people to abandon social distancing, something public health officials had feared might happen if masks gave people a false sense of security.

“What we really were able to achieve is to demonstrate that masks are effective against COVID-19, even under a rigorous and systematic evaluation that was done in the throes of the pandemic,” said Ashley Styczynski, MD, who was an infectious disease fellow at Stanford (Calif.) University when she collaborated on the study with other colleagues at Stanford, Yale, and Innovations for Poverty Action, a large research and policy nonprofit organization that currently works in 22 countries.

“And so, I think people who have been holding out on wearing masks because [they] felt like there wasn’t enough evidence for it, we’re hoping this will really help bridge that gap for them,” she said.

It included more than 600 unions – or local governmental districts in Bangladesh – and roughly 340,000 people.

Half of the districts were given cloth or surgical face masks along with continual reminders to wear them properly; the other half were tracked with no intervention. Blood tests of people who developed symptoms during the study verified their infections.

Compared to villages that didn’t mask, those in which masks of any type were worn had about 9% fewer symptomatic cases of COVID-19. The finding was statistically significant and was unlikely to have occurred by chance alone.

“Somebody could read this study and say, ‘OK, you reduced COVID-19 by 9%. Big deal.’ And what I would respond to that would be that, if anything, we think that that is a substantial underestimate,” Dr. Styczynski said.

One reason they think they underestimated the effectiveness of masks is that they tested only people who were having symptoms, so people who had only very mild or asymptomatic infections were missed.

Another reason is that, among people who had symptoms, only one-third agreed to undergo a blood test. The effect may have been bigger had participation been universal.

Local transmission may have played a role, too. Rates of COVID-19 in Bangladesh were relatively low during the study. Most infections were caused by the B.1.1.7, or Alpha, variant.

Since then, Delta has taken over. Delta is thought to be more transmissible, and some studies have suggested that people infected with Delta shed more viral particles. Masks may be more effective when more virus is circulating.

The investigators also found important differences by age and by the type of mask. Villages in which surgical masks were worn had 11% fewer COVID-19 cases than villages in which masks were not worn. In villages in which cloth masks were worn, on the other hand, infections were reduced by only 5%.

The cloth masks were substantial. Each had three layers – two layers of fabric with an outer layer of polypropylene. On testing, the filtration efficiency of the cloth masks was only about 37%, compared with 95% for the three-layer surgical masks, which were also made of polypropylene.

Masks were most effective for older individuals. People aged 50-60 years who wore surgical masks were 23% less likely to test positive for COVID, compared with their peers who didn’t wear masks. For people older than 60, the reduction in risk was greater – 35%.
 

Rigorous research

The study took place over a period of 8 weeks in each district. The interventions were rolled out in waves, with the first starting in November 2020 and the last in January 2021.

Investigators gave each household free cloth or surgical face masks and showed families a video about proper mask wearing with promotional messages from the prime minister, a head imam, and a national cricket star. They also handed out free masks.

Previous studies have shown that people aren’t always truthful about wearing masks in public. In Kenya, for example, 88% of people answering a phone survey said that they wore masks regularly, but researchers determined that only 10% of them actually did so.

Investigators in the Bangladesh study didn’t just ask people if they’d worn masks, they stationed themselves in public markets, mosques, tea stalls, and on roads that were the main entrances to the villages and took notes.

They also tested various ways to educate people and to remind them to wear masks. They found that four factors were effective at promoting the wearing of masks, and they gave them an acronym – NORM.

• N for no-cost masks.
• O for offering information through the video and local leaders.
• R for regular reminders to people by investigators who stand in public markets and offer masks or encourage anyone who wasn’t wearing one or wasn’t wearing it correctly.
• M for modeling, in which local leaders, such as imams, wear masks and remind their followers to wear them.

These four measures tripled the wearing of masks in the intervention communities, from a baseline level of 13% to 42%. People continued to wear their masks properly for about 2 weeks after the study ended, indicating that they’d gotten used to wearing them.

Dr. Styczynski said that nothing else – not text message reminders, or signs posted in public places, or local incentives – moved the needle on mask wearing.
 

Saved lives and money

The study found that the strategy was cost effective, too. Giving masks to a large population and getting people to use them costs about $10,000 per life saved from COVID, on par with the cost of deploying mosquito nets to save people from malaria, Dr. Styczynski said.

“I think that what we’ve been able to show is that this is a really important tool to be used globally, especially as countries have delays in getting access to vaccines and rolling them out,” she said.

Dr. Styczynski said masks will continue to be important even in countries such as the United States, where vaccines aren’t stopping transmission 100% and there are still large portions of the population who are unvaccinated, such as children.

“If we want to reduce COVID-19 here, it’s really important that we consider the ongoing utility of masks, in addition to vaccines, and not really thinking of them as one or the other,” she said.

The study was funded by a grant from GiveWell.org. The funder had no role in the study design, interpretation, or the decision to publish.

A version of this article first appeared on Medscape.com.

Several health care-associated infections in U.S. hospitals spiked in 2020 compared to the previous year, according to a Centers for Disease Control and Prevention analysis published Sept. 2 in Infection Control and Hospital Epidemiology. Soaring hospitalization rates, sicker patients who required more frequent and intense care, and staffing and supply shortages caused by the COVID-19 pandemic are thought to have contributed to this increase.

This is the first increase in health care–associated infections since 2015.

These findings “are a reflection of the enormous stress that COVID has placed on our health care system,” Arjun Srinivasan, MD (Capt, USPHS), the associate director of the CDC’s Health care-Associated Infection Prevention Programs, Atlanta, told this news organization. He was not an author of the article, but he supervised the research. “We don’t want anyone to read this report and think that it represents a failure of the individual provider or a failure of health care providers in this country in their care of COVID patients,” he said. He noted that health care professionals have provided “tremendously good care to patients under extremely difficult circumstances.”

“People don’t fail – systems fail – and that’s what happened here,” he said. “Our systems that we need to have in place to prevent health care–associated infection simply were not as strong as they needed to be to survive this challenge.”

In the study, researchers used data reported to the National Healthcare Safety Network, the CDC’s tracking system for health care–associated infections. The team compared national standard infection ratios – calculated by dividing the number of reported infections by the number of predicted infections – between 2019 and 2020 for six routinely tracked events:

• Central line–associated bloodstream infections.
• Catheter-associated urinary tract infections (CAUTIs).
• Ventilator-associated events (VAEs).
• Infections associated with colon surgery and abdominal hysterectomy.
• Clostridioides difficile infections.
• Methicillin-resistant Staphylococcus aureus (MRSA) infections.

Infections were estimated using regression models created with baseline data from 2015.

“The new report highlights the need for health care facilities to strengthen their infection prevention programs and support them with adequate resources so that they can handle emerging threats to public health, while at the same time ensuring that gains made in combating HAIs [health care–associated infections] are not lost,” said the Association for Professionals in Infection Control and Epidemiology in a statement.

The analysis revealed significant national increases in central line–associated bloodstream infections, CAUTIs, VAEs, and MRSA infections in 2020 compared to 2019. Among all infection types, the greatest increase was in central-line infections, which were 46% to 47% higher in the third quarter and fourth quarter (Q4) of 2020 relative to the same periods the previous year. VAEs rose by 45%, MRSA infections increased by 34%, and CAUTIs increased by 19% in Q4 of 2020 compared to 2019.

The influx of sicker patients in hospitals throughout 2020 led to more frequent and longer use of medical devices such as catheters and ventilators. The use of these devices increases risk for infection, David P. Calfee, MD, chief medical epidemiologist at the New York–Presbyterian/Weill Cornell Medical Center, said in an interview. He is an editor of Infection Control and Hospital Epidemiology and was not involved with the study. Shortages in personal protective equipment and crowded intensive care units could also have affected how care was delivered, he said. These factors could have led to “reductions in the ability to provide some of the types of care that are needed to optimally reduce the risk of infection.”

There was either no change or decreases in infections associated with colon surgery or abdominal hysterectomy, likely because there were fewer elective surgeries performed, said Dr. Srinivasan. C. difficile–associated infections also decreased throughout 2020 compared to the previous year. Common practices to prevent the spread of COVID-19 in hospitals, such as environmental cleaning, use of personal protective equipment, and patient isolation, likely helped to curb the spread of C. difficile. Although these mitigating procedures do help protect against MRSA infection, many other factors, notably, the use of medical devices such as ventilators and catheters, can increase the risk for MRSA infection, Dr. Srinivasan added.

Although more research is needed to identify the reasons for these spikes in infection, the findings help quantify the scope of these increases across the United States, Dr. Calfee said. The data allow hospitals and health care professionals to “look back at what we did and then think forward in terms of what we can do different in the future,” he added, “so that these stresses to the system have less of an impact on how we are able to provide care.”

Dr. Srinivasan and Dr. Calfee report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Several health care-associated infections in U.S. hospitals spiked in 2020 compared to the previous year, according to a Centers for Disease Control and Prevention analysis published Sept. 2 in Infection Control and Hospital Epidemiology. Soaring hospitalization rates, sicker patients who required more frequent and intense care, and staffing and supply shortages caused by the COVID-19 pandemic are thought to have contributed to this increase.

This is the first increase in health care–associated infections since 2015.

These findings “are a reflection of the enormous stress that COVID has placed on our health care system,” Arjun Srinivasan, MD (Capt, USPHS), the associate director of the CDC’s Health care-Associated Infection Prevention Programs, Atlanta, told this news organization. He was not an author of the article, but he supervised the research. “We don’t want anyone to read this report and think that it represents a failure of the individual provider or a failure of health care providers in this country in their care of COVID patients,” he said. He noted that health care professionals have provided “tremendously good care to patients under extremely difficult circumstances.”

“People don’t fail – systems fail – and that’s what happened here,” he said. “Our systems that we need to have in place to prevent health care–associated infection simply were not as strong as they needed to be to survive this challenge.”

In the study, researchers used data reported to the National Healthcare Safety Network, the CDC’s tracking system for health care–associated infections. The team compared national standard infection ratios – calculated by dividing the number of reported infections by the number of predicted infections – between 2019 and 2020 for six routinely tracked events:

• Central line–associated bloodstream infections.
• Catheter-associated urinary tract infections (CAUTIs).
• Ventilator-associated events (VAEs).
• Infections associated with colon surgery and abdominal hysterectomy.
• Clostridioides difficile infections.
• Methicillin-resistant Staphylococcus aureus (MRSA) infections.

