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FDA moves to ban menthol in cigarettes
The Food and Drug Administration said that within a year it will ban menthol in cigarettes and ban all flavors including menthol in cigars.
Menthol makes it easier to start smoking, and also enhances the effects of nicotine, making it more addictive and harder to quit, the FDA said in announcing its actions on Thursday.
Nineteen organizations – including the American Academy of Pediatrics, American Cancer Society, American College of Chest Physicians, American Medical Association, American Heart Association, and the National Medical Association – have pushed the FDA to ban menthol for years. The agency banned all flavors in cigarettes in 2009 but did not take any action against menthol. In 2013, the groups filed a petition demanding that the FDA ban menthol, too. The agency responded months later with a notice that it would start the process.
But it never took any action. Action on Smoking and Health and the African American Tobacco Control Leadership Council, later joined by the AMA and the NMA, sued in 2020 to compel the agency to do something. Now it has finally agreed to act.
The African American Tobacco Control Leadership Council welcomed the move but said the fight is not over and encouraged tobacco control activists to fight to ban menthol tobacco products at the local, state and federal level. “We know that this rule-making process could take years and we know that the tobacco industry will continue to do everything in their power to derail any attempt to remove their deadly products from the market,” Phillip Gardiner, MD, council cochair, said in a statement.
The AMA is urging the FDA to quickly implement the ban and remove the products “without further delay,” AMA President Susan R. Bailey, MD, said in a statement.
“FDA’s long-awaited decision to take action to eliminate menthol flavoring in cigarettes and all flavors in cigars ends a decades-long deference to the tobacco industry, which has repeatedly demonstrated its willingness to profit from products that result in death,” Lisa Lacasse, president of the American Cancer Society Cancer Action Network, said in her own statement.
Ms. Lacasse said banning menthol will help eliminate health disparities. She said 86% of Black people who smoke use menthol cigarettes, compared with 46% of Hispanic people who smoke, 39% of Asian people who smoke, and 29% of White people who smoke. “FDA’s actions today send a clear message that Big Tobacco’s strategy to profit off addicting Black communities will no longer be tolerated,” she said.
Not all groups are on board, however. The American Civil Liberties Union and several other organizations wrote to the country’s top health officials urging them to reconsider.
“Such a ban will trigger criminal penalties which will disproportionately impact people of color, as well as prioritize criminalization over public health and harm reduction,” the letter says. “A ban will also lead to unconstitutional policing and other negative interactions with local law enforcement.”
The letter calls the proposed ban “well intentioned,” but said any effort to reduce death and disease from tobacco “must avoid solutions that will create yet another reason for armed police to engage citizens on the street based on pretext or conduct that does not pose a threat to public safety.”
Instead of a ban, the organizations said, policy makers should consider increased education for adults and minors, stop-smoking programs, and increased funding for health centers in communities of color.
The Biden administration, however, pressed the point that banning menthol will bring many positives. Acting FDA Commissioner Janet Woodcock, MD said in a statement that banning menthol “will help significantly reduce youth initiation, increase the chances of smoking cessation among current smokers, and address health disparities experienced by communities of color, low-income populations, and LGBTQ-plus individuals, all of whom are far more likely to use these tobacco products.”
The FDA cited data showing that, in the first year or so after a ban goes into effect, an additional 923,000 smokers would quit, including 230,000 African Americans. Another study suggests that 633,000 deaths would be averted, including 237,000 Black Americans.
Dr. Woodcock added that, “armed with strong scientific evidence, and with full support from the [Biden] administration, we believe these actions will launch us on a trajectory toward ending tobacco-related disease and death in the U.S.”
The FDA estimates that 18.6 million Americans who are current smokers use menthol cigarettes, with a disproportionately high number being Black people. Menthol cigarette use among Black and Hispanic youth increased from 2011 to 2018, but declined for non-Hispanic White youth.
Flavored mass-produced cigars and cigarillos are disproportionately popular among youth, especially non-Hispanic Black high school students, who in 2020 reported past 30-day cigar smoking at levels twice as high as their White counterparts, said the FDA. Three-quarters of 12- to 17-year-olds reported they smoke cigars because they like the flavors. In 2020, more young people tried a cigar every day than tried a cigarette, reports the agency.
“This long-overdue decision will protect future generations of young people from nicotine addiction, especially Black children and communities, which have disproportionately suffered from menthol tobacco use due to targeted efforts from the tobacco industry,” Lee Savio Beers, MD, president of the American Academy of Pediatrics, said in a statement.
The FDA’s announcement “is only a first step that must be followed with urgent, comprehensive action to remove these flavored products from the market,” he said.
A version of this article first appeared on WebMD.com.
The Food and Drug Administration said that within a year it will ban menthol in cigarettes and ban all flavors including menthol in cigars.
Menthol makes it easier to start smoking, and also enhances the effects of nicotine, making it more addictive and harder to quit, the FDA said in announcing its actions on Thursday.
Nineteen organizations – including the American Academy of Pediatrics, American Cancer Society, American College of Chest Physicians, American Medical Association, American Heart Association, and the National Medical Association – have pushed the FDA to ban menthol for years. The agency banned all flavors in cigarettes in 2009 but did not take any action against menthol. In 2013, the groups filed a petition demanding that the FDA ban menthol, too. The agency responded months later with a notice that it would start the process.
But it never took any action. Action on Smoking and Health and the African American Tobacco Control Leadership Council, later joined by the AMA and the NMA, sued in 2020 to compel the agency to do something. Now it has finally agreed to act.
The African American Tobacco Control Leadership Council welcomed the move but said the fight is not over and encouraged tobacco control activists to fight to ban menthol tobacco products at the local, state and federal level. “We know that this rule-making process could take years and we know that the tobacco industry will continue to do everything in their power to derail any attempt to remove their deadly products from the market,” Phillip Gardiner, MD, council cochair, said in a statement.
The AMA is urging the FDA to quickly implement the ban and remove the products “without further delay,” AMA President Susan R. Bailey, MD, said in a statement.
“FDA’s long-awaited decision to take action to eliminate menthol flavoring in cigarettes and all flavors in cigars ends a decades-long deference to the tobacco industry, which has repeatedly demonstrated its willingness to profit from products that result in death,” Lisa Lacasse, president of the American Cancer Society Cancer Action Network, said in her own statement.
Ms. Lacasse said banning menthol will help eliminate health disparities. She said 86% of Black people who smoke use menthol cigarettes, compared with 46% of Hispanic people who smoke, 39% of Asian people who smoke, and 29% of White people who smoke. “FDA’s actions today send a clear message that Big Tobacco’s strategy to profit off addicting Black communities will no longer be tolerated,” she said.
Not all groups are on board, however. The American Civil Liberties Union and several other organizations wrote to the country’s top health officials urging them to reconsider.
“Such a ban will trigger criminal penalties which will disproportionately impact people of color, as well as prioritize criminalization over public health and harm reduction,” the letter says. “A ban will also lead to unconstitutional policing and other negative interactions with local law enforcement.”
The letter calls the proposed ban “well intentioned,” but said any effort to reduce death and disease from tobacco “must avoid solutions that will create yet another reason for armed police to engage citizens on the street based on pretext or conduct that does not pose a threat to public safety.”
Instead of a ban, the organizations said, policy makers should consider increased education for adults and minors, stop-smoking programs, and increased funding for health centers in communities of color.
The Biden administration, however, pressed the point that banning menthol will bring many positives. Acting FDA Commissioner Janet Woodcock, MD said in a statement that banning menthol “will help significantly reduce youth initiation, increase the chances of smoking cessation among current smokers, and address health disparities experienced by communities of color, low-income populations, and LGBTQ-plus individuals, all of whom are far more likely to use these tobacco products.”
The FDA cited data showing that, in the first year or so after a ban goes into effect, an additional 923,000 smokers would quit, including 230,000 African Americans. Another study suggests that 633,000 deaths would be averted, including 237,000 Black Americans.
Dr. Woodcock added that, “armed with strong scientific evidence, and with full support from the [Biden] administration, we believe these actions will launch us on a trajectory toward ending tobacco-related disease and death in the U.S.”
The FDA estimates that 18.6 million Americans who are current smokers use menthol cigarettes, with a disproportionately high number being Black people. Menthol cigarette use among Black and Hispanic youth increased from 2011 to 2018, but declined for non-Hispanic White youth.
Flavored mass-produced cigars and cigarillos are disproportionately popular among youth, especially non-Hispanic Black high school students, who in 2020 reported past 30-day cigar smoking at levels twice as high as their White counterparts, said the FDA. Three-quarters of 12- to 17-year-olds reported they smoke cigars because they like the flavors. In 2020, more young people tried a cigar every day than tried a cigarette, reports the agency.
“This long-overdue decision will protect future generations of young people from nicotine addiction, especially Black children and communities, which have disproportionately suffered from menthol tobacco use due to targeted efforts from the tobacco industry,” Lee Savio Beers, MD, president of the American Academy of Pediatrics, said in a statement.
The FDA’s announcement “is only a first step that must be followed with urgent, comprehensive action to remove these flavored products from the market,” he said.
A version of this article first appeared on WebMD.com.
The Food and Drug Administration said that within a year it will ban menthol in cigarettes and ban all flavors including menthol in cigars.
Menthol makes it easier to start smoking, and also enhances the effects of nicotine, making it more addictive and harder to quit, the FDA said in announcing its actions on Thursday.
Nineteen organizations – including the American Academy of Pediatrics, American Cancer Society, American College of Chest Physicians, American Medical Association, American Heart Association, and the National Medical Association – have pushed the FDA to ban menthol for years. The agency banned all flavors in cigarettes in 2009 but did not take any action against menthol. In 2013, the groups filed a petition demanding that the FDA ban menthol, too. The agency responded months later with a notice that it would start the process.
But it never took any action. Action on Smoking and Health and the African American Tobacco Control Leadership Council, later joined by the AMA and the NMA, sued in 2020 to compel the agency to do something. Now it has finally agreed to act.
The African American Tobacco Control Leadership Council welcomed the move but said the fight is not over and encouraged tobacco control activists to fight to ban menthol tobacco products at the local, state and federal level. “We know that this rule-making process could take years and we know that the tobacco industry will continue to do everything in their power to derail any attempt to remove their deadly products from the market,” Phillip Gardiner, MD, council cochair, said in a statement.
The AMA is urging the FDA to quickly implement the ban and remove the products “without further delay,” AMA President Susan R. Bailey, MD, said in a statement.
“FDA’s long-awaited decision to take action to eliminate menthol flavoring in cigarettes and all flavors in cigars ends a decades-long deference to the tobacco industry, which has repeatedly demonstrated its willingness to profit from products that result in death,” Lisa Lacasse, president of the American Cancer Society Cancer Action Network, said in her own statement.
Ms. Lacasse said banning menthol will help eliminate health disparities. She said 86% of Black people who smoke use menthol cigarettes, compared with 46% of Hispanic people who smoke, 39% of Asian people who smoke, and 29% of White people who smoke. “FDA’s actions today send a clear message that Big Tobacco’s strategy to profit off addicting Black communities will no longer be tolerated,” she said.
Not all groups are on board, however. The American Civil Liberties Union and several other organizations wrote to the country’s top health officials urging them to reconsider.
“Such a ban will trigger criminal penalties which will disproportionately impact people of color, as well as prioritize criminalization over public health and harm reduction,” the letter says. “A ban will also lead to unconstitutional policing and other negative interactions with local law enforcement.”
The letter calls the proposed ban “well intentioned,” but said any effort to reduce death and disease from tobacco “must avoid solutions that will create yet another reason for armed police to engage citizens on the street based on pretext or conduct that does not pose a threat to public safety.”
Instead of a ban, the organizations said, policy makers should consider increased education for adults and minors, stop-smoking programs, and increased funding for health centers in communities of color.
