Pulmonary Health Hub

Almost all patients with both obstructive sleep apnea syndrome and severe asthma fell into the obesity phenotype, not the allergy phenotype, based on data from nearly 1,500 adults.

Both asthma and sleep-disordered breathing are common conditions worldwide, and previous research suggests that obstructive sleep apnea syndrome (OSAS) and severe asthma in particular could be associated, wrote Laurent Portel, MD, of Centre Hospitalier de Libourne, France, and colleagues.

“Even if the underlying mechanisms are not well established, it is clear that both OSAS and obesity act to aggravate existing asthma, making it more difficult to control,” they said. However, the pathology of this relationship is not well-understood, and data on severe asthma phenotypes and OSAS are limited, they said.

In a study published in Respiratory Medicine and Research, the investigators reviewed data from 1,465 patients older than 18 years with severe asthma who were part of a larger, prospective multicenter study of the management of asthma patients. The larger study, developed by the Collège des Pneumologues des Hôpitaux Généraux (CPHG) is known as the FASE-CPHG (France Asthme SEvère-CPHG) and includes 104 nonacademic hospitals in France.

Diagnosis of OSAS was reported by physicians; diagnosis of severe asthma was based on the Global Initiative for Asthma criteria. The average age of the patients was 54.4 years, 63% were women, and 60% were nonsmokers.

A total of 161 patients were diagnosed with OSAS. The researchers conducted a cluster analysis on 1,424 patients, including 156 of the OSAS patients. They identified five clusters: early-onset atopic asthma (690 patients), obese asthma (153 patients), late-onset asthma (299 patients), eosinophilic asthma (143 patients), and aspirin sensitivity asthma (139 patients).

All 153 patients in the obese asthma cluster had OSAS, by contrast, none of the patients in the early atopic asthma cluster had OSAS.

Overall, obesity, male sex, high blood pressure, depression, late-onset asthma, and early-onset atopic asthma were independently associated with OSAS, with odds ratios of 5.782, 3.047, 2.875, 2.552, 1.789, and 0.622, respectively.

Notably, OSAS patients were more frequently treated with long-term oral corticosteroids than those without OSAS (30% vs. 15%, P < .0001), the researchers said. “It is possible that this treatment may be responsible for obesity, and it represents a well-known risk factor for developing OSAS,” they wrote.

Uncontrolled asthma was significantly more common in OSAS patients than in those without OSAS (77.7% vs. 69%, P = .03), and significantly more OSAS patients reported no or occasional physical activity (79.8% vs. 68.2%, P ≤ .001).

The study findings were limited by several factors including the lack of patients from primary care or university hospitals, which may limit the generalizability of the results, the reliance on physician statements for diagnosis of OSAS, and the lack of data on OSAS severity or treatment, the researchers noted.

However, the results fill a needed gap in the literature because of the limited data on severe asthma patients in real life, and identifying severe asthma patients by phenotype may help identify those at greatest risk for OSAS, they said.

“Identified patients could more easily benefit from specific examinations such as poly(somno)graphy and, consequently, could benefit from a better management of both asthma and OSAS,” they emphasized.

The larger FASE-CPHG study was supported in part by ALK, AstraZeneca, Boehringer Ingelheim, GSK, and Le Nouveau Souffle. The researchers had no financial conflicts to disclose.

Almost all patients with both obstructive sleep apnea syndrome and severe asthma fell into the obesity phenotype, not the allergy phenotype, based on data from nearly 1,500 adults.

Both asthma and sleep-disordered breathing are common conditions worldwide, and previous research suggests that obstructive sleep apnea syndrome (OSAS) and severe asthma in particular could be associated, wrote Laurent Portel, MD, of Centre Hospitalier de Libourne, France, and colleagues.

“Even if the underlying mechanisms are not well established, it is clear that both OSAS and obesity act to aggravate existing asthma, making it more difficult to control,” they said. However, the pathology of this relationship is not well-understood, and data on severe asthma phenotypes and OSAS are limited, they said.

In a study published in Respiratory Medicine and Research, the investigators reviewed data from 1,465 patients older than 18 years with severe asthma who were part of a larger, prospective multicenter study of the management of asthma patients. The larger study, developed by the Collège des Pneumologues des Hôpitaux Généraux (CPHG) is known as the FASE-CPHG (France Asthme SEvère-CPHG) and includes 104 nonacademic hospitals in France.

Diagnosis of OSAS was reported by physicians; diagnosis of severe asthma was based on the Global Initiative for Asthma criteria. The average age of the patients was 54.4 years, 63% were women, and 60% were nonsmokers.

A total of 161 patients were diagnosed with OSAS. The researchers conducted a cluster analysis on 1,424 patients, including 156 of the OSAS patients. They identified five clusters: early-onset atopic asthma (690 patients), obese asthma (153 patients), late-onset asthma (299 patients), eosinophilic asthma (143 patients), and aspirin sensitivity asthma (139 patients).

All 153 patients in the obese asthma cluster had OSAS, by contrast, none of the patients in the early atopic asthma cluster had OSAS.

Overall, obesity, male sex, high blood pressure, depression, late-onset asthma, and early-onset atopic asthma were independently associated with OSAS, with odds ratios of 5.782, 3.047, 2.875, 2.552, 1.789, and 0.622, respectively.

Notably, OSAS patients were more frequently treated with long-term oral corticosteroids than those without OSAS (30% vs. 15%, P < .0001), the researchers said. “It is possible that this treatment may be responsible for obesity, and it represents a well-known risk factor for developing OSAS,” they wrote.

Uncontrolled asthma was significantly more common in OSAS patients than in those without OSAS (77.7% vs. 69%, P = .03), and significantly more OSAS patients reported no or occasional physical activity (79.8% vs. 68.2%, P ≤ .001).

The study findings were limited by several factors including the lack of patients from primary care or university hospitals, which may limit the generalizability of the results, the reliance on physician statements for diagnosis of OSAS, and the lack of data on OSAS severity or treatment, the researchers noted.

However, the results fill a needed gap in the literature because of the limited data on severe asthma patients in real life, and identifying severe asthma patients by phenotype may help identify those at greatest risk for OSAS, they said.

“Identified patients could more easily benefit from specific examinations such as poly(somno)graphy and, consequently, could benefit from a better management of both asthma and OSAS,” they emphasized.

The larger FASE-CPHG study was supported in part by ALK, AstraZeneca, Boehringer Ingelheim, GSK, and Le Nouveau Souffle. The researchers had no financial conflicts to disclose.

Almost all patients with both obstructive sleep apnea syndrome and severe asthma fell into the obesity phenotype, not the allergy phenotype, based on data from nearly 1,500 adults.

Both asthma and sleep-disordered breathing are common conditions worldwide, and previous research suggests that obstructive sleep apnea syndrome (OSAS) and severe asthma in particular could be associated, wrote Laurent Portel, MD, of Centre Hospitalier de Libourne, France, and colleagues.

“Even if the underlying mechanisms are not well established, it is clear that both OSAS and obesity act to aggravate existing asthma, making it more difficult to control,” they said. However, the pathology of this relationship is not well-understood, and data on severe asthma phenotypes and OSAS are limited, they said.

In a study published in Respiratory Medicine and Research, the investigators reviewed data from 1,465 patients older than 18 years with severe asthma who were part of a larger, prospective multicenter study of the management of asthma patients. The larger study, developed by the Collège des Pneumologues des Hôpitaux Généraux (CPHG) is known as the FASE-CPHG (France Asthme SEvère-CPHG) and includes 104 nonacademic hospitals in France.

Diagnosis of OSAS was reported by physicians; diagnosis of severe asthma was based on the Global Initiative for Asthma criteria. The average age of the patients was 54.4 years, 63% were women, and 60% were nonsmokers.

A total of 161 patients were diagnosed with OSAS. The researchers conducted a cluster analysis on 1,424 patients, including 156 of the OSAS patients. They identified five clusters: early-onset atopic asthma (690 patients), obese asthma (153 patients), late-onset asthma (299 patients), eosinophilic asthma (143 patients), and aspirin sensitivity asthma (139 patients).

All 153 patients in the obese asthma cluster had OSAS, by contrast, none of the patients in the early atopic asthma cluster had OSAS.

Overall, obesity, male sex, high blood pressure, depression, late-onset asthma, and early-onset atopic asthma were independently associated with OSAS, with odds ratios of 5.782, 3.047, 2.875, 2.552, 1.789, and 0.622, respectively.

Notably, OSAS patients were more frequently treated with long-term oral corticosteroids than those without OSAS (30% vs. 15%, P < .0001), the researchers said. “It is possible that this treatment may be responsible for obesity, and it represents a well-known risk factor for developing OSAS,” they wrote.

Uncontrolled asthma was significantly more common in OSAS patients than in those without OSAS (77.7% vs. 69%, P = .03), and significantly more OSAS patients reported no or occasional physical activity (79.8% vs. 68.2%, P ≤ .001).

The study findings were limited by several factors including the lack of patients from primary care or university hospitals, which may limit the generalizability of the results, the reliance on physician statements for diagnosis of OSAS, and the lack of data on OSAS severity or treatment, the researchers noted.

However, the results fill a needed gap in the literature because of the limited data on severe asthma patients in real life, and identifying severe asthma patients by phenotype may help identify those at greatest risk for OSAS, they said.

“Identified patients could more easily benefit from specific examinations such as poly(somno)graphy and, consequently, could benefit from a better management of both asthma and OSAS,” they emphasized.

The larger FASE-CPHG study was supported in part by ALK, AstraZeneca, Boehringer Ingelheim, GSK, and Le Nouveau Souffle. The researchers had no financial conflicts to disclose.

The American College of Cardiology has issued an expert consensus clinical guidance document for the evaluation and management of adults with key cardiovascular consequences of COVID-19.

The document makes recommendations on how to evaluate and manage COVID-associated myocarditis and long COVID and gives advice on resumption of exercise following COVID-19 infection.

The clinical guidance was published online March 16 in the Journal of the American College of Cardiology.

AlexLMX/Getty Images

“The best means to diagnose and treat myocarditis and long COVID following SARS-CoV-2 infection continues to evolve,” said Ty Gluckman, MD, MHA, cochair of the expert consensus decision pathway. “This document attempts to provide key recommendations for how to evaluate and manage adults with these conditions, including guidance for safe return to play for both competitive and noncompetitive athletes.”

The authors of the guidance note that COVID-19 can be associated with various abnormalities in cardiac testing and a wide range of cardiovascular complications. For some patients, cardiac symptoms such as chest pain, shortness of breath, fatigue, and palpitations persist, lasting months after the initial illness, and evidence of myocardial injury has also been observed in both symptomatic and asymptomatic individuals, as well as after receipt of the COVID-19 mRNA vaccine. 

“For clinicians treating these individuals, a growing number of questions exist related to evaluation and management of these conditions, as well as safe resumption of physical activity,” they say. This report is intended to provide practical guidance on these issues.
 

Myocarditis

The report states that myocarditis has been recognized as a rare but serious complication of SARS-CoV-2 infection as well as COVID-19 mRNA vaccination.

It defines myocarditis as: 1.cardiac symptoms such as chest pain, dyspnea, palpitations, or syncope; 2. elevated cardiac troponin; and 3. abnormal electrocardiographic, echocardiographic, cardiac MRI, and/or histopathologic findings on biopsy.

The document makes the following recommendations in regard to COVID-related myocarditis:

When there is increased suspicion for cardiac involvement with COVID-19, initial testing should consist of an ECG, measurement of cardiac troponin, and an echocardiogram. Cardiology consultation is recommended for those with a rising cardiac troponin and/or echocardiographic abnormalities. Cardiac MRI is recommended in hemodynamically stable patients with suspected myocarditis.

Hospitalization is recommended for patients with definite myocarditis, ideally at an advanced heart failure center. Patients with fulminant myocarditis should be managed at centers with an expertise in advanced heart failure, mechanical circulatory support, and other advanced therapies.

Patients with myocarditis and COVID-19 pneumonia (with an ongoing need for supplemental oxygen) should be treated with corticosteroids. For patients with suspected pericardial involvement, treatment with NSAIDs, colchicine, and/or prednisone is reasonable. Intravenous corticosteroids may be considered in those with suspected or confirmed COVID-19 myocarditis with hemodynamic compromise or MIS-A (multisystem inflammatory syndrome in adults). Empiric use of corticosteroids may also be considered in those with biopsy evidence of severe myocardial infiltrates or fulminant myocarditis, balanced against infection risk.

As appropriate, guideline-directed medical therapy for heart failure should be initiated and continued after discharge.

The document notes that myocarditis following COVID-19 mRNA vaccination is rare, with highest rates seen in young males after the second vaccine dose. As of May 22, 2021, the U.S. Vaccine Adverse Event Reporting System noted rates of 40.6 cases per million after the second vaccine dose among male individuals aged 12-29 years and 2.4 cases per million among male individuals aged 30 and older. Corresponding rates in female individuals were 4.2 and 1 cases per million, respectively.

But the report says that COVID-19 vaccination is associated with “a very favorable benefit-to-risk ratio” for all age and sex groups evaluated thus far.

In general, vaccine-associated myocarditis should be diagnosed, categorized, and treated in a manner analogous to myocarditis following SARS-CoV-2 infection, the guidance advises.
 

Long COVID

The document refers to long COVID as postacute sequelae of SARS-CoV-2 infection (PASC), and reports that this condition is experienced by up to 10%-30% of infected individuals. It is defined by a constellation of new, returning, or persistent health problems experienced by individuals 4 or more weeks after COVID-19 infection.

Although individuals with this condition may experience wide-ranging symptoms, the symptoms that draw increased attention to the cardiovascular system include tachycardia, exercise intolerance, chest pain, and shortness of breath.

Nicole Bhave, MD, cochair of the expert consensus decision pathway, says: “There appears to be a ‘downward spiral’ for long-COVID patients. Fatigue and decreased exercise capacity lead to diminished activity and bed rest, in turn leading to worsening symptoms and decreased quality of life.” She adds that “the writing committee recommends a basic cardiopulmonary evaluation performed up front to determine if further specialty care and formalized medical therapy is needed for these patients.”

The authors propose two terms to better understand potential etiologies for those with cardiovascular symptoms:

PASC-CVD, or PASC-cardiovascular disease, refers to a broad group of cardiovascular conditions (including myocarditis) that manifest at least 4 weeks after COVID-19 infection.

PASC-CVS, or PASC-cardiovascular syndrome, includes a wide range of cardiovascular symptoms without objective evidence of cardiovascular disease following standard diagnostic testing.

The document makes the following recommendations for the management of PASC-CVD and PASC-CVS.

For patients with cardiovascular symptoms and suspected PASC, the authors suggest that a reasonable initial testing approach includes basic laboratory testing, including cardiac troponin, an ECG, an echocardiogram, an ambulatory rhythm monitor, chest imaging, and/or pulmonary function tests.

Cardiology consultation is recommended for patients with PASC who have abnormal cardiac test results, known cardiovascular disease with new or worsening symptoms, documented cardiac complications during SARS-CoV-2 infection, and/or persistent cardiopulmonary symptoms that are not otherwise explained.

Recumbent or semirecumbent exercise (for example, rowing, swimming, or cycling) is recommended initially for PASC-CVS patients with tachycardia, exercise/orthostatic intolerance, and/or deconditioning, with transition to upright exercise as orthostatic intolerance improves. Exercise duration should also be short (5-10 minutes/day) initially, with gradual increases as functional capacity improves.

Salt and fluid loading represent nonpharmacologic interventions that may provide symptomatic relief for patients with tachycardia, palpitations, and/or orthostatic hypotension.

Beta-blockers, nondihydropyridine calcium-channel blockers, ivabradine, fludrocortisone, and midodrine may be used empirically as well.
 

Return to play for athletes

The authors note that concerns about possible cardiac injury after COVID-19 fueled early apprehension regarding the safety of competitive sports for athletes recovering from the infection.

But they say that subsequent data from large registries have demonstrated an overall low prevalence of clinical myocarditis, without a rise in the rate of adverse cardiac events. Based on this, updated guidance is provided with a practical, evidence-based framework to guide resumption of athletics and intense exercise training.

They make the following recommendations:

• For athletes recovering from COVID-19 with ongoing cardiopulmonary symptoms (chest pain, shortness of breath, palpitations, lightheadedness) or those requiring hospitalization with increased suspicion for cardiac involvement, further evaluation with triad testing – an ECG, measurement of cardiac troponin, and an echocardiogram – should be performed.
• For those with abnormal test results, further evaluation with cardiac MRI should be considered. Individuals diagnosed with clinical myocarditis should abstain from exercise for 3-6 months.
• Cardiac testing is not recommended for asymptomatic individuals following COVID-19 infection. Individuals should abstain from training for 3 days to ensure that symptoms do not develop.
• For those with mild or moderate noncardiopulmonary symptoms (fever, lethargy, muscle aches), training may resume after symptom resolution.
• For those with remote infection (≥3 months) without ongoing cardiopulmonary symptoms, a gradual increase in exercise is recommended without the need for cardiac testing.

Based on the low prevalence of myocarditis observed in competitive athletes with COVID-19, the authors note that these recommendations can be reasonably applied to high-school athletes (aged 14 and older) along with adult recreational exercise enthusiasts.

Future study is needed, however, to better understand how long cardiac abnormalities persist following COVID-19 infection and the role of exercise training in long COVID.

The authors conclude that the current guidance is intended to help clinicians understand not only when testing may be warranted, but also when it is not.

“Given that it reflects the current state of knowledge through early 2022, it is anticipated that recommendations will change over time as our understanding evolves,” they say.

The 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19: Myocarditis, Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), and Return to Play will be discussed in a session at the American College of Cardiology’s annual scientific session meeting in Washington in April.

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

The American College of Cardiology has issued an expert consensus clinical guidance document for the evaluation and management of adults with key cardiovascular consequences of COVID-19.

The document makes recommendations on how to evaluate and manage COVID-associated myocarditis and long COVID and gives advice on resumption of exercise following COVID-19 infection.

The clinical guidance was published online March 16 in the Journal of the American College of Cardiology.

AlexLMX/Getty Images

“The best means to diagnose and treat myocarditis and long COVID following SARS-CoV-2 infection continues to evolve,” said Ty Gluckman, MD, MHA, cochair of the expert consensus decision pathway. “This document attempts to provide key recommendations for how to evaluate and manage adults with these conditions, including guidance for safe return to play for both competitive and noncompetitive athletes.”

The authors of the guidance note that COVID-19 can be associated with various abnormalities in cardiac testing and a wide range of cardiovascular complications. For some patients, cardiac symptoms such as chest pain, shortness of breath, fatigue, and palpitations persist, lasting months after the initial illness, and evidence of myocardial injury has also been observed in both symptomatic and asymptomatic individuals, as well as after receipt of the COVID-19 mRNA vaccine. 

“For clinicians treating these individuals, a growing number of questions exist related to evaluation and management of these conditions, as well as safe resumption of physical activity,” they say. This report is intended to provide practical guidance on these issues.
 

Myocarditis

The report states that myocarditis has been recognized as a rare but serious complication of SARS-CoV-2 infection as well as COVID-19 mRNA vaccination.

It defines myocarditis as: 1.cardiac symptoms such as chest pain, dyspnea, palpitations, or syncope; 2. elevated cardiac troponin; and 3. abnormal electrocardiographic, echocardiographic, cardiac MRI, and/or histopathologic findings on biopsy.