Infections were estimated using regression models created with baseline data from 2015.

“The new report highlights the need for health care facilities to strengthen their infection prevention programs and support them with adequate resources so that they can handle emerging threats to public health, while at the same time ensuring that gains made in combating HAIs [health care–associated infections] are not lost,” said the Association for Professionals in Infection Control and Epidemiology in a statement.

The analysis revealed significant national increases in central line–associated bloodstream infections, CAUTIs, VAEs, and MRSA infections in 2020 compared to 2019. Among all infection types, the greatest increase was in central-line infections, which were 46% to 47% higher in the third quarter and fourth quarter (Q4) of 2020 relative to the same periods the previous year. VAEs rose by 45%, MRSA infections increased by 34%, and CAUTIs increased by 19% in Q4 of 2020 compared to 2019.

The influx of sicker patients in hospitals throughout 2020 led to more frequent and longer use of medical devices such as catheters and ventilators. The use of these devices increases risk for infection, David P. Calfee, MD, chief medical epidemiologist at the New York–Presbyterian/Weill Cornell Medical Center, said in an interview. He is an editor of Infection Control and Hospital Epidemiology and was not involved with the study. Shortages in personal protective equipment and crowded intensive care units could also have affected how care was delivered, he said. These factors could have led to “reductions in the ability to provide some of the types of care that are needed to optimally reduce the risk of infection.”

There was either no change or decreases in infections associated with colon surgery or abdominal hysterectomy, likely because there were fewer elective surgeries performed, said Dr. Srinivasan. C. difficile–associated infections also decreased throughout 2020 compared to the previous year. Common practices to prevent the spread of COVID-19 in hospitals, such as environmental cleaning, use of personal protective equipment, and patient isolation, likely helped to curb the spread of C. difficile. Although these mitigating procedures do help protect against MRSA infection, many other factors, notably, the use of medical devices such as ventilators and catheters, can increase the risk for MRSA infection, Dr. Srinivasan added.

Although more research is needed to identify the reasons for these spikes in infection, the findings help quantify the scope of these increases across the United States, Dr. Calfee said. The data allow hospitals and health care professionals to “look back at what we did and then think forward in terms of what we can do different in the future,” he added, “so that these stresses to the system have less of an impact on how we are able to provide care.”

Dr. Srinivasan and Dr. Calfee report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Several health care-associated infections in U.S. hospitals spiked in 2020 compared to the previous year, according to a Centers for Disease Control and Prevention analysis published Sept. 2 in Infection Control and Hospital Epidemiology. Soaring hospitalization rates, sicker patients who required more frequent and intense care, and staffing and supply shortages caused by the COVID-19 pandemic are thought to have contributed to this increase.

This is the first increase in health care–associated infections since 2015.

These findings “are a reflection of the enormous stress that COVID has placed on our health care system,” Arjun Srinivasan, MD (Capt, USPHS), the associate director of the CDC’s Health care-Associated Infection Prevention Programs, Atlanta, told this news organization. He was not an author of the article, but he supervised the research. “We don’t want anyone to read this report and think that it represents a failure of the individual provider or a failure of health care providers in this country in their care of COVID patients,” he said. He noted that health care professionals have provided “tremendously good care to patients under extremely difficult circumstances.”

“People don’t fail – systems fail – and that’s what happened here,” he said. “Our systems that we need to have in place to prevent health care–associated infection simply were not as strong as they needed to be to survive this challenge.”

In the study, researchers used data reported to the National Healthcare Safety Network, the CDC’s tracking system for health care–associated infections. The team compared national standard infection ratios – calculated by dividing the number of reported infections by the number of predicted infections – between 2019 and 2020 for six routinely tracked events:

• Central line–associated bloodstream infections.
• Catheter-associated urinary tract infections (CAUTIs).
• Ventilator-associated events (VAEs).
• Infections associated with colon surgery and abdominal hysterectomy.
• Clostridioides difficile infections.
• Methicillin-resistant Staphylococcus aureus (MRSA) infections.

Infections were estimated using regression models created with baseline data from 2015.

“The new report highlights the need for health care facilities to strengthen their infection prevention programs and support them with adequate resources so that they can handle emerging threats to public health, while at the same time ensuring that gains made in combating HAIs [health care–associated infections] are not lost,” said the Association for Professionals in Infection Control and Epidemiology in a statement.

The analysis revealed significant national increases in central line–associated bloodstream infections, CAUTIs, VAEs, and MRSA infections in 2020 compared to 2019. Among all infection types, the greatest increase was in central-line infections, which were 46% to 47% higher in the third quarter and fourth quarter (Q4) of 2020 relative to the same periods the previous year. VAEs rose by 45%, MRSA infections increased by 34%, and CAUTIs increased by 19% in Q4 of 2020 compared to 2019.

The influx of sicker patients in hospitals throughout 2020 led to more frequent and longer use of medical devices such as catheters and ventilators. The use of these devices increases risk for infection, David P. Calfee, MD, chief medical epidemiologist at the New York–Presbyterian/Weill Cornell Medical Center, said in an interview. He is an editor of Infection Control and Hospital Epidemiology and was not involved with the study. Shortages in personal protective equipment and crowded intensive care units could also have affected how care was delivered, he said. These factors could have led to “reductions in the ability to provide some of the types of care that are needed to optimally reduce the risk of infection.”

There was either no change or decreases in infections associated with colon surgery or abdominal hysterectomy, likely because there were fewer elective surgeries performed, said Dr. Srinivasan. C. difficile–associated infections also decreased throughout 2020 compared to the previous year. Common practices to prevent the spread of COVID-19 in hospitals, such as environmental cleaning, use of personal protective equipment, and patient isolation, likely helped to curb the spread of C. difficile. Although these mitigating procedures do help protect against MRSA infection, many other factors, notably, the use of medical devices such as ventilators and catheters, can increase the risk for MRSA infection, Dr. Srinivasan added.

Although more research is needed to identify the reasons for these spikes in infection, the findings help quantify the scope of these increases across the United States, Dr. Calfee said. The data allow hospitals and health care professionals to “look back at what we did and then think forward in terms of what we can do different in the future,” he added, “so that these stresses to the system have less of an impact on how we are able to provide care.”

Dr. Srinivasan and Dr. Calfee report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Last year, Katherine Gill, MBChB, an HIV prevention researcher in Cape Town, South Africa, realized how jaded she’d become to vaccine research when the Pfizer COVID-19 vaccine came back as 95% effective. In her career conducting HIV clinical trials, she had never seen anything like it. Even HIV prevention methods she had studied that had worked, such as the dapivirine ring, had an overall efficacy of 30%.

The COVID-19 success story started to soften her views toward another vaccine trial she was helping to conduct, a trial in HIV that used the same platform as Johnson & Johnson’s successful COVID-19 vaccine.

“When the COVID vaccine was cracked so quickly and seemingly quite easily, I did start to think, ‘Well, maybe … maybe this will work for HIV,’ “ she said in an interview.

That turned out to be false hope. The National Institutes of Health (NIH) announced that the trial Dr. Gill was helping to conduct, HVTN 705, was stopping early because it hadn’t generated enough of an immune response in participants to justify continuing. It was the second HIV vaccine to fail in the last year. It’s also the latest in what has been a litany of disappointments in the attempt to boost the human immune system to fight HIV without the need for ongoing HIV treatment.

In HVTN 705, known as the Imbokodo study (imbokodo is a Zulu word that’s part of a saying about women being strong as rocks), researchers used the platform made up of a common cold virus, adenovirus 26, to deliver a computer-generated mosaic of HIV antigens to participants’ immune systems. That mosaic of antigens is meant to goose the immune system into recognizing HIV if it were exposed to it.

When HIV enters the body, it infiltrates immune cells and replicates within them. To the rest of the immune system, those cells still register as just typical T-cells. The rest of the immune system can’t see that the virus is spreading through the very cells meant to protect the body from illness. That, plus the armor of sugary glycoproteins encasing the virus, has made HIV nearly impervious to vaccination.

Then, those so-called “prime” shots were followed by a second shot that targets glycoprotein 140, on the most common HIV subtype (or clade) in Africa, clade C. In the Imbokodo trial, a total of 2,637 women from five sub-Saharan African countries received shots at baseline, 3 months, 6 months, and 1 year. Then researchers followed the women from month 7 to 2 years after their third dose, testing their blood to see if their immune systems had generated the immune response the vaccine was meant to induce – and whether such immune response was associated with lower rates of HIV.

When researchers looked at the first 2 years of data, they learned that the vaccine was safe. And they found a total of 114 new cases of HIV – 51 among women who received the vaccine and 63 among those who received a placebo. That’s a 25.2% efficacy rate – but it wasn’t statistically significant.

The results are frustrating, said Carl Dieffenbach, PhD, director of the AIDS division at the National Institute of Allergy and Infectious Diseases (NIAID). NIAID is one of the funders of the study.

“This [trial] is a little more confounding, in that there is this low level of statistically insignificant difference between vaccine and placebo that starts somewhere around month 9 and then just kind of indolently is maintained over the next 15 months,” he said in an interview. “That’s kind of frustrating. Does it mean there’s a signal or is this just chance? Because that’s what statistics tell us, not to believe your last data point.”

What this means for the future direction of vaccine research is unclear. A sister study to Imbokodo, called Mosaico, recently finished enrolling participants. Mosaico uses the same adenovirus 26 platform, but it’s loaded with different antigens and targets a different glycoprotein for a different HIV subtype. If that trial shows success, it could mean that the platform is right, but the targets in the Imbokodo vaccine were wrong.

Dr. Dieffenbach said that before NIAID decides what to do with Mosaico they’ve asked researchers to analyze the data on the people who did respond, to see if those people have some specific variant of HIV or some other biomarker that could be used to form the next iteration of an HIV vaccine candidate. Only after that will they make a decision about Mosaico.

But he added that it does make him wonder if vaccine approaches that rely on nonneutralizing antibodies like this one have a ceiling of effectiveness that’s just too low to alter the course of the epidemic.