The Biden administration, however, pressed the point that banning menthol will bring many positives. Acting FDA Commissioner Janet Woodcock, MD said in a statement that banning menthol “will help significantly reduce youth initiation, increase the chances of smoking cessation among current smokers, and address health disparities experienced by communities of color, low-income populations, and LGBTQ-plus individuals, all of whom are far more likely to use these tobacco products.”
The FDA cited data showing that, in the first year or so after a ban goes into effect, an additional 923,000 smokers would quit, including 230,000 African Americans. Another study suggests that 633,000 deaths would be averted, including 237,000 Black Americans.
Dr. Woodcock added that, “armed with strong scientific evidence, and with full support from the [Biden] administration, we believe these actions will launch us on a trajectory toward ending tobacco-related disease and death in the U.S.”
The FDA estimates that 18.6 million Americans who are current smokers use menthol cigarettes, with a disproportionately high number being Black people. Menthol cigarette use among Black and Hispanic youth increased from 2011 to 2018, but declined for non-Hispanic White youth.
Flavored mass-produced cigars and cigarillos are disproportionately popular among youth, especially non-Hispanic Black high school students, who in 2020 reported past 30-day cigar smoking at levels twice as high as their White counterparts, said the FDA. Three-quarters of 12- to 17-year-olds reported they smoke cigars because they like the flavors. In 2020, more young people tried a cigar every day than tried a cigarette, reports the agency.
“This long-overdue decision will protect future generations of young people from nicotine addiction, especially Black children and communities, which have disproportionately suffered from menthol tobacco use due to targeted efforts from the tobacco industry,” Lee Savio Beers, MD, president of the American Academy of Pediatrics, said in a statement.
The FDA’s announcement “is only a first step that must be followed with urgent, comprehensive action to remove these flavored products from the market,” he said.
A version of this article first appeared on WebMD.com.
Short-term oxygen prescriptions lead to inappropriate long-term use
In past posts for this news organization, I’ve railed against the cost of inappropriate prescriptions for oxygen. A recent review recommended against prescribing oxygen for patients with isolated exertional or nocturnal desaturations, and recently published randomized trials found no demonstrable benefit to oxygen use in the absence of resting hypoxemia. a common practice in clinics where I’ve worked. However, oxygen prescriptions at hospital discharge are a far more pernicious cause of wasted resources.
Prescriptions at hospital discharge, sometimes referred to as short-term oxygen therapy (STOT), account for a large proportion of total oxygen use. Past data have shown that the term “STOT” is a misnomer, as most patients provided with oxygen at discharge are never reevaluated and become long-term oxygen users. The high cost of durable medical equipment related to oxygen delivery prompted the American Thoracic Society and American College of Chest Physicians to recommend postdischarge reassessment of oxygen needs in their Choosing Wisely campaign for adult pulmonary medicine.
A recent study published in the Annals of the American Thoracic Society (Ann ATS) highlights the benefits available if we decide to “choose wisely.” The authors studied patients covered by Veterans Affairs and discharged on STOT between 2006 and 2011. Only 43.6% (287/659) had complete reassessment (oxygen testing at rest and with ambulation) within 90 days. Of those, 124 (43.2%) were eligible for discontinuation via Centers for Medicare & Medicaid Services guidelines. A total of 70.7% (466/659) were tested at rest, and only 15.7% (73/466) had resting hypoxemia. If one accepts the results of the recently published Long-Term Oxygen Treatment Trial, this means that 84.3% (393/466) would be eligible for oxygen discontinuation.
The Ann ATS study provides a blueprint for how we might improve these dismal numbers. There were five separate sites reviewed in their paper. At one site, reassessment occurred in 78.5% of STOT patients and 100% had oxygen discontinued when appropriate. What was their secret? An automatic alert system and a dedicated clinic, coordinator, and respiratory therapist. Also, among the 124 patients who had a full reassessment and no longer qualified for oxygen, 86.3% had it discontinued.
There are countless reasons why STOT is common, but discontinuation is not. Most COPD exacerbations are managed by nonpulmonologists on general medicine wards prior to discharge. In my experience, these physicians are reluctant to release a patient with exertional hypoxia without STOT. They also assume that the pulmonary clinic will do its job during the obligatory outpatient follow-up appointment they schedule with us. At the follow-up, the patient and physician are reluctant to stop therapy because of psychological dependence and therapeutic overconfidence, respectively.
In summary, STOT following hospitalization comprises the majority of all oxygen prescriptions. Historically, the United States provides far more oxygen than other developed countries, and only CMS reimbursement changes have bent the “overprescription” curve. The Ann ATS study shows that a well-designed program at the hospital level can put oxygen decisions back in the hands of providers.
Let’s “choose wisely” and follow what works, or we’ll have only ourselves to blame when reimbursement decisions are taken out of our hands.
A version of this article first appeared on Medscape.com.
In past posts for this news organization, I’ve railed against the cost of inappropriate prescriptions for oxygen. A recent review recommended against prescribing oxygen for patients with isolated exertional or nocturnal desaturations, and recently published randomized trials found no demonstrable benefit to oxygen use in the absence of resting hypoxemia. a common practice in clinics where I’ve worked. However, oxygen prescriptions at hospital discharge are a far more pernicious cause of wasted resources.
Prescriptions at hospital discharge, sometimes referred to as short-term oxygen therapy (STOT), account for a large proportion of total oxygen use. Past data have shown that the term “STOT” is a misnomer, as most patients provided with oxygen at discharge are never reevaluated and become long-term oxygen users. The high cost of durable medical equipment related to oxygen delivery prompted the American Thoracic Society and American College of Chest Physicians to recommend postdischarge reassessment of oxygen needs in their Choosing Wisely campaign for adult pulmonary medicine.
A recent study published in the Annals of the American Thoracic Society (Ann ATS) highlights the benefits available if we decide to “choose wisely.” The authors studied patients covered by Veterans Affairs and discharged on STOT between 2006 and 2011. Only 43.6% (287/659) had complete reassessment (oxygen testing at rest and with ambulation) within 90 days. Of those, 124 (43.2%) were eligible for discontinuation via Centers for Medicare & Medicaid Services guidelines. A total of 70.7% (466/659) were tested at rest, and only 15.7% (73/466) had resting hypoxemia. If one accepts the results of the recently published Long-Term Oxygen Treatment Trial, this means that 84.3% (393/466) would be eligible for oxygen discontinuation.
The Ann ATS study provides a blueprint for how we might improve these dismal numbers. There were five separate sites reviewed in their paper. At one site, reassessment occurred in 78.5% of STOT patients and 100% had oxygen discontinued when appropriate. What was their secret? An automatic alert system and a dedicated clinic, coordinator, and respiratory therapist. Also, among the 124 patients who had a full reassessment and no longer qualified for oxygen, 86.3% had it discontinued.
There are countless reasons why STOT is common, but discontinuation is not. Most COPD exacerbations are managed by nonpulmonologists on general medicine wards prior to discharge. In my experience, these physicians are reluctant to release a patient with exertional hypoxia without STOT. They also assume that the pulmonary clinic will do its job during the obligatory outpatient follow-up appointment they schedule with us. At the follow-up, the patient and physician are reluctant to stop therapy because of psychological dependence and therapeutic overconfidence, respectively.
In summary, STOT following hospitalization comprises the majority of all oxygen prescriptions. Historically, the United States provides far more oxygen than other developed countries, and only CMS reimbursement changes have bent the “overprescription” curve. The Ann ATS study shows that a well-designed program at the hospital level can put oxygen decisions back in the hands of providers.
Let’s “choose wisely” and follow what works, or we’ll have only ourselves to blame when reimbursement decisions are taken out of our hands.
A version of this article first appeared on Medscape.com.
In past posts for this news organization, I’ve railed against the cost of inappropriate prescriptions for oxygen. A recent review recommended against prescribing oxygen for patients with isolated exertional or nocturnal desaturations, and recently published randomized trials found no demonstrable benefit to oxygen use in the absence of resting hypoxemia. a common practice in clinics where I’ve worked. However, oxygen prescriptions at hospital discharge are a far more pernicious cause of wasted resources.
Prescriptions at hospital discharge, sometimes referred to as short-term oxygen therapy (STOT), account for a large proportion of total oxygen use. Past data have shown that the term “STOT” is a misnomer, as most patients provided with oxygen at discharge are never reevaluated and become long-term oxygen users. The high cost of durable medical equipment related to oxygen delivery prompted the American Thoracic Society and American College of Chest Physicians to recommend postdischarge reassessment of oxygen needs in their Choosing Wisely campaign for adult pulmonary medicine.
A recent study published in the Annals of the American Thoracic Society (Ann ATS) highlights the benefits available if we decide to “choose wisely.” The authors studied patients covered by Veterans Affairs and discharged on STOT between 2006 and 2011. Only 43.6% (287/659) had complete reassessment (oxygen testing at rest and with ambulation) within 90 days. Of those, 124 (43.2%) were eligible for discontinuation via Centers for Medicare & Medicaid Services guidelines. A total of 70.7% (466/659) were tested at rest, and only 15.7% (73/466) had resting hypoxemia. If one accepts the results of the recently published Long-Term Oxygen Treatment Trial, this means that 84.3% (393/466) would be eligible for oxygen discontinuation.
The Ann ATS study provides a blueprint for how we might improve these dismal numbers. There were five separate sites reviewed in their paper. At one site, reassessment occurred in 78.5% of STOT patients and 100% had oxygen discontinued when appropriate. What was their secret? An automatic alert system and a dedicated clinic, coordinator, and respiratory therapist. Also, among the 124 patients who had a full reassessment and no longer qualified for oxygen, 86.3% had it discontinued.
There are countless reasons why STOT is common, but discontinuation is not. Most COPD exacerbations are managed by nonpulmonologists on general medicine wards prior to discharge. In my experience, these physicians are reluctant to release a patient with exertional hypoxia without STOT. They also assume that the pulmonary clinic will do its job during the obligatory outpatient follow-up appointment they schedule with us. At the follow-up, the patient and physician are reluctant to stop therapy because of psychological dependence and therapeutic overconfidence, respectively.
In summary, STOT following hospitalization comprises the majority of all oxygen prescriptions. Historically, the United States provides far more oxygen than other developed countries, and only CMS reimbursement changes have bent the “overprescription” curve. The Ann ATS study shows that a well-designed program at the hospital level can put oxygen decisions back in the hands of providers.
Let’s “choose wisely” and follow what works, or we’ll have only ourselves to blame when reimbursement decisions are taken out of our hands.
A version of this article first appeared on Medscape.com.
Pediatric bronchiolitis: Less is more
A common cause of infant morbidity and hospitalization in developed countries, infant viral bronchiolitis, has long been bedeviled by treatment uncertainty beyond supportive care.
Rationales for most pharmacologic treatments continue to be debated, and clinical practice guidelines generally advise respiratory and hydration support, discouraging the use of chest radiography, albuterol, glucocorticoids, antibiotics, and epinephrine.
Despite evidence that the latter interventions are ineffective, they are still too often applied, according to two recent studies, one in Pediatrics, the other in JAMA Pediatrics.
“The pull of the therapeutic vacuum surrounding this disease has been noted in the pages of this journal for at least 50 years, with Wright and Beem writing in 1965 that ‘energies should not be frittered away by the annoyance of unnecessary or futile medications and procedures’ for the child with bronchiolitis,” said emergency physicians Matthew J. Lipshaw, MD, MS, of the Cincinnati Children’s Hospital Medical Center, and Todd A. Florin, MD, MSCE, of Ann and Robert H. Lurie Children’s Hospital of Chicago.
These remarks came in their editorial in Pediatrics wryly titled: “Don’t Just Do Something, Stand There” and published online to accompany a recent study of three network meta-analyses.
Led by Sarah A. Elliott, PhD, of the Alberta Research Centre for Health Evidence at the University of Alberta in Edmonton, this analysis amalgamated 150 randomized, controlled trials comparing a placebo or active comparator with any bronchodilator, glucocorticoid steroid, hypertonic saline solution, antibiotic, helium-oxygen therapy, or high-flow oxygen therapy. It then looked at the following outcomes in children aged 2 years and younger: hospital admission rate on day 1, hospital admission rate within 7 days, and total hospital length of stay.