The document makes the following recommendations in regard to COVID-related myocarditis:

When there is increased suspicion for cardiac involvement with COVID-19, initial testing should consist of an ECG, measurement of cardiac troponin, and an echocardiogram. Cardiology consultation is recommended for those with a rising cardiac troponin and/or echocardiographic abnormalities. Cardiac MRI is recommended in hemodynamically stable patients with suspected myocarditis.

Hospitalization is recommended for patients with definite myocarditis, ideally at an advanced heart failure center. Patients with fulminant myocarditis should be managed at centers with an expertise in advanced heart failure, mechanical circulatory support, and other advanced therapies.

Patients with myocarditis and COVID-19 pneumonia (with an ongoing need for supplemental oxygen) should be treated with corticosteroids. For patients with suspected pericardial involvement, treatment with NSAIDs, colchicine, and/or prednisone is reasonable. Intravenous corticosteroids may be considered in those with suspected or confirmed COVID-19 myocarditis with hemodynamic compromise or MIS-A (multisystem inflammatory syndrome in adults). Empiric use of corticosteroids may also be considered in those with biopsy evidence of severe myocardial infiltrates or fulminant myocarditis, balanced against infection risk.

As appropriate, guideline-directed medical therapy for heart failure should be initiated and continued after discharge.

The document notes that myocarditis following COVID-19 mRNA vaccination is rare, with highest rates seen in young males after the second vaccine dose. As of May 22, 2021, the U.S. Vaccine Adverse Event Reporting System noted rates of 40.6 cases per million after the second vaccine dose among male individuals aged 12-29 years and 2.4 cases per million among male individuals aged 30 and older. Corresponding rates in female individuals were 4.2 and 1 cases per million, respectively.

But the report says that COVID-19 vaccination is associated with “a very favorable benefit-to-risk ratio” for all age and sex groups evaluated thus far.

In general, vaccine-associated myocarditis should be diagnosed, categorized, and treated in a manner analogous to myocarditis following SARS-CoV-2 infection, the guidance advises.
 

Long COVID

The document refers to long COVID as postacute sequelae of SARS-CoV-2 infection (PASC), and reports that this condition is experienced by up to 10%-30% of infected individuals. It is defined by a constellation of new, returning, or persistent health problems experienced by individuals 4 or more weeks after COVID-19 infection.

Although individuals with this condition may experience wide-ranging symptoms, the symptoms that draw increased attention to the cardiovascular system include tachycardia, exercise intolerance, chest pain, and shortness of breath.

Nicole Bhave, MD, cochair of the expert consensus decision pathway, says: “There appears to be a ‘downward spiral’ for long-COVID patients. Fatigue and decreased exercise capacity lead to diminished activity and bed rest, in turn leading to worsening symptoms and decreased quality of life.” She adds that “the writing committee recommends a basic cardiopulmonary evaluation performed up front to determine if further specialty care and formalized medical therapy is needed for these patients.”

The authors propose two terms to better understand potential etiologies for those with cardiovascular symptoms:

PASC-CVD, or PASC-cardiovascular disease, refers to a broad group of cardiovascular conditions (including myocarditis) that manifest at least 4 weeks after COVID-19 infection.

PASC-CVS, or PASC-cardiovascular syndrome, includes a wide range of cardiovascular symptoms without objective evidence of cardiovascular disease following standard diagnostic testing.

The document makes the following recommendations for the management of PASC-CVD and PASC-CVS.

For patients with cardiovascular symptoms and suspected PASC, the authors suggest that a reasonable initial testing approach includes basic laboratory testing, including cardiac troponin, an ECG, an echocardiogram, an ambulatory rhythm monitor, chest imaging, and/or pulmonary function tests.

Cardiology consultation is recommended for patients with PASC who have abnormal cardiac test results, known cardiovascular disease with new or worsening symptoms, documented cardiac complications during SARS-CoV-2 infection, and/or persistent cardiopulmonary symptoms that are not otherwise explained.

Recumbent or semirecumbent exercise (for example, rowing, swimming, or cycling) is recommended initially for PASC-CVS patients with tachycardia, exercise/orthostatic intolerance, and/or deconditioning, with transition to upright exercise as orthostatic intolerance improves. Exercise duration should also be short (5-10 minutes/day) initially, with gradual increases as functional capacity improves.

Salt and fluid loading represent nonpharmacologic interventions that may provide symptomatic relief for patients with tachycardia, palpitations, and/or orthostatic hypotension.

Beta-blockers, nondihydropyridine calcium-channel blockers, ivabradine, fludrocortisone, and midodrine may be used empirically as well.
 

Return to play for athletes

The authors note that concerns about possible cardiac injury after COVID-19 fueled early apprehension regarding the safety of competitive sports for athletes recovering from the infection.

But they say that subsequent data from large registries have demonstrated an overall low prevalence of clinical myocarditis, without a rise in the rate of adverse cardiac events. Based on this, updated guidance is provided with a practical, evidence-based framework to guide resumption of athletics and intense exercise training.

They make the following recommendations:

• For athletes recovering from COVID-19 with ongoing cardiopulmonary symptoms (chest pain, shortness of breath, palpitations, lightheadedness) or those requiring hospitalization with increased suspicion for cardiac involvement, further evaluation with triad testing – an ECG, measurement of cardiac troponin, and an echocardiogram – should be performed.
• For those with abnormal test results, further evaluation with cardiac MRI should be considered. Individuals diagnosed with clinical myocarditis should abstain from exercise for 3-6 months.
• Cardiac testing is not recommended for asymptomatic individuals following COVID-19 infection. Individuals should abstain from training for 3 days to ensure that symptoms do not develop.
• For those with mild or moderate noncardiopulmonary symptoms (fever, lethargy, muscle aches), training may resume after symptom resolution.
• For those with remote infection (≥3 months) without ongoing cardiopulmonary symptoms, a gradual increase in exercise is recommended without the need for cardiac testing.

Based on the low prevalence of myocarditis observed in competitive athletes with COVID-19, the authors note that these recommendations can be reasonably applied to high-school athletes (aged 14 and older) along with adult recreational exercise enthusiasts.

Future study is needed, however, to better understand how long cardiac abnormalities persist following COVID-19 infection and the role of exercise training in long COVID.

The authors conclude that the current guidance is intended to help clinicians understand not only when testing may be warranted, but also when it is not.

“Given that it reflects the current state of knowledge through early 2022, it is anticipated that recommendations will change over time as our understanding evolves,” they say.

The 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19: Myocarditis, Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), and Return to Play will be discussed in a session at the American College of Cardiology’s annual scientific session meeting in Washington in April.

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

The American College of Cardiology has issued an expert consensus clinical guidance document for the evaluation and management of adults with key cardiovascular consequences of COVID-19.

The document makes recommendations on how to evaluate and manage COVID-associated myocarditis and long COVID and gives advice on resumption of exercise following COVID-19 infection.

The clinical guidance was published online March 16 in the Journal of the American College of Cardiology.

AlexLMX/Getty Images

“The best means to diagnose and treat myocarditis and long COVID following SARS-CoV-2 infection continues to evolve,” said Ty Gluckman, MD, MHA, cochair of the expert consensus decision pathway. “This document attempts to provide key recommendations for how to evaluate and manage adults with these conditions, including guidance for safe return to play for both competitive and noncompetitive athletes.”

The authors of the guidance note that COVID-19 can be associated with various abnormalities in cardiac testing and a wide range of cardiovascular complications. For some patients, cardiac symptoms such as chest pain, shortness of breath, fatigue, and palpitations persist, lasting months after the initial illness, and evidence of myocardial injury has also been observed in both symptomatic and asymptomatic individuals, as well as after receipt of the COVID-19 mRNA vaccine. 

“For clinicians treating these individuals, a growing number of questions exist related to evaluation and management of these conditions, as well as safe resumption of physical activity,” they say. This report is intended to provide practical guidance on these issues.
 

Myocarditis

The report states that myocarditis has been recognized as a rare but serious complication of SARS-CoV-2 infection as well as COVID-19 mRNA vaccination.

It defines myocarditis as: 1.cardiac symptoms such as chest pain, dyspnea, palpitations, or syncope; 2. elevated cardiac troponin; and 3. abnormal electrocardiographic, echocardiographic, cardiac MRI, and/or histopathologic findings on biopsy.

The document makes the following recommendations in regard to COVID-related myocarditis:

When there is increased suspicion for cardiac involvement with COVID-19, initial testing should consist of an ECG, measurement of cardiac troponin, and an echocardiogram. Cardiology consultation is recommended for those with a rising cardiac troponin and/or echocardiographic abnormalities. Cardiac MRI is recommended in hemodynamically stable patients with suspected myocarditis.

Hospitalization is recommended for patients with definite myocarditis, ideally at an advanced heart failure center. Patients with fulminant myocarditis should be managed at centers with an expertise in advanced heart failure, mechanical circulatory support, and other advanced therapies.

Patients with myocarditis and COVID-19 pneumonia (with an ongoing need for supplemental oxygen) should be treated with corticosteroids. For patients with suspected pericardial involvement, treatment with NSAIDs, colchicine, and/or prednisone is reasonable. Intravenous corticosteroids may be considered in those with suspected or confirmed COVID-19 myocarditis with hemodynamic compromise or MIS-A (multisystem inflammatory syndrome in adults). Empiric use of corticosteroids may also be considered in those with biopsy evidence of severe myocardial infiltrates or fulminant myocarditis, balanced against infection risk.

As appropriate, guideline-directed medical therapy for heart failure should be initiated and continued after discharge.

The document notes that myocarditis following COVID-19 mRNA vaccination is rare, with highest rates seen in young males after the second vaccine dose. As of May 22, 2021, the U.S. Vaccine Adverse Event Reporting System noted rates of 40.6 cases per million after the second vaccine dose among male individuals aged 12-29 years and 2.4 cases per million among male individuals aged 30 and older. Corresponding rates in female individuals were 4.2 and 1 cases per million, respectively.

But the report says that COVID-19 vaccination is associated with “a very favorable benefit-to-risk ratio” for all age and sex groups evaluated thus far.

In general, vaccine-associated myocarditis should be diagnosed, categorized, and treated in a manner analogous to myocarditis following SARS-CoV-2 infection, the guidance advises.
 

Long COVID

The document refers to long COVID as postacute sequelae of SARS-CoV-2 infection (PASC), and reports that this condition is experienced by up to 10%-30% of infected individuals. It is defined by a constellation of new, returning, or persistent health problems experienced by individuals 4 or more weeks after COVID-19 infection.

Although individuals with this condition may experience wide-ranging symptoms, the symptoms that draw increased attention to the cardiovascular system include tachycardia, exercise intolerance, chest pain, and shortness of breath.

Nicole Bhave, MD, cochair of the expert consensus decision pathway, says: “There appears to be a ‘downward spiral’ for long-COVID patients. Fatigue and decreased exercise capacity lead to diminished activity and bed rest, in turn leading to worsening symptoms and decreased quality of life.” She adds that “the writing committee recommends a basic cardiopulmonary evaluation performed up front to determine if further specialty care and formalized medical therapy is needed for these patients.”

The authors propose two terms to better understand potential etiologies for those with cardiovascular symptoms:

PASC-CVD, or PASC-cardiovascular disease, refers to a broad group of cardiovascular conditions (including myocarditis) that manifest at least 4 weeks after COVID-19 infection.

PASC-CVS, or PASC-cardiovascular syndrome, includes a wide range of cardiovascular symptoms without objective evidence of cardiovascular disease following standard diagnostic testing.

The document makes the following recommendations for the management of PASC-CVD and PASC-CVS.

For patients with cardiovascular symptoms and suspected PASC, the authors suggest that a reasonable initial testing approach includes basic laboratory testing, including cardiac troponin, an ECG, an echocardiogram, an ambulatory rhythm monitor, chest imaging, and/or pulmonary function tests.

Cardiology consultation is recommended for patients with PASC who have abnormal cardiac test results, known cardiovascular disease with new or worsening symptoms, documented cardiac complications during SARS-CoV-2 infection, and/or persistent cardiopulmonary symptoms that are not otherwise explained.

Recumbent or semirecumbent exercise (for example, rowing, swimming, or cycling) is recommended initially for PASC-CVS patients with tachycardia, exercise/orthostatic intolerance, and/or deconditioning, with transition to upright exercise as orthostatic intolerance improves. Exercise duration should also be short (5-10 minutes/day) initially, with gradual increases as functional capacity improves.

Salt and fluid loading represent nonpharmacologic interventions that may provide symptomatic relief for patients with tachycardia, palpitations, and/or orthostatic hypotension.

Beta-blockers, nondihydropyridine calcium-channel blockers, ivabradine, fludrocortisone, and midodrine may be used empirically as well.
 

Return to play for athletes

The authors note that concerns about possible cardiac injury after COVID-19 fueled early apprehension regarding the safety of competitive sports for athletes recovering from the infection.

But they say that subsequent data from large registries have demonstrated an overall low prevalence of clinical myocarditis, without a rise in the rate of adverse cardiac events. Based on this, updated guidance is provided with a practical, evidence-based framework to guide resumption of athletics and intense exercise training.

They make the following recommendations:

• For athletes recovering from COVID-19 with ongoing cardiopulmonary symptoms (chest pain, shortness of breath, palpitations, lightheadedness) or those requiring hospitalization with increased suspicion for cardiac involvement, further evaluation with triad testing – an ECG, measurement of cardiac troponin, and an echocardiogram – should be performed.
• For those with abnormal test results, further evaluation with cardiac MRI should be considered. Individuals diagnosed with clinical myocarditis should abstain from exercise for 3-6 months.
• Cardiac testing is not recommended for asymptomatic individuals following COVID-19 infection. Individuals should abstain from training for 3 days to ensure that symptoms do not develop.
• For those with mild or moderate noncardiopulmonary symptoms (fever, lethargy, muscle aches), training may resume after symptom resolution.
• For those with remote infection (≥3 months) without ongoing cardiopulmonary symptoms, a gradual increase in exercise is recommended without the need for cardiac testing.

Based on the low prevalence of myocarditis observed in competitive athletes with COVID-19, the authors note that these recommendations can be reasonably applied to high-school athletes (aged 14 and older) along with adult recreational exercise enthusiasts.

Future study is needed, however, to better understand how long cardiac abnormalities persist following COVID-19 infection and the role of exercise training in long COVID.

The authors conclude that the current guidance is intended to help clinicians understand not only when testing may be warranted, but also when it is not.

“Given that it reflects the current state of knowledge through early 2022, it is anticipated that recommendations will change over time as our understanding evolves,” they say.

The 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19: Myocarditis, Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), and Return to Play will be discussed in a session at the American College of Cardiology’s annual scientific session meeting in Washington in April.

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

In assessing and managing patients presenting with acute, life-threatening asthma, if the exacerbation does not resolve relatively quickly, clinicians need to start looking for other causes of the patient’s respiratory distress, a review of the literature suggests.

“I think one of the most important points of this review is that asthma is a self-limiting disease, and it’s important to understand that with appropriate treatment and immediate response to it, exacerbations will get better with time,” Orlando Garner, MD, Baylor College of Medicine, Houston, said in an interview.

“So I think one of the key points is, if these exacerbations do not resolve within 24-48 hours, clinicians need to start thinking: ‘This could be something else,’ and not get stuck in the diagnosis that this is an asthmatic patient who is having an exacerbation. If the distress doesn’t resolve within 48 hours, it’s time to look for other clues,” he stressed.

The study was published online in the journal CHEST^®.

Appropriate triage

Appropriate triage is key in the management of acute asthma, Dr. Garner and colleagues pointed out. A simplified severity score for the evaluation of asthma in the ED can help in this regard. Depending on the presence or absence of a number of key signs and symptoms, patients can be readily categorized as having mild, moderate, or severe asthma. “Static assessments and dynamic assessments of acute asthma exacerbation in the ED can also help triage patients,” the authors added.

Static assessment involves assessing the severity at presentation, which in turn determines the aggressiveness of initial treatment. Objective static assessments include the measurement of peak expiratory flow (PEF) or forced expiratory volume in 1 second (FEV₁). A severe exacerbation is usually defined as a PEF or an FEV₁ of less than 50%-60% of predicted normal values, the authors noted.

Dynamic assessment is more helpful than static assessment because it gauges response to treatment. “A lack of improvement in expiratory flow rates after initial bronchodilator therapy with continuous or worsening symptoms suggests need for hospitalization,” Dr. Garner and colleagues observed. The main treatment goals for patients with acute asthma are reversal of bronchospasm and correction of hypoxemia.

These are achieved at least initially with conventional agents, such as repeated doses of inhaled short-acting beta₂-agonists, inhaled short-acting anticholinergics, systemic corticosteroids, and occasionally intravenous magnesium sulfate. If there is concomitant hypoxemia, oxygen therapy should be initiated as well. Patients who have evidence of hypercapnic respiratory failure or diaphragmatic fatigue need to be admitted to the intensive care unit, the authors indicated.

For these patients, clinicians need to remember that there are therapies other than inhalers, such as epinephrine and systemic terbutaline. During a life-threatening asthma episode, airflow in the medium and small airways often becomes turbulent, increasing the work of breathing, the researchers pointed out.

Heliox, a combination of helium and oxygen, reduces turbulent flow, they noted, although FiO₂ requirements need to be less than 30% in order for it to work. “Heliox can be used in patients with severe bronchospasm who do not respond to the conventional therapies,” the authors noted, “[but] therapy should be abandoned if there is no clinical improvement after 15 minutes of use.”

Although none of the biologics such as dupilumab (Dupixent) has yet been approved for the treatment of acute exacerbations, Dr. Garner predicts they will become the “future of medicine” for patients with severe asthma as well.
 

Ventilation in life-threatening asthma

Rapid sequence intubation is generally recommended for patients who require mechanical ventilation, but as an alternative, “we are advocating a slower approach, where we get patients to slow down their breathing and relax them with something like ketamine infusions and wait before we given them a paralytic to see if the work of breathing improves,” Dr. Garner said. Bag-mask ventilation should be avoided because it can worsen dynamic hyperinflation or cause barotrauma.

Salvage therapies such as the use of bronchoscopy with N-acetylcysteine instilled directly into the airway is another option in cases in which mucus plugging is considered to be the main driver of airflow limitation.

Asked to comment, Brit Long, MD, an emergency medicine physician at the Brooke Army Medical Center in San Antonio, Tex., felt the review was extremely useful and well done.

“We see these patients very frequently, and being able to assess them right away and get an accurate picture of what’s going on is very important,” he said in an interview. The one thing that is often more difficult, at least in the ED, is obtaining a PEF or the FEV₁ – “both very helpful if the patient can do them, but if the patient is critically ill, it’s more likely you will not be able to get those assessments, and if patients are speaking in one-word sentences and are working really hard to breathe, that’s a severe exacerbation, and they need immediate intervention.” Dr. Long also liked all the essential treatments the authors recommended that patients be given immediately, although he noted that Heliox is not going to be available in most EDs.

On the other hand, he agreed with the authors’ recommendation to take a slower approach to mechanical ventilation, if it is needed at all. “I try my best to absolutely avoid intubating these patients – you are not fixing the issue with mechanical ventilation, you are just creating further problems.

“And while I see the entire spectrum of asthma patients from very mild to severe patients, these authors did a good job in explaining what the goals of treatment are and what to do with the severe ones,” he said.

Dr. Garner and Dr. Long disclosed no relevant financial relationships.