“I think we’ve discovered that there’s not a floor to [these nonneutralizing approaches], but there probably is a ceiling,” he said. “I don’t know if we’re going to get better than” a 25%-29% efficacy rate with those approaches.

The Imbokodo findings reminded Mitchell Warren, executive director of the global HIV prevention nonprofit, AVAC, of the data released in January from the Antibody Mediated Prevention (AMP) trial. That trial pitted the broadly neutralizing antibody (bNAb) VCR01 against HIV – and mostly, it lost.

VCR01 worked only on HIV variants that 30% of participants had. But in those 30%, it was 75% effective at preventing HIV. Now you have Imbokodo, with its potential 25% activity against HIV, something that may have been a fluke. This, to Mr. Warren, requires a rethinking of the whole HIV vaccine enterprise while “doubling, tripling, quadrupling down” on the HIV prevention methods we know work, such as preexposure prophylaxis (PrEP).

Dr. Dieffenbach agreed. To clinicians, Dr. Dieffenbach said the message of this HIV vaccine trial is flush with urgency: “Get your HIV-negative, at-risk people on PrEP tomorrow.”

There are now two pills approved for HIV prevention, both of which have been found to be up to 99% effective when taken consistently. A third option, injectable cabotegravir (Vocabria), has been submitted to the Food and Drug Administration for approval. The federal Ready, Set, PrEP program makes the pill available for free for those who qualify, and recently the Biden administration reaffirmed that, under the Affordable Care Act, insurance companies should cover all costs associated with PrEP, including lab work and exam visits.

But for the 157 women who participated in the trial at Dr. Gill’s site in Masiphumelele, on the southwestern tip of South Africa, the trial was personal, said Jason Naidoo, community liaison officer at the Desmond Tutu HIV Foundation, which conducted a portion of the study. These were women whose parents, siblings, or children were living with HIV or had died from AIDS-defining illnesses, he said. Their lives were chaotic, traveling at a moment’s notice to hometowns on the Eastern Cape, an 11-hour car ride away – longer by bus – for traditional prayers, funerals, and other important events.

Mr. Naidoo remembers arranging buses for the women to return for scheduled clinic visits, leaving the Eastern Cape in the afternoon and arriving in Masiphumelele in the early morning hours, just to keep the clinic appointment. Then, they’d turn around and return east.

They did this for 3 years, he said.

“The fact that these participants have stuck to this and been dedicated amidst all of the chaos talks about their commitment to actually having a vaccine for HIV,” he said. “They know their own risk profile as young Black women in South Africa, and they understand the need for an intervention for the future generations.

“So you can understand the emotion and the sense of sadness, the disappointment – the incredible [dis]belief that this [the failure of the vaccine] could have happened, because the expectations are so, so high.”

For Dr. Gill, who is lead investigator for Imbokodo in Masiphumelele, the weariness toward vaccines is back. Another trial is underway for an HIV vaccine with a platform that was successful in COVID-19 – using messenger RNA (mRNA), like the Pfizer and Moderna COVID-19 vaccines did.

“I think we need to be careful,” she said, “thinking that the mRNA vaccines are going to crack it.”

Dr. Dieffenbach, Dr. Gill, and Mr. Naidoo have disclosed no relevant financial relationships. The study was funded by Janssen, a Johnson & Johnson company, with NIAID and the Bill and Melinda Gates Foundation.

A version of this article first appeared on Medscape.com.

Last year, Katherine Gill, MBChB, an HIV prevention researcher in Cape Town, South Africa, realized how jaded she’d become to vaccine research when the Pfizer COVID-19 vaccine came back as 95% effective. In her career conducting HIV clinical trials, she had never seen anything like it. Even HIV prevention methods she had studied that had worked, such as the dapivirine ring, had an overall efficacy of 30%.

The COVID-19 success story started to soften her views toward another vaccine trial she was helping to conduct, a trial in HIV that used the same platform as Johnson & Johnson’s successful COVID-19 vaccine.

“When the COVID vaccine was cracked so quickly and seemingly quite easily, I did start to think, ‘Well, maybe … maybe this will work for HIV,’ “ she said in an interview.

That turned out to be false hope. The National Institutes of Health (NIH) announced that the trial Dr. Gill was helping to conduct, HVTN 705, was stopping early because it hadn’t generated enough of an immune response in participants to justify continuing. It was the second HIV vaccine to fail in the last year. It’s also the latest in what has been a litany of disappointments in the attempt to boost the human immune system to fight HIV without the need for ongoing HIV treatment.

In HVTN 705, known as the Imbokodo study (imbokodo is a Zulu word that’s part of a saying about women being strong as rocks), researchers used the platform made up of a common cold virus, adenovirus 26, to deliver a computer-generated mosaic of HIV antigens to participants’ immune systems. That mosaic of antigens is meant to goose the immune system into recognizing HIV if it were exposed to it.

When HIV enters the body, it infiltrates immune cells and replicates within them. To the rest of the immune system, those cells still register as just typical T-cells. The rest of the immune system can’t see that the virus is spreading through the very cells meant to protect the body from illness. That, plus the armor of sugary glycoproteins encasing the virus, has made HIV nearly impervious to vaccination.

Then, those so-called “prime” shots were followed by a second shot that targets glycoprotein 140, on the most common HIV subtype (or clade) in Africa, clade C. In the Imbokodo trial, a total of 2,637 women from five sub-Saharan African countries received shots at baseline, 3 months, 6 months, and 1 year. Then researchers followed the women from month 7 to 2 years after their third dose, testing their blood to see if their immune systems had generated the immune response the vaccine was meant to induce – and whether such immune response was associated with lower rates of HIV.

When researchers looked at the first 2 years of data, they learned that the vaccine was safe. And they found a total of 114 new cases of HIV – 51 among women who received the vaccine and 63 among those who received a placebo. That’s a 25.2% efficacy rate – but it wasn’t statistically significant.

The results are frustrating, said Carl Dieffenbach, PhD, director of the AIDS division at the National Institute of Allergy and Infectious Diseases (NIAID). NIAID is one of the funders of the study.

“This [trial] is a little more confounding, in that there is this low level of statistically insignificant difference between vaccine and placebo that starts somewhere around month 9 and then just kind of indolently is maintained over the next 15 months,” he said in an interview. “That’s kind of frustrating. Does it mean there’s a signal or is this just chance? Because that’s what statistics tell us, not to believe your last data point.”

What this means for the future direction of vaccine research is unclear. A sister study to Imbokodo, called Mosaico, recently finished enrolling participants. Mosaico uses the same adenovirus 26 platform, but it’s loaded with different antigens and targets a different glycoprotein for a different HIV subtype. If that trial shows success, it could mean that the platform is right, but the targets in the Imbokodo vaccine were wrong.

Dr. Dieffenbach said that before NIAID decides what to do with Mosaico they’ve asked researchers to analyze the data on the people who did respond, to see if those people have some specific variant of HIV or some other biomarker that could be used to form the next iteration of an HIV vaccine candidate. Only after that will they make a decision about Mosaico.

But he added that it does make him wonder if vaccine approaches that rely on nonneutralizing antibodies like this one have a ceiling of effectiveness that’s just too low to alter the course of the epidemic.

“I think we’ve discovered that there’s not a floor to [these nonneutralizing approaches], but there probably is a ceiling,” he said. “I don’t know if we’re going to get better than” a 25%-29% efficacy rate with those approaches.

The Imbokodo findings reminded Mitchell Warren, executive director of the global HIV prevention nonprofit, AVAC, of the data released in January from the Antibody Mediated Prevention (AMP) trial. That trial pitted the broadly neutralizing antibody (bNAb) VCR01 against HIV – and mostly, it lost.

VCR01 worked only on HIV variants that 30% of participants had. But in those 30%, it was 75% effective at preventing HIV. Now you have Imbokodo, with its potential 25% activity against HIV, something that may have been a fluke. This, to Mr. Warren, requires a rethinking of the whole HIV vaccine enterprise while “doubling, tripling, quadrupling down” on the HIV prevention methods we know work, such as preexposure prophylaxis (PrEP).

Dr. Dieffenbach agreed. To clinicians, Dr. Dieffenbach said the message of this HIV vaccine trial is flush with urgency: “Get your HIV-negative, at-risk people on PrEP tomorrow.”

There are now two pills approved for HIV prevention, both of which have been found to be up to 99% effective when taken consistently. A third option, injectable cabotegravir (Vocabria), has been submitted to the Food and Drug Administration for approval. The federal Ready, Set, PrEP program makes the pill available for free for those who qualify, and recently the Biden administration reaffirmed that, under the Affordable Care Act, insurance companies should cover all costs associated with PrEP, including lab work and exam visits.

But for the 157 women who participated in the trial at Dr. Gill’s site in Masiphumelele, on the southwestern tip of South Africa, the trial was personal, said Jason Naidoo, community liaison officer at the Desmond Tutu HIV Foundation, which conducted a portion of the study. These were women whose parents, siblings, or children were living with HIV or had died from AIDS-defining illnesses, he said. Their lives were chaotic, traveling at a moment’s notice to hometowns on the Eastern Cape, an 11-hour car ride away – longer by bus – for traditional prayers, funerals, and other important events.

Mr. Naidoo remembers arranging buses for the women to return for scheduled clinic visits, leaving the Eastern Cape in the afternoon and arriving in Masiphumelele in the early morning hours, just to keep the clinic appointment. Then, they’d turn around and return east.

They did this for 3 years, he said.

“The fact that these participants have stuck to this and been dedicated amidst all of the chaos talks about their commitment to actually having a vaccine for HIV,” he said. “They know their own risk profile as young Black women in South Africa, and they understand the need for an intervention for the future generations.

“So you can understand the emotion and the sense of sadness, the disappointment – the incredible [dis]belief that this [the failure of the vaccine] could have happened, because the expectations are so, so high.”

For Dr. Gill, who is lead investigator for Imbokodo in Masiphumelele, the weariness toward vaccines is back. Another trial is underway for an HIV vaccine with a platform that was successful in COVID-19 – using messenger RNA (mRNA), like the Pfizer and Moderna COVID-19 vaccines did.

“I think we need to be careful,” she said, “thinking that the mRNA vaccines are going to crack it.”