Few treatments seemed more effective than nebulized placebo (0.9% saline) for short-term outcomes, the authors found. While nebulized epinephrine and nebulized hypertonic saline plus salbutamol appeared to reduce admission rates during the index ED presentation, and hypertonic saline, alone or in combination with epinephrine, seemed to reduce hospital stays, such treatment had no effect on admissions within 7 days of initial presentation. Furthermore, most benefits disappeared in higher-quality studies.
Concluding, albeit with weak evidence and low confidence, that some benefit might accrue with hypertonic saline with salbutamol to reduce admission rates on initial presentation to the ED, the authors called for well-designed studies on treatments in inpatients and outpatients.
According to Dr. Lipshaw, assistant professor of clinical pediatrics, the lack of benefit observed in superior studies limits the applicability of Dr. Elliott and colleagues’ results to immediate clinical practice. “These findings could be used, however, to target future high-quality studies toward the medications that they found might be useful,” he said in an interview.
For the present, other recent research augurs well for strategically reducing unnecessary care. In a paper published online in JAMA Pediatrics, Libby Haskell, MN, of the ED at Starship Children’s Hospital in Auckland, New Zealand, and associates reported on a cluster-randomized, controlled trial of targeted interventions.
Conducted in 2017 at 26 hospitals and with 3,727 babies in New Zealand and Australia, the study addressed drivers of non–evidence-based approaches with behavior-modifying approaches such as on-site clinical leads, stakeholder meetings, a train-the-trainer workshop, education, and audit and feedback.
The authors reported a 14.1% difference in rates of compliance during the first 24 hours of hospitalization favoring the intervention group for all five bronchiolitis guideline recommendations. The greatest change was seen in albuterol and chest radiography use, with other improvements in ED visits, inpatient consultations, and throughout hospitalization.
“These results provide clinicians and hospitals with clear implementation strategies to address unnecessary treatment of infants with bronchiolitis,” Dr. Haskell’s group wrote. Dr. Lipshaw agreed that multifaceted deimplementation packages including clinician and family education, audit and feedback, and clinical decision support have been successful. “Haskell et al. demonstrated that it is possible to successfully deimplement non–evidence-based practices for bronchiolitis with targeted inventions,” he said. “It would be wonderful to see their success replicated in the U.S.”
Why the slow adoption of guidelines?
The American Academy of Pediatrics issued bronchiolitis guidelines for babies to 23 months in 2014 and updated them in 2018. Why, then, has care in some centers been seemingly all over the map and counter to guidelines? “Both parents and clinicians are acting in what they believe to be the best interests of the child, and in the absence of high-value interventions, can feel the need to do something, even if that something is not supported by evidence,” Dr. Lipshaw said.
Furthermore, with children in obvious distress, breathing fast and with difficulty, and sometimes unable to eat or drink, “we feel like we should have some way to make them feel better quicker. Unfortunately, none of the medications we have tried seem to be useful for most children, and we are left with supportive care measures such as suctioning their noses, giving them oxygen if their oxygen is low, and giving them fluids if they are dehydrated.”
Other physicians agree that taking a less-is-more approach can be challenging and even counterintuitive. “To families, seeing their child’s doctor ‘doing less’ can be frustrating,” admitted Diana S. Lee, MD, assistant professor of pediatrics at Icahn School of Medicine at Mount Sinai, New York.
Beyond that, altering practice behavior will need more than guidelines, Dr. Lee said in an interview. “Haskell et al. showed targeted behavior-change interventions improved compliance with bronchiolitis guidelines, but such change requires motivation and resources, and the sustainability of this effect over time remains to be seen.”
At Dr. Lipshaw’s institution, treatment depends on the attending physician, “but we have an emergency department care algorithm, which does not recommend any inhaled medications or steroids in accordance with the 2014 AAP guidelines,” he said.
Similarly at Mount Sinai, practitioners strive to follow the AAP guidelines, although their implementation has not been immediate, Dr. Lee said. “This is a situation where we must make the effort to choose not to do more, given current evidence.”
But Michelle Dunn, MD, an attending physician in the division of general pediatrics at the Children’s Hospital of Philadelphia, said the American practice norm already tends more to the observance than the breach of the guidelines, noting that since 2014 quality improvement efforts have been made throughout the country. “At our institution, we have effectively reduced the use of albuterol in patients with bronchiolitis and we use evidence-based therapy as much as possible, which in the case of bronchiolitis generally involves supportive management alone,” she said in an interview.
Still, Dr. Dunn added, many patients receive unnecessary diagnostic testing and ineffective therapies, with some providers facing psychological barriers to doing less. “However, with more and more evidence to support this, hopefully, physicians will become more comfortable with this.”
To that end, Dr. Lipshaw’s editorial urges physicians to “curb the rampant use of therapies repeatedly revealed to be ineffective,” citing team engagement, clear practice guidelines, and information technology as key factors in deimplementation. In the meantime, his mantra remains: “Don’t just do something, stand there.”
The study by Dr. Elliot and colleagues was supported by the Canadian Institutes of Health Research Knowledge Synthesis grant program. One coauthor is supported by a University of Ottawa Tier I Research Chair in Pediatric Emergency Medicine. Another is supported by a Tier 1 Canada Research Chair in Knowledge Synthesis and Translation and the Stollery Science Laboratory. Dr. Lipshaw and Dr. Florin disclosed no financial relationships relevant to their commentary. Dr. Haskell and colleagues were supported, variously, by the National Health and Medical Research Council of New Zealand, the Center of Research Excellence for Pediatric Emergency Medicine, the Victorian Government’s Operational Infrastructure Support Program, Cure Kids New Zealand, the Royal Children’s Hospital Foundation, and the Starship Foundation. Dr. Lee and Dr. Dunn had no competing interests to disclose with regard to their comments.
A common cause of infant morbidity and hospitalization in developed countries, infant viral bronchiolitis, has long been bedeviled by treatment uncertainty beyond supportive care.
Rationales for most pharmacologic treatments continue to be debated, and clinical practice guidelines generally advise respiratory and hydration support, discouraging the use of chest radiography, albuterol, glucocorticoids, antibiotics, and epinephrine.
Despite evidence that the latter interventions are ineffective, they are still too often applied, according to two recent studies, one in Pediatrics, the other in JAMA Pediatrics.
“The pull of the therapeutic vacuum surrounding this disease has been noted in the pages of this journal for at least 50 years, with Wright and Beem writing in 1965 that ‘energies should not be frittered away by the annoyance of unnecessary or futile medications and procedures’ for the child with bronchiolitis,” said emergency physicians Matthew J. Lipshaw, MD, MS, of the Cincinnati Children’s Hospital Medical Center, and Todd A. Florin, MD, MSCE, of Ann and Robert H. Lurie Children’s Hospital of Chicago.
These remarks came in their editorial in Pediatrics wryly titled: “Don’t Just Do Something, Stand There” and published online to accompany a recent study of three network meta-analyses.
Led by Sarah A. Elliott, PhD, of the Alberta Research Centre for Health Evidence at the University of Alberta in Edmonton, this analysis amalgamated 150 randomized, controlled trials comparing a placebo or active comparator with any bronchodilator, glucocorticoid steroid, hypertonic saline solution, antibiotic, helium-oxygen therapy, or high-flow oxygen therapy. It then looked at the following outcomes in children aged 2 years and younger: hospital admission rate on day 1, hospital admission rate within 7 days, and total hospital length of stay.
Few treatments seemed more effective than nebulized placebo (0.9% saline) for short-term outcomes, the authors found. While nebulized epinephrine and nebulized hypertonic saline plus salbutamol appeared to reduce admission rates during the index ED presentation, and hypertonic saline, alone or in combination with epinephrine, seemed to reduce hospital stays, such treatment had no effect on admissions within 7 days of initial presentation. Furthermore, most benefits disappeared in higher-quality studies.
Concluding, albeit with weak evidence and low confidence, that some benefit might accrue with hypertonic saline with salbutamol to reduce admission rates on initial presentation to the ED, the authors called for well-designed studies on treatments in inpatients and outpatients.
According to Dr. Lipshaw, assistant professor of clinical pediatrics, the lack of benefit observed in superior studies limits the applicability of Dr. Elliott and colleagues’ results to immediate clinical practice. “These findings could be used, however, to target future high-quality studies toward the medications that they found might be useful,” he said in an interview.
For the present, other recent research augurs well for strategically reducing unnecessary care. In a paper published online in JAMA Pediatrics, Libby Haskell, MN, of the ED at Starship Children’s Hospital in Auckland, New Zealand, and associates reported on a cluster-randomized, controlled trial of targeted interventions.
Conducted in 2017 at 26 hospitals and with 3,727 babies in New Zealand and Australia, the study addressed drivers of non–evidence-based approaches with behavior-modifying approaches such as on-site clinical leads, stakeholder meetings, a train-the-trainer workshop, education, and audit and feedback.
The authors reported a 14.1% difference in rates of compliance during the first 24 hours of hospitalization favoring the intervention group for all five bronchiolitis guideline recommendations. The greatest change was seen in albuterol and chest radiography use, with other improvements in ED visits, inpatient consultations, and throughout hospitalization.
“These results provide clinicians and hospitals with clear implementation strategies to address unnecessary treatment of infants with bronchiolitis,” Dr. Haskell’s group wrote. Dr. Lipshaw agreed that multifaceted deimplementation packages including clinician and family education, audit and feedback, and clinical decision support have been successful. “Haskell et al. demonstrated that it is possible to successfully deimplement non–evidence-based practices for bronchiolitis with targeted inventions,” he said. “It would be wonderful to see their success replicated in the U.S.”
Why the slow adoption of guidelines?
The American Academy of Pediatrics issued bronchiolitis guidelines for babies to 23 months in 2014 and updated them in 2018. Why, then, has care in some centers been seemingly all over the map and counter to guidelines? “Both parents and clinicians are acting in what they believe to be the best interests of the child, and in the absence of high-value interventions, can feel the need to do something, even if that something is not supported by evidence,” Dr. Lipshaw said.
Furthermore, with children in obvious distress, breathing fast and with difficulty, and sometimes unable to eat or drink, “we feel like we should have some way to make them feel better quicker. Unfortunately, none of the medications we have tried seem to be useful for most children, and we are left with supportive care measures such as suctioning their noses, giving them oxygen if their oxygen is low, and giving them fluids if they are dehydrated.”
Other physicians agree that taking a less-is-more approach can be challenging and even counterintuitive. “To families, seeing their child’s doctor ‘doing less’ can be frustrating,” admitted Diana S. Lee, MD, assistant professor of pediatrics at Icahn School of Medicine at Mount Sinai, New York.
Beyond that, altering practice behavior will need more than guidelines, Dr. Lee said in an interview. “Haskell et al. showed targeted behavior-change interventions improved compliance with bronchiolitis guidelines, but such change requires motivation and resources, and the sustainability of this effect over time remains to be seen.”
At Dr. Lipshaw’s institution, treatment depends on the attending physician, “but we have an emergency department care algorithm, which does not recommend any inhaled medications or steroids in accordance with the 2014 AAP guidelines,” he said.
Similarly at Mount Sinai, practitioners strive to follow the AAP guidelines, although their implementation has not been immediate, Dr. Lee said. “This is a situation where we must make the effort to choose not to do more, given current evidence.”
But Michelle Dunn, MD, an attending physician in the division of general pediatrics at the Children’s Hospital of Philadelphia, said the American practice norm already tends more to the observance than the breach of the guidelines, noting that since 2014 quality improvement efforts have been made throughout the country. “At our institution, we have effectively reduced the use of albuterol in patients with bronchiolitis and we use evidence-based therapy as much as possible, which in the case of bronchiolitis generally involves supportive management alone,” she said in an interview.
Still, Dr. Dunn added, many patients receive unnecessary diagnostic testing and ineffective therapies, with some providers facing psychological barriers to doing less. “However, with more and more evidence to support this, hopefully, physicians will become more comfortable with this.”