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

In assessing and managing patients presenting with acute, life-threatening asthma, if the exacerbation does not resolve relatively quickly, clinicians need to start looking for other causes of the patient’s respiratory distress, a review of the literature suggests.

“I think one of the most important points of this review is that asthma is a self-limiting disease, and it’s important to understand that with appropriate treatment and immediate response to it, exacerbations will get better with time,” Orlando Garner, MD, Baylor College of Medicine, Houston, said in an interview.

“So I think one of the key points is, if these exacerbations do not resolve within 24-48 hours, clinicians need to start thinking: ‘This could be something else,’ and not get stuck in the diagnosis that this is an asthmatic patient who is having an exacerbation. If the distress doesn’t resolve within 48 hours, it’s time to look for other clues,” he stressed.

The study was published online in the journal CHEST^®.

Appropriate triage

Appropriate triage is key in the management of acute asthma, Dr. Garner and colleagues pointed out. A simplified severity score for the evaluation of asthma in the ED can help in this regard. Depending on the presence or absence of a number of key signs and symptoms, patients can be readily categorized as having mild, moderate, or severe asthma. “Static assessments and dynamic assessments of acute asthma exacerbation in the ED can also help triage patients,” the authors added.

Static assessment involves assessing the severity at presentation, which in turn determines the aggressiveness of initial treatment. Objective static assessments include the measurement of peak expiratory flow (PEF) or forced expiratory volume in 1 second (FEV₁). A severe exacerbation is usually defined as a PEF or an FEV₁ of less than 50%-60% of predicted normal values, the authors noted.

Dynamic assessment is more helpful than static assessment because it gauges response to treatment. “A lack of improvement in expiratory flow rates after initial bronchodilator therapy with continuous or worsening symptoms suggests need for hospitalization,” Dr. Garner and colleagues observed. The main treatment goals for patients with acute asthma are reversal of bronchospasm and correction of hypoxemia.

These are achieved at least initially with conventional agents, such as repeated doses of inhaled short-acting beta₂-agonists, inhaled short-acting anticholinergics, systemic corticosteroids, and occasionally intravenous magnesium sulfate. If there is concomitant hypoxemia, oxygen therapy should be initiated as well. Patients who have evidence of hypercapnic respiratory failure or diaphragmatic fatigue need to be admitted to the intensive care unit, the authors indicated.

For these patients, clinicians need to remember that there are therapies other than inhalers, such as epinephrine and systemic terbutaline. During a life-threatening asthma episode, airflow in the medium and small airways often becomes turbulent, increasing the work of breathing, the researchers pointed out.

Heliox, a combination of helium and oxygen, reduces turbulent flow, they noted, although FiO₂ requirements need to be less than 30% in order for it to work. “Heliox can be used in patients with severe bronchospasm who do not respond to the conventional therapies,” the authors noted, “[but] therapy should be abandoned if there is no clinical improvement after 15 minutes of use.”

Although none of the biologics such as dupilumab (Dupixent) has yet been approved for the treatment of acute exacerbations, Dr. Garner predicts they will become the “future of medicine” for patients with severe asthma as well.
 

Ventilation in life-threatening asthma

Rapid sequence intubation is generally recommended for patients who require mechanical ventilation, but as an alternative, “we are advocating a slower approach, where we get patients to slow down their breathing and relax them with something like ketamine infusions and wait before we given them a paralytic to see if the work of breathing improves,” Dr. Garner said. Bag-mask ventilation should be avoided because it can worsen dynamic hyperinflation or cause barotrauma.

Salvage therapies such as the use of bronchoscopy with N-acetylcysteine instilled directly into the airway is another option in cases in which mucus plugging is considered to be the main driver of airflow limitation.

Asked to comment, Brit Long, MD, an emergency medicine physician at the Brooke Army Medical Center in San Antonio, Tex., felt the review was extremely useful and well done.

“We see these patients very frequently, and being able to assess them right away and get an accurate picture of what’s going on is very important,” he said in an interview. The one thing that is often more difficult, at least in the ED, is obtaining a PEF or the FEV₁ – “both very helpful if the patient can do them, but if the patient is critically ill, it’s more likely you will not be able to get those assessments, and if patients are speaking in one-word sentences and are working really hard to breathe, that’s a severe exacerbation, and they need immediate intervention.” Dr. Long also liked all the essential treatments the authors recommended that patients be given immediately, although he noted that Heliox is not going to be available in most EDs.

On the other hand, he agreed with the authors’ recommendation to take a slower approach to mechanical ventilation, if it is needed at all. “I try my best to absolutely avoid intubating these patients – you are not fixing the issue with mechanical ventilation, you are just creating further problems.

“And while I see the entire spectrum of asthma patients from very mild to severe patients, these authors did a good job in explaining what the goals of treatment are and what to do with the severe ones,” he said.

Dr. Garner and Dr. Long disclosed no relevant financial relationships.

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

In assessing and managing patients presenting with acute, life-threatening asthma, if the exacerbation does not resolve relatively quickly, clinicians need to start looking for other causes of the patient’s respiratory distress, a review of the literature suggests.

“I think one of the most important points of this review is that asthma is a self-limiting disease, and it’s important to understand that with appropriate treatment and immediate response to it, exacerbations will get better with time,” Orlando Garner, MD, Baylor College of Medicine, Houston, said in an interview.

“So I think one of the key points is, if these exacerbations do not resolve within 24-48 hours, clinicians need to start thinking: ‘This could be something else,’ and not get stuck in the diagnosis that this is an asthmatic patient who is having an exacerbation. If the distress doesn’t resolve within 48 hours, it’s time to look for other clues,” he stressed.

The study was published online in the journal CHEST^®.

Appropriate triage

Appropriate triage is key in the management of acute asthma, Dr. Garner and colleagues pointed out. A simplified severity score for the evaluation of asthma in the ED can help in this regard. Depending on the presence or absence of a number of key signs and symptoms, patients can be readily categorized as having mild, moderate, or severe asthma. “Static assessments and dynamic assessments of acute asthma exacerbation in the ED can also help triage patients,” the authors added.

Static assessment involves assessing the severity at presentation, which in turn determines the aggressiveness of initial treatment. Objective static assessments include the measurement of peak expiratory flow (PEF) or forced expiratory volume in 1 second (FEV₁). A severe exacerbation is usually defined as a PEF or an FEV₁ of less than 50%-60% of predicted normal values, the authors noted.

Dynamic assessment is more helpful than static assessment because it gauges response to treatment. “A lack of improvement in expiratory flow rates after initial bronchodilator therapy with continuous or worsening symptoms suggests need for hospitalization,” Dr. Garner and colleagues observed. The main treatment goals for patients with acute asthma are reversal of bronchospasm and correction of hypoxemia.

These are achieved at least initially with conventional agents, such as repeated doses of inhaled short-acting beta₂-agonists, inhaled short-acting anticholinergics, systemic corticosteroids, and occasionally intravenous magnesium sulfate. If there is concomitant hypoxemia, oxygen therapy should be initiated as well. Patients who have evidence of hypercapnic respiratory failure or diaphragmatic fatigue need to be admitted to the intensive care unit, the authors indicated.

For these patients, clinicians need to remember that there are therapies other than inhalers, such as epinephrine and systemic terbutaline. During a life-threatening asthma episode, airflow in the medium and small airways often becomes turbulent, increasing the work of breathing, the researchers pointed out.

Heliox, a combination of helium and oxygen, reduces turbulent flow, they noted, although FiO₂ requirements need to be less than 30% in order for it to work. “Heliox can be used in patients with severe bronchospasm who do not respond to the conventional therapies,” the authors noted, “[but] therapy should be abandoned if there is no clinical improvement after 15 minutes of use.”

Although none of the biologics such as dupilumab (Dupixent) has yet been approved for the treatment of acute exacerbations, Dr. Garner predicts they will become the “future of medicine” for patients with severe asthma as well.
 

Ventilation in life-threatening asthma

Rapid sequence intubation is generally recommended for patients who require mechanical ventilation, but as an alternative, “we are advocating a slower approach, where we get patients to slow down their breathing and relax them with something like ketamine infusions and wait before we given them a paralytic to see if the work of breathing improves,” Dr. Garner said. Bag-mask ventilation should be avoided because it can worsen dynamic hyperinflation or cause barotrauma.

Salvage therapies such as the use of bronchoscopy with N-acetylcysteine instilled directly into the airway is another option in cases in which mucus plugging is considered to be the main driver of airflow limitation.

Asked to comment, Brit Long, MD, an emergency medicine physician at the Brooke Army Medical Center in San Antonio, Tex., felt the review was extremely useful and well done.

“We see these patients very frequently, and being able to assess them right away and get an accurate picture of what’s going on is very important,” he said in an interview. The one thing that is often more difficult, at least in the ED, is obtaining a PEF or the FEV₁ – “both very helpful if the patient can do them, but if the patient is critically ill, it’s more likely you will not be able to get those assessments, and if patients are speaking in one-word sentences and are working really hard to breathe, that’s a severe exacerbation, and they need immediate intervention.” Dr. Long also liked all the essential treatments the authors recommended that patients be given immediately, although he noted that Heliox is not going to be available in most EDs.

On the other hand, he agreed with the authors’ recommendation to take a slower approach to mechanical ventilation, if it is needed at all. “I try my best to absolutely avoid intubating these patients – you are not fixing the issue with mechanical ventilation, you are just creating further problems.

“And while I see the entire spectrum of asthma patients from very mild to severe patients, these authors did a good job in explaining what the goals of treatment are and what to do with the severe ones,” he said.

Dr. Garner and Dr. Long disclosed no relevant financial relationships.

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

The U.S. Food and Drug Administration approved the first generic of Symbicort (budesonide and formoterol fumarate dihydrate) inhalation aerosol for the treatment of asthma in patients 6 years of age and older and for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

The approval was given for a complex generic drug-device combination product – a metered-dose inhaler that contains both budesonide (a corticosteroid that reduces inflammation) and formoterol (a long-acting bronchodilator that relaxes muscles in the airways to improve breathing). It is intended to be used as two inhalations, two times a day (usually morning and night, about 12 hours apart), to treat both diseases by preventing symptoms, such as wheezing for those with asthma and for improved breathing for patients with COPD.

The inhaler is approved at two strengths (160/4.5 mcg/actuation and 80/4.5 mcg/actuation), according to the March 15 FDA announcement. The device is not intended for the treatment of acute asthma.

“Today’s approval of the first generic for one of the most commonly prescribed complex drug-device combination products to treat asthma and COPD is another step forward in our commitment to bring generic copies of complex drugs to the market, which can improve quality of life and help reduce the cost of treatment,” said Sally Choe, PhD, director of the Office of Generic Drugs in the FDA’s Center for Drug Evaluation and Research.

The most common side effects associated with budesonide and formoterol fumarate dihydrate oral inhalation aerosol for those with asthma are nasopharyngitis pain, sinusitis, influenza, back pain, nasal congestion, stomach discomfort, vomiting, and oral candidiasis (thrush). For those with COPD, the most common side effects are nasopharyngitis, oral candidiasis, bronchitis, sinusitis, and upper respiratory tract infection, the FDA reported.

The approval of this generic drug-device combination was granted to Mylan Pharmaceuticals.

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

The U.S. Food and Drug Administration approved the first generic of Symbicort (budesonide and formoterol fumarate dihydrate) inhalation aerosol for the treatment of asthma in patients 6 years of age and older and for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

The approval was given for a complex generic drug-device combination product – a metered-dose inhaler that contains both budesonide (a corticosteroid that reduces inflammation) and formoterol (a long-acting bronchodilator that relaxes muscles in the airways to improve breathing). It is intended to be used as two inhalations, two times a day (usually morning and night, about 12 hours apart), to treat both diseases by preventing symptoms, such as wheezing for those with asthma and for improved breathing for patients with COPD.

The inhaler is approved at two strengths (160/4.5 mcg/actuation and 80/4.5 mcg/actuation), according to the March 15 FDA announcement. The device is not intended for the treatment of acute asthma.

“Today’s approval of the first generic for one of the most commonly prescribed complex drug-device combination products to treat asthma and COPD is another step forward in our commitment to bring generic copies of complex drugs to the market, which can improve quality of life and help reduce the cost of treatment,” said Sally Choe, PhD, director of the Office of Generic Drugs in the FDA’s Center for Drug Evaluation and Research.

The most common side effects associated with budesonide and formoterol fumarate dihydrate oral inhalation aerosol for those with asthma are nasopharyngitis pain, sinusitis, influenza, back pain, nasal congestion, stomach discomfort, vomiting, and oral candidiasis (thrush). For those with COPD, the most common side effects are nasopharyngitis, oral candidiasis, bronchitis, sinusitis, and upper respiratory tract infection, the FDA reported.

The approval of this generic drug-device combination was granted to Mylan Pharmaceuticals.

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

The U.S. Food and Drug Administration approved the first generic of Symbicort (budesonide and formoterol fumarate dihydrate) inhalation aerosol for the treatment of asthma in patients 6 years of age and older and for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

The approval was given for a complex generic drug-device combination product – a metered-dose inhaler that contains both budesonide (a corticosteroid that reduces inflammation) and formoterol (a long-acting bronchodilator that relaxes muscles in the airways to improve breathing). It is intended to be used as two inhalations, two times a day (usually morning and night, about 12 hours apart), to treat both diseases by preventing symptoms, such as wheezing for those with asthma and for improved breathing for patients with COPD.

The inhaler is approved at two strengths (160/4.5 mcg/actuation and 80/4.5 mcg/actuation), according to the March 15 FDA announcement. The device is not intended for the treatment of acute asthma.

“Today’s approval of the first generic for one of the most commonly prescribed complex drug-device combination products to treat asthma and COPD is another step forward in our commitment to bring generic copies of complex drugs to the market, which can improve quality of life and help reduce the cost of treatment,” said Sally Choe, PhD, director of the Office of Generic Drugs in the FDA’s Center for Drug Evaluation and Research.

The most common side effects associated with budesonide and formoterol fumarate dihydrate oral inhalation aerosol for those with asthma are nasopharyngitis pain, sinusitis, influenza, back pain, nasal congestion, stomach discomfort, vomiting, and oral candidiasis (thrush). For those with COPD, the most common side effects are nasopharyngitis, oral candidiasis, bronchitis, sinusitis, and upper respiratory tract infection, the FDA reported.

The approval of this generic drug-device combination was granted to Mylan Pharmaceuticals.

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

PHOENIX – Before considering oral steroids or biologic therapies, many people with difficult-to-control asthma can reduce symptoms by addressing medication adherence and inhaler technique – and digital monitoring devices can play a key role.

Often physicians “will approach a patient about a biologic if they’re not responding to standard therapy. But we need to sometimes go back to those basic building blocks, like, are you taking the standard therapy?” William C. Anderson, MD, codirector of the multidisciplinary asthma clinic at Children’s Hospital Colorado, Aurora, said in an interview.

At the annual meeting of the American Academy of Allergy, Asthma, and Immunology, he and others presented data highlighting the diagnostic and therapeutic potential of digital monitoring devices for difficult-to-control asthma, the theme of the 2022s meeting.

The Global Initiative for Asthma (GINA) defines asthma as “difficult to control” if it remains uncontrolled despite medium- or high-dose inhaled corticosteroids with a second controller or with maintenance oral steroids, or if the asthma requires high-dose treatment to curb symptoms and exacerbations. About 17% of adult asthma patients have difficult-to-control asthma, according to the 2021 GINA report. 

However, correcting for inhaling technique and adherence cuts the 17% down to just 3.7%, Giselle Mosnaim, MD, an allergist at NorthShore University HealthSystem outside Chicago and AAAAI immediate past president, told attendees at a Feb. 25 session on digital technologies for asthma management.

The CRITIKAL study, which reviewed data from more than 5,000 asthma patients, “showed that, if you have critical errors in inhaler technique, this leads to worse asthma outcomes and increased asthma exacerbations,” Dr. Mosnaim said. Sadly, it also shows that, from 1975 to 2014, despite new devices and new technologies, “we still have poor inhaler technique.”

As for ways to measure adherence, physician judgments tend to be inaccurate, patient self-reporting has proved unreliable, and prescription refill data doesn’t indicate whether patients actually used the medications. “The ideal measure of adherence should be objective, accurate and unobtrusive to minimize impact on patient behavior and allow reliable data collection in real-world settings,” Dr. Mosnaim said. “So electronic medication monitors are the gold standard.” 
 

Tracking adherence

A closing afternoon session featured three presentations on research tracking adherence and outcomes in difficult-to-treat asthma patients – two pediatric cohorts and one across all ages. All studies used the Propeller Health sensor, a Food and Drug Administration–cleared device that attaches to the patient’s inhaler and automatically collects information on where, when, and how often they use their medication. The sensor then sends that information to a data cloud accessible to the patient and their health care professional.

Dr. Anderson’s team scoured a nationwide Propeller Health database for 8,000 patients using the digital monitors with controller therapies for asthma or chronic obstructive pulmonary disease (COPD). The study explored whether adherence differed for once-daily versus twice-daily medications, and if adherence differed based on patient age (4-60+ years).

For both asthma and COPD patients, those on once-daily regimens had higher medication adherence, compared with those who were prescribed twice-daily therapies. Plus, a greater proportion of once-daily patients met the prespecified 80% adherence threshold.

Looking across ages, medication use in the youngest group (aged 4-11 years) looked comparable with 30-somethings, “probably because parents are the ones giving the drug,” Dr. Anderson said. Mirroring patterns from other studies, adherence levels dipped in adolescents and young adults, relative to other age subsets.

Since this population-level analysis didn’t include individualized data on exacerbations or asthma control, “we can’t relate this to outcomes,” Dr. Anderson noted. But he said the data correlating medication use with adherence suggest that once-daily formulations may be the better option.

In one of the two pediatric studies, Matt McCulloch, MD, an allergy and immunology fellow working with Dr. Anderson, and colleagues reviewed charts of 40 children who received care at the Colorado Children’s multidisciplinary asthma clinic between 2018 and 2021. Half of these patients used Propeller Health sensors with their daily inhaled controller; the other patients were matched for age, ethnicity, sex, medication level, and disease control and severity – but had no electronic monitoring device.

On the whole, children who used digital monitoring for 12 months did not fare much better than matched controls on lung function (judged by forced expiratory volume) or asthma control (measured by Asthma Control Test scores).

However, within the digital monitoring group, patients who stayed on the Propeller system for 12 months did have better asthma control, fewer exacerbations, and improved asthma severity scores (measured by the Composite Asthma Severity Index), compared with when they first began digital monitoring. These children had all received care at the clinic for a while before their families opted for the electronic sensor, so “the effect wouldn’t have just been from starting in the clinic,” Dr. McCulloch said in an interview.

The gains came despite waning medication adherence. Similar to other digital monitoring studies, use of daily controller therapies in this retrospective analysis began at 50%-80% but dropped considerably during the first 4-5 months before settling into the 20%-30% range by 1 year.

Rachelle Ramsey, PhD, a pediatric research psychologist at Cincinnati Children’s Hospital Medical Center, presented data from 20 children with difficult-to-treat asthma who received 8 weeks of a digital adherence intervention during a 12-month treatment period. They analyzed three subsets – each with interventions based on how well the patients were managing daily controller therapy at baseline.