Dr. Dieffenbach, Dr. Gill, and Mr. Naidoo have disclosed no relevant financial relationships. The study was funded by Janssen, a Johnson & Johnson company, with NIAID and the Bill and Melinda Gates Foundation.

A version of this article first appeared on Medscape.com.

Last year, Katherine Gill, MBChB, an HIV prevention researcher in Cape Town, South Africa, realized how jaded she’d become to vaccine research when the Pfizer COVID-19 vaccine came back as 95% effective. In her career conducting HIV clinical trials, she had never seen anything like it. Even HIV prevention methods she had studied that had worked, such as the dapivirine ring, had an overall efficacy of 30%.

The COVID-19 success story started to soften her views toward another vaccine trial she was helping to conduct, a trial in HIV that used the same platform as Johnson & Johnson’s successful COVID-19 vaccine.

“When the COVID vaccine was cracked so quickly and seemingly quite easily, I did start to think, ‘Well, maybe … maybe this will work for HIV,’ “ she said in an interview.

That turned out to be false hope. The National Institutes of Health (NIH) announced that the trial Dr. Gill was helping to conduct, HVTN 705, was stopping early because it hadn’t generated enough of an immune response in participants to justify continuing. It was the second HIV vaccine to fail in the last year. It’s also the latest in what has been a litany of disappointments in the attempt to boost the human immune system to fight HIV without the need for ongoing HIV treatment.

In HVTN 705, known as the Imbokodo study (imbokodo is a Zulu word that’s part of a saying about women being strong as rocks), researchers used the platform made up of a common cold virus, adenovirus 26, to deliver a computer-generated mosaic of HIV antigens to participants’ immune systems. That mosaic of antigens is meant to goose the immune system into recognizing HIV if it were exposed to it.

When HIV enters the body, it infiltrates immune cells and replicates within them. To the rest of the immune system, those cells still register as just typical T-cells. The rest of the immune system can’t see that the virus is spreading through the very cells meant to protect the body from illness. That, plus the armor of sugary glycoproteins encasing the virus, has made HIV nearly impervious to vaccination.

Then, those so-called “prime” shots were followed by a second shot that targets glycoprotein 140, on the most common HIV subtype (or clade) in Africa, clade C. In the Imbokodo trial, a total of 2,637 women from five sub-Saharan African countries received shots at baseline, 3 months, 6 months, and 1 year. Then researchers followed the women from month 7 to 2 years after their third dose, testing their blood to see if their immune systems had generated the immune response the vaccine was meant to induce – and whether such immune response was associated with lower rates of HIV.

When researchers looked at the first 2 years of data, they learned that the vaccine was safe. And they found a total of 114 new cases of HIV – 51 among women who received the vaccine and 63 among those who received a placebo. That’s a 25.2% efficacy rate – but it wasn’t statistically significant.

The results are frustrating, said Carl Dieffenbach, PhD, director of the AIDS division at the National Institute of Allergy and Infectious Diseases (NIAID). NIAID is one of the funders of the study.

“This [trial] is a little more confounding, in that there is this low level of statistically insignificant difference between vaccine and placebo that starts somewhere around month 9 and then just kind of indolently is maintained over the next 15 months,” he said in an interview. “That’s kind of frustrating. Does it mean there’s a signal or is this just chance? Because that’s what statistics tell us, not to believe your last data point.”

What this means for the future direction of vaccine research is unclear. A sister study to Imbokodo, called Mosaico, recently finished enrolling participants. Mosaico uses the same adenovirus 26 platform, but it’s loaded with different antigens and targets a different glycoprotein for a different HIV subtype. If that trial shows success, it could mean that the platform is right, but the targets in the Imbokodo vaccine were wrong.

Dr. Dieffenbach said that before NIAID decides what to do with Mosaico they’ve asked researchers to analyze the data on the people who did respond, to see if those people have some specific variant of HIV or some other biomarker that could be used to form the next iteration of an HIV vaccine candidate. Only after that will they make a decision about Mosaico.

But he added that it does make him wonder if vaccine approaches that rely on nonneutralizing antibodies like this one have a ceiling of effectiveness that’s just too low to alter the course of the epidemic.

“I think we’ve discovered that there’s not a floor to [these nonneutralizing approaches], but there probably is a ceiling,” he said. “I don’t know if we’re going to get better than” a 25%-29% efficacy rate with those approaches.

The Imbokodo findings reminded Mitchell Warren, executive director of the global HIV prevention nonprofit, AVAC, of the data released in January from the Antibody Mediated Prevention (AMP) trial. That trial pitted the broadly neutralizing antibody (bNAb) VCR01 against HIV – and mostly, it lost.

VCR01 worked only on HIV variants that 30% of participants had. But in those 30%, it was 75% effective at preventing HIV. Now you have Imbokodo, with its potential 25% activity against HIV, something that may have been a fluke. This, to Mr. Warren, requires a rethinking of the whole HIV vaccine enterprise while “doubling, tripling, quadrupling down” on the HIV prevention methods we know work, such as preexposure prophylaxis (PrEP).

Dr. Dieffenbach agreed. To clinicians, Dr. Dieffenbach said the message of this HIV vaccine trial is flush with urgency: “Get your HIV-negative, at-risk people on PrEP tomorrow.”

There are now two pills approved for HIV prevention, both of which have been found to be up to 99% effective when taken consistently. A third option, injectable cabotegravir (Vocabria), has been submitted to the Food and Drug Administration for approval. The federal Ready, Set, PrEP program makes the pill available for free for those who qualify, and recently the Biden administration reaffirmed that, under the Affordable Care Act, insurance companies should cover all costs associated with PrEP, including lab work and exam visits.

But for the 157 women who participated in the trial at Dr. Gill’s site in Masiphumelele, on the southwestern tip of South Africa, the trial was personal, said Jason Naidoo, community liaison officer at the Desmond Tutu HIV Foundation, which conducted a portion of the study. These were women whose parents, siblings, or children were living with HIV or had died from AIDS-defining illnesses, he said. Their lives were chaotic, traveling at a moment’s notice to hometowns on the Eastern Cape, an 11-hour car ride away – longer by bus – for traditional prayers, funerals, and other important events.

Mr. Naidoo remembers arranging buses for the women to return for scheduled clinic visits, leaving the Eastern Cape in the afternoon and arriving in Masiphumelele in the early morning hours, just to keep the clinic appointment. Then, they’d turn around and return east.

They did this for 3 years, he said.

“The fact that these participants have stuck to this and been dedicated amidst all of the chaos talks about their commitment to actually having a vaccine for HIV,” he said. “They know their own risk profile as young Black women in South Africa, and they understand the need for an intervention for the future generations.

“So you can understand the emotion and the sense of sadness, the disappointment – the incredible [dis]belief that this [the failure of the vaccine] could have happened, because the expectations are so, so high.”

For Dr. Gill, who is lead investigator for Imbokodo in Masiphumelele, the weariness toward vaccines is back. Another trial is underway for an HIV vaccine with a platform that was successful in COVID-19 – using messenger RNA (mRNA), like the Pfizer and Moderna COVID-19 vaccines did.

“I think we need to be careful,” she said, “thinking that the mRNA vaccines are going to crack it.”

Dr. Dieffenbach, Dr. Gill, and Mr. Naidoo have disclosed no relevant financial relationships. The study was funded by Janssen, a Johnson & Johnson company, with NIAID and the Bill and Melinda Gates Foundation.

A version of this article first appeared on Medscape.com.

Hepatocellular cancer (HCC) is the most common type of hepatic cancers, accounting for 65% of all hepatic cancers.¹ Among all cancers, HCC is one of the fastest growing causes of death in the United States, and the rate of new HCC cases are on the rise over several decades.² There are many risk factors leading to HCC, including alcohol use, obesity, and smoking. Infection with hepatitis C virus (HCV) poses a significant risk.¹

The pathogenesis of HCV-induced carcinogenesis is mediated by a unique host-induced immunologic response. Viral replication induces production of inflammatory factors, such as tumor necrosis factor (TNF-α), interferon (IFN), and oxidative stress on hepatocytes, resulting in cell injury, death, and regeneration. Repetitive cycles of cellular death and regeneration induce fibrosis, which may lead to cirrhosis.³ Hence, early treatment of HCV infection and achieving sustained virologic response (SVR) may lead to decreased incidence and mortality associated with HCC.

Treatment of HCV infection has become more effective with the development of direct-acting antivirals (DAAs) leading to SVR in > 90% of patients compared with 40 to 50% with IFN-based treatment.^4,5 DAAs have been proved safe and highly effective in eradicating HCV infection even in patients with advanced liver disease with decompensated cirrhosis.⁶ Although achieving SVR indicates a complete cure from chronic HCV infection, several studies have shown subsequent risk of developing HCC persists even after successful HCV treatment.^7-9 Some studies show that using DAAs to achieve SVR in patients with HCV infection leads to a decreased relative risk of HCC development compared with patients who do not receive treatment.^10-12 But data on HCC risk following DAA-induced SVR vs IFN-induced SVR are somewhat conflicting.

Much of the information regarding the association between SVR and HCC has been gleaned from large data banks without accounting for individual patient characteristics that can be obtained through full chart review. Due to small sample sizes in many chart review studies, the impact that SVR from DAA therapy has on the progression and severity of HCC is not entirely clear. The aim of our study is to evaluate the effect of HCV treatment and SVR status on overall survival (OS) in patients with HCC. Second, we aim to compare survival benefits, if any exist, among the 2 major HCV treatment modalities (IFN vs DAA).

Methods

We performed a retrospective review of patients at Memphis Veterans Affairs Medical Center (VAMC) in Tennessee to determine whether treatment for HCV infection in general, and achieving SVR in particular, makes a difference in progression, recurrence, or OS among patients with HCV infection who develop HCC. We identified 111 patients with a diagnosis of both HCV and new or recurrent HCC lesions from November 2008 to March 2019 (Table 1). We divided these patients based on their HCV treatment status, SVR status, and treatment types (IFN vs DAA).

The inclusion criteria were patients aged > 18 years treated at the Memphis VAMC who have HCV infection and developed HCC. Exclusion criteria were patients who developed HCC from other causes such as alcoholic steatohepatitis, hepatitis B virus infection, hemochromatosis, patients without HCV infection, and patients who were not established at the Memphis VAMC. This protocol was approved by the Memphis VAMC Institutional Review Board.