To that end, Dr. Lipshaw’s editorial urges physicians to “curb the rampant use of therapies repeatedly revealed to be ineffective,” citing team engagement, clear practice guidelines, and information technology as key factors in deimplementation. In the meantime, his mantra remains: “Don’t just do something, stand there.”
The study by Dr. Elliot and colleagues was supported by the Canadian Institutes of Health Research Knowledge Synthesis grant program. One coauthor is supported by a University of Ottawa Tier I Research Chair in Pediatric Emergency Medicine. Another is supported by a Tier 1 Canada Research Chair in Knowledge Synthesis and Translation and the Stollery Science Laboratory. Dr. Lipshaw and Dr. Florin disclosed no financial relationships relevant to their commentary. Dr. Haskell and colleagues were supported, variously, by the National Health and Medical Research Council of New Zealand, the Center of Research Excellence for Pediatric Emergency Medicine, the Victorian Government’s Operational Infrastructure Support Program, Cure Kids New Zealand, the Royal Children’s Hospital Foundation, and the Starship Foundation. Dr. Lee and Dr. Dunn had no competing interests to disclose with regard to their comments.
A common cause of infant morbidity and hospitalization in developed countries, infant viral bronchiolitis, has long been bedeviled by treatment uncertainty beyond supportive care.
Rationales for most pharmacologic treatments continue to be debated, and clinical practice guidelines generally advise respiratory and hydration support, discouraging the use of chest radiography, albuterol, glucocorticoids, antibiotics, and epinephrine.
Despite evidence that the latter interventions are ineffective, they are still too often applied, according to two recent studies, one in Pediatrics, the other in JAMA Pediatrics.
“The pull of the therapeutic vacuum surrounding this disease has been noted in the pages of this journal for at least 50 years, with Wright and Beem writing in 1965 that ‘energies should not be frittered away by the annoyance of unnecessary or futile medications and procedures’ for the child with bronchiolitis,” said emergency physicians Matthew J. Lipshaw, MD, MS, of the Cincinnati Children’s Hospital Medical Center, and Todd A. Florin, MD, MSCE, of Ann and Robert H. Lurie Children’s Hospital of Chicago.
These remarks came in their editorial in Pediatrics wryly titled: “Don’t Just Do Something, Stand There” and published online to accompany a recent study of three network meta-analyses.
Led by Sarah A. Elliott, PhD, of the Alberta Research Centre for Health Evidence at the University of Alberta in Edmonton, this analysis amalgamated 150 randomized, controlled trials comparing a placebo or active comparator with any bronchodilator, glucocorticoid steroid, hypertonic saline solution, antibiotic, helium-oxygen therapy, or high-flow oxygen therapy. It then looked at the following outcomes in children aged 2 years and younger: hospital admission rate on day 1, hospital admission rate within 7 days, and total hospital length of stay.
Few treatments seemed more effective than nebulized placebo (0.9% saline) for short-term outcomes, the authors found. While nebulized epinephrine and nebulized hypertonic saline plus salbutamol appeared to reduce admission rates during the index ED presentation, and hypertonic saline, alone or in combination with epinephrine, seemed to reduce hospital stays, such treatment had no effect on admissions within 7 days of initial presentation. Furthermore, most benefits disappeared in higher-quality studies.
Concluding, albeit with weak evidence and low confidence, that some benefit might accrue with hypertonic saline with salbutamol to reduce admission rates on initial presentation to the ED, the authors called for well-designed studies on treatments in inpatients and outpatients.
According to Dr. Lipshaw, assistant professor of clinical pediatrics, the lack of benefit observed in superior studies limits the applicability of Dr. Elliott and colleagues’ results to immediate clinical practice. “These findings could be used, however, to target future high-quality studies toward the medications that they found might be useful,” he said in an interview.
For the present, other recent research augurs well for strategically reducing unnecessary care. In a paper published online in JAMA Pediatrics, Libby Haskell, MN, of the ED at Starship Children’s Hospital in Auckland, New Zealand, and associates reported on a cluster-randomized, controlled trial of targeted interventions.
Conducted in 2017 at 26 hospitals and with 3,727 babies in New Zealand and Australia, the study addressed drivers of non–evidence-based approaches with behavior-modifying approaches such as on-site clinical leads, stakeholder meetings, a train-the-trainer workshop, education, and audit and feedback.
The authors reported a 14.1% difference in rates of compliance during the first 24 hours of hospitalization favoring the intervention group for all five bronchiolitis guideline recommendations. The greatest change was seen in albuterol and chest radiography use, with other improvements in ED visits, inpatient consultations, and throughout hospitalization.
“These results provide clinicians and hospitals with clear implementation strategies to address unnecessary treatment of infants with bronchiolitis,” Dr. Haskell’s group wrote. Dr. Lipshaw agreed that multifaceted deimplementation packages including clinician and family education, audit and feedback, and clinical decision support have been successful. “Haskell et al. demonstrated that it is possible to successfully deimplement non–evidence-based practices for bronchiolitis with targeted inventions,” he said. “It would be wonderful to see their success replicated in the U.S.”
Why the slow adoption of guidelines?
The American Academy of Pediatrics issued bronchiolitis guidelines for babies to 23 months in 2014 and updated them in 2018. Why, then, has care in some centers been seemingly all over the map and counter to guidelines? “Both parents and clinicians are acting in what they believe to be the best interests of the child, and in the absence of high-value interventions, can feel the need to do something, even if that something is not supported by evidence,” Dr. Lipshaw said.
Furthermore, with children in obvious distress, breathing fast and with difficulty, and sometimes unable to eat or drink, “we feel like we should have some way to make them feel better quicker. Unfortunately, none of the medications we have tried seem to be useful for most children, and we are left with supportive care measures such as suctioning their noses, giving them oxygen if their oxygen is low, and giving them fluids if they are dehydrated.”
Other physicians agree that taking a less-is-more approach can be challenging and even counterintuitive. “To families, seeing their child’s doctor ‘doing less’ can be frustrating,” admitted Diana S. Lee, MD, assistant professor of pediatrics at Icahn School of Medicine at Mount Sinai, New York.
Beyond that, altering practice behavior will need more than guidelines, Dr. Lee said in an interview. “Haskell et al. showed targeted behavior-change interventions improved compliance with bronchiolitis guidelines, but such change requires motivation and resources, and the sustainability of this effect over time remains to be seen.”
At Dr. Lipshaw’s institution, treatment depends on the attending physician, “but we have an emergency department care algorithm, which does not recommend any inhaled medications or steroids in accordance with the 2014 AAP guidelines,” he said.
Similarly at Mount Sinai, practitioners strive to follow the AAP guidelines, although their implementation has not been immediate, Dr. Lee said. “This is a situation where we must make the effort to choose not to do more, given current evidence.”
But Michelle Dunn, MD, an attending physician in the division of general pediatrics at the Children’s Hospital of Philadelphia, said the American practice norm already tends more to the observance than the breach of the guidelines, noting that since 2014 quality improvement efforts have been made throughout the country. “At our institution, we have effectively reduced the use of albuterol in patients with bronchiolitis and we use evidence-based therapy as much as possible, which in the case of bronchiolitis generally involves supportive management alone,” she said in an interview.
Still, Dr. Dunn added, many patients receive unnecessary diagnostic testing and ineffective therapies, with some providers facing psychological barriers to doing less. “However, with more and more evidence to support this, hopefully, physicians will become more comfortable with this.”
To that end, Dr. Lipshaw’s editorial urges physicians to “curb the rampant use of therapies repeatedly revealed to be ineffective,” citing team engagement, clear practice guidelines, and information technology as key factors in deimplementation. In the meantime, his mantra remains: “Don’t just do something, stand there.”
The study by Dr. Elliot and colleagues was supported by the Canadian Institutes of Health Research Knowledge Synthesis grant program. One coauthor is supported by a University of Ottawa Tier I Research Chair in Pediatric Emergency Medicine. Another is supported by a Tier 1 Canada Research Chair in Knowledge Synthesis and Translation and the Stollery Science Laboratory. Dr. Lipshaw and Dr. Florin disclosed no financial relationships relevant to their commentary. Dr. Haskell and colleagues were supported, variously, by the National Health and Medical Research Council of New Zealand, the Center of Research Excellence for Pediatric Emergency Medicine, the Victorian Government’s Operational Infrastructure Support Program, Cure Kids New Zealand, the Royal Children’s Hospital Foundation, and the Starship Foundation. Dr. Lee and Dr. Dunn had no competing interests to disclose with regard to their comments.
New guidelines advise expanded use of high-flow nasal oxygen for patients with ARDS
Hospitalized patients with acute respiratory failure can benefit from high-flow nasal oxygen in certain settings, according to a new clinical guideline from the American College of Physicians.
High-flow nasal oxygen (HFNO) has demonstrated advantages including improved oxygenation and ventilation, wrote Arianne K. Baldomero, MD, of Minneapolis Veterans Affairs Health Care System and the University of Minnesota, Minneapolis, and colleagues. “However, the comparative benefits and harms of HFNO in clinical outcomes, including mortality, intubation, hospital length of stay, patient comfort, clearance of airway secretions, and reduced work of breathing are not well known.”
In the guideline, published in Annals of Internal Medicine, the authors recommend the use of high-flow nasal oxygen in hospitalized patients for initial or postextubation management of acute respiratory failure. The target population includes those patients treated in hospital wards, EDs, intermediate/step-down units, and ICUs.
Use of HFNO therapy as a form of noninvasive respiratory support for hospitalized patients has increased in recent years. The treatment involves delivering warm, humidified oxygen via nasal cannula at a flow level higher than the patient’s inspiratory flow.
Potential benefits of HFNO include greater patient comfort, improved compliance, and psychological benefits, according to the authors. HFNO also can be used as respiratory support in critically ill patients for a number of indications including respiratory failure or support post extubation; however, treatment of patients with COVID-19 and related conditions were not considered in the guideline.
The guideline was based on evidence comparing HFNO with conventional oxygen therapy (COT) and noninvasive ventilation (NIV). The authors reviewed 29 randomized, controlled trials that showed clinically meaningful outcomes in HFNO patients, as well as similar rates of, or reductions in, mortality, intubations, and hospital-acquired pneumonia, and increased reports of patient comfort. Data also supported the safety of HFNO with few, if any, contraindications other than problems with fitting the nasal cannula.
Across several trials comparing HFNO and NIV for initial management of acute respiratory failure, HFNO reduced all-cause mortality, intubation, and hospital-acquired pneumonia, although the authors categorized the results as “low-certainty evidence.” HFNO was not more effective than NIV for postextubation management. Based trials comparing HFNO and COT for postextubation management, the authors concluded that HFNO may reduce rates of reintubation and improve patient comfort, also with low-certainty evidence.
The research was limited by a lack of studies comparing HFNO with NIV or COT for acute respiratory failure in patients who were post lung transplantation, or for those with pulmonary embolism, pulmonary arterial hypertension, or asthma, the authors said. Other limitations included the variation in study design, study populations, and treatment protocols across the included studies. Additional research is needed to better identify the patients most likely to benefit from HFNO, according to type of acute respiratory failure.
Despite these limitations, the results support the guideline recommendation for HFNO in cases of acute respiratory failure and postextubation management. However, “broad applicability, including required clinician and health system experience and resource use, remains unknown,” the authors concluded.
Research catches up with practice
The guidelines are important at this time because “the medical literature over the past 3-4 years is catching up to what hospitalists, pulmonologists, and critical care specialists have been doing clinically over the past 6-8 years with perceived better results, Jacqueline W. Fincher, MD, MACP, President of the American College of Physicians, said in an interview.
“HFNO has been used to a varying degree over the last 6-8 years by physicians with much-perceived improved benefit in patients who are hypoxemic on usual noninvasive therapy or conventional oxygen therapy with the impending need for intubation or post extubation,” Dr. Fincher said. “During the COVID pandemic particularly with the attack on the respiratory system with COVID pneumonia and frequently associated ARDS [acute respiratory distress syndrome], the use of HFNO has been enormously helpful in trying to keep patients well oxygenated without having to intubate or reintubate them.