One patient with high (>80%) baseline adherence just received digital monitoring. The seven patients who began the study with intermediate (50%-80%) adherence received digital monitoring plus prescriptive text messaging. And the 12 children with poorest (<50%) baseline adherence received digital monitoring and a telehealth session in which a behavioral health specialist helped them set goals and create strategies to overcome barriers – for example, keeping the inhaler near their toothbrush in order to pair medication use with a daily habit.

“Overall, we found that matching Propeller with a behavioral intervention really improved adherence,” Dr. Ramsey said in an interview. While patients were receiving the intervention, adherence averaged across all groups increased from 39% to 76%. However, once the intervention period ended, the group’s adherence regressed toward baseline (36%).

Although adherence did not associate with clinical gains in this small study, the use of digital monitoring to improve medication adherence has translated to better outcomes in other recent efforts.
 

Remote monitoring

In a quality improvement project in the United Kingdom, nurses asked difficult-to-control asthma patients if they understood how to use their corticosteroid/long-acting beta₂-agonist (LABA) inhalers and if they were adhering to treatment guidelines.

Those who answered yes to these questions were invited to a 28-day study that involved swapping their steroid/LABA inhalers for a different controller/bronchodilator (fluticasone/salmeterol) with INCA (Inhaler Compliance Assessment), a device that not only tracks adherence but also uses acoustics to gauge inhaler technique.

Among the 23 patients who participated, many had better clinical outcomes after 28 days of INCA monitoring. As Dr. Mosnaim told attendees, “what was amazing is so many of the patients that had been these difficult-to-control asthmatics who would have gone on to oral steroids or perhaps a biologic – lo and behold, you put them on a digital inhaler, and what do you see?” In two-thirds of the patients, “you see FeNo [a test that measures airway inflammation by detecting nitric oxide in exhalations] goes down. You see spirometry improve. You see the asthma control questionnaire improve. You see blood eosinophils go down.”

And in a 2020 randomized trial, Dr. Mosnaim and colleagues recruited 100 adults with uncontrolled asthma who had prescriptions for a daily inhaled corticosteroid and a short-acting beta-agonist (SABA) inhaler. Participants received Propeller sensors for their steroid and SABA inhalers. After a 2-week run-in period to calculate baseline corticosteroid adherence and SABA use for all participants, half the participants were randomly assigned to the control group, which had the app and sensor in silent mode, merely to collect data on medication use – whereas the treatment group received reminders, alerts, and monthly phone calls from providers who gave feedback on adherence and technique.

After 3 months of digital monitoring, patients didn’t use their rescue medication quite as often – as judged by a rise in the percentage of SABA-free days, compared with when they began the study. But the change in SABA-free days relative to baseline was more pronounced in the treatment group (19%) than in the control group (6%).

As seen in the other digital monitoring studies, adherence to daily corticosteroids fell with time, but the drop was milder in treated participants (2%) versus the control group (17%). So in this study, digital monitoring plus mobile app reminders and clinician feedback “prevented against fall in adherence to inhaled steroids over time,” Dr. Mosnaim said.

These results are “very encouraging” and offer “proof of concept that this type of remote monitoring could work,” Thanai Pongdee, MD, an allergist-immunologist with the Mayo Clinic in Rochester, Minn., said in an interview. One limitation was that the study was too short to measure exacerbation rates. A yearlong analysis would be “really fascinating because you’d catch all the seasons of the year – all the pollen seasons, all these things that could exacerbate you. Some people’s asthma can be quite seasonal.”

More important, the clinical utility of digital sensors will depend on how physicians choose to use them. If the doctor puts out a “blanket recommendation for using it but doesn’t ask you about it or doesn’t use the data to inform your care, then I think people just lose engagement and lose excitement over it,” Dr. Ramsey said. But if the health care team “asks you about the data or looks at the data with you or shows you how valuable this can be to your care, then I think that changes things.”

Building these analyses and interactions into the clinic workflow isn’t trivial. “If you have this wealth of data coming in, how are you going to look at it? Are you going to have an individual person assigned to this role? How are you going to respond to alerts?” Dr. Anderson asked.

In addition, because some digital monitors issue alerts when a patient’s asthma is not well controlled, some providers worry about liability if “something bad were to happen if you had that data but didn’t act upon it,” he said. Yet he noted that remote data monitoring is already used routinely in other areas of medicine, such as managing diabetes and heart conditions, “and it’s not like people are getting dinged for that stuff.”

Another issue is cost. Insurance only covers digital monitors in select cases, but it’s a bit of a catch-22. Insurers “don’t want to cover it until they get the data, but you can’t get the data until insurance covers it,” said Dr. Anderson, who added that “this year we finally got CPT reimbursement codes for monitoring devices.”

On the whole, studies of digital medication monitors suggest that better outcomes require “a good partnership between the health care provider and the patient,” Dr. Pongdee said. “It wasn’t like you could just put these things on and expect them to help. You still need that personal relationship to get the optimal results. We can have all this technology, but you still can’t take the people out of it.”

Dr. Mosnaim reported receiving current research grant support from GlaxoSmithKline, Novartis, Sanofi-Regeneron, and Teva; and past research grant support from AstraZeneca, Alk-Abello, and Genentech. She is immediate past president of the AAAAI, and directs the board of directors for the American Board of Allergy and Immunology. Dr. Anderson has served as a consultant for Regeneron, GlaxoSmithKline, and AstraZeneca, and has received research support from Colorado Medicaid. Dr. McCulloch and Dr. Ramsey disclosed no relevant financial relationships. Dr. Pongdee serves as an at-large director on the American Academy of Allergy, Asthma and Immunology board of directors. He receives grant funding from GlaxoSmithKline, and the Mayo Clinic is a trial site for GlaxoSmithKline and AstraZeneca.

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

PHOENIX – Before considering oral steroids or biologic therapies, many people with difficult-to-control asthma can reduce symptoms by addressing medication adherence and inhaler technique – and digital monitoring devices can play a key role.

Often physicians “will approach a patient about a biologic if they’re not responding to standard therapy. But we need to sometimes go back to those basic building blocks, like, are you taking the standard therapy?” William C. Anderson, MD, codirector of the multidisciplinary asthma clinic at Children’s Hospital Colorado, Aurora, said in an interview.

At the annual meeting of the American Academy of Allergy, Asthma, and Immunology, he and others presented data highlighting the diagnostic and therapeutic potential of digital monitoring devices for difficult-to-control asthma, the theme of the 2022s meeting.

The Global Initiative for Asthma (GINA) defines asthma as “difficult to control” if it remains uncontrolled despite medium- or high-dose inhaled corticosteroids with a second controller or with maintenance oral steroids, or if the asthma requires high-dose treatment to curb symptoms and exacerbations. About 17% of adult asthma patients have difficult-to-control asthma, according to the 2021 GINA report. 

However, correcting for inhaling technique and adherence cuts the 17% down to just 3.7%, Giselle Mosnaim, MD, an allergist at NorthShore University HealthSystem outside Chicago and AAAAI immediate past president, told attendees at a Feb. 25 session on digital technologies for asthma management.

The CRITIKAL study, which reviewed data from more than 5,000 asthma patients, “showed that, if you have critical errors in inhaler technique, this leads to worse asthma outcomes and increased asthma exacerbations,” Dr. Mosnaim said. Sadly, it also shows that, from 1975 to 2014, despite new devices and new technologies, “we still have poor inhaler technique.”

As for ways to measure adherence, physician judgments tend to be inaccurate, patient self-reporting has proved unreliable, and prescription refill data doesn’t indicate whether patients actually used the medications. “The ideal measure of adherence should be objective, accurate and unobtrusive to minimize impact on patient behavior and allow reliable data collection in real-world settings,” Dr. Mosnaim said. “So electronic medication monitors are the gold standard.” 
 

Tracking adherence

A closing afternoon session featured three presentations on research tracking adherence and outcomes in difficult-to-treat asthma patients – two pediatric cohorts and one across all ages. All studies used the Propeller Health sensor, a Food and Drug Administration–cleared device that attaches to the patient’s inhaler and automatically collects information on where, when, and how often they use their medication. The sensor then sends that information to a data cloud accessible to the patient and their health care professional.

Dr. Anderson’s team scoured a nationwide Propeller Health database for 8,000 patients using the digital monitors with controller therapies for asthma or chronic obstructive pulmonary disease (COPD). The study explored whether adherence differed for once-daily versus twice-daily medications, and if adherence differed based on patient age (4-60+ years).

For both asthma and COPD patients, those on once-daily regimens had higher medication adherence, compared with those who were prescribed twice-daily therapies. Plus, a greater proportion of once-daily patients met the prespecified 80% adherence threshold.

Looking across ages, medication use in the youngest group (aged 4-11 years) looked comparable with 30-somethings, “probably because parents are the ones giving the drug,” Dr. Anderson said. Mirroring patterns from other studies, adherence levels dipped in adolescents and young adults, relative to other age subsets.

Since this population-level analysis didn’t include individualized data on exacerbations or asthma control, “we can’t relate this to outcomes,” Dr. Anderson noted. But he said the data correlating medication use with adherence suggest that once-daily formulations may be the better option.

In one of the two pediatric studies, Matt McCulloch, MD, an allergy and immunology fellow working with Dr. Anderson, and colleagues reviewed charts of 40 children who received care at the Colorado Children’s multidisciplinary asthma clinic between 2018 and 2021. Half of these patients used Propeller Health sensors with their daily inhaled controller; the other patients were matched for age, ethnicity, sex, medication level, and disease control and severity – but had no electronic monitoring device.

On the whole, children who used digital monitoring for 12 months did not fare much better than matched controls on lung function (judged by forced expiratory volume) or asthma control (measured by Asthma Control Test scores).

However, within the digital monitoring group, patients who stayed on the Propeller system for 12 months did have better asthma control, fewer exacerbations, and improved asthma severity scores (measured by the Composite Asthma Severity Index), compared with when they first began digital monitoring. These children had all received care at the clinic for a while before their families opted for the electronic sensor, so “the effect wouldn’t have just been from starting in the clinic,” Dr. McCulloch said in an interview.

The gains came despite waning medication adherence. Similar to other digital monitoring studies, use of daily controller therapies in this retrospective analysis began at 50%-80% but dropped considerably during the first 4-5 months before settling into the 20%-30% range by 1 year.

Rachelle Ramsey, PhD, a pediatric research psychologist at Cincinnati Children’s Hospital Medical Center, presented data from 20 children with difficult-to-treat asthma who received 8 weeks of a digital adherence intervention during a 12-month treatment period. They analyzed three subsets – each with interventions based on how well the patients were managing daily controller therapy at baseline.

One patient with high (>80%) baseline adherence just received digital monitoring. The seven patients who began the study with intermediate (50%-80%) adherence received digital monitoring plus prescriptive text messaging. And the 12 children with poorest (<50%) baseline adherence received digital monitoring and a telehealth session in which a behavioral health specialist helped them set goals and create strategies to overcome barriers – for example, keeping the inhaler near their toothbrush in order to pair medication use with a daily habit.

“Overall, we found that matching Propeller with a behavioral intervention really improved adherence,” Dr. Ramsey said in an interview. While patients were receiving the intervention, adherence averaged across all groups increased from 39% to 76%. However, once the intervention period ended, the group’s adherence regressed toward baseline (36%).

Although adherence did not associate with clinical gains in this small study, the use of digital monitoring to improve medication adherence has translated to better outcomes in other recent efforts.
 

Remote monitoring

In a quality improvement project in the United Kingdom, nurses asked difficult-to-control asthma patients if they understood how to use their corticosteroid/long-acting beta₂-agonist (LABA) inhalers and if they were adhering to treatment guidelines.

Those who answered yes to these questions were invited to a 28-day study that involved swapping their steroid/LABA inhalers for a different controller/bronchodilator (fluticasone/salmeterol) with INCA (Inhaler Compliance Assessment), a device that not only tracks adherence but also uses acoustics to gauge inhaler technique.

Among the 23 patients who participated, many had better clinical outcomes after 28 days of INCA monitoring. As Dr. Mosnaim told attendees, “what was amazing is so many of the patients that had been these difficult-to-control asthmatics who would have gone on to oral steroids or perhaps a biologic – lo and behold, you put them on a digital inhaler, and what do you see?” In two-thirds of the patients, “you see FeNo [a test that measures airway inflammation by detecting nitric oxide in exhalations] goes down. You see spirometry improve. You see the asthma control questionnaire improve. You see blood eosinophils go down.”

And in a 2020 randomized trial, Dr. Mosnaim and colleagues recruited 100 adults with uncontrolled asthma who had prescriptions for a daily inhaled corticosteroid and a short-acting beta-agonist (SABA) inhaler. Participants received Propeller sensors for their steroid and SABA inhalers. After a 2-week run-in period to calculate baseline corticosteroid adherence and SABA use for all participants, half the participants were randomly assigned to the control group, which had the app and sensor in silent mode, merely to collect data on medication use – whereas the treatment group received reminders, alerts, and monthly phone calls from providers who gave feedback on adherence and technique.

After 3 months of digital monitoring, patients didn’t use their rescue medication quite as often – as judged by a rise in the percentage of SABA-free days, compared with when they began the study. But the change in SABA-free days relative to baseline was more pronounced in the treatment group (19%) than in the control group (6%).

As seen in the other digital monitoring studies, adherence to daily corticosteroids fell with time, but the drop was milder in treated participants (2%) versus the control group (17%). So in this study, digital monitoring plus mobile app reminders and clinician feedback “prevented against fall in adherence to inhaled steroids over time,” Dr. Mosnaim said.

These results are “very encouraging” and offer “proof of concept that this type of remote monitoring could work,” Thanai Pongdee, MD, an allergist-immunologist with the Mayo Clinic in Rochester, Minn., said in an interview. One limitation was that the study was too short to measure exacerbation rates. A yearlong analysis would be “really fascinating because you’d catch all the seasons of the year – all the pollen seasons, all these things that could exacerbate you. Some people’s asthma can be quite seasonal.”

More important, the clinical utility of digital sensors will depend on how physicians choose to use them. If the doctor puts out a “blanket recommendation for using it but doesn’t ask you about it or doesn’t use the data to inform your care, then I think people just lose engagement and lose excitement over it,” Dr. Ramsey said. But if the health care team “asks you about the data or looks at the data with you or shows you how valuable this can be to your care, then I think that changes things.”

Building these analyses and interactions into the clinic workflow isn’t trivial. “If you have this wealth of data coming in, how are you going to look at it? Are you going to have an individual person assigned to this role? How are you going to respond to alerts?” Dr. Anderson asked.

In addition, because some digital monitors issue alerts when a patient’s asthma is not well controlled, some providers worry about liability if “something bad were to happen if you had that data but didn’t act upon it,” he said. Yet he noted that remote data monitoring is already used routinely in other areas of medicine, such as managing diabetes and heart conditions, “and it’s not like people are getting dinged for that stuff.”

Another issue is cost. Insurance only covers digital monitors in select cases, but it’s a bit of a catch-22. Insurers “don’t want to cover it until they get the data, but you can’t get the data until insurance covers it,” said Dr. Anderson, who added that “this year we finally got CPT reimbursement codes for monitoring devices.”

On the whole, studies of digital medication monitors suggest that better outcomes require “a good partnership between the health care provider and the patient,” Dr. Pongdee said. “It wasn’t like you could just put these things on and expect them to help. You still need that personal relationship to get the optimal results. We can have all this technology, but you still can’t take the people out of it.”

Dr. Mosnaim reported receiving current research grant support from GlaxoSmithKline, Novartis, Sanofi-Regeneron, and Teva; and past research grant support from AstraZeneca, Alk-Abello, and Genentech. She is immediate past president of the AAAAI, and directs the board of directors for the American Board of Allergy and Immunology. Dr. Anderson has served as a consultant for Regeneron, GlaxoSmithKline, and AstraZeneca, and has received research support from Colorado Medicaid. Dr. McCulloch and Dr. Ramsey disclosed no relevant financial relationships. Dr. Pongdee serves as an at-large director on the American Academy of Allergy, Asthma and Immunology board of directors. He receives grant funding from GlaxoSmithKline, and the Mayo Clinic is a trial site for GlaxoSmithKline and AstraZeneca.

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

PHOENIX – Before considering oral steroids or biologic therapies, many people with difficult-to-control asthma can reduce symptoms by addressing medication adherence and inhaler technique – and digital monitoring devices can play a key role.

Often physicians “will approach a patient about a biologic if they’re not responding to standard therapy. But we need to sometimes go back to those basic building blocks, like, are you taking the standard therapy?” William C. Anderson, MD, codirector of the multidisciplinary asthma clinic at Children’s Hospital Colorado, Aurora, said in an interview.

At the annual meeting of the American Academy of Allergy, Asthma, and Immunology, he and others presented data highlighting the diagnostic and therapeutic potential of digital monitoring devices for difficult-to-control asthma, the theme of the 2022s meeting.

The Global Initiative for Asthma (GINA) defines asthma as “difficult to control” if it remains uncontrolled despite medium- or high-dose inhaled corticosteroids with a second controller or with maintenance oral steroids, or if the asthma requires high-dose treatment to curb symptoms and exacerbations. About 17% of adult asthma patients have difficult-to-control asthma, according to the 2021 GINA report. 

However, correcting for inhaling technique and adherence cuts the 17% down to just 3.7%, Giselle Mosnaim, MD, an allergist at NorthShore University HealthSystem outside Chicago and AAAAI immediate past president, told attendees at a Feb. 25 session on digital technologies for asthma management.

The CRITIKAL study, which reviewed data from more than 5,000 asthma patients, “showed that, if you have critical errors in inhaler technique, this leads to worse asthma outcomes and increased asthma exacerbations,” Dr. Mosnaim said. Sadly, it also shows that, from 1975 to 2014, despite new devices and new technologies, “we still have poor inhaler technique.”

As for ways to measure adherence, physician judgments tend to be inaccurate, patient self-reporting has proved unreliable, and prescription refill data doesn’t indicate whether patients actually used the medications. “The ideal measure of adherence should be objective, accurate and unobtrusive to minimize impact on patient behavior and allow reliable data collection in real-world settings,” Dr. Mosnaim said. “So electronic medication monitors are the gold standard.” 
 

Tracking adherence

A closing afternoon session featured three presentations on research tracking adherence and outcomes in difficult-to-treat asthma patients – two pediatric cohorts and one across all ages. All studies used the Propeller Health sensor, a Food and Drug Administration–cleared device that attaches to the patient’s inhaler and automatically collects information on where, when, and how often they use their medication. The sensor then sends that information to a data cloud accessible to the patient and their health care professional.

Dr. Anderson’s team scoured a nationwide Propeller Health database for 8,000 patients using the digital monitors with controller therapies for asthma or chronic obstructive pulmonary disease (COPD). The study explored whether adherence differed for once-daily versus twice-daily medications, and if adherence differed based on patient age (4-60+ years).

For both asthma and COPD patients, those on once-daily regimens had higher medication adherence, compared with those who were prescribed twice-daily therapies. Plus, a greater proportion of once-daily patients met the prespecified 80% adherence threshold.

Looking across ages, medication use in the youngest group (aged 4-11 years) looked comparable with 30-somethings, “probably because parents are the ones giving the drug,” Dr. Anderson said. Mirroring patterns from other studies, adherence levels dipped in adolescents and young adults, relative to other age subsets.

Since this population-level analysis didn’t include individualized data on exacerbations or asthma control, “we can’t relate this to outcomes,” Dr. Anderson noted. But he said the data correlating medication use with adherence suggest that once-daily formulations may be the better option.