Statistical Analysis

OS was measured from the date of HCC diagnosis to the date of death or last follow-up. Progression-free survival (PFS) was defined from the date of HCC treatment initiation to the date of first HCC recurrence. We compared survival data for the SVR and non-SVR subgroups, the HCV treatment vs non-HCV treatment subgroups, and the IFN therapy vs DAA therapy subgroups, using the Kaplan-Meier method. The differences between subgroups were assessed using a log-rank test. Multivariate analysis using Cox proportional hazards regression model was used to identify factors that had significant impact on OS. Those factors included age; race; alcohol, tobacco, and illicit drug use; SVR status; HCV treatment status; IFN-based regimen vs DAA; MELD, and Child-Pugh scores. The results were expressed as hazard ratios (HRs) and 95% CI. Calculations were made using Statistical Analysis SAS and IBM SPSS software.

Results

The study included 111 patients. The mean age was 65.7 years; all were male and half of were Black patients. The gender imbalance was due to the predominantly male patient population at Memphis VAMC. Among 111 patients with HCV infection and HCC, 68 patients were treated for HCV infection and had significantly improved OS and PFS compared with the nontreatment group. The median 5-year OS was 44.6 months (95% CI, 966-3202) in the treated HCV infection group compared with 15.1 months in the untreated HCV infection group with a Wilcoxon P = .0005 (Figure 1). Similarly, patients treated for HCV infection had a significantly better 5-year PFS of 15.3 months (95% CI, 294-726) compared with the nontreatment group 9.5 months (95% CI, 205-405) with a Wilcoxon P = .04 (Figure 2).

Among 68 patients treated for HCV infection, 51 achieved SVR, and 34 achieved SVR after the diagnosis of HCC. Patients who achieved SVR had an improved 5-year OS when compared with patients who did not achieve SVR (median 65.8 months [95% CI, 1222-NA] vs 15.7 months [95% CI, 242-853], Wilcoxon P < .001) (Figure 3). Similarly, patients with SVR had improved 5-year PFS when compared with the non-SVR group (median 20.5 months [95% CI, 431-914] vs 8.9 months [95% CI, 191-340], Wilcoxon P = .007 (Figure 4). Achievement of SVR after HCC diagnosis suggests a significantly improved OS (HR 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI, 0.23-1.82, P = .41)

Discussion

The survival benefit of HCV eradication and achieving SVR status has been well established in patients with HCC.¹³ In a retrospective cohort study of 250 patients with HCV infection who had received curative treatment for HCC, multivariate analysis demonstrated that achieving SVR is an independent predictor of OS.¹⁴ The 3-year and 5-year OS rates were 97% and 94% for the SVR group, and 91% and 60% for the non‐SVR group, respectively (P < .001). Similarly, according to Sou and colleagues, of 122 patients with HCV-related HCC, patients with SVR had longer OS than patients with no SVR (P = .04).¹⁵ One of the hypotheses that could explain the survival benefit in patients who achieved SVR is the effect of achieving SVR in reducing persistent liver inflammation and associated liver mortality, and therefore lowering risks of complication in patients with HCC.¹⁶ In our study, multivariate analysis shows that achieving SVR is associated with significant improved OS (HR, 0.33). In contrast, patients with HCC who have not achieved SVR are associated with worse survival (HR, 3.24). This finding supports early treatment of HCV to obtain SVR in HCV-related patients with HCC, even after development of HCC.

Among 68 patients treated for HCV infection, 45 patients were treated after HCC diagnosis, and 34 patients achieved SVR after HCC diagnosis. The average time between HCV infection treatment after HCC diagnosis was 6 months. Our data suggested that achievement of SVR after HCC diagnosis suggests an improved OS (HR, 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI,0.23-1.82; P = .41). This lack of statistical significance is likely due to small sample size of patients achieving SVR prior to HCC diagnosis. Our results are consistent with the findings regarding the efficacy and timing of DAA treatment in patients with active HCC. According to Singal and colleagues, achieving SVR after DAA therapy may result in improved liver function and facilitate additional HCC-directed therapy, which potentially improves survival.^17-19

Nagaoki and colleagues found that there was no significant difference in OS in patients with HCC between the DAA and IFN groups. According to the study, the 3-year and 5-year OS rates were 96% and 96% for DAA patients and 93% and 73% for IFN patients, respectively (P = .16).¹⁴ This finding is consistent with the results of our study. HCV treatment type (IFN vs DAA) was not found to be associated with either OS or PFS time, regardless of time period.

Limitations

Our findings were limited in that our study population is too small to conduct further subset analysis that would allow statistical significance of those subsets, such as the suggested benefit of SVR in patients who presented with HCC after antiviral therapy. Another limitation is the all-male population, likely a result of the older veteran population at the Memphis VAMC. The mean age at diagnosis was 65 years, which is slightly higher than the general population. Compared to the SEER database, HCC is most frequently diagnosed among people aged 55 to 64 years.²³ The age difference was likely due to our aging veteran population.

Further studies are needed to determine the significance of SVR on HCC recurrence and treatment. Immunotherapy is now first-line treatment for patients with local advanced HCC. All the immunotherapy studies excluded patients with active HCV infection. Hence, we need more data on HCV treatment timing among patients scheduled to start treatment with immunotherapy.

Conclusions

In a population of older veterans, treatment of HCV infection leads to OS benefit among patients with HCC. In addition, patients with HCV infection who achieve SVR have an OS benefit over patients unable to achieve SVR. The type of treatment, DAA vs IFN-based regimen, did not show significant survival benefit.

Hepatocellular cancer (HCC) is the most common type of hepatic cancers, accounting for 65% of all hepatic cancers.¹ Among all cancers, HCC is one of the fastest growing causes of death in the United States, and the rate of new HCC cases are on the rise over several decades.² There are many risk factors leading to HCC, including alcohol use, obesity, and smoking. Infection with hepatitis C virus (HCV) poses a significant risk.¹

The pathogenesis of HCV-induced carcinogenesis is mediated by a unique host-induced immunologic response. Viral replication induces production of inflammatory factors, such as tumor necrosis factor (TNF-α), interferon (IFN), and oxidative stress on hepatocytes, resulting in cell injury, death, and regeneration. Repetitive cycles of cellular death and regeneration induce fibrosis, which may lead to cirrhosis.³ Hence, early treatment of HCV infection and achieving sustained virologic response (SVR) may lead to decreased incidence and mortality associated with HCC.

Treatment of HCV infection has become more effective with the development of direct-acting antivirals (DAAs) leading to SVR in > 90% of patients compared with 40 to 50% with IFN-based treatment.^4,5 DAAs have been proved safe and highly effective in eradicating HCV infection even in patients with advanced liver disease with decompensated cirrhosis.⁶ Although achieving SVR indicates a complete cure from chronic HCV infection, several studies have shown subsequent risk of developing HCC persists even after successful HCV treatment.^7-9 Some studies show that using DAAs to achieve SVR in patients with HCV infection leads to a decreased relative risk of HCC development compared with patients who do not receive treatment.^10-12 But data on HCC risk following DAA-induced SVR vs IFN-induced SVR are somewhat conflicting.

Much of the information regarding the association between SVR and HCC has been gleaned from large data banks without accounting for individual patient characteristics that can be obtained through full chart review. Due to small sample sizes in many chart review studies, the impact that SVR from DAA therapy has on the progression and severity of HCC is not entirely clear. The aim of our study is to evaluate the effect of HCV treatment and SVR status on overall survival (OS) in patients with HCC. Second, we aim to compare survival benefits, if any exist, among the 2 major HCV treatment modalities (IFN vs DAA).

Methods

We performed a retrospective review of patients at Memphis Veterans Affairs Medical Center (VAMC) in Tennessee to determine whether treatment for HCV infection in general, and achieving SVR in particular, makes a difference in progression, recurrence, or OS among patients with HCV infection who develop HCC. We identified 111 patients with a diagnosis of both HCV and new or recurrent HCC lesions from November 2008 to March 2019 (Table 1). We divided these patients based on their HCV treatment status, SVR status, and treatment types (IFN vs DAA).

The inclusion criteria were patients aged > 18 years treated at the Memphis VAMC who have HCV infection and developed HCC. Exclusion criteria were patients who developed HCC from other causes such as alcoholic steatohepatitis, hepatitis B virus infection, hemochromatosis, patients without HCV infection, and patients who were not established at the Memphis VAMC. This protocol was approved by the Memphis VAMC Institutional Review Board.

Statistical Analysis

OS was measured from the date of HCC diagnosis to the date of death or last follow-up. Progression-free survival (PFS) was defined from the date of HCC treatment initiation to the date of first HCC recurrence. We compared survival data for the SVR and non-SVR subgroups, the HCV treatment vs non-HCV treatment subgroups, and the IFN therapy vs DAA therapy subgroups, using the Kaplan-Meier method. The differences between subgroups were assessed using a log-rank test. Multivariate analysis using Cox proportional hazards regression model was used to identify factors that had significant impact on OS. Those factors included age; race; alcohol, tobacco, and illicit drug use; SVR status; HCV treatment status; IFN-based regimen vs DAA; MELD, and Child-Pugh scores. The results were expressed as hazard ratios (HRs) and 95% CI. Calculations were made using Statistical Analysis SAS and IBM SPSS software.

Results

The study included 111 patients. The mean age was 65.7 years; all were male and half of were Black patients. The gender imbalance was due to the predominantly male patient population at Memphis VAMC. Among 111 patients with HCV infection and HCC, 68 patients were treated for HCV infection and had significantly improved OS and PFS compared with the nontreatment group. The median 5-year OS was 44.6 months (95% CI, 966-3202) in the treated HCV infection group compared with 15.1 months in the untreated HCV infection group with a Wilcoxon P = .0005 (Figure 1). Similarly, patients treated for HCV infection had a significantly better 5-year PFS of 15.3 months (95% CI, 294-726) compared with the nontreatment group 9.5 months (95% CI, 205-405) with a Wilcoxon P = .04 (Figure 2).