“We now have the medical literature that supports what has been seen clinically to make the recommendations and guidelines based on the scientific evidence,” Dr. Fincher added. “If we can avoid intubation associated with the patient being sedated, unable to eat, talk, or meaningfully participate in their care or get the patient off the ventilator sooner for the same reasons, then we have significantly improved the quality of their care, decreased their risk of infection, decreased their days in the ICU and the hospital, we will have succeeded in providing the best care possible. The availability of HFNO, with much greater comfort to the patient than being intubated, is a great tool in the toolbox of respiratory care.”
Dr. Fincher said she was not surprised by any of the recommendations. “We knew the use of HFNO helped but we were surprised by the evidence of the degree to which it is enormously helpful to patients.
“The good news is that HFNO is readily available at most hospitals, but it really requires an intensive care unit and a team of physicians, nurses, and respiratory therapists to be familiar with its use and work closely together to monitor the patient for significant changes in their respiratory status to titrate therapy,” she noted.
Looking ahead, some areas in need of more research that might impact updates to the guidelines include “What are some areas in need of more research that might impact future updates to these guidelines? Specifics on whether initiating HFNO earlier in the course of the patient’s hypoxemic illness is better or worse, as well as the use of HFNO outside of the ICU setting,” Dr. Fincher said. “The needed monitoring of the patient to know whether their respiratory status was deteriorating and how fast would be critical along with the specific indications for titration of the HFNO.”
The evidence review was commissioned and funded by the ACP. The data come from work supported by and conducted at the Minneapolis VA Health Care System. Lead author Dr. Baldomero was supported in part by the National Institutes of Health National Center for Advancing Translational Sciences.
Hospitalized patients with acute respiratory failure can benefit from high-flow nasal oxygen in certain settings, according to a new clinical guideline from the American College of Physicians.
High-flow nasal oxygen (HFNO) has demonstrated advantages including improved oxygenation and ventilation, wrote Arianne K. Baldomero, MD, of Minneapolis Veterans Affairs Health Care System and the University of Minnesota, Minneapolis, and colleagues. “However, the comparative benefits and harms of HFNO in clinical outcomes, including mortality, intubation, hospital length of stay, patient comfort, clearance of airway secretions, and reduced work of breathing are not well known.”
In the guideline, published in Annals of Internal Medicine, the authors recommend the use of high-flow nasal oxygen in hospitalized patients for initial or postextubation management of acute respiratory failure. The target population includes those patients treated in hospital wards, EDs, intermediate/step-down units, and ICUs.
Use of HFNO therapy as a form of noninvasive respiratory support for hospitalized patients has increased in recent years. The treatment involves delivering warm, humidified oxygen via nasal cannula at a flow level higher than the patient’s inspiratory flow.
Potential benefits of HFNO include greater patient comfort, improved compliance, and psychological benefits, according to the authors. HFNO also can be used as respiratory support in critically ill patients for a number of indications including respiratory failure or support post extubation; however, treatment of patients with COVID-19 and related conditions were not considered in the guideline.
The guideline was based on evidence comparing HFNO with conventional oxygen therapy (COT) and noninvasive ventilation (NIV). The authors reviewed 29 randomized, controlled trials that showed clinically meaningful outcomes in HFNO patients, as well as similar rates of, or reductions in, mortality, intubations, and hospital-acquired pneumonia, and increased reports of patient comfort. Data also supported the safety of HFNO with few, if any, contraindications other than problems with fitting the nasal cannula.
Across several trials comparing HFNO and NIV for initial management of acute respiratory failure, HFNO reduced all-cause mortality, intubation, and hospital-acquired pneumonia, although the authors categorized the results as “low-certainty evidence.” HFNO was not more effective than NIV for postextubation management. Based trials comparing HFNO and COT for postextubation management, the authors concluded that HFNO may reduce rates of reintubation and improve patient comfort, also with low-certainty evidence.
The research was limited by a lack of studies comparing HFNO with NIV or COT for acute respiratory failure in patients who were post lung transplantation, or for those with pulmonary embolism, pulmonary arterial hypertension, or asthma, the authors said. Other limitations included the variation in study design, study populations, and treatment protocols across the included studies. Additional research is needed to better identify the patients most likely to benefit from HFNO, according to type of acute respiratory failure.
Despite these limitations, the results support the guideline recommendation for HFNO in cases of acute respiratory failure and postextubation management. However, “broad applicability, including required clinician and health system experience and resource use, remains unknown,” the authors concluded.
Research catches up with practice
The guidelines are important at this time because “the medical literature over the past 3-4 years is catching up to what hospitalists, pulmonologists, and critical care specialists have been doing clinically over the past 6-8 years with perceived better results, Jacqueline W. Fincher, MD, MACP, President of the American College of Physicians, said in an interview.
“HFNO has been used to a varying degree over the last 6-8 years by physicians with much-perceived improved benefit in patients who are hypoxemic on usual noninvasive therapy or conventional oxygen therapy with the impending need for intubation or post extubation,” Dr. Fincher said. “During the COVID pandemic particularly with the attack on the respiratory system with COVID pneumonia and frequently associated ARDS [acute respiratory distress syndrome], the use of HFNO has been enormously helpful in trying to keep patients well oxygenated without having to intubate or reintubate them.
“We now have the medical literature that supports what has been seen clinically to make the recommendations and guidelines based on the scientific evidence,” Dr. Fincher added. “If we can avoid intubation associated with the patient being sedated, unable to eat, talk, or meaningfully participate in their care or get the patient off the ventilator sooner for the same reasons, then we have significantly improved the quality of their care, decreased their risk of infection, decreased their days in the ICU and the hospital, we will have succeeded in providing the best care possible. The availability of HFNO, with much greater comfort to the patient than being intubated, is a great tool in the toolbox of respiratory care.”
Dr. Fincher said she was not surprised by any of the recommendations. “We knew the use of HFNO helped but we were surprised by the evidence of the degree to which it is enormously helpful to patients.
“The good news is that HFNO is readily available at most hospitals, but it really requires an intensive care unit and a team of physicians, nurses, and respiratory therapists to be familiar with its use and work closely together to monitor the patient for significant changes in their respiratory status to titrate therapy,” she noted.
Looking ahead, some areas in need of more research that might impact updates to the guidelines include “What are some areas in need of more research that might impact future updates to these guidelines? Specifics on whether initiating HFNO earlier in the course of the patient’s hypoxemic illness is better or worse, as well as the use of HFNO outside of the ICU setting,” Dr. Fincher said. “The needed monitoring of the patient to know whether their respiratory status was deteriorating and how fast would be critical along with the specific indications for titration of the HFNO.”
The evidence review was commissioned and funded by the ACP. The data come from work supported by and conducted at the Minneapolis VA Health Care System. Lead author Dr. Baldomero was supported in part by the National Institutes of Health National Center for Advancing Translational Sciences.
Hospitalized patients with acute respiratory failure can benefit from high-flow nasal oxygen in certain settings, according to a new clinical guideline from the American College of Physicians.
High-flow nasal oxygen (HFNO) has demonstrated advantages including improved oxygenation and ventilation, wrote Arianne K. Baldomero, MD, of Minneapolis Veterans Affairs Health Care System and the University of Minnesota, Minneapolis, and colleagues. “However, the comparative benefits and harms of HFNO in clinical outcomes, including mortality, intubation, hospital length of stay, patient comfort, clearance of airway secretions, and reduced work of breathing are not well known.”
In the guideline, published in Annals of Internal Medicine, the authors recommend the use of high-flow nasal oxygen in hospitalized patients for initial or postextubation management of acute respiratory failure. The target population includes those patients treated in hospital wards, EDs, intermediate/step-down units, and ICUs.
Use of HFNO therapy as a form of noninvasive respiratory support for hospitalized patients has increased in recent years. The treatment involves delivering warm, humidified oxygen via nasal cannula at a flow level higher than the patient’s inspiratory flow.
Potential benefits of HFNO include greater patient comfort, improved compliance, and psychological benefits, according to the authors. HFNO also can be used as respiratory support in critically ill patients for a number of indications including respiratory failure or support post extubation; however, treatment of patients with COVID-19 and related conditions were not considered in the guideline.
The guideline was based on evidence comparing HFNO with conventional oxygen therapy (COT) and noninvasive ventilation (NIV). The authors reviewed 29 randomized, controlled trials that showed clinically meaningful outcomes in HFNO patients, as well as similar rates of, or reductions in, mortality, intubations, and hospital-acquired pneumonia, and increased reports of patient comfort. Data also supported the safety of HFNO with few, if any, contraindications other than problems with fitting the nasal cannula.
Across several trials comparing HFNO and NIV for initial management of acute respiratory failure, HFNO reduced all-cause mortality, intubation, and hospital-acquired pneumonia, although the authors categorized the results as “low-certainty evidence.” HFNO was not more effective than NIV for postextubation management. Based trials comparing HFNO and COT for postextubation management, the authors concluded that HFNO may reduce rates of reintubation and improve patient comfort, also with low-certainty evidence.
The research was limited by a lack of studies comparing HFNO with NIV or COT for acute respiratory failure in patients who were post lung transplantation, or for those with pulmonary embolism, pulmonary arterial hypertension, or asthma, the authors said. Other limitations included the variation in study design, study populations, and treatment protocols across the included studies. Additional research is needed to better identify the patients most likely to benefit from HFNO, according to type of acute respiratory failure.
Despite these limitations, the results support the guideline recommendation for HFNO in cases of acute respiratory failure and postextubation management. However, “broad applicability, including required clinician and health system experience and resource use, remains unknown,” the authors concluded.
Research catches up with practice
The guidelines are important at this time because “the medical literature over the past 3-4 years is catching up to what hospitalists, pulmonologists, and critical care specialists have been doing clinically over the past 6-8 years with perceived better results, Jacqueline W. Fincher, MD, MACP, President of the American College of Physicians, said in an interview.
“HFNO has been used to a varying degree over the last 6-8 years by physicians with much-perceived improved benefit in patients who are hypoxemic on usual noninvasive therapy or conventional oxygen therapy with the impending need for intubation or post extubation,” Dr. Fincher said. “During the COVID pandemic particularly with the attack on the respiratory system with COVID pneumonia and frequently associated ARDS [acute respiratory distress syndrome], the use of HFNO has been enormously helpful in trying to keep patients well oxygenated without having to intubate or reintubate them.
“We now have the medical literature that supports what has been seen clinically to make the recommendations and guidelines based on the scientific evidence,” Dr. Fincher added. “If we can avoid intubation associated with the patient being sedated, unable to eat, talk, or meaningfully participate in their care or get the patient off the ventilator sooner for the same reasons, then we have significantly improved the quality of their care, decreased their risk of infection, decreased their days in the ICU and the hospital, we will have succeeded in providing the best care possible. The availability of HFNO, with much greater comfort to the patient than being intubated, is a great tool in the toolbox of respiratory care.”
Dr. Fincher said she was not surprised by any of the recommendations. “We knew the use of HFNO helped but we were surprised by the evidence of the degree to which it is enormously helpful to patients.
“The good news is that HFNO is readily available at most hospitals, but it really requires an intensive care unit and a team of physicians, nurses, and respiratory therapists to be familiar with its use and work closely together to monitor the patient for significant changes in their respiratory status to titrate therapy,” she noted.
Looking ahead, some areas in need of more research that might impact updates to the guidelines include “What are some areas in need of more research that might impact future updates to these guidelines? Specifics on whether initiating HFNO earlier in the course of the patient’s hypoxemic illness is better or worse, as well as the use of HFNO outside of the ICU setting,” Dr. Fincher said. “The needed monitoring of the patient to know whether their respiratory status was deteriorating and how fast would be critical along with the specific indications for titration of the HFNO.”