In one of the two pediatric studies, Matt McCulloch, MD, an allergy and immunology fellow working with Dr. Anderson, and colleagues reviewed charts of 40 children who received care at the Colorado Children’s multidisciplinary asthma clinic between 2018 and 2021. Half of these patients used Propeller Health sensors with their daily inhaled controller; the other patients were matched for age, ethnicity, sex, medication level, and disease control and severity – but had no electronic monitoring device.

On the whole, children who used digital monitoring for 12 months did not fare much better than matched controls on lung function (judged by forced expiratory volume) or asthma control (measured by Asthma Control Test scores).

However, within the digital monitoring group, patients who stayed on the Propeller system for 12 months did have better asthma control, fewer exacerbations, and improved asthma severity scores (measured by the Composite Asthma Severity Index), compared with when they first began digital monitoring. These children had all received care at the clinic for a while before their families opted for the electronic sensor, so “the effect wouldn’t have just been from starting in the clinic,” Dr. McCulloch said in an interview.

The gains came despite waning medication adherence. Similar to other digital monitoring studies, use of daily controller therapies in this retrospective analysis began at 50%-80% but dropped considerably during the first 4-5 months before settling into the 20%-30% range by 1 year.

Rachelle Ramsey, PhD, a pediatric research psychologist at Cincinnati Children’s Hospital Medical Center, presented data from 20 children with difficult-to-treat asthma who received 8 weeks of a digital adherence intervention during a 12-month treatment period. They analyzed three subsets – each with interventions based on how well the patients were managing daily controller therapy at baseline.

One patient with high (>80%) baseline adherence just received digital monitoring. The seven patients who began the study with intermediate (50%-80%) adherence received digital monitoring plus prescriptive text messaging. And the 12 children with poorest (<50%) baseline adherence received digital monitoring and a telehealth session in which a behavioral health specialist helped them set goals and create strategies to overcome barriers – for example, keeping the inhaler near their toothbrush in order to pair medication use with a daily habit.

“Overall, we found that matching Propeller with a behavioral intervention really improved adherence,” Dr. Ramsey said in an interview. While patients were receiving the intervention, adherence averaged across all groups increased from 39% to 76%. However, once the intervention period ended, the group’s adherence regressed toward baseline (36%).

Although adherence did not associate with clinical gains in this small study, the use of digital monitoring to improve medication adherence has translated to better outcomes in other recent efforts.
 

Remote monitoring

In a quality improvement project in the United Kingdom, nurses asked difficult-to-control asthma patients if they understood how to use their corticosteroid/long-acting beta₂-agonist (LABA) inhalers and if they were adhering to treatment guidelines.

Those who answered yes to these questions were invited to a 28-day study that involved swapping their steroid/LABA inhalers for a different controller/bronchodilator (fluticasone/salmeterol) with INCA (Inhaler Compliance Assessment), a device that not only tracks adherence but also uses acoustics to gauge inhaler technique.

Among the 23 patients who participated, many had better clinical outcomes after 28 days of INCA monitoring. As Dr. Mosnaim told attendees, “what was amazing is so many of the patients that had been these difficult-to-control asthmatics who would have gone on to oral steroids or perhaps a biologic – lo and behold, you put them on a digital inhaler, and what do you see?” In two-thirds of the patients, “you see FeNo [a test that measures airway inflammation by detecting nitric oxide in exhalations] goes down. You see spirometry improve. You see the asthma control questionnaire improve. You see blood eosinophils go down.”

And in a 2020 randomized trial, Dr. Mosnaim and colleagues recruited 100 adults with uncontrolled asthma who had prescriptions for a daily inhaled corticosteroid and a short-acting beta-agonist (SABA) inhaler. Participants received Propeller sensors for their steroid and SABA inhalers. After a 2-week run-in period to calculate baseline corticosteroid adherence and SABA use for all participants, half the participants were randomly assigned to the control group, which had the app and sensor in silent mode, merely to collect data on medication use – whereas the treatment group received reminders, alerts, and monthly phone calls from providers who gave feedback on adherence and technique.

After 3 months of digital monitoring, patients didn’t use their rescue medication quite as often – as judged by a rise in the percentage of SABA-free days, compared with when they began the study. But the change in SABA-free days relative to baseline was more pronounced in the treatment group (19%) than in the control group (6%).

As seen in the other digital monitoring studies, adherence to daily corticosteroids fell with time, but the drop was milder in treated participants (2%) versus the control group (17%). So in this study, digital monitoring plus mobile app reminders and clinician feedback “prevented against fall in adherence to inhaled steroids over time,” Dr. Mosnaim said.

These results are “very encouraging” and offer “proof of concept that this type of remote monitoring could work,” Thanai Pongdee, MD, an allergist-immunologist with the Mayo Clinic in Rochester, Minn., said in an interview. One limitation was that the study was too short to measure exacerbation rates. A yearlong analysis would be “really fascinating because you’d catch all the seasons of the year – all the pollen seasons, all these things that could exacerbate you. Some people’s asthma can be quite seasonal.”

More important, the clinical utility of digital sensors will depend on how physicians choose to use them. If the doctor puts out a “blanket recommendation for using it but doesn’t ask you about it or doesn’t use the data to inform your care, then I think people just lose engagement and lose excitement over it,” Dr. Ramsey said. But if the health care team “asks you about the data or looks at the data with you or shows you how valuable this can be to your care, then I think that changes things.”

Building these analyses and interactions into the clinic workflow isn’t trivial. “If you have this wealth of data coming in, how are you going to look at it? Are you going to have an individual person assigned to this role? How are you going to respond to alerts?” Dr. Anderson asked.

In addition, because some digital monitors issue alerts when a patient’s asthma is not well controlled, some providers worry about liability if “something bad were to happen if you had that data but didn’t act upon it,” he said. Yet he noted that remote data monitoring is already used routinely in other areas of medicine, such as managing diabetes and heart conditions, “and it’s not like people are getting dinged for that stuff.”

Another issue is cost. Insurance only covers digital monitors in select cases, but it’s a bit of a catch-22. Insurers “don’t want to cover it until they get the data, but you can’t get the data until insurance covers it,” said Dr. Anderson, who added that “this year we finally got CPT reimbursement codes for monitoring devices.”

On the whole, studies of digital medication monitors suggest that better outcomes require “a good partnership between the health care provider and the patient,” Dr. Pongdee said. “It wasn’t like you could just put these things on and expect them to help. You still need that personal relationship to get the optimal results. We can have all this technology, but you still can’t take the people out of it.”

Dr. Mosnaim reported receiving current research grant support from GlaxoSmithKline, Novartis, Sanofi-Regeneron, and Teva; and past research grant support from AstraZeneca, Alk-Abello, and Genentech. She is immediate past president of the AAAAI, and directs the board of directors for the American Board of Allergy and Immunology. Dr. Anderson has served as a consultant for Regeneron, GlaxoSmithKline, and AstraZeneca, and has received research support from Colorado Medicaid. Dr. McCulloch and Dr. Ramsey disclosed no relevant financial relationships. Dr. Pongdee serves as an at-large director on the American Academy of Allergy, Asthma and Immunology board of directors. He receives grant funding from GlaxoSmithKline, and the Mayo Clinic is a trial site for GlaxoSmithKline and AstraZeneca.

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

Heavier smoking significantly increased mortality in adults with progressive fibrosing interstitial lung disease (PF-ILD), based on data from 377 individuals.

The negative impact of smoking on pulmonary diseases is well documented, but the specific impact on patients with PF-ILD has not been well studied, Mark Platenburg, MD, of St. Antonious Hospital, Nieuwegein, the Netherlands, and colleagues wrote in Respiratory Medicine .

GaryPhoto/ThinkStock

“Patients with PF-ILD or IPF [idiopathic pulmonary fibrosis] are prone to early mortality, indicating a need for prognostic [bio]marker studies for precision medicine,” they said.

The researchers identified adults older than 18 years with PF-ILD who were diagnosed at a single center. All study participants had at least 10% fibrosis, and showed either a decline of at least 10% in forced vital capacity, a 5.0%-9.9% relative FVC decline plus progressive respiratory symptoms and/or an increase in extent of fibrosis on subsequent high-resolution (HRCT progression), or progressive respiratory symptoms and HRCT progression over 24 months after ILD diagnosis.

Pack-years of smoking was a prognostic variable; the researchers also compared median transplant-free survival in heavy smokers and mild to moderate smokers. They also investigated the association between smoking quantity and emphysema in the study population.

Overall, the increased risk for mortality was 11%, 22%, and 44% in patients with 10, 20, and 40 pack-years of smoking, respectively.

Both the unadjusted and adjusted hazard ratio for pack-years were significant (1.014, P < .001 and 1.011, P = .022, respectively).

The median transplant-free survival of ever-smokers versus never-smokers with PF-ILD was 3.3 years versus 4.8 years; median transplant-free survival was 3.0 years for heavy smokers and 3.8 years for mild to moderate smokers. Similarly, median survival was 4.2 years in never-smokers versus 3.0 years in former smokers.

Emphysema was significantly more comment in heavy smokers, compared with never smokers and mild to moderate smokers (P < .001 for both).

“We observed a gradual decrease in survival starting from never to mild-moderate and subsequent heavy smokers supporting our finding that [pack-years] is an independent predictor for mortality in PF-ILD,” the researchers wrote. “This is an important message that clinicians could convey to their ILD patients, but also to patients at-risk for ILD.”

The study findings were limited by several factors, mainly the retrospective design, incomplete data for some patients, and lack of data on comorbidities, the researchers noted. However, the results strengthen the evidence for the detrimental effect of heavy smoking in PF-ILD, they said. Consequently, “efforts to reduce pack-years in those with, and at risk for, PF-ILD may translate into a survival benefit and should have high priority in clinical practice.”

The study was supported by grants from ZonMw TopZorg Care and TZO. The researchers had no financial conflicts to disclose.

Heavier smoking significantly increased mortality in adults with progressive fibrosing interstitial lung disease (PF-ILD), based on data from 377 individuals.

The negative impact of smoking on pulmonary diseases is well documented, but the specific impact on patients with PF-ILD has not been well studied, Mark Platenburg, MD, of St. Antonious Hospital, Nieuwegein, the Netherlands, and colleagues wrote in Respiratory Medicine .

GaryPhoto/ThinkStock

“Patients with PF-ILD or IPF [idiopathic pulmonary fibrosis] are prone to early mortality, indicating a need for prognostic [bio]marker studies for precision medicine,” they said.

The researchers identified adults older than 18 years with PF-ILD who were diagnosed at a single center. All study participants had at least 10% fibrosis, and showed either a decline of at least 10% in forced vital capacity, a 5.0%-9.9% relative FVC decline plus progressive respiratory symptoms and/or an increase in extent of fibrosis on subsequent high-resolution (HRCT progression), or progressive respiratory symptoms and HRCT progression over 24 months after ILD diagnosis.

Pack-years of smoking was a prognostic variable; the researchers also compared median transplant-free survival in heavy smokers and mild to moderate smokers. They also investigated the association between smoking quantity and emphysema in the study population.

Overall, the increased risk for mortality was 11%, 22%, and 44% in patients with 10, 20, and 40 pack-years of smoking, respectively.

Both the unadjusted and adjusted hazard ratio for pack-years were significant (1.014, P < .001 and 1.011, P = .022, respectively).

The median transplant-free survival of ever-smokers versus never-smokers with PF-ILD was 3.3 years versus 4.8 years; median transplant-free survival was 3.0 years for heavy smokers and 3.8 years for mild to moderate smokers. Similarly, median survival was 4.2 years in never-smokers versus 3.0 years in former smokers.

Emphysema was significantly more comment in heavy smokers, compared with never smokers and mild to moderate smokers (P < .001 for both).

“We observed a gradual decrease in survival starting from never to mild-moderate and subsequent heavy smokers supporting our finding that [pack-years] is an independent predictor for mortality in PF-ILD,” the researchers wrote. “This is an important message that clinicians could convey to their ILD patients, but also to patients at-risk for ILD.”

The study findings were limited by several factors, mainly the retrospective design, incomplete data for some patients, and lack of data on comorbidities, the researchers noted. However, the results strengthen the evidence for the detrimental effect of heavy smoking in PF-ILD, they said. Consequently, “efforts to reduce pack-years in those with, and at risk for, PF-ILD may translate into a survival benefit and should have high priority in clinical practice.”

The study was supported by grants from ZonMw TopZorg Care and TZO. The researchers had no financial conflicts to disclose.

Heavier smoking significantly increased mortality in adults with progressive fibrosing interstitial lung disease (PF-ILD), based on data from 377 individuals.

The negative impact of smoking on pulmonary diseases is well documented, but the specific impact on patients with PF-ILD has not been well studied, Mark Platenburg, MD, of St. Antonious Hospital, Nieuwegein, the Netherlands, and colleagues wrote in Respiratory Medicine .

GaryPhoto/ThinkStock

“Patients with PF-ILD or IPF [idiopathic pulmonary fibrosis] are prone to early mortality, indicating a need for prognostic [bio]marker studies for precision medicine,” they said.

The researchers identified adults older than 18 years with PF-ILD who were diagnosed at a single center. All study participants had at least 10% fibrosis, and showed either a decline of at least 10% in forced vital capacity, a 5.0%-9.9% relative FVC decline plus progressive respiratory symptoms and/or an increase in extent of fibrosis on subsequent high-resolution (HRCT progression), or progressive respiratory symptoms and HRCT progression over 24 months after ILD diagnosis.

Pack-years of smoking was a prognostic variable; the researchers also compared median transplant-free survival in heavy smokers and mild to moderate smokers. They also investigated the association between smoking quantity and emphysema in the study population.

Overall, the increased risk for mortality was 11%, 22%, and 44% in patients with 10, 20, and 40 pack-years of smoking, respectively.

Both the unadjusted and adjusted hazard ratio for pack-years were significant (1.014, P < .001 and 1.011, P = .022, respectively).

The median transplant-free survival of ever-smokers versus never-smokers with PF-ILD was 3.3 years versus 4.8 years; median transplant-free survival was 3.0 years for heavy smokers and 3.8 years for mild to moderate smokers. Similarly, median survival was 4.2 years in never-smokers versus 3.0 years in former smokers.

Emphysema was significantly more comment in heavy smokers, compared with never smokers and mild to moderate smokers (P < .001 for both).

“We observed a gradual decrease in survival starting from never to mild-moderate and subsequent heavy smokers supporting our finding that [pack-years] is an independent predictor for mortality in PF-ILD,” the researchers wrote. “This is an important message that clinicians could convey to their ILD patients, but also to patients at-risk for ILD.”

The study findings were limited by several factors, mainly the retrospective design, incomplete data for some patients, and lack of data on comorbidities, the researchers noted. However, the results strengthen the evidence for the detrimental effect of heavy smoking in PF-ILD, they said. Consequently, “efforts to reduce pack-years in those with, and at risk for, PF-ILD may translate into a survival benefit and should have high priority in clinical practice.”

The study was supported by grants from ZonMw TopZorg Care and TZO. The researchers had no financial conflicts to disclose.

The Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee has chosen the influenza vaccine strains for the 2022-2023 season in the northern hemisphere, which begins in the fall of 2022.

On March 3, the committee unanimously voted to endorse the World Health Organization’s recommendations as to which influenza strains to include for coverage by vaccines for the upcoming flu season. Two of the four recommended strains are different from last season.

The committee also heard updates on flu activity this season. So far, data from the U.S. Flu Vaccine Effectiveness (VE) network, which consists of seven study sites, have not shown that the vaccine is protective against influenza A. “We can say that it is not highly effective,” Brendan Flannery, PhD, who leads the U.S. Flu VE network for the Centers for Disease Control and Prevention, said in an interview. He was not involved with the advisory committee meeting. Flu activity this season has been low, he explained, so there are fewer cases his team can use to estimate vaccine efficacy. “If there’s some benefit, it’s hard for us to show that now,” he said.
 

Vaccine strains

The panel voted to include a A/Darwin/9/2021-like strain for the H3N2 component of the vaccine; this is changed from A/Cambodia/e0826360/2020. For the influenza B Victoria lineage component, the committee voted to include a B/Austria/1359417/2021-like virus, a swap from this year’s B/Washington/02/2019-like virus. These changes apply to the egg-based, cell-culture, and recombinant vaccines. Both new strains were included in WHO’s 2022 influenza vaccine strain recommendations for the southern hemisphere.

For the influenza A H1N1 component, the group also agreed to include a A/Victoria/2570/2019 (H1N1) pdm09-like virus for the egg-based vaccine and the A/Wisconsin/588/2019 (H1N1) pdm09-like virus for cell culture or recombinant vaccines. These strains were included for the 2021-2022 season. The panel also voted for the inclusion of a B/Phuket/3073/2013-like virus (B/Yamagata lineage) as the second influenza B strain for the quadrivalent egg-based, cell culture, or recombinant vaccines, which is unchanged from this flu season.
 

‘Sporadic’ flu activity

While there was an uptick in influenza activity this year compared to the 2020-2021 season, hospitalization rates are lower than in the four seasons preceding the pandemic (from 2016-2017 to 2019-2020). As of Feb. 26, the cumulative hospitalization rate for this flu season was 5.2 hospitalizations per 100,000 individuals. There have been eight pediatric deaths due to influenza so far this season, compared to one pediatric death reported to the CDC during the 2020-2021 flu season.

About 4.1% of specimens tested at clinical laboratories were positive for flu. Since Oct. 30, 2.7% of specimens have been positive for influenza this season. Nearly all viruses detected (97.7%) have been influenza A.

Lisa Grohskopf, MD, MPH, a medical officer in the influenza division at the CDC who presented the data at the meeting, described flu activity this season as “sporadic” and noted that activity is increasing in some areas of the country. According to CDC’s weekly influenza surveillance report, most states had minimal influenza-like illness (ILI) activity, although Arkansas, Idaho, Iowa, Kansas, Minnesota, and Utah had slightly higher ILI activity as of Feb. 26. Champaign-Urbana, Illinois; St. Cloud, Minnesota; and Brownwood, Texas, had the highest levels of flu activity in the country.
 

Low vaccine effectiveness

As of Jan. 22, results from the U.S. Flu VE network do not show statistically significant evidence that the flu vaccine is effective. Currently, the vaccine is estimated to be 8% effective against preventing influenza A infection (95% confidence interval, –31% to 36%) and 14% effective against preventing A/H3N2 infection (95% CI, –28% to 43%) for people aged 6 months and older.

The network did not have enough data to provide age-specific VE estimates or estimates of effectiveness against influenza B. This could be due to low flu activity relative to prepandemic years, Dr. Flannery said. Of the 2,758 individuals enrolled in the VE flu network this season, just 147 (5%) tested positive for the flu this season. This is the lowest positivity rate observed in the Flu VE network participants with respiratory illness over the past 10 flu seasons, Dr. Grohskopf noted. In comparison, estimates from the 2019 to 2020 season included 4,112 individuals, and 1,060 tested positive for flu.

“We are really at the bare minimum of what we can use for a flu vaccine effectiveness estimate,” Dr. Flannery said about the more recent data. The network was not able to produce any estimates about flu vaccine effectiveness for the 2020-2021 season because of historically low flu activity.