Among 68 patients treated for HCV infection, 51 achieved SVR, and 34 achieved SVR after the diagnosis of HCC. Patients who achieved SVR had an improved 5-year OS when compared with patients who did not achieve SVR (median 65.8 months [95% CI, 1222-NA] vs 15.7 months [95% CI, 242-853], Wilcoxon P < .001) (Figure 3). Similarly, patients with SVR had improved 5-year PFS when compared with the non-SVR group (median 20.5 months [95% CI, 431-914] vs 8.9 months [95% CI, 191-340], Wilcoxon P = .007 (Figure 4). Achievement of SVR after HCC diagnosis suggests a significantly improved OS (HR 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI, 0.23-1.82, P = .41)

Discussion

The survival benefit of HCV eradication and achieving SVR status has been well established in patients with HCC.¹³ In a retrospective cohort study of 250 patients with HCV infection who had received curative treatment for HCC, multivariate analysis demonstrated that achieving SVR is an independent predictor of OS.¹⁴ The 3-year and 5-year OS rates were 97% and 94% for the SVR group, and 91% and 60% for the non‐SVR group, respectively (P < .001). Similarly, according to Sou and colleagues, of 122 patients with HCV-related HCC, patients with SVR had longer OS than patients with no SVR (P = .04).¹⁵ One of the hypotheses that could explain the survival benefit in patients who achieved SVR is the effect of achieving SVR in reducing persistent liver inflammation and associated liver mortality, and therefore lowering risks of complication in patients with HCC.¹⁶ In our study, multivariate analysis shows that achieving SVR is associated with significant improved OS (HR, 0.33). In contrast, patients with HCC who have not achieved SVR are associated with worse survival (HR, 3.24). This finding supports early treatment of HCV to obtain SVR in HCV-related patients with HCC, even after development of HCC.

Among 68 patients treated for HCV infection, 45 patients were treated after HCC diagnosis, and 34 patients achieved SVR after HCC diagnosis. The average time between HCV infection treatment after HCC diagnosis was 6 months. Our data suggested that achievement of SVR after HCC diagnosis suggests an improved OS (HR, 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI,0.23-1.82; P = .41). This lack of statistical significance is likely due to small sample size of patients achieving SVR prior to HCC diagnosis. Our results are consistent with the findings regarding the efficacy and timing of DAA treatment in patients with active HCC. According to Singal and colleagues, achieving SVR after DAA therapy may result in improved liver function and facilitate additional HCC-directed therapy, which potentially improves survival.^17-19

Nagaoki and colleagues found that there was no significant difference in OS in patients with HCC between the DAA and IFN groups. According to the study, the 3-year and 5-year OS rates were 96% and 96% for DAA patients and 93% and 73% for IFN patients, respectively (P = .16).¹⁴ This finding is consistent with the results of our study. HCV treatment type (IFN vs DAA) was not found to be associated with either OS or PFS time, regardless of time period.

Limitations

Our findings were limited in that our study population is too small to conduct further subset analysis that would allow statistical significance of those subsets, such as the suggested benefit of SVR in patients who presented with HCC after antiviral therapy. Another limitation is the all-male population, likely a result of the older veteran population at the Memphis VAMC. The mean age at diagnosis was 65 years, which is slightly higher than the general population. Compared to the SEER database, HCC is most frequently diagnosed among people aged 55 to 64 years.²³ The age difference was likely due to our aging veteran population.

Further studies are needed to determine the significance of SVR on HCC recurrence and treatment. Immunotherapy is now first-line treatment for patients with local advanced HCC. All the immunotherapy studies excluded patients with active HCV infection. Hence, we need more data on HCV treatment timing among patients scheduled to start treatment with immunotherapy.

Conclusions

In a population of older veterans, treatment of HCV infection leads to OS benefit among patients with HCC. In addition, patients with HCV infection who achieve SVR have an OS benefit over patients unable to achieve SVR. The type of treatment, DAA vs IFN-based regimen, did not show significant survival benefit.

Hepatocellular cancer (HCC) is the most common type of hepatic cancers, accounting for 65% of all hepatic cancers.¹ Among all cancers, HCC is one of the fastest growing causes of death in the United States, and the rate of new HCC cases are on the rise over several decades.² There are many risk factors leading to HCC, including alcohol use, obesity, and smoking. Infection with hepatitis C virus (HCV) poses a significant risk.¹

The pathogenesis of HCV-induced carcinogenesis is mediated by a unique host-induced immunologic response. Viral replication induces production of inflammatory factors, such as tumor necrosis factor (TNF-α), interferon (IFN), and oxidative stress on hepatocytes, resulting in cell injury, death, and regeneration. Repetitive cycles of cellular death and regeneration induce fibrosis, which may lead to cirrhosis.³ Hence, early treatment of HCV infection and achieving sustained virologic response (SVR) may lead to decreased incidence and mortality associated with HCC.

Treatment of HCV infection has become more effective with the development of direct-acting antivirals (DAAs) leading to SVR in > 90% of patients compared with 40 to 50% with IFN-based treatment.^4,5 DAAs have been proved safe and highly effective in eradicating HCV infection even in patients with advanced liver disease with decompensated cirrhosis.⁶ Although achieving SVR indicates a complete cure from chronic HCV infection, several studies have shown subsequent risk of developing HCC persists even after successful HCV treatment.^7-9 Some studies show that using DAAs to achieve SVR in patients with HCV infection leads to a decreased relative risk of HCC development compared with patients who do not receive treatment.^10-12 But data on HCC risk following DAA-induced SVR vs IFN-induced SVR are somewhat conflicting.

Much of the information regarding the association between SVR and HCC has been gleaned from large data banks without accounting for individual patient characteristics that can be obtained through full chart review. Due to small sample sizes in many chart review studies, the impact that SVR from DAA therapy has on the progression and severity of HCC is not entirely clear. The aim of our study is to evaluate the effect of HCV treatment and SVR status on overall survival (OS) in patients with HCC. Second, we aim to compare survival benefits, if any exist, among the 2 major HCV treatment modalities (IFN vs DAA).

Methods

We performed a retrospective review of patients at Memphis Veterans Affairs Medical Center (VAMC) in Tennessee to determine whether treatment for HCV infection in general, and achieving SVR in particular, makes a difference in progression, recurrence, or OS among patients with HCV infection who develop HCC. We identified 111 patients with a diagnosis of both HCV and new or recurrent HCC lesions from November 2008 to March 2019 (Table 1). We divided these patients based on their HCV treatment status, SVR status, and treatment types (IFN vs DAA).

The inclusion criteria were patients aged > 18 years treated at the Memphis VAMC who have HCV infection and developed HCC. Exclusion criteria were patients who developed HCC from other causes such as alcoholic steatohepatitis, hepatitis B virus infection, hemochromatosis, patients without HCV infection, and patients who were not established at the Memphis VAMC. This protocol was approved by the Memphis VAMC Institutional Review Board.

Statistical Analysis

OS was measured from the date of HCC diagnosis to the date of death or last follow-up. Progression-free survival (PFS) was defined from the date of HCC treatment initiation to the date of first HCC recurrence. We compared survival data for the SVR and non-SVR subgroups, the HCV treatment vs non-HCV treatment subgroups, and the IFN therapy vs DAA therapy subgroups, using the Kaplan-Meier method. The differences between subgroups were assessed using a log-rank test. Multivariate analysis using Cox proportional hazards regression model was used to identify factors that had significant impact on OS. Those factors included age; race; alcohol, tobacco, and illicit drug use; SVR status; HCV treatment status; IFN-based regimen vs DAA; MELD, and Child-Pugh scores. The results were expressed as hazard ratios (HRs) and 95% CI. Calculations were made using Statistical Analysis SAS and IBM SPSS software.

Results

The study included 111 patients. The mean age was 65.7 years; all were male and half of were Black patients. The gender imbalance was due to the predominantly male patient population at Memphis VAMC. Among 111 patients with HCV infection and HCC, 68 patients were treated for HCV infection and had significantly improved OS and PFS compared with the nontreatment group. The median 5-year OS was 44.6 months (95% CI, 966-3202) in the treated HCV infection group compared with 15.1 months in the untreated HCV infection group with a Wilcoxon P = .0005 (Figure 1). Similarly, patients treated for HCV infection had a significantly better 5-year PFS of 15.3 months (95% CI, 294-726) compared with the nontreatment group 9.5 months (95% CI, 205-405) with a Wilcoxon P = .04 (Figure 2).

Among 68 patients treated for HCV infection, 51 achieved SVR, and 34 achieved SVR after the diagnosis of HCC. Patients who achieved SVR had an improved 5-year OS when compared with patients who did not achieve SVR (median 65.8 months [95% CI, 1222-NA] vs 15.7 months [95% CI, 242-853], Wilcoxon P < .001) (Figure 3). Similarly, patients with SVR had improved 5-year PFS when compared with the non-SVR group (median 20.5 months [95% CI, 431-914] vs 8.9 months [95% CI, 191-340], Wilcoxon P = .007 (Figure 4). Achievement of SVR after HCC diagnosis suggests a significantly improved OS (HR 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI, 0.23-1.82, P = .41)

Discussion

The survival benefit of HCV eradication and achieving SVR status has been well established in patients with HCC.¹³ In a retrospective cohort study of 250 patients with HCV infection who had received curative treatment for HCC, multivariate analysis demonstrated that achieving SVR is an independent predictor of OS.¹⁴ The 3-year and 5-year OS rates were 97% and 94% for the SVR group, and 91% and 60% for the non‐SVR group, respectively (P < .001). Similarly, according to Sou and colleagues, of 122 patients with HCV-related HCC, patients with SVR had longer OS than patients with no SVR (P = .04).¹⁵ One of the hypotheses that could explain the survival benefit in patients who achieved SVR is the effect of achieving SVR in reducing persistent liver inflammation and associated liver mortality, and therefore lowering risks of complication in patients with HCC.¹⁶ In our study, multivariate analysis shows that achieving SVR is associated with significant improved OS (HR, 0.33). In contrast, patients with HCC who have not achieved SVR are associated with worse survival (HR, 3.24). This finding supports early treatment of HCV to obtain SVR in HCV-related patients with HCC, even after development of HCC.