The evidence review was commissioned and funded by the ACP. The data come from work supported by and conducted at the Minneapolis VA Health Care System. Lead author Dr. Baldomero was supported in part by the National Institutes of Health National Center for Advancing Translational Sciences.
FROM THE ANNALS OF INTERNAL MEDICINE
FDA expands use of SLIT pollen allergy treatment to children
The Food and Drug Administration has approved a new indication for ALK’s under-the-tongue immunotherapy tablet Ragwitek (Ambrosia artemisiifolia) to treat ragweed pollen–induced hay fever in children aged 5-17 years.
Ragwitek received FDA approval in 2014 to treat short ragweed pollen–induced hay fever, with or without allergic rhinoconjunctivitis, in adults aged 18-65 years.
The approval for Ragwitek comes with a boxed warning regarding a risk for life-threatening allergic reactions associated with the immunotherapy treatment, including anaphylaxis and severe laryngopharyngeal restriction. The package insert specifies that physicians should prescribe autoinjectable epinephrine with the drug.
“Ragwitek tablets provide a new immunotherapy treatment option for children and adolescents with seasonal ragweed allergies which often causes uncomfortable nasal symptoms and red, itchy eyes during the late summer and early fall,” David I. Bernstein, MD, University of Cincinnati, Bernstein Clinical Research, said in a company press release.
Short ragweed pollen is one of the most common weed allergies. Allergic rhinitis, or hay fever, affects 10%-30% of the population worldwide, according to the American Academy of Allergy Asthma & Immunology. In the United States, approximately 7.7% of adults and 7.2% of children were diagnosed with it annually, according to the Centers for Disease Control and Prevention.
The new indication was based partly on data from a phase 3 clinical trial in children with short ragweed–induced allergic rhinitis, or hay fever, published in the Journal of Allergy and Clinical Immunology. In the study, researchers evaluated the efficacy and safety of the treatment in 1,022 participants aged 5-17 years with a history of ragweed-induced rhinoconjunctivitis and sensitivity to ragweed over a 20- to 28-week treatment period.
Researchers found that Ragwitek improved symptoms in children and adolescents and decreased their use of symptom-relieving medication, compared with placebo.
Among children and adolescents aged 5-17 years, the most common adverse reactions reported were throat irritation/tickle (48.3% in the Ragwitek group vs. 17.7% in the placebo group), itching in the mouth (47.8% vs. 11.2%), itching in the ear (33.9% vs. 6.3%), mouth pain (18.9% vs. 4.5%), swelling of the lips (13.8% vs. 1.2%), nausea (11.5% vs. 3.3%), swelling of the tongue (11.3% vs. 0.8%), throat swelling (10.7% vs. 1.6%), and stomach pain (10.1% vs. 4.5%).
The FDA also recommends that Ragwitek not be prescribed to people with severe, unstable, or uncontrolled asthma, those with a history of severe systemic allergic reactions, and those with a history of eosinophilic esophagitis. The immunotherapy treatment also may not be suitable for people who are unresponsive to epinephrine or inhaled bronchodilators.
In addition, the treatment is not approved for the immediate relief of allergic symptoms in children or adults. The once-daily treatment, which contains an extract from short ragweed pollen, should begin 12 weeks before the start of ragweed pollen season and continue throughout the season, according to the FDA.
Dr. Bernstein said that the under-the-tongue immunotherapy works by targeting the specific allergy trigger and reducing allergy symptoms by “stimulating the immune system.”
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved a new indication for ALK’s under-the-tongue immunotherapy tablet Ragwitek (Ambrosia artemisiifolia) to treat ragweed pollen–induced hay fever in children aged 5-17 years.
Ragwitek received FDA approval in 2014 to treat short ragweed pollen–induced hay fever, with or without allergic rhinoconjunctivitis, in adults aged 18-65 years.
The approval for Ragwitek comes with a boxed warning regarding a risk for life-threatening allergic reactions associated with the immunotherapy treatment, including anaphylaxis and severe laryngopharyngeal restriction. The package insert specifies that physicians should prescribe autoinjectable epinephrine with the drug.
“Ragwitek tablets provide a new immunotherapy treatment option for children and adolescents with seasonal ragweed allergies which often causes uncomfortable nasal symptoms and red, itchy eyes during the late summer and early fall,” David I. Bernstein, MD, University of Cincinnati, Bernstein Clinical Research, said in a company press release.
Short ragweed pollen is one of the most common weed allergies. Allergic rhinitis, or hay fever, affects 10%-30% of the population worldwide, according to the American Academy of Allergy Asthma & Immunology. In the United States, approximately 7.7% of adults and 7.2% of children were diagnosed with it annually, according to the Centers for Disease Control and Prevention.
The new indication was based partly on data from a phase 3 clinical trial in children with short ragweed–induced allergic rhinitis, or hay fever, published in the Journal of Allergy and Clinical Immunology. In the study, researchers evaluated the efficacy and safety of the treatment in 1,022 participants aged 5-17 years with a history of ragweed-induced rhinoconjunctivitis and sensitivity to ragweed over a 20- to 28-week treatment period.
Researchers found that Ragwitek improved symptoms in children and adolescents and decreased their use of symptom-relieving medication, compared with placebo.
Among children and adolescents aged 5-17 years, the most common adverse reactions reported were throat irritation/tickle (48.3% in the Ragwitek group vs. 17.7% in the placebo group), itching in the mouth (47.8% vs. 11.2%), itching in the ear (33.9% vs. 6.3%), mouth pain (18.9% vs. 4.5%), swelling of the lips (13.8% vs. 1.2%), nausea (11.5% vs. 3.3%), swelling of the tongue (11.3% vs. 0.8%), throat swelling (10.7% vs. 1.6%), and stomach pain (10.1% vs. 4.5%).
The FDA also recommends that Ragwitek not be prescribed to people with severe, unstable, or uncontrolled asthma, those with a history of severe systemic allergic reactions, and those with a history of eosinophilic esophagitis. The immunotherapy treatment also may not be suitable for people who are unresponsive to epinephrine or inhaled bronchodilators.
In addition, the treatment is not approved for the immediate relief of allergic symptoms in children or adults. The once-daily treatment, which contains an extract from short ragweed pollen, should begin 12 weeks before the start of ragweed pollen season and continue throughout the season, according to the FDA.
Dr. Bernstein said that the under-the-tongue immunotherapy works by targeting the specific allergy trigger and reducing allergy symptoms by “stimulating the immune system.”
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved a new indication for ALK’s under-the-tongue immunotherapy tablet Ragwitek (Ambrosia artemisiifolia) to treat ragweed pollen–induced hay fever in children aged 5-17 years.
Ragwitek received FDA approval in 2014 to treat short ragweed pollen–induced hay fever, with or without allergic rhinoconjunctivitis, in adults aged 18-65 years.
The approval for Ragwitek comes with a boxed warning regarding a risk for life-threatening allergic reactions associated with the immunotherapy treatment, including anaphylaxis and severe laryngopharyngeal restriction. The package insert specifies that physicians should prescribe autoinjectable epinephrine with the drug.
“Ragwitek tablets provide a new immunotherapy treatment option for children and adolescents with seasonal ragweed allergies which often causes uncomfortable nasal symptoms and red, itchy eyes during the late summer and early fall,” David I. Bernstein, MD, University of Cincinnati, Bernstein Clinical Research, said in a company press release.
Short ragweed pollen is one of the most common weed allergies. Allergic rhinitis, or hay fever, affects 10%-30% of the population worldwide, according to the American Academy of Allergy Asthma & Immunology. In the United States, approximately 7.7% of adults and 7.2% of children were diagnosed with it annually, according to the Centers for Disease Control and Prevention.
The new indication was based partly on data from a phase 3 clinical trial in children with short ragweed–induced allergic rhinitis, or hay fever, published in the Journal of Allergy and Clinical Immunology. In the study, researchers evaluated the efficacy and safety of the treatment in 1,022 participants aged 5-17 years with a history of ragweed-induced rhinoconjunctivitis and sensitivity to ragweed over a 20- to 28-week treatment period.
Researchers found that Ragwitek improved symptoms in children and adolescents and decreased their use of symptom-relieving medication, compared with placebo.
Among children and adolescents aged 5-17 years, the most common adverse reactions reported were throat irritation/tickle (48.3% in the Ragwitek group vs. 17.7% in the placebo group), itching in the mouth (47.8% vs. 11.2%), itching in the ear (33.9% vs. 6.3%), mouth pain (18.9% vs. 4.5%), swelling of the lips (13.8% vs. 1.2%), nausea (11.5% vs. 3.3%), swelling of the tongue (11.3% vs. 0.8%), throat swelling (10.7% vs. 1.6%), and stomach pain (10.1% vs. 4.5%).
The FDA also recommends that Ragwitek not be prescribed to people with severe, unstable, or uncontrolled asthma, those with a history of severe systemic allergic reactions, and those with a history of eosinophilic esophagitis. The immunotherapy treatment also may not be suitable for people who are unresponsive to epinephrine or inhaled bronchodilators.
In addition, the treatment is not approved for the immediate relief of allergic symptoms in children or adults. The once-daily treatment, which contains an extract from short ragweed pollen, should begin 12 weeks before the start of ragweed pollen season and continue throughout the season, according to the FDA.
Dr. Bernstein said that the under-the-tongue immunotherapy works by targeting the specific allergy trigger and reducing allergy symptoms by “stimulating the immune system.”
A version of this article first appeared on Medscape.com.
Vaccinating homebound patients is an uphill battle
There are about 2 million to 4 million homebound patients in the United States, according to a webinar from The Trust for America’s Health, which was broadcast in March. But many of these individuals have not been vaccinated yet because of logistical challenges.
Some homebound COVID-19 immunization programs are administering Moderna and Pfizer vaccines to their patients, but many state, city, and local programs administered the Johnson & Johnson vaccine after it was cleared for use by the Food and Drug Administration in February 2021. The efficacy of the one-shot vaccine, as well as it being easier to store and ship than the Moderna and Pfizer vaccines, makes getting it to homebound patients less challenging.
“With Pfizer and Moderna, transportation is a challenge because the temperature demands and the fragility of [messenger] RNA–based vaccines,” Brent Feorene, executive director of the American Academy of Home Care Medicine, said in an interview. That’s why [the Johnson & Johnson] vaccine held such promise – it’s less fragile, [can be stored in] higher temperatures, and was a one shot.”
Other hurdles to getting homebound patients vaccinated had already been in place prior to the 10-day-pause on using the J&J vaccine that occurred for federal agencies to consider possible serious side effects linked to it.
Many roadblocks to vaccination
Although many homebound patients can’t readily go out into the community and be exposed to the COVID-19 virus themselves, they are dependent on caregivers and family members who do go out into the community.
“Their friends, family, neighbors, home health aides, and other kinds of health care workers come into the home,” said Shawn Amer, clinical program director at Central Ohio Primary Care in Columbus.
Nurses from Ms. Amer’s practice vaccinated approximately ten homebound patients with the J&J vaccine through a pilot program in March. Then on April 24, nurses from Central Ohio Primary Care vaccinated just under 40 homebound patients and about a handful of their caregivers who were not able to get their vaccines elsewhere, according to Ms. Amer. This time they used the Pfizer vaccine and will be returning to these patients’ homes on May 15 to administer the second dose.
“Any time you are getting in the car and adding miles, it adds complexity,” Ms. Amer said.
“We called patients 24 to 36 hours before coming to their homes to make sure they were ready, but we learned that just because the healthcare power of attorney agrees to a patient getting vaccinated does not mean that patient will be willing to get the vaccine when the nurse shows up," she noted.
Ms. Amer elaborated that three patients with dementia refused the vaccine when nurses arrived at their home on April 24.
“We had to pivot and find other people,” Ms. Amer. Her practice ended up having to waste one shot.
Expenses are greater
The higher costs of getting homebound patients vaccinated is an additional hurdle to getting these vulnerable individuals protected by COVID-19 shots.