The Department of Defense also presented vaccine efficacy estimates for the 2021–2022 season. The vaccine has been 36% effective (95% CI, 28%-44%) against all strains of the virus, 33% effective against influenza A (95% CI, 24%-41%), 32% effective against A/H3N2 (95% CI, 3%-53%), and 59% effective against influenza B (95% CI, 42%-71%). These results are from a young, healthy adult population, Lieutenant Commander Courtney Gustin, DrPH, MSN, told the panel, and they may not be reflective of efficacy rates across all age groups.

Though these findings suggest there is low to no measurable benefit against influenza A, Dr. Flannery said the CDC still recommends getting the flu vaccine, as it can be protective against other circulating flu strains. “We have been able to demonstrate protection against other H3 [viruses], B viruses, and H1 viruses in the past,” he said. And as these results only show protection against mild disease, “there is still possibility that there’s benefit against more severe disease,” he added. Studies measuring effectiveness against more severe outcomes are not yet available.

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

The Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee has chosen the influenza vaccine strains for the 2022-2023 season in the northern hemisphere, which begins in the fall of 2022.

On March 3, the committee unanimously voted to endorse the World Health Organization’s recommendations as to which influenza strains to include for coverage by vaccines for the upcoming flu season. Two of the four recommended strains are different from last season.

The committee also heard updates on flu activity this season. So far, data from the U.S. Flu Vaccine Effectiveness (VE) network, which consists of seven study sites, have not shown that the vaccine is protective against influenza A. “We can say that it is not highly effective,” Brendan Flannery, PhD, who leads the U.S. Flu VE network for the Centers for Disease Control and Prevention, said in an interview. He was not involved with the advisory committee meeting. Flu activity this season has been low, he explained, so there are fewer cases his team can use to estimate vaccine efficacy. “If there’s some benefit, it’s hard for us to show that now,” he said.
 

Vaccine strains

The panel voted to include a A/Darwin/9/2021-like strain for the H3N2 component of the vaccine; this is changed from A/Cambodia/e0826360/2020. For the influenza B Victoria lineage component, the committee voted to include a B/Austria/1359417/2021-like virus, a swap from this year’s B/Washington/02/2019-like virus. These changes apply to the egg-based, cell-culture, and recombinant vaccines. Both new strains were included in WHO’s 2022 influenza vaccine strain recommendations for the southern hemisphere.

For the influenza A H1N1 component, the group also agreed to include a A/Victoria/2570/2019 (H1N1) pdm09-like virus for the egg-based vaccine and the A/Wisconsin/588/2019 (H1N1) pdm09-like virus for cell culture or recombinant vaccines. These strains were included for the 2021-2022 season. The panel also voted for the inclusion of a B/Phuket/3073/2013-like virus (B/Yamagata lineage) as the second influenza B strain for the quadrivalent egg-based, cell culture, or recombinant vaccines, which is unchanged from this flu season.
 

‘Sporadic’ flu activity

While there was an uptick in influenza activity this year compared to the 2020-2021 season, hospitalization rates are lower than in the four seasons preceding the pandemic (from 2016-2017 to 2019-2020). As of Feb. 26, the cumulative hospitalization rate for this flu season was 5.2 hospitalizations per 100,000 individuals. There have been eight pediatric deaths due to influenza so far this season, compared to one pediatric death reported to the CDC during the 2020-2021 flu season.

About 4.1% of specimens tested at clinical laboratories were positive for flu. Since Oct. 30, 2.7% of specimens have been positive for influenza this season. Nearly all viruses detected (97.7%) have been influenza A.

Lisa Grohskopf, MD, MPH, a medical officer in the influenza division at the CDC who presented the data at the meeting, described flu activity this season as “sporadic” and noted that activity is increasing in some areas of the country. According to CDC’s weekly influenza surveillance report, most states had minimal influenza-like illness (ILI) activity, although Arkansas, Idaho, Iowa, Kansas, Minnesota, and Utah had slightly higher ILI activity as of Feb. 26. Champaign-Urbana, Illinois; St. Cloud, Minnesota; and Brownwood, Texas, had the highest levels of flu activity in the country.
 

Low vaccine effectiveness

As of Jan. 22, results from the U.S. Flu VE network do not show statistically significant evidence that the flu vaccine is effective. Currently, the vaccine is estimated to be 8% effective against preventing influenza A infection (95% confidence interval, –31% to 36%) and 14% effective against preventing A/H3N2 infection (95% CI, –28% to 43%) for people aged 6 months and older.

The network did not have enough data to provide age-specific VE estimates or estimates of effectiveness against influenza B. This could be due to low flu activity relative to prepandemic years, Dr. Flannery said. Of the 2,758 individuals enrolled in the VE flu network this season, just 147 (5%) tested positive for the flu this season. This is the lowest positivity rate observed in the Flu VE network participants with respiratory illness over the past 10 flu seasons, Dr. Grohskopf noted. In comparison, estimates from the 2019 to 2020 season included 4,112 individuals, and 1,060 tested positive for flu.

“We are really at the bare minimum of what we can use for a flu vaccine effectiveness estimate,” Dr. Flannery said about the more recent data. The network was not able to produce any estimates about flu vaccine effectiveness for the 2020-2021 season because of historically low flu activity.

The Department of Defense also presented vaccine efficacy estimates for the 2021–2022 season. The vaccine has been 36% effective (95% CI, 28%-44%) against all strains of the virus, 33% effective against influenza A (95% CI, 24%-41%), 32% effective against A/H3N2 (95% CI, 3%-53%), and 59% effective against influenza B (95% CI, 42%-71%). These results are from a young, healthy adult population, Lieutenant Commander Courtney Gustin, DrPH, MSN, told the panel, and they may not be reflective of efficacy rates across all age groups.

Though these findings suggest there is low to no measurable benefit against influenza A, Dr. Flannery said the CDC still recommends getting the flu vaccine, as it can be protective against other circulating flu strains. “We have been able to demonstrate protection against other H3 [viruses], B viruses, and H1 viruses in the past,” he said. And as these results only show protection against mild disease, “there is still possibility that there’s benefit against more severe disease,” he added. Studies measuring effectiveness against more severe outcomes are not yet available.

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

The Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee has chosen the influenza vaccine strains for the 2022-2023 season in the northern hemisphere, which begins in the fall of 2022.

On March 3, the committee unanimously voted to endorse the World Health Organization’s recommendations as to which influenza strains to include for coverage by vaccines for the upcoming flu season. Two of the four recommended strains are different from last season.

The committee also heard updates on flu activity this season. So far, data from the U.S. Flu Vaccine Effectiveness (VE) network, which consists of seven study sites, have not shown that the vaccine is protective against influenza A. “We can say that it is not highly effective,” Brendan Flannery, PhD, who leads the U.S. Flu VE network for the Centers for Disease Control and Prevention, said in an interview. He was not involved with the advisory committee meeting. Flu activity this season has been low, he explained, so there are fewer cases his team can use to estimate vaccine efficacy. “If there’s some benefit, it’s hard for us to show that now,” he said.
 

Vaccine strains

The panel voted to include a A/Darwin/9/2021-like strain for the H3N2 component of the vaccine; this is changed from A/Cambodia/e0826360/2020. For the influenza B Victoria lineage component, the committee voted to include a B/Austria/1359417/2021-like virus, a swap from this year’s B/Washington/02/2019-like virus. These changes apply to the egg-based, cell-culture, and recombinant vaccines. Both new strains were included in WHO’s 2022 influenza vaccine strain recommendations for the southern hemisphere.

For the influenza A H1N1 component, the group also agreed to include a A/Victoria/2570/2019 (H1N1) pdm09-like virus for the egg-based vaccine and the A/Wisconsin/588/2019 (H1N1) pdm09-like virus for cell culture or recombinant vaccines. These strains were included for the 2021-2022 season. The panel also voted for the inclusion of a B/Phuket/3073/2013-like virus (B/Yamagata lineage) as the second influenza B strain for the quadrivalent egg-based, cell culture, or recombinant vaccines, which is unchanged from this flu season.
 

‘Sporadic’ flu activity

While there was an uptick in influenza activity this year compared to the 2020-2021 season, hospitalization rates are lower than in the four seasons preceding the pandemic (from 2016-2017 to 2019-2020). As of Feb. 26, the cumulative hospitalization rate for this flu season was 5.2 hospitalizations per 100,000 individuals. There have been eight pediatric deaths due to influenza so far this season, compared to one pediatric death reported to the CDC during the 2020-2021 flu season.

About 4.1% of specimens tested at clinical laboratories were positive for flu. Since Oct. 30, 2.7% of specimens have been positive for influenza this season. Nearly all viruses detected (97.7%) have been influenza A.

Lisa Grohskopf, MD, MPH, a medical officer in the influenza division at the CDC who presented the data at the meeting, described flu activity this season as “sporadic” and noted that activity is increasing in some areas of the country. According to CDC’s weekly influenza surveillance report, most states had minimal influenza-like illness (ILI) activity, although Arkansas, Idaho, Iowa, Kansas, Minnesota, and Utah had slightly higher ILI activity as of Feb. 26. Champaign-Urbana, Illinois; St. Cloud, Minnesota; and Brownwood, Texas, had the highest levels of flu activity in the country.
 

Low vaccine effectiveness

As of Jan. 22, results from the U.S. Flu VE network do not show statistically significant evidence that the flu vaccine is effective. Currently, the vaccine is estimated to be 8% effective against preventing influenza A infection (95% confidence interval, –31% to 36%) and 14% effective against preventing A/H3N2 infection (95% CI, –28% to 43%) for people aged 6 months and older.

The network did not have enough data to provide age-specific VE estimates or estimates of effectiveness against influenza B. This could be due to low flu activity relative to prepandemic years, Dr. Flannery said. Of the 2,758 individuals enrolled in the VE flu network this season, just 147 (5%) tested positive for the flu this season. This is the lowest positivity rate observed in the Flu VE network participants with respiratory illness over the past 10 flu seasons, Dr. Grohskopf noted. In comparison, estimates from the 2019 to 2020 season included 4,112 individuals, and 1,060 tested positive for flu.

“We are really at the bare minimum of what we can use for a flu vaccine effectiveness estimate,” Dr. Flannery said about the more recent data. The network was not able to produce any estimates about flu vaccine effectiveness for the 2020-2021 season because of historically low flu activity.

The Department of Defense also presented vaccine efficacy estimates for the 2021–2022 season. The vaccine has been 36% effective (95% CI, 28%-44%) against all strains of the virus, 33% effective against influenza A (95% CI, 24%-41%), 32% effective against A/H3N2 (95% CI, 3%-53%), and 59% effective against influenza B (95% CI, 42%-71%). These results are from a young, healthy adult population, Lieutenant Commander Courtney Gustin, DrPH, MSN, told the panel, and they may not be reflective of efficacy rates across all age groups.

Though these findings suggest there is low to no measurable benefit against influenza A, Dr. Flannery said the CDC still recommends getting the flu vaccine, as it can be protective against other circulating flu strains. “We have been able to demonstrate protection against other H3 [viruses], B viruses, and H1 viruses in the past,” he said. And as these results only show protection against mild disease, “there is still possibility that there’s benefit against more severe disease,” he added. Studies measuring effectiveness against more severe outcomes are not yet available.

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

As the COVID-19 pandemic winds down – for the time being at least – efforts are ramping up to develop next-generation vaccines that can protect against future novel coronaviruses and variants. Several projects are presenting clever combinations of viral parts to the immune system that evoke a robust and hopefully lasting response.

The coming generation of “pan” vaccines aims to tamp down SARS-CoV-2, its closest relatives, and whatever may come into tamer respiratory viruses like the common cold. Whatever the eventual components of this new generation of vaccines, experts agree on the goal: preventing severe disease and death. And a broader approach is critical.

“All the vaccines have been amazing. But we’re playing a whack-a-mole game with the variants. We need to take a step back and ask if a pan-variant vaccine is possible. That’s important because Omicron isn’t the last variant,” said Jacob Lemieux, MD, PhD, instructor in medicine and infectious disease specialist at Massachusetts General Hospital, Boston.
 

A broad spectrum vaccine

The drive to create a vaccine that would deter multiple coronaviruses arose early, among many researchers. An article published in Nature in May 2020 by National Institute of Allergy and Infectious Diseases researcher Luca T. Giurgea, MD, and colleagues said it all in the title: “Universal coronavirus vaccines: the time to start is now.”

Their concerns? The diversity of bat coronaviruses poised to jump into humans; the high mutability of the spike gene that the immune response recognizes; and the persistence of mutations in an RNA virus, which can’t repair errors. 

Work on broader vaccines began in several labs as SARS-CoV-2 spawned variant after variant.

On Sept. 28, NIAID announced funding for developing ‘pan-coronavirus’ vaccines – the quotation marks theirs to indicate that a magic bullet against any new coronavirus is unrealistic. “These new awards are designed to look ahead and prepare for the next generation of coronaviruses with pandemic potential,” said NIAID director Anthony S. Fauci, MD. An initial three awards went to groups at the University of Wisconsin, Brigham and Women’s Hospital, and Duke University.

President Biden mentioned the NIAID funding in his State of the Union Address. He also talked about how the Biomedical Advanced Research and Development Authority, founded in 2006 to prepare for public health emergencies, is spearheading development of new vaccine platforms and vaccines that target a broader swath of pathogen parts.

Meanwhile, individual researchers from eclectic fields are finding new ways to prevent future pandemics.

Artem Babaian, PhD, a computational biologist at the University of Cambridge (England), had the idea to probe National Institutes of Health genome databases, going back more than a decade, for overlooked novel coronaviruses. He started the project while he was between jobs as the pandemic was unfurling, using a telltale enzyme unique to the RNA viruses to fish out COVID cousins. The work is published in Nature and the data freely available at serratus.io.

Among the nearly 132,000 novel RNA viruses Dr. Babaian’s team found, 9 were from previously unrecognized coronaviruses. The novel nine came from “ecologically diverse sources”: a seahorse, an axolotl, an eel, and several fishes. Deciphering the topographies of these coronaviruses may provide clues to developing vaccines that stay ahead of future pandemics.

But optics are important in keeping expectations reasonable. “‘Universal vaccine’ is a misnomer. I think about it as ‘broad spectrum vaccines.’ It’s critical to be up front that these vaccines can never guarantee immunity against all coronaviruses. There are no absolutes in biology, but they hopefully will work against the dangers that we do know exist. A vaccine that mimics exposure to many coronaviruses could protect against a currently unknown coronavirus, especially if slower-evolving antigens are included,” Dr. Babaian said in an interview.

Nikolai Petrovsky, MD, PhD, of Flinders University, Adelaide, and the biotechnology company Vaccine Pty, agrees, calling a literal pan-coronavirus vaccine a “pipe dream. What I do think is achievable is a broadly protective, pan–CoV-19 vaccine – I can say that because we have already developed and tested it, combining antigens rather than trying just one that can do everything.”
 

Immunity lures

The broader vaccines in development display viral antigens, such as spike proteins, to the immune system on diverse frameworks. Here are a few approaches.

Ferritin nanoparticles: A candidate vaccine from the emerging infectious diseases branch of Water Reed National Military Medical Center began phase 1 human trials in April 2021. Called SpFN, the vaccine consists of arrays of ferritin nanoparticles linked to spike proteins from various variants and species. Ferritin is a protein that binds and stores iron in the body.

“The repetitive and ordered display of the coronavirus spike protein on a multifaced nanoparticle may stimulate immunity in such a way as to translate into significantly broader protection,” said Walter Reed’s branch director and vaccine coinventor Kayvon Modjarrad, MD, PhD.

A second vaccine targets only the “bullseye” part of the spike that the virus uses to attach and gain access to human cells, called the receptor-binding domain (RBD), of SARS-CoV-2 variants and of the virus behind the original SARS. The preclinical data appeared in Science Translational Medicine.

Barton Haynes, MD and colleagues at the Duke Human Vaccine Institute are also using ferritin to design and develop a “pan-betacoronavirus vaccine,” referring to the genus to which SARS-CoV-2 belongs. They say their results in macaques, published in Nature, “demonstrate that current mRNA-based vaccines may provide some protection from future outbreaks of zoonotic betacoronaviruses.”

Mosaic nanoparticles: Graduate student Alexander Cohen is leading an effort at CalTech, in the lab of Pamela Bjorkman, PhD, that uses nanoparticles consisting of proteins from a bacterium (Strep pyogenes) to which RBDs from spike proteins of four or eight different betacoronaviruses are attached. The strategy demonstrates that the whole is greater than the sum of the parts.

“Alex’s results show that it is possible to raise diverse neutralizing antibody responses, even against coronavirus strains that were not represented on the injected nanoparticle. We are hopeful that this technology could be used to protect against future animal coronaviruses that cross into humans,” said Dr. Björkman. The work appeared in Science.

Candidate vaccines from Inovio Pharmaceuticals also use a mosaic spike strategy, but with DNA rings (plasmids) rather than nanoparticles. One version works against pre-Omicron variants and is being tested against Omicron, and another with “pan–COVID-19” coverage has tested well in animal models. Inovio’s vaccines are delivered into the skin using a special device that applies an electric pulse that increases the cells’ permeability.

Chimeric spikes: Yet another approach is to fashion vaccines from various parts of the betacoronaviruses that are most closely related to SARS-CoV-2 – the pathogens behind Middle East respiratory syndrome and severe acute respiratory syndrome as well as several bat viruses and a few pangolin ones. The abundance and ubiquity of these viruses provide a toolbox of sorts, with instructions written in the language of RNA, from which to select, dissect, recombine, and customize vaccines.

“SARS-like viruses can recombine and exhibit great genetic diversity in several parts of the genome. We designed chimeric spikes to improve coverage of a multiplexed vaccine,” said David Martinez, PhD.

His team at the University of North Carolina at Chapel Hill has developed mRNA vaccines that deliver “scrambled coronavirus spikes” representing various parts, not just the RBD, as described in Science.

In mice, the chimeric vaccines elicit robust T- and B-cell immune responses, which stimulate antibody production and control other facets of building immunity.
 

Beyond the spike bullseye

The challenge of developing pan-coronavirus vaccines is dual. “The very best vaccines are highly specific to each strain, and the universal vaccines have to sacrifice effectiveness to get broad coverage. Life is a trade-off.” Dr. Petrovsky told this news organization. 

Efforts to broaden vaccine efficacy venture beyond targeting the RBD bullseyes of the spike triplets that festoon the virus. Some projects are focusing on less changeable spike parts that are more alike among less closely related coronaviruses than is the mutation-prone RBD. For example, the peptides that twist into the “stem-helix” portion of the part of the spike that adheres to host cells are the basis of some candidate vaccines now in preclinical studies.

Still other vaccines aren’t spike based at all. French company Osivax, for example, is working on a vaccine that targets the nucleocapsid protein that shields the viral RNA. The hope is that presenting various faces of the pathogen may spark immunity beyond an initial antibody rush and evoke more diverse and lasting T-cell responses.

With the myriad efforts to back up the first generation of COVID-19 vaccines with new ones offering broader protection, it appears that science may have finally learned from history.

“After the SARS outbreak, we lost interest and failed to complete development of a vaccine for use in case of a recurrent outbreak. We must not make the same mistake again,” Dr. Giurgea and colleagues wrote in their Nature article about universal coronavirus vaccines.

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

As the COVID-19 pandemic winds down – for the time being at least – efforts are ramping up to develop next-generation vaccines that can protect against future novel coronaviruses and variants. Several projects are presenting clever combinations of viral parts to the immune system that evoke a robust and hopefully lasting response.