Among 68 patients treated for HCV infection, 45 patients were treated after HCC diagnosis, and 34 patients achieved SVR after HCC diagnosis. The average time between HCV infection treatment after HCC diagnosis was 6 months. Our data suggested that achievement of SVR after HCC diagnosis suggests an improved OS (HR, 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI,0.23-1.82; P = .41). This lack of statistical significance is likely due to small sample size of patients achieving SVR prior to HCC diagnosis. Our results are consistent with the findings regarding the efficacy and timing of DAA treatment in patients with active HCC. According to Singal and colleagues, achieving SVR after DAA therapy may result in improved liver function and facilitate additional HCC-directed therapy, which potentially improves survival.^17-19

Nagaoki and colleagues found that there was no significant difference in OS in patients with HCC between the DAA and IFN groups. According to the study, the 3-year and 5-year OS rates were 96% and 96% for DAA patients and 93% and 73% for IFN patients, respectively (P = .16).¹⁴ This finding is consistent with the results of our study. HCV treatment type (IFN vs DAA) was not found to be associated with either OS or PFS time, regardless of time period.

Limitations

Our findings were limited in that our study population is too small to conduct further subset analysis that would allow statistical significance of those subsets, such as the suggested benefit of SVR in patients who presented with HCC after antiviral therapy. Another limitation is the all-male population, likely a result of the older veteran population at the Memphis VAMC. The mean age at diagnosis was 65 years, which is slightly higher than the general population. Compared to the SEER database, HCC is most frequently diagnosed among people aged 55 to 64 years.²³ The age difference was likely due to our aging veteran population.

Further studies are needed to determine the significance of SVR on HCC recurrence and treatment. Immunotherapy is now first-line treatment for patients with local advanced HCC. All the immunotherapy studies excluded patients with active HCV infection. Hence, we need more data on HCV treatment timing among patients scheduled to start treatment with immunotherapy.

Conclusions

In a population of older veterans, treatment of HCV infection leads to OS benefit among patients with HCC. In addition, patients with HCV infection who achieve SVR have an OS benefit over patients unable to achieve SVR. The type of treatment, DAA vs IFN-based regimen, did not show significant survival benefit.

Many Americans are clamoring for a booster dose of a COVID-19 vaccine after reports of rising numbers of breakthrough infections, and demand increased after the Biden administration said those shots would be offered starting on Sept. 20.

That plan, which was first announced on Aug. 18, has raised eyebrows because it comes in advance of regulatory reviews by the Food and Drug Administration and recommendations from the Centers for Disease Control and Prevention. Those reviews are needed to determine whether third doses of these vaccines are effective or even safe. The move could have important legal ramifications for doctors and patients, too.

On Aug. 31, two high-level officials in the FDA’s Office of Vaccines Research and Review abruptly resigned amid reports that they were angry that the Biden administration was making decisions that should be left up to that agency.

So far, data show that the vaccines are highly effective at preventing the most severe consequences of COVID-19 – hospitalization and death – even regarding the Delta variant. The World Health Organization has urged wealthy nations such as the United States not to offer boosters so that the limited supply of vaccines can be directed to countries with fewer resources.
 

White House supports boosters

In a recent press briefing, Jeff Zients, the White House COVID-19 response coordinator, defended the move.

“You know, the booster decision, which you referenced ... was made by and announced by the nation’s leading public health officials, including Dr. Walensky; Dr. Fauci; Surgeon General Vivek Murthy; Dr. Janet Woodcock; the FDA acting commissioner, Dr. Francis Collins; Dr. Kessler; and others,” Mr. Zients said.

“And as our medical experts laid out, having reviewed all of the available data, it is in their clinical judgment that it is time to prepare Americans for a booster shot.”

He said a target date of Sept. 20 was announced so as to give states and practitioners time to prepare. He also said the move to give boosters was meant to help the United States stay ahead of a rapidly changing virus. Mr. Zients added that whether boosters will be administered starting on Sept. 20 depends on the FDA’s and CDC’s giving the go-ahead.

“Booster doses are going to be handled the same way all vaccines are handled,” said Kristen Nordlund, a CDC spokesperson. “Companies will have to provide data to FDA. FDA will have to make a decision and authorize the use of those, and ACIP [the Advisory Committee on Immunization Practices] will have to look at the evidence as well and make recommendations on top of FDA’s regulatory action,” she said.

Ms. Nordlund agreed that the planned Sept. 20 start date for boosters was something to which they aspired and was not necessarily set.

Historically, the FDA has needed at least 4 months to review a change to a vaccine’s approval, even on an accelerated schedule. Reviewers use that time to assess data regarding individual patients in a study, to review raw data, and essentially to check a drug company’s math and conclusions. The Biden administration’s timeline would shorten that review period from months to just a few weeks.
 

‘FDA in a very difficult position’

After the FDA approves, the ACIP of the CDC must meet to review the evidence and make recommendations on the use of the boosters in the United States.

Pfizer says it completed its submission for a supplemental biologics license application to the FDA on Aug. 27. To meet a Sept. 20 timeline, the entire process would have to be completed within 3 weeks.

“I don’t think that was handled, you know, ideally,” said Peter Lurie, MD, president of the Center for Science in the Public Interest and former associate commissioner of public health strategy and analysis at the FDA.

“It puts FDA in a very difficult position,” Dr. Lurie said. “It’s almost as if the decision has been made and they’re just checking a box, and that is, you know, contrary to the what FDA – at least the internal people at FDA – have been trying to do for ages.”

He said the agency took great pains with the emergency use authorizations and the full approvals of the vaccines to work as rapidly but thoroughly as possible. They did not skip steps.

“I think all of that reflected very well on the agency,” Dr. Lurie said. “And I think it worked out well in terms of trust in the vaccines.”

Although additional doses of vaccine are expected to be safe, little is known about side effects or adverse events after a third dose.

“It’s critical to wait for additional data and regulatory allowance for booster doses,” Sara Oliver, MD, a member of the CDC’s epidemic intelligence service, said in an Aug. 30 presentation to the ACIP, which is charged with making recommendations for use of all vaccines in the United States.
 

Boosters already being given

But after the White House announced that boosters were on the way, many people are not waiting.

Many health care practitioners and pharmacies have already been giving people third doses of vaccines, even if they are not among the immunocompromised – the group for which the shots are currently approved.

“You can walk into a pharmacy and ask for a third dose. Depending on which pharmacy you go to, you may get it,” said Helen Talbot, MD, associate professor of medicine at Vanderbilt University, Nashville, Tenn., and a member of the ACIP.

She says she has a friend who recently went for a checkup and was offered a third dose. His physician is already giving extra doses to everyone who is older than 65.

Dr. Talbot said that in fairness, pharmacies in the United States are throwing away doses of vaccine because they are expiring before they get used.

“Many of us may or may not be ready to give a third dose but would rather give someone a third dose than throw a vaccine away,” she said.
 

Consequences of a third shot

But giving or getting a third dose before approval by the FDA may have legal consequences.

In the ACIP meeting on Aug. 30, Demetre Daskalakis, MD, who leads vaccine equity efforts at the CDC, cautioned that physicians who give extra doses of the vaccine before the FDA and CDC have signed off may be in violation of practitioner agreements with the federal government and might not be covered by the federal PREP Act. The PREP Act provides immunity from lawsuits for people who administer COVID-19 vaccines and compensates patients in the event of injury. Patients who get a vaccine and suffer a rare but serious side effect may lose the ability to claim compensation offered by the act.

“Many of us gasped when he said that,” Dr. Talbot said, “because that’s a big deal.”

The ACIP signaled that it is considering recommending boosters for a much narrower slice of the American population than the Biden administration has suggested.

They said that so far, the data point only to the need for boosters for seniors, who are the patients most likely to experience breakthrough infections that require hospitalization, and health care workers, who are needed now more than ever and cannot work if they’re sick.

In a White House news briefing Aug. 31, CDC Director Rochelle Walensky, MD, was asked about the ACIP’s conclusions and whether she believed there were enough data to recommend booster shots for most Americans 8 months after their last dose.

“The ACIP did not review international data that actually has led us to be even more concerned about increased risk of vaccine effectiveness waning against hospitalization, severe disease, and death. They will be reviewing that as well,” she said.

A version of this article first appeared on Medscape.com.

Many Americans are clamoring for a booster dose of a COVID-19 vaccine after reports of rising numbers of breakthrough infections, and demand increased after the Biden administration said those shots would be offered starting on Sept. 20.

That plan, which was first announced on Aug. 18, has raised eyebrows because it comes in advance of regulatory reviews by the Food and Drug Administration and recommendations from the Centers for Disease Control and Prevention. Those reviews are needed to determine whether third doses of these vaccines are effective or even safe. The move could have important legal ramifications for doctors and patients, too.

On Aug. 31, two high-level officials in the FDA’s Office of Vaccines Research and Review abruptly resigned amid reports that they were angry that the Biden administration was making decisions that should be left up to that agency.

So far, data show that the vaccines are highly effective at preventing the most severe consequences of COVID-19 – hospitalization and death – even regarding the Delta variant. The World Health Organization has urged wealthy nations such as the United States not to offer boosters so that the limited supply of vaccines can be directed to countries with fewer resources.
 

White House supports boosters

In a recent press briefing, Jeff Zients, the White House COVID-19 response coordinator, defended the move.

“You know, the booster decision, which you referenced ... was made by and announced by the nation’s leading public health officials, including Dr. Walensky; Dr. Fauci; Surgeon General Vivek Murthy; Dr. Janet Woodcock; the FDA acting commissioner, Dr. Francis Collins; Dr. Kessler; and others,” Mr. Zients said.

“And as our medical experts laid out, having reviewed all of the available data, it is in their clinical judgment that it is time to prepare Americans for a booster shot.”

He said a target date of Sept. 20 was announced so as to give states and practitioners time to prepare. He also said the move to give boosters was meant to help the United States stay ahead of a rapidly changing virus. Mr. Zients added that whether boosters will be administered starting on Sept. 20 depends on the FDA’s and CDC’s giving the go-ahead.

“Booster doses are going to be handled the same way all vaccines are handled,” said Kristen Nordlund, a CDC spokesperson. “Companies will have to provide data to FDA. FDA will have to make a decision and authorize the use of those, and ACIP [the Advisory Committee on Immunization Practices] will have to look at the evidence as well and make recommendations on top of FDA’s regulatory action,” she said.