Vaccinating patients in their homes “doesn’t require a lot of technology, but it does require a lot of time” and the staffing expense becomes part of the challenge, Ms. Amer noted.
For each of the two days that Central Ohio Primary Care provides the Pfizer vaccine to homebound patients, the practice needs to pay seven nurses to administer the vaccine, Ms. Amer explained.
There have also been reports of organizations that administer the vaccines – which are free for patients because the federal government is paying for them – not being paid enough by Medicare to cover staff time and efforts to vaccinate patients in their homes, Kaiser Health News reported. According to the Centers for Medicare & Medicaid Services, they pay $40 for the administration of a single-dose COVID-19 vaccine and, for COVID-19 vaccines requiring multiple doses, Medicare pays approximately $40 for each dose in the series. These rates were implemented after March 15. Before that date, the rates were even lower, with the Medicare reimbursement rates for initial doses of COVID-19 vaccines being $16.94 and final doses being $28.39.
William Dombi, president of the National Association for Home Care & Hospice, told Kaiser Health News that the actual cost of these homebound visits are closer to $150 or $160.
“The reimbursement for the injection is pretty minimal,” Mr. Feorene said. “So unless you’re a larger organization and able to have staff to deploy some of your smaller practices, just couldn’t afford to do it.”
Many homebound patients have also been unable to get the lifesaving shots because of logistical roadblocks and many practices not being able to do home visits.
“I think that initially when the [Centers for Disease Control and Prevention] came out with vaccine guidance for medical providers, they offered no guidance for in-home medical providers and we had to go back and ask for that, which they did produce,” Mr. Feorene said. “And we’re grateful for that. But I think just this general understanding that there is a population of folks that are [limited to their home], that they do receive medical care and other care in the home, and that we have to remember that the medical providers who provide care in the home are also primary care providers.”
Furthermore, trying to navigate or find programs delivering vaccines to the homebound can be difficult depending on where a patient lives.
While some programs have been launched on the country or city level – the New York Fire Department launched a pilot program to bring the Johnson & Johnson vaccine to homebound seniors – other programs have been spearheaded by hospital networks like Northwell and Mount Sinai. However, many of these hospital networks only reach out to people who already have a relationship with the hospital.
Ms Amer said identifying homebound patients and reaching out to them can be tough and can contribute to the logistics and time involved in setting patients up for the vaccine.
“Reaching some of these patients is difficult,” Ms. Amer noted. “Sometimes the best way to reach them or get a hold of them is through their caregiver. And so do you have the right phone number? Do you have the right name?”
Overcoming the challenges
With the absence of a national plan targeting homebound patients, many local initiatives were launched to help these individuals get vaccinated. Local fire department paramedics have gone door to door to administer the COVID-19 vaccine in cities like Chicago, New York, and Miami. The suspension of the Johnson & Johnson vaccine resulted in the suspension of in-home vaccinations for some people in New York City. However, the program resumed after the FDA and CDC lifted the pause on April 24.
Health systems like Mount Sinai vaccinated approximately 530 people through the Mount Sinai Visiting Doctors Program, including patients and their caregivers, according to Peter Gliatto, MD, associate director of the Mount Sinai Visiting Doctors Program.
“In different cities, townships, and jurisdictions, different health departments and different provider groups are approaching [the distribution of the COVID-19 vaccine] slightly differently,” Ms. Amer said. So a lot of the decisions surrounding the distribution of shots are local or dependent on local resourcing.
People who live in rural areas present a unique challenge, but Mr. Feorene said reaching out to local emergency medical services or the local health departments can provide some insight on what their town is doing to vaccinate homebound patients.
“I think understanding what a [public health department] is doing would be the very first place to start,” Mr. Feorene said in an interview.
If a patient is bedridden and is mobile enough to sit in a car, Mr. Feorene also recommends finding out if there are vaccine fairs “within a reasonable driving distance.”
Ms. Amer said continuing this mission of getting homebound patients vaccinated is necessary for public health.
“Even if it’s going to take longer to vaccinate these homebound patients, we still have to make an effort. So much of the country’s vaccine efforts have been focused on getting as many shots in as many arms as quickly as possible. And that is definitely super important,” she said.
Ms. Amer is working with her practice’s primary care physicians to try to identify all of those patients who are functionally debilitated or unable to leave their home to get vaccinated and that Central Ohio Primary Care will vaccinate more homebound patients, she added.
The experts interviewed in this article have no conflicts.
Katie Lennon contributed to this report.
This article was updated 4/29/21.
There are about 2 million to 4 million homebound patients in the United States, according to a webinar from The Trust for America’s Health, which was broadcast in March. But many of these individuals have not been vaccinated yet because of logistical challenges.
Some homebound COVID-19 immunization programs are administering Moderna and Pfizer vaccines to their patients, but many state, city, and local programs administered the Johnson & Johnson vaccine after it was cleared for use by the Food and Drug Administration in February 2021. The efficacy of the one-shot vaccine, as well as it being easier to store and ship than the Moderna and Pfizer vaccines, makes getting it to homebound patients less challenging.
“With Pfizer and Moderna, transportation is a challenge because the temperature demands and the fragility of [messenger] RNA–based vaccines,” Brent Feorene, executive director of the American Academy of Home Care Medicine, said in an interview. That’s why [the Johnson & Johnson] vaccine held such promise – it’s less fragile, [can be stored in] higher temperatures, and was a one shot.”
Other hurdles to getting homebound patients vaccinated had already been in place prior to the 10-day-pause on using the J&J vaccine that occurred for federal agencies to consider possible serious side effects linked to it.
Many roadblocks to vaccination
Although many homebound patients can’t readily go out into the community and be exposed to the COVID-19 virus themselves, they are dependent on caregivers and family members who do go out into the community.
“Their friends, family, neighbors, home health aides, and other kinds of health care workers come into the home,” said Shawn Amer, clinical program director at Central Ohio Primary Care in Columbus.
Nurses from Ms. Amer’s practice vaccinated approximately ten homebound patients with the J&J vaccine through a pilot program in March. Then on April 24, nurses from Central Ohio Primary Care vaccinated just under 40 homebound patients and about a handful of their caregivers who were not able to get their vaccines elsewhere, according to Ms. Amer. This time they used the Pfizer vaccine and will be returning to these patients’ homes on May 15 to administer the second dose.
“Any time you are getting in the car and adding miles, it adds complexity,” Ms. Amer said.
“We called patients 24 to 36 hours before coming to their homes to make sure they were ready, but we learned that just because the healthcare power of attorney agrees to a patient getting vaccinated does not mean that patient will be willing to get the vaccine when the nurse shows up," she noted.
Ms. Amer elaborated that three patients with dementia refused the vaccine when nurses arrived at their home on April 24.
“We had to pivot and find other people,” Ms. Amer. Her practice ended up having to waste one shot.
Expenses are greater
The higher costs of getting homebound patients vaccinated is an additional hurdle to getting these vulnerable individuals protected by COVID-19 shots.
Vaccinating patients in their homes “doesn’t require a lot of technology, but it does require a lot of time” and the staffing expense becomes part of the challenge, Ms. Amer noted.
For each of the two days that Central Ohio Primary Care provides the Pfizer vaccine to homebound patients, the practice needs to pay seven nurses to administer the vaccine, Ms. Amer explained.
There have also been reports of organizations that administer the vaccines – which are free for patients because the federal government is paying for them – not being paid enough by Medicare to cover staff time and efforts to vaccinate patients in their homes, Kaiser Health News reported. According to the Centers for Medicare & Medicaid Services, they pay $40 for the administration of a single-dose COVID-19 vaccine and, for COVID-19 vaccines requiring multiple doses, Medicare pays approximately $40 for each dose in the series. These rates were implemented after March 15. Before that date, the rates were even lower, with the Medicare reimbursement rates for initial doses of COVID-19 vaccines being $16.94 and final doses being $28.39.
William Dombi, president of the National Association for Home Care & Hospice, told Kaiser Health News that the actual cost of these homebound visits are closer to $150 or $160.
“The reimbursement for the injection is pretty minimal,” Mr. Feorene said. “So unless you’re a larger organization and able to have staff to deploy some of your smaller practices, just couldn’t afford to do it.”
Many homebound patients have also been unable to get the lifesaving shots because of logistical roadblocks and many practices not being able to do home visits.
“I think that initially when the [Centers for Disease Control and Prevention] came out with vaccine guidance for medical providers, they offered no guidance for in-home medical providers and we had to go back and ask for that, which they did produce,” Mr. Feorene said. “And we’re grateful for that. But I think just this general understanding that there is a population of folks that are [limited to their home], that they do receive medical care and other care in the home, and that we have to remember that the medical providers who provide care in the home are also primary care providers.”
Furthermore, trying to navigate or find programs delivering vaccines to the homebound can be difficult depending on where a patient lives.
While some programs have been launched on the country or city level – the New York Fire Department launched a pilot program to bring the Johnson & Johnson vaccine to homebound seniors – other programs have been spearheaded by hospital networks like Northwell and Mount Sinai. However, many of these hospital networks only reach out to people who already have a relationship with the hospital.
Ms Amer said identifying homebound patients and reaching out to them can be tough and can contribute to the logistics and time involved in setting patients up for the vaccine.
“Reaching some of these patients is difficult,” Ms. Amer noted. “Sometimes the best way to reach them or get a hold of them is through their caregiver. And so do you have the right phone number? Do you have the right name?”
Overcoming the challenges
With the absence of a national plan targeting homebound patients, many local initiatives were launched to help these individuals get vaccinated. Local fire department paramedics have gone door to door to administer the COVID-19 vaccine in cities like Chicago, New York, and Miami. The suspension of the Johnson & Johnson vaccine resulted in the suspension of in-home vaccinations for some people in New York City. However, the program resumed after the FDA and CDC lifted the pause on April 24.
Health systems like Mount Sinai vaccinated approximately 530 people through the Mount Sinai Visiting Doctors Program, including patients and their caregivers, according to Peter Gliatto, MD, associate director of the Mount Sinai Visiting Doctors Program.
“In different cities, townships, and jurisdictions, different health departments and different provider groups are approaching [the distribution of the COVID-19 vaccine] slightly differently,” Ms. Amer said. So a lot of the decisions surrounding the distribution of shots are local or dependent on local resourcing.
People who live in rural areas present a unique challenge, but Mr. Feorene said reaching out to local emergency medical services or the local health departments can provide some insight on what their town is doing to vaccinate homebound patients.
“I think understanding what a [public health department] is doing would be the very first place to start,” Mr. Feorene said in an interview.
If a patient is bedridden and is mobile enough to sit in a car, Mr. Feorene also recommends finding out if there are vaccine fairs “within a reasonable driving distance.”
Ms. Amer said continuing this mission of getting homebound patients vaccinated is necessary for public health.
“Even if it’s going to take longer to vaccinate these homebound patients, we still have to make an effort. So much of the country’s vaccine efforts have been focused on getting as many shots in as many arms as quickly as possible. And that is definitely super important,” she said.
Ms. Amer is working with her practice’s primary care physicians to try to identify all of those patients who are functionally debilitated or unable to leave their home to get vaccinated and that Central Ohio Primary Care will vaccinate more homebound patients, she added.
The experts interviewed in this article have no conflicts.
Katie Lennon contributed to this report.
This article was updated 4/29/21.
There are about 2 million to 4 million homebound patients in the United States, according to a webinar from The Trust for America’s Health, which was broadcast in March. But many of these individuals have not been vaccinated yet because of logistical challenges.
Some homebound COVID-19 immunization programs are administering Moderna and Pfizer vaccines to their patients, but many state, city, and local programs administered the Johnson & Johnson vaccine after it was cleared for use by the Food and Drug Administration in February 2021. The efficacy of the one-shot vaccine, as well as it being easier to store and ship than the Moderna and Pfizer vaccines, makes getting it to homebound patients less challenging.