The coming generation of “pan” vaccines aims to tamp down SARS-CoV-2, its closest relatives, and whatever may come into tamer respiratory viruses like the common cold. Whatever the eventual components of this new generation of vaccines, experts agree on the goal: preventing severe disease and death. And a broader approach is critical.

“All the vaccines have been amazing. But we’re playing a whack-a-mole game with the variants. We need to take a step back and ask if a pan-variant vaccine is possible. That’s important because Omicron isn’t the last variant,” said Jacob Lemieux, MD, PhD, instructor in medicine and infectious disease specialist at Massachusetts General Hospital, Boston.
 

A broad spectrum vaccine

The drive to create a vaccine that would deter multiple coronaviruses arose early, among many researchers. An article published in Nature in May 2020 by National Institute of Allergy and Infectious Diseases researcher Luca T. Giurgea, MD, and colleagues said it all in the title: “Universal coronavirus vaccines: the time to start is now.”

Their concerns? The diversity of bat coronaviruses poised to jump into humans; the high mutability of the spike gene that the immune response recognizes; and the persistence of mutations in an RNA virus, which can’t repair errors. 

Work on broader vaccines began in several labs as SARS-CoV-2 spawned variant after variant.

On Sept. 28, NIAID announced funding for developing ‘pan-coronavirus’ vaccines – the quotation marks theirs to indicate that a magic bullet against any new coronavirus is unrealistic. “These new awards are designed to look ahead and prepare for the next generation of coronaviruses with pandemic potential,” said NIAID director Anthony S. Fauci, MD. An initial three awards went to groups at the University of Wisconsin, Brigham and Women’s Hospital, and Duke University.

President Biden mentioned the NIAID funding in his State of the Union Address. He also talked about how the Biomedical Advanced Research and Development Authority, founded in 2006 to prepare for public health emergencies, is spearheading development of new vaccine platforms and vaccines that target a broader swath of pathogen parts.

Meanwhile, individual researchers from eclectic fields are finding new ways to prevent future pandemics.

Artem Babaian, PhD, a computational biologist at the University of Cambridge (England), had the idea to probe National Institutes of Health genome databases, going back more than a decade, for overlooked novel coronaviruses. He started the project while he was between jobs as the pandemic was unfurling, using a telltale enzyme unique to the RNA viruses to fish out COVID cousins. The work is published in Nature and the data freely available at serratus.io.

Among the nearly 132,000 novel RNA viruses Dr. Babaian’s team found, 9 were from previously unrecognized coronaviruses. The novel nine came from “ecologically diverse sources”: a seahorse, an axolotl, an eel, and several fishes. Deciphering the topographies of these coronaviruses may provide clues to developing vaccines that stay ahead of future pandemics.

But optics are important in keeping expectations reasonable. “‘Universal vaccine’ is a misnomer. I think about it as ‘broad spectrum vaccines.’ It’s critical to be up front that these vaccines can never guarantee immunity against all coronaviruses. There are no absolutes in biology, but they hopefully will work against the dangers that we do know exist. A vaccine that mimics exposure to many coronaviruses could protect against a currently unknown coronavirus, especially if slower-evolving antigens are included,” Dr. Babaian said in an interview.

Nikolai Petrovsky, MD, PhD, of Flinders University, Adelaide, and the biotechnology company Vaccine Pty, agrees, calling a literal pan-coronavirus vaccine a “pipe dream. What I do think is achievable is a broadly protective, pan–CoV-19 vaccine – I can say that because we have already developed and tested it, combining antigens rather than trying just one that can do everything.”
 

Immunity lures

The broader vaccines in development display viral antigens, such as spike proteins, to the immune system on diverse frameworks. Here are a few approaches.

Ferritin nanoparticles: A candidate vaccine from the emerging infectious diseases branch of Water Reed National Military Medical Center began phase 1 human trials in April 2021. Called SpFN, the vaccine consists of arrays of ferritin nanoparticles linked to spike proteins from various variants and species. Ferritin is a protein that binds and stores iron in the body.

“The repetitive and ordered display of the coronavirus spike protein on a multifaced nanoparticle may stimulate immunity in such a way as to translate into significantly broader protection,” said Walter Reed’s branch director and vaccine coinventor Kayvon Modjarrad, MD, PhD.

A second vaccine targets only the “bullseye” part of the spike that the virus uses to attach and gain access to human cells, called the receptor-binding domain (RBD), of SARS-CoV-2 variants and of the virus behind the original SARS. The preclinical data appeared in Science Translational Medicine.

Barton Haynes, MD and colleagues at the Duke Human Vaccine Institute are also using ferritin to design and develop a “pan-betacoronavirus vaccine,” referring to the genus to which SARS-CoV-2 belongs. They say their results in macaques, published in Nature, “demonstrate that current mRNA-based vaccines may provide some protection from future outbreaks of zoonotic betacoronaviruses.”

Mosaic nanoparticles: Graduate student Alexander Cohen is leading an effort at CalTech, in the lab of Pamela Bjorkman, PhD, that uses nanoparticles consisting of proteins from a bacterium (Strep pyogenes) to which RBDs from spike proteins of four or eight different betacoronaviruses are attached. The strategy demonstrates that the whole is greater than the sum of the parts.

“Alex’s results show that it is possible to raise diverse neutralizing antibody responses, even against coronavirus strains that were not represented on the injected nanoparticle. We are hopeful that this technology could be used to protect against future animal coronaviruses that cross into humans,” said Dr. Björkman. The work appeared in Science.

Candidate vaccines from Inovio Pharmaceuticals also use a mosaic spike strategy, but with DNA rings (plasmids) rather than nanoparticles. One version works against pre-Omicron variants and is being tested against Omicron, and another with “pan–COVID-19” coverage has tested well in animal models. Inovio’s vaccines are delivered into the skin using a special device that applies an electric pulse that increases the cells’ permeability.

Chimeric spikes: Yet another approach is to fashion vaccines from various parts of the betacoronaviruses that are most closely related to SARS-CoV-2 – the pathogens behind Middle East respiratory syndrome and severe acute respiratory syndrome as well as several bat viruses and a few pangolin ones. The abundance and ubiquity of these viruses provide a toolbox of sorts, with instructions written in the language of RNA, from which to select, dissect, recombine, and customize vaccines.

“SARS-like viruses can recombine and exhibit great genetic diversity in several parts of the genome. We designed chimeric spikes to improve coverage of a multiplexed vaccine,” said David Martinez, PhD.

His team at the University of North Carolina at Chapel Hill has developed mRNA vaccines that deliver “scrambled coronavirus spikes” representing various parts, not just the RBD, as described in Science.

In mice, the chimeric vaccines elicit robust T- and B-cell immune responses, which stimulate antibody production and control other facets of building immunity.
 

Beyond the spike bullseye

The challenge of developing pan-coronavirus vaccines is dual. “The very best vaccines are highly specific to each strain, and the universal vaccines have to sacrifice effectiveness to get broad coverage. Life is a trade-off.” Dr. Petrovsky told this news organization. 

Efforts to broaden vaccine efficacy venture beyond targeting the RBD bullseyes of the spike triplets that festoon the virus. Some projects are focusing on less changeable spike parts that are more alike among less closely related coronaviruses than is the mutation-prone RBD. For example, the peptides that twist into the “stem-helix” portion of the part of the spike that adheres to host cells are the basis of some candidate vaccines now in preclinical studies.

Still other vaccines aren’t spike based at all. French company Osivax, for example, is working on a vaccine that targets the nucleocapsid protein that shields the viral RNA. The hope is that presenting various faces of the pathogen may spark immunity beyond an initial antibody rush and evoke more diverse and lasting T-cell responses.

With the myriad efforts to back up the first generation of COVID-19 vaccines with new ones offering broader protection, it appears that science may have finally learned from history.

“After the SARS outbreak, we lost interest and failed to complete development of a vaccine for use in case of a recurrent outbreak. We must not make the same mistake again,” Dr. Giurgea and colleagues wrote in their Nature article about universal coronavirus vaccines.

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

As the COVID-19 pandemic winds down – for the time being at least – efforts are ramping up to develop next-generation vaccines that can protect against future novel coronaviruses and variants. Several projects are presenting clever combinations of viral parts to the immune system that evoke a robust and hopefully lasting response.

The coming generation of “pan” vaccines aims to tamp down SARS-CoV-2, its closest relatives, and whatever may come into tamer respiratory viruses like the common cold. Whatever the eventual components of this new generation of vaccines, experts agree on the goal: preventing severe disease and death. And a broader approach is critical.

“All the vaccines have been amazing. But we’re playing a whack-a-mole game with the variants. We need to take a step back and ask if a pan-variant vaccine is possible. That’s important because Omicron isn’t the last variant,” said Jacob Lemieux, MD, PhD, instructor in medicine and infectious disease specialist at Massachusetts General Hospital, Boston.
 

A broad spectrum vaccine

The drive to create a vaccine that would deter multiple coronaviruses arose early, among many researchers. An article published in Nature in May 2020 by National Institute of Allergy and Infectious Diseases researcher Luca T. Giurgea, MD, and colleagues said it all in the title: “Universal coronavirus vaccines: the time to start is now.”

Their concerns? The diversity of bat coronaviruses poised to jump into humans; the high mutability of the spike gene that the immune response recognizes; and the persistence of mutations in an RNA virus, which can’t repair errors. 

Work on broader vaccines began in several labs as SARS-CoV-2 spawned variant after variant.

On Sept. 28, NIAID announced funding for developing ‘pan-coronavirus’ vaccines – the quotation marks theirs to indicate that a magic bullet against any new coronavirus is unrealistic. “These new awards are designed to look ahead and prepare for the next generation of coronaviruses with pandemic potential,” said NIAID director Anthony S. Fauci, MD. An initial three awards went to groups at the University of Wisconsin, Brigham and Women’s Hospital, and Duke University.

President Biden mentioned the NIAID funding in his State of the Union Address. He also talked about how the Biomedical Advanced Research and Development Authority, founded in 2006 to prepare for public health emergencies, is spearheading development of new vaccine platforms and vaccines that target a broader swath of pathogen parts.

Meanwhile, individual researchers from eclectic fields are finding new ways to prevent future pandemics.

Artem Babaian, PhD, a computational biologist at the University of Cambridge (England), had the idea to probe National Institutes of Health genome databases, going back more than a decade, for overlooked novel coronaviruses. He started the project while he was between jobs as the pandemic was unfurling, using a telltale enzyme unique to the RNA viruses to fish out COVID cousins. The work is published in Nature and the data freely available at serratus.io.

Among the nearly 132,000 novel RNA viruses Dr. Babaian’s team found, 9 were from previously unrecognized coronaviruses. The novel nine came from “ecologically diverse sources”: a seahorse, an axolotl, an eel, and several fishes. Deciphering the topographies of these coronaviruses may provide clues to developing vaccines that stay ahead of future pandemics.

But optics are important in keeping expectations reasonable. “‘Universal vaccine’ is a misnomer. I think about it as ‘broad spectrum vaccines.’ It’s critical to be up front that these vaccines can never guarantee immunity against all coronaviruses. There are no absolutes in biology, but they hopefully will work against the dangers that we do know exist. A vaccine that mimics exposure to many coronaviruses could protect against a currently unknown coronavirus, especially if slower-evolving antigens are included,” Dr. Babaian said in an interview.

Nikolai Petrovsky, MD, PhD, of Flinders University, Adelaide, and the biotechnology company Vaccine Pty, agrees, calling a literal pan-coronavirus vaccine a “pipe dream. What I do think is achievable is a broadly protective, pan–CoV-19 vaccine – I can say that because we have already developed and tested it, combining antigens rather than trying just one that can do everything.”
 

Immunity lures

The broader vaccines in development display viral antigens, such as spike proteins, to the immune system on diverse frameworks. Here are a few approaches.

Ferritin nanoparticles: A candidate vaccine from the emerging infectious diseases branch of Water Reed National Military Medical Center began phase 1 human trials in April 2021. Called SpFN, the vaccine consists of arrays of ferritin nanoparticles linked to spike proteins from various variants and species. Ferritin is a protein that binds and stores iron in the body.

“The repetitive and ordered display of the coronavirus spike protein on a multifaced nanoparticle may stimulate immunity in such a way as to translate into significantly broader protection,” said Walter Reed’s branch director and vaccine coinventor Kayvon Modjarrad, MD, PhD.

A second vaccine targets only the “bullseye” part of the spike that the virus uses to attach and gain access to human cells, called the receptor-binding domain (RBD), of SARS-CoV-2 variants and of the virus behind the original SARS. The preclinical data appeared in Science Translational Medicine.

Barton Haynes, MD and colleagues at the Duke Human Vaccine Institute are also using ferritin to design and develop a “pan-betacoronavirus vaccine,” referring to the genus to which SARS-CoV-2 belongs. They say their results in macaques, published in Nature, “demonstrate that current mRNA-based vaccines may provide some protection from future outbreaks of zoonotic betacoronaviruses.”

Mosaic nanoparticles: Graduate student Alexander Cohen is leading an effort at CalTech, in the lab of Pamela Bjorkman, PhD, that uses nanoparticles consisting of proteins from a bacterium (Strep pyogenes) to which RBDs from spike proteins of four or eight different betacoronaviruses are attached. The strategy demonstrates that the whole is greater than the sum of the parts.

“Alex’s results show that it is possible to raise diverse neutralizing antibody responses, even against coronavirus strains that were not represented on the injected nanoparticle. We are hopeful that this technology could be used to protect against future animal coronaviruses that cross into humans,” said Dr. Björkman. The work appeared in Science.

Candidate vaccines from Inovio Pharmaceuticals also use a mosaic spike strategy, but with DNA rings (plasmids) rather than nanoparticles. One version works against pre-Omicron variants and is being tested against Omicron, and another with “pan–COVID-19” coverage has tested well in animal models. Inovio’s vaccines are delivered into the skin using a special device that applies an electric pulse that increases the cells’ permeability.

Chimeric spikes: Yet another approach is to fashion vaccines from various parts of the betacoronaviruses that are most closely related to SARS-CoV-2 – the pathogens behind Middle East respiratory syndrome and severe acute respiratory syndrome as well as several bat viruses and a few pangolin ones. The abundance and ubiquity of these viruses provide a toolbox of sorts, with instructions written in the language of RNA, from which to select, dissect, recombine, and customize vaccines.

“SARS-like viruses can recombine and exhibit great genetic diversity in several parts of the genome. We designed chimeric spikes to improve coverage of a multiplexed vaccine,” said David Martinez, PhD.

His team at the University of North Carolina at Chapel Hill has developed mRNA vaccines that deliver “scrambled coronavirus spikes” representing various parts, not just the RBD, as described in Science.

In mice, the chimeric vaccines elicit robust T- and B-cell immune responses, which stimulate antibody production and control other facets of building immunity.
 

Beyond the spike bullseye

The challenge of developing pan-coronavirus vaccines is dual. “The very best vaccines are highly specific to each strain, and the universal vaccines have to sacrifice effectiveness to get broad coverage. Life is a trade-off.” Dr. Petrovsky told this news organization. 

Efforts to broaden vaccine efficacy venture beyond targeting the RBD bullseyes of the spike triplets that festoon the virus. Some projects are focusing on less changeable spike parts that are more alike among less closely related coronaviruses than is the mutation-prone RBD. For example, the peptides that twist into the “stem-helix” portion of the part of the spike that adheres to host cells are the basis of some candidate vaccines now in preclinical studies.

Still other vaccines aren’t spike based at all. French company Osivax, for example, is working on a vaccine that targets the nucleocapsid protein that shields the viral RNA. The hope is that presenting various faces of the pathogen may spark immunity beyond an initial antibody rush and evoke more diverse and lasting T-cell responses.

With the myriad efforts to back up the first generation of COVID-19 vaccines with new ones offering broader protection, it appears that science may have finally learned from history.

“After the SARS outbreak, we lost interest and failed to complete development of a vaccine for use in case of a recurrent outbreak. We must not make the same mistake again,” Dr. Giurgea and colleagues wrote in their Nature article about universal coronavirus vaccines.

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

Data from the first 6 months after the rollout of mRNA COVID-19 vaccines in the United States released today show that adverse effects from shots are typically mild and short-lived.

Findings of the large study, compiled after nearly 300 million doses were administered, were published online March 7 in The Lancet Infectious Diseases.

Researchers, led by Hannah G. Rosenblum, MD, with the Centers for Disease Control and Prevention COVID Response Team, used passive U.S. surveillance data collected through the Vaccine Adverse Event Reporting System (VAERS), and the active system, v-safe, starting in December 2020 through the first 6 months of the U.S. COVID-19 vaccination program. V-safe is a voluntary, smartphone-based system set up in 2020 specifically for monitoring reactions to COVID-19 and health effects after vaccination. The health effects information from v-safe is presented in this study for the first time.

Of the 298.7 million doses of mRNA vaccines administered in the U.S. during the study period, VAERS processed 340,522 reports. Of those, 313,499 (92.1%) were nonserious; 22,527 (6.6%) were serious (nondeath); and 4,496 (1.3%) were deaths.

From v-safe reporting, researchers learned that about 71% of the 7.9 million participants reported local or systemic reactions, more frequently after dose 2 than after dose 1. Of those reporting reactions after dose 1, about two-thirds (68.6%) reported a local reaction and 52.7% reported a systemic reaction.

Among other findings:

• Injection-site pain occurred after dose 1 in 66.2% of participants and 68.6% after dose 2.
• One-third of participants (33.9%) reported fatigue after dose 1 and 55.7% after dose 2.
• Headache was reported among 27% of participants after dose 1 and 46.2% after dose 2.
• When injection site pain, fatigue, or headaches were reported, the reports were usually in the first week after vaccination.
• Reports of being unable to work or do normal daily activities, or instances of seeking medical care, occurred more commonly after dose 2 (32.1%) than after dose 1 (11.9%). Fewer than 1% of participants reported seeking medical care after dose 1 or 2 of the vaccine.
• Reactions and health effects were reported more often in female than in male recipients, and in people younger than 65 years, compared with older people.
• Serious adverse events, including myocarditis, have been identified following mRNA vaccinations, but the events are rare.

The authors wrote that these results are consistent with preauthorization clinical trials and early postauthorization reports.

“On the basis of our findings, mild to moderate transient reactogenicity should be anticipated,” they said, “particularly among younger and female vaccine recipients.”
 

‘Robust and reassuring data’

“The safety monitoring of the mRNA COVID-19 vaccines stands out as the most comprehensive of any vaccine in U.S. history. The use of these complementary monitoring systems has provided robust and reassuring data,” Matthew S. Krantz, MD, with the division of allergy, pulmonary, and critical care medicine at Vanderbilt University, Nashville, Tenn., and Elizabeth J. Phillips, MD, with the department of pathology, microbiology, and immunology at Vanderbilt, wrote in a related commentary in The Lancet Infectious Diseases.

They point out that the v-safe reports of reactions are consistent with those reported from clinical trials and a large population study in the United Kingdom.

Dr. Phillips said in a press release, “[A]lthough approximately one in 1,000 individuals vaccinated may have an adverse effect, most of these are nonserious. No unusual patterns emerged in the cause of death or serious adverse effects among VAERS reports. For adverse events of special interest, it is reassuring that there were no unexpected signals other than myopericarditis and anaphylaxis, already known to be associated with mRNA vaccines.”

The study authors and editorialists have disclosed no relevant financial relationships.

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

Data from the first 6 months after the rollout of mRNA COVID-19 vaccines in the United States released today show that adverse effects from shots are typically mild and short-lived.