Ms. Nordlund agreed that the planned Sept. 20 start date for boosters was something to which they aspired and was not necessarily set.

Historically, the FDA has needed at least 4 months to review a change to a vaccine’s approval, even on an accelerated schedule. Reviewers use that time to assess data regarding individual patients in a study, to review raw data, and essentially to check a drug company’s math and conclusions. The Biden administration’s timeline would shorten that review period from months to just a few weeks.
 

‘FDA in a very difficult position’

After the FDA approves, the ACIP of the CDC must meet to review the evidence and make recommendations on the use of the boosters in the United States.

Pfizer says it completed its submission for a supplemental biologics license application to the FDA on Aug. 27. To meet a Sept. 20 timeline, the entire process would have to be completed within 3 weeks.

“I don’t think that was handled, you know, ideally,” said Peter Lurie, MD, president of the Center for Science in the Public Interest and former associate commissioner of public health strategy and analysis at the FDA.

“It puts FDA in a very difficult position,” Dr. Lurie said. “It’s almost as if the decision has been made and they’re just checking a box, and that is, you know, contrary to the what FDA – at least the internal people at FDA – have been trying to do for ages.”

He said the agency took great pains with the emergency use authorizations and the full approvals of the vaccines to work as rapidly but thoroughly as possible. They did not skip steps.

“I think all of that reflected very well on the agency,” Dr. Lurie said. “And I think it worked out well in terms of trust in the vaccines.”

Although additional doses of vaccine are expected to be safe, little is known about side effects or adverse events after a third dose.

“It’s critical to wait for additional data and regulatory allowance for booster doses,” Sara Oliver, MD, a member of the CDC’s epidemic intelligence service, said in an Aug. 30 presentation to the ACIP, which is charged with making recommendations for use of all vaccines in the United States.
 

Boosters already being given

But after the White House announced that boosters were on the way, many people are not waiting.

Many health care practitioners and pharmacies have already been giving people third doses of vaccines, even if they are not among the immunocompromised – the group for which the shots are currently approved.

“You can walk into a pharmacy and ask for a third dose. Depending on which pharmacy you go to, you may get it,” said Helen Talbot, MD, associate professor of medicine at Vanderbilt University, Nashville, Tenn., and a member of the ACIP.

She says she has a friend who recently went for a checkup and was offered a third dose. His physician is already giving extra doses to everyone who is older than 65.

Dr. Talbot said that in fairness, pharmacies in the United States are throwing away doses of vaccine because they are expiring before they get used.

“Many of us may or may not be ready to give a third dose but would rather give someone a third dose than throw a vaccine away,” she said.
 

Consequences of a third shot

But giving or getting a third dose before approval by the FDA may have legal consequences.

In the ACIP meeting on Aug. 30, Demetre Daskalakis, MD, who leads vaccine equity efforts at the CDC, cautioned that physicians who give extra doses of the vaccine before the FDA and CDC have signed off may be in violation of practitioner agreements with the federal government and might not be covered by the federal PREP Act. The PREP Act provides immunity from lawsuits for people who administer COVID-19 vaccines and compensates patients in the event of injury. Patients who get a vaccine and suffer a rare but serious side effect may lose the ability to claim compensation offered by the act.

“Many of us gasped when he said that,” Dr. Talbot said, “because that’s a big deal.”

The ACIP signaled that it is considering recommending boosters for a much narrower slice of the American population than the Biden administration has suggested.

They said that so far, the data point only to the need for boosters for seniors, who are the patients most likely to experience breakthrough infections that require hospitalization, and health care workers, who are needed now more than ever and cannot work if they’re sick.

In a White House news briefing Aug. 31, CDC Director Rochelle Walensky, MD, was asked about the ACIP’s conclusions and whether she believed there were enough data to recommend booster shots for most Americans 8 months after their last dose.

“The ACIP did not review international data that actually has led us to be even more concerned about increased risk of vaccine effectiveness waning against hospitalization, severe disease, and death. They will be reviewing that as well,” she said.

A version of this article first appeared on Medscape.com.

Many Americans are clamoring for a booster dose of a COVID-19 vaccine after reports of rising numbers of breakthrough infections, and demand increased after the Biden administration said those shots would be offered starting on Sept. 20.

That plan, which was first announced on Aug. 18, has raised eyebrows because it comes in advance of regulatory reviews by the Food and Drug Administration and recommendations from the Centers for Disease Control and Prevention. Those reviews are needed to determine whether third doses of these vaccines are effective or even safe. The move could have important legal ramifications for doctors and patients, too.

On Aug. 31, two high-level officials in the FDA’s Office of Vaccines Research and Review abruptly resigned amid reports that they were angry that the Biden administration was making decisions that should be left up to that agency.

So far, data show that the vaccines are highly effective at preventing the most severe consequences of COVID-19 – hospitalization and death – even regarding the Delta variant. The World Health Organization has urged wealthy nations such as the United States not to offer boosters so that the limited supply of vaccines can be directed to countries with fewer resources.
 

White House supports boosters

In a recent press briefing, Jeff Zients, the White House COVID-19 response coordinator, defended the move.

“You know, the booster decision, which you referenced ... was made by and announced by the nation’s leading public health officials, including Dr. Walensky; Dr. Fauci; Surgeon General Vivek Murthy; Dr. Janet Woodcock; the FDA acting commissioner, Dr. Francis Collins; Dr. Kessler; and others,” Mr. Zients said.

“And as our medical experts laid out, having reviewed all of the available data, it is in their clinical judgment that it is time to prepare Americans for a booster shot.”

He said a target date of Sept. 20 was announced so as to give states and practitioners time to prepare. He also said the move to give boosters was meant to help the United States stay ahead of a rapidly changing virus. Mr. Zients added that whether boosters will be administered starting on Sept. 20 depends on the FDA’s and CDC’s giving the go-ahead.

“Booster doses are going to be handled the same way all vaccines are handled,” said Kristen Nordlund, a CDC spokesperson. “Companies will have to provide data to FDA. FDA will have to make a decision and authorize the use of those, and ACIP [the Advisory Committee on Immunization Practices] will have to look at the evidence as well and make recommendations on top of FDA’s regulatory action,” she said.

Ms. Nordlund agreed that the planned Sept. 20 start date for boosters was something to which they aspired and was not necessarily set.

Historically, the FDA has needed at least 4 months to review a change to a vaccine’s approval, even on an accelerated schedule. Reviewers use that time to assess data regarding individual patients in a study, to review raw data, and essentially to check a drug company’s math and conclusions. The Biden administration’s timeline would shorten that review period from months to just a few weeks.
 

‘FDA in a very difficult position’

After the FDA approves, the ACIP of the CDC must meet to review the evidence and make recommendations on the use of the boosters in the United States.

Pfizer says it completed its submission for a supplemental biologics license application to the FDA on Aug. 27. To meet a Sept. 20 timeline, the entire process would have to be completed within 3 weeks.

“I don’t think that was handled, you know, ideally,” said Peter Lurie, MD, president of the Center for Science in the Public Interest and former associate commissioner of public health strategy and analysis at the FDA.

“It puts FDA in a very difficult position,” Dr. Lurie said. “It’s almost as if the decision has been made and they’re just checking a box, and that is, you know, contrary to the what FDA – at least the internal people at FDA – have been trying to do for ages.”

He said the agency took great pains with the emergency use authorizations and the full approvals of the vaccines to work as rapidly but thoroughly as possible. They did not skip steps.

“I think all of that reflected very well on the agency,” Dr. Lurie said. “And I think it worked out well in terms of trust in the vaccines.”

Although additional doses of vaccine are expected to be safe, little is known about side effects or adverse events after a third dose.

“It’s critical to wait for additional data and regulatory allowance for booster doses,” Sara Oliver, MD, a member of the CDC’s epidemic intelligence service, said in an Aug. 30 presentation to the ACIP, which is charged with making recommendations for use of all vaccines in the United States.
 

Boosters already being given

But after the White House announced that boosters were on the way, many people are not waiting.

Many health care practitioners and pharmacies have already been giving people third doses of vaccines, even if they are not among the immunocompromised – the group for which the shots are currently approved.

“You can walk into a pharmacy and ask for a third dose. Depending on which pharmacy you go to, you may get it,” said Helen Talbot, MD, associate professor of medicine at Vanderbilt University, Nashville, Tenn., and a member of the ACIP.

She says she has a friend who recently went for a checkup and was offered a third dose. His physician is already giving extra doses to everyone who is older than 65.

Dr. Talbot said that in fairness, pharmacies in the United States are throwing away doses of vaccine because they are expiring before they get used.

“Many of us may or may not be ready to give a third dose but would rather give someone a third dose than throw a vaccine away,” she said.
 

Consequences of a third shot

But giving or getting a third dose before approval by the FDA may have legal consequences.

In the ACIP meeting on Aug. 30, Demetre Daskalakis, MD, who leads vaccine equity efforts at the CDC, cautioned that physicians who give extra doses of the vaccine before the FDA and CDC have signed off may be in violation of practitioner agreements with the federal government and might not be covered by the federal PREP Act. The PREP Act provides immunity from lawsuits for people who administer COVID-19 vaccines and compensates patients in the event of injury. Patients who get a vaccine and suffer a rare but serious side effect may lose the ability to claim compensation offered by the act.

“Many of us gasped when he said that,” Dr. Talbot said, “because that’s a big deal.”

The ACIP signaled that it is considering recommending boosters for a much narrower slice of the American population than the Biden administration has suggested.

They said that so far, the data point only to the need for boosters for seniors, who are the patients most likely to experience breakthrough infections that require hospitalization, and health care workers, who are needed now more than ever and cannot work if they’re sick.

In a White House news briefing Aug. 31, CDC Director Rochelle Walensky, MD, was asked about the ACIP’s conclusions and whether she believed there were enough data to recommend booster shots for most Americans 8 months after their last dose.

“The ACIP did not review international data that actually has led us to be even more concerned about increased risk of vaccine effectiveness waning against hospitalization, severe disease, and death. They will be reviewing that as well,” she said.

A version of this article first appeared on Medscape.com.