Findings of the large study, compiled after nearly 300 million doses were administered, were published online March 7 in The Lancet Infectious Diseases.

Researchers, led by Hannah G. Rosenblum, MD, with the Centers for Disease Control and Prevention COVID Response Team, used passive U.S. surveillance data collected through the Vaccine Adverse Event Reporting System (VAERS), and the active system, v-safe, starting in December 2020 through the first 6 months of the U.S. COVID-19 vaccination program. V-safe is a voluntary, smartphone-based system set up in 2020 specifically for monitoring reactions to COVID-19 and health effects after vaccination. The health effects information from v-safe is presented in this study for the first time.

Of the 298.7 million doses of mRNA vaccines administered in the U.S. during the study period, VAERS processed 340,522 reports. Of those, 313,499 (92.1%) were nonserious; 22,527 (6.6%) were serious (nondeath); and 4,496 (1.3%) were deaths.

From v-safe reporting, researchers learned that about 71% of the 7.9 million participants reported local or systemic reactions, more frequently after dose 2 than after dose 1. Of those reporting reactions after dose 1, about two-thirds (68.6%) reported a local reaction and 52.7% reported a systemic reaction.

Among other findings:

• Injection-site pain occurred after dose 1 in 66.2% of participants and 68.6% after dose 2.
• One-third of participants (33.9%) reported fatigue after dose 1 and 55.7% after dose 2.
• Headache was reported among 27% of participants after dose 1 and 46.2% after dose 2.
• When injection site pain, fatigue, or headaches were reported, the reports were usually in the first week after vaccination.
• Reports of being unable to work or do normal daily activities, or instances of seeking medical care, occurred more commonly after dose 2 (32.1%) than after dose 1 (11.9%). Fewer than 1% of participants reported seeking medical care after dose 1 or 2 of the vaccine.
• Reactions and health effects were reported more often in female than in male recipients, and in people younger than 65 years, compared with older people.
• Serious adverse events, including myocarditis, have been identified following mRNA vaccinations, but the events are rare.

The authors wrote that these results are consistent with preauthorization clinical trials and early postauthorization reports.

“On the basis of our findings, mild to moderate transient reactogenicity should be anticipated,” they said, “particularly among younger and female vaccine recipients.”
 

‘Robust and reassuring data’

“The safety monitoring of the mRNA COVID-19 vaccines stands out as the most comprehensive of any vaccine in U.S. history. The use of these complementary monitoring systems has provided robust and reassuring data,” Matthew S. Krantz, MD, with the division of allergy, pulmonary, and critical care medicine at Vanderbilt University, Nashville, Tenn., and Elizabeth J. Phillips, MD, with the department of pathology, microbiology, and immunology at Vanderbilt, wrote in a related commentary in The Lancet Infectious Diseases.

They point out that the v-safe reports of reactions are consistent with those reported from clinical trials and a large population study in the United Kingdom.

Dr. Phillips said in a press release, “[A]lthough approximately one in 1,000 individuals vaccinated may have an adverse effect, most of these are nonserious. No unusual patterns emerged in the cause of death or serious adverse effects among VAERS reports. For adverse events of special interest, it is reassuring that there were no unexpected signals other than myopericarditis and anaphylaxis, already known to be associated with mRNA vaccines.”

The study authors and editorialists have disclosed no relevant financial relationships.

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

Data from the first 6 months after the rollout of mRNA COVID-19 vaccines in the United States released today show that adverse effects from shots are typically mild and short-lived.

Findings of the large study, compiled after nearly 300 million doses were administered, were published online March 7 in The Lancet Infectious Diseases.

Researchers, led by Hannah G. Rosenblum, MD, with the Centers for Disease Control and Prevention COVID Response Team, used passive U.S. surveillance data collected through the Vaccine Adverse Event Reporting System (VAERS), and the active system, v-safe, starting in December 2020 through the first 6 months of the U.S. COVID-19 vaccination program. V-safe is a voluntary, smartphone-based system set up in 2020 specifically for monitoring reactions to COVID-19 and health effects after vaccination. The health effects information from v-safe is presented in this study for the first time.

Of the 298.7 million doses of mRNA vaccines administered in the U.S. during the study period, VAERS processed 340,522 reports. Of those, 313,499 (92.1%) were nonserious; 22,527 (6.6%) were serious (nondeath); and 4,496 (1.3%) were deaths.

From v-safe reporting, researchers learned that about 71% of the 7.9 million participants reported local or systemic reactions, more frequently after dose 2 than after dose 1. Of those reporting reactions after dose 1, about two-thirds (68.6%) reported a local reaction and 52.7% reported a systemic reaction.

Among other findings:

• Injection-site pain occurred after dose 1 in 66.2% of participants and 68.6% after dose 2.
• One-third of participants (33.9%) reported fatigue after dose 1 and 55.7% after dose 2.
• Headache was reported among 27% of participants after dose 1 and 46.2% after dose 2.
• When injection site pain, fatigue, or headaches were reported, the reports were usually in the first week after vaccination.
• Reports of being unable to work or do normal daily activities, or instances of seeking medical care, occurred more commonly after dose 2 (32.1%) than after dose 1 (11.9%). Fewer than 1% of participants reported seeking medical care after dose 1 or 2 of the vaccine.
• Reactions and health effects were reported more often in female than in male recipients, and in people younger than 65 years, compared with older people.
• Serious adverse events, including myocarditis, have been identified following mRNA vaccinations, but the events are rare.

The authors wrote that these results are consistent with preauthorization clinical trials and early postauthorization reports.

“On the basis of our findings, mild to moderate transient reactogenicity should be anticipated,” they said, “particularly among younger and female vaccine recipients.”
 

‘Robust and reassuring data’

“The safety monitoring of the mRNA COVID-19 vaccines stands out as the most comprehensive of any vaccine in U.S. history. The use of these complementary monitoring systems has provided robust and reassuring data,” Matthew S. Krantz, MD, with the division of allergy, pulmonary, and critical care medicine at Vanderbilt University, Nashville, Tenn., and Elizabeth J. Phillips, MD, with the department of pathology, microbiology, and immunology at Vanderbilt, wrote in a related commentary in The Lancet Infectious Diseases.

They point out that the v-safe reports of reactions are consistent with those reported from clinical trials and a large population study in the United Kingdom.

Dr. Phillips said in a press release, “[A]lthough approximately one in 1,000 individuals vaccinated may have an adverse effect, most of these are nonserious. No unusual patterns emerged in the cause of death or serious adverse effects among VAERS reports. For adverse events of special interest, it is reassuring that there were no unexpected signals other than myopericarditis and anaphylaxis, already known to be associated with mRNA vaccines.”

The study authors and editorialists have disclosed no relevant financial relationships.

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

A single injection of the experimental agent nirsevimab ahead of respiratory syncytial virus (RSV) season protects healthy infants from lower respiratory tract infections associated with the pathogen, according to the results of a phase 3 study.

A previously published trial showed that a single dose of nirsevimab was effective in preterm infants. The ability to protect all babies from RSV, which causes bronchiolitis and pneumonia and is a leading cause of hospitalization for this age group, “would be a paradigm shift in the approach to this disease,” William Muller, MD, PhD, of the Lurie Children’s Hospital of Chicago and a coauthor of the study, said in a statement.

The primary endpoint of the study was medically attended lower respiratory tract infections linked to RSV. The single injection of nirsevimab was associated with a 74.5% reduction in such infections (P < .001), according to Dr. Muller’s group, who published their findings March 2 in the New England Journal of Medicine.

Nirsevimab, a monoclonal antibody to the RSV fusion protein being developed by AstraZeneca and Sanofi, has an extended half-life, which may allow one dose to confer protection throughout a season. The only approved option to prevent RSV, palivizumab (Synagis), is used for high-risk infants, and five injections are needed to cover a viral season.
 

Nearly 1,500 infants in more than 20 countries studied

To assess the effectiveness of nirsevimab in late-preterm and term infants, investigators at 160 sites randomly assigned 1,490 babies born at a gestational age of at least 35 weeks to receive an intramuscular injection of nirsevimab or placebo.

During the 150 days after injection, medically attended RSV-associated lower respiratory tract infections occurred in 12 of 994 infants who received nirsevimab, compared with 25 of 496 babies who received placebo (1.2% vs. 5%).

Six of 994 infants who received nirsevimab were hospitalized for RSV-associated lower respiratory tract infections, compared with 8 of 496 infants in the placebo group (0.6% vs. 1.6%; P = .07). The proportion of children hospitalized for any respiratory illness as a result of RSV was 0.9% among those who received nirsevimab, compared with 2.2% among those who received placebo.

Serious adverse events occurred in 6.8% of the nirsevimab group and 7.3% of the placebo group. None of these events, including three deaths in the nirsevimab group, was considered related to nirsevimab or placebo, according to the researchers. One infant who received nirsevimab had a generalized macular rash without systemic features that did not require treatment and resolved in 20 days, they said.

Antidrug antibodies were detected in 6.1% of the nirsevimab group and in 1.1% of the placebo group. These antidrug antibodies tended to develop later and did not affect nirsevimab pharmacokinetics during the RSV season, the researchers reported. How they might affect subsequent doses of nirsevimab is not known, they added.

In a separate report in the journal, researcher Joseph Domachowske, MD, SUNY Upstate Medical University, Syracuse, New York, and colleagues described safety results from an ongoing study of nirsevimab that includes infants with congenital heart disease, chronic lung disease, and prematurity.

In this trial, infants received nirsevimab or palivizumab, and the treatments appeared to have similar safety profiles, the authors reported.

Other approaches to RSV protection include passive antibodies acquired from maternal vaccination in pregnancy and active vaccination of infants.

The publication follows news last month that GlaxoSmithKline is pausing a maternal RSV vaccine trial, which “had the same goal of protecting babies against severe RSV infection,” said Louis Bont, MD, PhD, with University Medical Center Utrecht, the Netherlands.

RSV infection is one of the deadliest diseases during infancy, and the nirsevimab trial, conducted in more than 20 countries, is “gamechanging,” Dr. Bont told this news organization. Still, researchers will need to monitor for RSV resistance to this treatment, he said.

Whether nirsevimab prevents the development of reactive airway disease and asthma is another open question, he said.

“Finally, we need to keep in mind that RSV mortality is almost limited to the developing world, and it is unlikely that this novel drug will become available to these countries in the coming years,” Dr. Bont said. “Nevertheless, nirsevimab has the potential to seriously decrease the annual overwhelming number of RSV infected babies.”

Nirsevimab may have advantages in low- and middle-income countries, including its potential to be incorporated into established immunization programs and to be given seasonally, said Amy Sarah Ginsburg, MD, MPH, of the University of Washington, Seattle. “However, cost remains a significant factor, as does susceptibility to pathogen escape,” she said.

MedImmune/AstraZeneca and Sanofi funded the nirsevimab studies. UMC Utrecht has received research grants and fees for advisory work from AstraZeneca for RSV-related work by Bont.

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

A single injection of the experimental agent nirsevimab ahead of respiratory syncytial virus (RSV) season protects healthy infants from lower respiratory tract infections associated with the pathogen, according to the results of a phase 3 study.

A previously published trial showed that a single dose of nirsevimab was effective in preterm infants. The ability to protect all babies from RSV, which causes bronchiolitis and pneumonia and is a leading cause of hospitalization for this age group, “would be a paradigm shift in the approach to this disease,” William Muller, MD, PhD, of the Lurie Children’s Hospital of Chicago and a coauthor of the study, said in a statement.

The primary endpoint of the study was medically attended lower respiratory tract infections linked to RSV. The single injection of nirsevimab was associated with a 74.5% reduction in such infections (P < .001), according to Dr. Muller’s group, who published their findings March 2 in the New England Journal of Medicine.

Nirsevimab, a monoclonal antibody to the RSV fusion protein being developed by AstraZeneca and Sanofi, has an extended half-life, which may allow one dose to confer protection throughout a season. The only approved option to prevent RSV, palivizumab (Synagis), is used for high-risk infants, and five injections are needed to cover a viral season.
 

Nearly 1,500 infants in more than 20 countries studied

To assess the effectiveness of nirsevimab in late-preterm and term infants, investigators at 160 sites randomly assigned 1,490 babies born at a gestational age of at least 35 weeks to receive an intramuscular injection of nirsevimab or placebo.

During the 150 days after injection, medically attended RSV-associated lower respiratory tract infections occurred in 12 of 994 infants who received nirsevimab, compared with 25 of 496 babies who received placebo (1.2% vs. 5%).

Six of 994 infants who received nirsevimab were hospitalized for RSV-associated lower respiratory tract infections, compared with 8 of 496 infants in the placebo group (0.6% vs. 1.6%; P = .07). The proportion of children hospitalized for any respiratory illness as a result of RSV was 0.9% among those who received nirsevimab, compared with 2.2% among those who received placebo.

Serious adverse events occurred in 6.8% of the nirsevimab group and 7.3% of the placebo group. None of these events, including three deaths in the nirsevimab group, was considered related to nirsevimab or placebo, according to the researchers. One infant who received nirsevimab had a generalized macular rash without systemic features that did not require treatment and resolved in 20 days, they said.

Antidrug antibodies were detected in 6.1% of the nirsevimab group and in 1.1% of the placebo group. These antidrug antibodies tended to develop later and did not affect nirsevimab pharmacokinetics during the RSV season, the researchers reported. How they might affect subsequent doses of nirsevimab is not known, they added.

In a separate report in the journal, researcher Joseph Domachowske, MD, SUNY Upstate Medical University, Syracuse, New York, and colleagues described safety results from an ongoing study of nirsevimab that includes infants with congenital heart disease, chronic lung disease, and prematurity.

In this trial, infants received nirsevimab or palivizumab, and the treatments appeared to have similar safety profiles, the authors reported.

Other approaches to RSV protection include passive antibodies acquired from maternal vaccination in pregnancy and active vaccination of infants.

The publication follows news last month that GlaxoSmithKline is pausing a maternal RSV vaccine trial, which “had the same goal of protecting babies against severe RSV infection,” said Louis Bont, MD, PhD, with University Medical Center Utrecht, the Netherlands.

RSV infection is one of the deadliest diseases during infancy, and the nirsevimab trial, conducted in more than 20 countries, is “gamechanging,” Dr. Bont told this news organization. Still, researchers will need to monitor for RSV resistance to this treatment, he said.

Whether nirsevimab prevents the development of reactive airway disease and asthma is another open question, he said.

“Finally, we need to keep in mind that RSV mortality is almost limited to the developing world, and it is unlikely that this novel drug will become available to these countries in the coming years,” Dr. Bont said. “Nevertheless, nirsevimab has the potential to seriously decrease the annual overwhelming number of RSV infected babies.”

Nirsevimab may have advantages in low- and middle-income countries, including its potential to be incorporated into established immunization programs and to be given seasonally, said Amy Sarah Ginsburg, MD, MPH, of the University of Washington, Seattle. “However, cost remains a significant factor, as does susceptibility to pathogen escape,” she said.

MedImmune/AstraZeneca and Sanofi funded the nirsevimab studies. UMC Utrecht has received research grants and fees for advisory work from AstraZeneca for RSV-related work by Bont.

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

A single injection of the experimental agent nirsevimab ahead of respiratory syncytial virus (RSV) season protects healthy infants from lower respiratory tract infections associated with the pathogen, according to the results of a phase 3 study.

A previously published trial showed that a single dose of nirsevimab was effective in preterm infants. The ability to protect all babies from RSV, which causes bronchiolitis and pneumonia and is a leading cause of hospitalization for this age group, “would be a paradigm shift in the approach to this disease,” William Muller, MD, PhD, of the Lurie Children’s Hospital of Chicago and a coauthor of the study, said in a statement.

The primary endpoint of the study was medically attended lower respiratory tract infections linked to RSV. The single injection of nirsevimab was associated with a 74.5% reduction in such infections (P < .001), according to Dr. Muller’s group, who published their findings March 2 in the New England Journal of Medicine.

Nirsevimab, a monoclonal antibody to the RSV fusion protein being developed by AstraZeneca and Sanofi, has an extended half-life, which may allow one dose to confer protection throughout a season. The only approved option to prevent RSV, palivizumab (Synagis), is used for high-risk infants, and five injections are needed to cover a viral season.
 

Nearly 1,500 infants in more than 20 countries studied

To assess the effectiveness of nirsevimab in late-preterm and term infants, investigators at 160 sites randomly assigned 1,490 babies born at a gestational age of at least 35 weeks to receive an intramuscular injection of nirsevimab or placebo.

During the 150 days after injection, medically attended RSV-associated lower respiratory tract infections occurred in 12 of 994 infants who received nirsevimab, compared with 25 of 496 babies who received placebo (1.2% vs. 5%).

Six of 994 infants who received nirsevimab were hospitalized for RSV-associated lower respiratory tract infections, compared with 8 of 496 infants in the placebo group (0.6% vs. 1.6%; P = .07). The proportion of children hospitalized for any respiratory illness as a result of RSV was 0.9% among those who received nirsevimab, compared with 2.2% among those who received placebo.

Serious adverse events occurred in 6.8% of the nirsevimab group and 7.3% of the placebo group. None of these events, including three deaths in the nirsevimab group, was considered related to nirsevimab or placebo, according to the researchers. One infant who received nirsevimab had a generalized macular rash without systemic features that did not require treatment and resolved in 20 days, they said.

Antidrug antibodies were detected in 6.1% of the nirsevimab group and in 1.1% of the placebo group. These antidrug antibodies tended to develop later and did not affect nirsevimab pharmacokinetics during the RSV season, the researchers reported. How they might affect subsequent doses of nirsevimab is not known, they added.

In a separate report in the journal, researcher Joseph Domachowske, MD, SUNY Upstate Medical University, Syracuse, New York, and colleagues described safety results from an ongoing study of nirsevimab that includes infants with congenital heart disease, chronic lung disease, and prematurity.

In this trial, infants received nirsevimab or palivizumab, and the treatments appeared to have similar safety profiles, the authors reported.

Other approaches to RSV protection include passive antibodies acquired from maternal vaccination in pregnancy and active vaccination of infants.

The publication follows news last month that GlaxoSmithKline is pausing a maternal RSV vaccine trial, which “had the same goal of protecting babies against severe RSV infection,” said Louis Bont, MD, PhD, with University Medical Center Utrecht, the Netherlands.

RSV infection is one of the deadliest diseases during infancy, and the nirsevimab trial, conducted in more than 20 countries, is “gamechanging,” Dr. Bont told this news organization. Still, researchers will need to monitor for RSV resistance to this treatment, he said.

Whether nirsevimab prevents the development of reactive airway disease and asthma is another open question, he said.

“Finally, we need to keep in mind that RSV mortality is almost limited to the developing world, and it is unlikely that this novel drug will become available to these countries in the coming years,” Dr. Bont said. “Nevertheless, nirsevimab has the potential to seriously decrease the annual overwhelming number of RSV infected babies.”

Nirsevimab may have advantages in low- and middle-income countries, including its potential to be incorporated into established immunization programs and to be given seasonally, said Amy Sarah Ginsburg, MD, MPH, of the University of Washington, Seattle. “However, cost remains a significant factor, as does susceptibility to pathogen escape,” she said.

MedImmune/AstraZeneca and Sanofi funded the nirsevimab studies. UMC Utrecht has received research grants and fees for advisory work from AstraZeneca for RSV-related work by Bont.

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