“With Pfizer and Moderna, transportation is a challenge because the temperature demands and the fragility of [messenger] RNA–based vaccines,” Brent Feorene, executive director of the American Academy of Home Care Medicine, said in an interview. That’s why [the Johnson & Johnson] vaccine held such promise – it’s less fragile, [can be stored in] higher temperatures, and was a one shot.”
Other hurdles to getting homebound patients vaccinated had already been in place prior to the 10-day-pause on using the J&J vaccine that occurred for federal agencies to consider possible serious side effects linked to it.
Many roadblocks to vaccination
Although many homebound patients can’t readily go out into the community and be exposed to the COVID-19 virus themselves, they are dependent on caregivers and family members who do go out into the community.
“Their friends, family, neighbors, home health aides, and other kinds of health care workers come into the home,” said Shawn Amer, clinical program director at Central Ohio Primary Care in Columbus.
Nurses from Ms. Amer’s practice vaccinated approximately ten homebound patients with the J&J vaccine through a pilot program in March. Then on April 24, nurses from Central Ohio Primary Care vaccinated just under 40 homebound patients and about a handful of their caregivers who were not able to get their vaccines elsewhere, according to Ms. Amer. This time they used the Pfizer vaccine and will be returning to these patients’ homes on May 15 to administer the second dose.
“Any time you are getting in the car and adding miles, it adds complexity,” Ms. Amer said.
“We called patients 24 to 36 hours before coming to their homes to make sure they were ready, but we learned that just because the healthcare power of attorney agrees to a patient getting vaccinated does not mean that patient will be willing to get the vaccine when the nurse shows up," she noted.
Ms. Amer elaborated that three patients with dementia refused the vaccine when nurses arrived at their home on April 24.
“We had to pivot and find other people,” Ms. Amer. Her practice ended up having to waste one shot.
Expenses are greater
The higher costs of getting homebound patients vaccinated is an additional hurdle to getting these vulnerable individuals protected by COVID-19 shots.
Vaccinating patients in their homes “doesn’t require a lot of technology, but it does require a lot of time” and the staffing expense becomes part of the challenge, Ms. Amer noted.
For each of the two days that Central Ohio Primary Care provides the Pfizer vaccine to homebound patients, the practice needs to pay seven nurses to administer the vaccine, Ms. Amer explained.
There have also been reports of organizations that administer the vaccines – which are free for patients because the federal government is paying for them – not being paid enough by Medicare to cover staff time and efforts to vaccinate patients in their homes, Kaiser Health News reported. According to the Centers for Medicare & Medicaid Services, they pay $40 for the administration of a single-dose COVID-19 vaccine and, for COVID-19 vaccines requiring multiple doses, Medicare pays approximately $40 for each dose in the series. These rates were implemented after March 15. Before that date, the rates were even lower, with the Medicare reimbursement rates for initial doses of COVID-19 vaccines being $16.94 and final doses being $28.39.
William Dombi, president of the National Association for Home Care & Hospice, told Kaiser Health News that the actual cost of these homebound visits are closer to $150 or $160.
“The reimbursement for the injection is pretty minimal,” Mr. Feorene said. “So unless you’re a larger organization and able to have staff to deploy some of your smaller practices, just couldn’t afford to do it.”
Many homebound patients have also been unable to get the lifesaving shots because of logistical roadblocks and many practices not being able to do home visits.
“I think that initially when the [Centers for Disease Control and Prevention] came out with vaccine guidance for medical providers, they offered no guidance for in-home medical providers and we had to go back and ask for that, which they did produce,” Mr. Feorene said. “And we’re grateful for that. But I think just this general understanding that there is a population of folks that are [limited to their home], that they do receive medical care and other care in the home, and that we have to remember that the medical providers who provide care in the home are also primary care providers.”
Furthermore, trying to navigate or find programs delivering vaccines to the homebound can be difficult depending on where a patient lives.
While some programs have been launched on the country or city level – the New York Fire Department launched a pilot program to bring the Johnson & Johnson vaccine to homebound seniors – other programs have been spearheaded by hospital networks like Northwell and Mount Sinai. However, many of these hospital networks only reach out to people who already have a relationship with the hospital.
Ms Amer said identifying homebound patients and reaching out to them can be tough and can contribute to the logistics and time involved in setting patients up for the vaccine.
“Reaching some of these patients is difficult,” Ms. Amer noted. “Sometimes the best way to reach them or get a hold of them is through their caregiver. And so do you have the right phone number? Do you have the right name?”
Overcoming the challenges
With the absence of a national plan targeting homebound patients, many local initiatives were launched to help these individuals get vaccinated. Local fire department paramedics have gone door to door to administer the COVID-19 vaccine in cities like Chicago, New York, and Miami. The suspension of the Johnson & Johnson vaccine resulted in the suspension of in-home vaccinations for some people in New York City. However, the program resumed after the FDA and CDC lifted the pause on April 24.
Health systems like Mount Sinai vaccinated approximately 530 people through the Mount Sinai Visiting Doctors Program, including patients and their caregivers, according to Peter Gliatto, MD, associate director of the Mount Sinai Visiting Doctors Program.
“In different cities, townships, and jurisdictions, different health departments and different provider groups are approaching [the distribution of the COVID-19 vaccine] slightly differently,” Ms. Amer said. So a lot of the decisions surrounding the distribution of shots are local or dependent on local resourcing.
People who live in rural areas present a unique challenge, but Mr. Feorene said reaching out to local emergency medical services or the local health departments can provide some insight on what their town is doing to vaccinate homebound patients.
“I think understanding what a [public health department] is doing would be the very first place to start,” Mr. Feorene said in an interview.
If a patient is bedridden and is mobile enough to sit in a car, Mr. Feorene also recommends finding out if there are vaccine fairs “within a reasonable driving distance.”
Ms. Amer said continuing this mission of getting homebound patients vaccinated is necessary for public health.
“Even if it’s going to take longer to vaccinate these homebound patients, we still have to make an effort. So much of the country’s vaccine efforts have been focused on getting as many shots in as many arms as quickly as possible. And that is definitely super important,” she said.
Ms. Amer is working with her practice’s primary care physicians to try to identify all of those patients who are functionally debilitated or unable to leave their home to get vaccinated and that Central Ohio Primary Care will vaccinate more homebound patients, she added.
The experts interviewed in this article have no conflicts.
Katie Lennon contributed to this report.
This article was updated 4/29/21.
Pneumonia risk soars in heart failure patients, especially HFpEF
Patients with heart failure get pneumonia at a rate almost three times greater than expected and, once they do get pneumonia, have about a fourfold greater risk of death, investigators for a retrospective analysis of 13,000 patients from two landmark randomized HF trials have found.
The investigators also found that HF patients with preserved ejection fraction (HFpEF) are at the highest risk of developing pneumonia. The findings underscore the importance of patients with HF getting a pneumonia vaccination, they found.
The analysis showed that 6.3% of patients in the PARADIGM-HF trial and 10.6% of those in the PARAGON-HF trial developed pneumonia, reported the study authors, led by John J.V. McMurray, MD, of the British Heart Foundation Cardiovascular Research Center at the University of Glasgow in Scotland (J Am Coll Cardiol. 2021;77:1961-73).
“The main reason for doing this study was the fact that many heart failure patients are not vaccinated, as they should be, against pneumonia – both pneumococcus and influenza vaccination,” Dr. McMurray said in an interview. “We wanted to document the frequency and consequences of pneumonia in patients with heart failure to help highlight this deficiency in care.”
Dr. McMurray said he believes this is the first study to document the incidence of pneumonia and pneumonia-related outcomes according to the two major ejection fraction phenotypes.
PARADIGM-HF and PARAGON-HF
The post hoc analysis consisted of 8,399 patients with HF with reduced ejection fraction (HFrEF) in PARADIGM-HF (Eur J Heart Fail. 2013 Sep;15[9]:1062-73) and 4,796 patients with HFpEF in PARAGON-HF (N Engl J Med. 2014 Sep 11;371[11]:993-1004). The analysis focused on the 528 and 510 patients in each study, respectively, who developed pneumonia. Those rates translated to an incidence rate of 29 per 1,000 patient-years (95% confidence interval, 27-31) in PARADIGM-HF and 39 per 1,000 patient-years (95% CI, 36-42) in PARAGON-HF.
After pneumonia, the risk of death in patients increased substantially. In PARADIGM-HF, the adjusted hazard ratio for the risk of death from any cause after pneumonia was 4.34 (95% CI, 3.73-5.05). In PARAGON-HF, it was 3.76 (95% CI, 3.09-4.58). HF patients who contracted pneumonia also tended to have HF longer than their counterparts who didn’t develop pneumonia, but the frequency of previous hospitalization for HF didn’t vary between the pneumonia and no-pneumonia groups.
Patients who developed pneumonia tended to be older (average age of 66.9 years vs. 64.6 years, P < .001) and male (83.9% vs. 77.8%, P < .001). The mean age of patients in PARADIGM-HF was almost a decade younger than those in PARAGON-HF, 64 vs. 73 years.
Pneumonia patients also had worse Kansas City Cardiomyopathy Questionnaire scores (76 vs. 80 on average), but no difference in New York Heart Association functional class. “In general, patients who developed pneumonia had more symptoms and signs and HF than those who did not develop pneumonia,” Dr. McMurray and colleagues wrote.
Pneumonia patients also had higher rates of chronic obstructive pulmonary disease (26% vs. 12%), diabetes (43% vs. 34%), and atrial fibrillation (46% vs. 36%).
Another reason for conducting the study, Dr. McMurray said, “was the prior findings in patients with coronary disease and acute myocardial infarction that the risk associated with an episode of pneumonia [e.g., in subsequent vascular events and deaths] persisted long after the acute event. We wanted to see if this was also the case for heart failure, and indeed it was.”
For example, the adjusted HR for cardiovascular death or hospitalization in the first month following an episode of pneumonia was 9.48 (range of 6.85-13.12, P < .001), leveling off to 1.59 after 3 months or more.
Vaccination crucial in HF patients
Dr. McMurray noted that this study emphasizes the importance of pneumonia vaccination for patients with HF. “Given that we have so few treatments to offer patients with HFpEF, this makes the potential value of vaccination in these patients all the greater,” he said.
The COVID-19 pandemic, Dr. McMurray said, is a “good reminder of the dangers of a respiratory infection and the importance of vaccination in these patients. COVID-19 has interesting parallels in being a systemic disease and one with postacute, persisting effects.”
The persistent risk for adverse cardiovascular events 3 months and later after pneumonia is a novel finding of the study, wrote Donna Mancini, MD, and Gregory Gibson, MD, in an invited commentary (J Am Coll Cardiol. 2021;77:1974-6). Both are with the Icahn School of Medicine at Mt. Sinai in New York. The post hoc study also “serves as an important reminder” of pneumonia risk in patients with HF, especially during the pandemic, they wrote.
“Although vaccination alone appears unlikely to be a panacea, it is a readily accessible tool for mitigating disease severity and improving outcomes,” Dr. Mancini and Dr. Gibson wrote. “After all, an ounce of prevention is worth a pound of cure.”
Novartis provided funding for the PARADIGM-HF and PARAGON-HF trials, and Dr. McMurray and coauthors disclosed financial relationships with Novartis. Dr. Mancini and Dr. Gibson have no relevant financial relationships to disclose.
Patients with heart failure get pneumonia at a rate almost three times greater than expected and, once they do get pneumonia, have about a fourfold greater risk of death, investigators for a retrospective analysis of 13,000 patients from two landmark randomized HF trials have found.
The investigators also found that HF patients with preserved ejection fraction (HFpEF) are at the highest risk of developing pneumonia. The findings underscore the importance of patients with HF getting a pneumonia vaccination, they found.
The analysis showed that 6.3% of patients in the PARADIGM-HF trial and 10.6% of those in the PARAGON-HF trial developed pneumonia, reported the study authors, led by John J.V. McMurray, MD, of the British Heart Foundation Cardiovascular Research Center at the University of Glasgow in Scotland (J Am Coll Cardiol. 2021;77:1961-73).
“The main reason for doing this study was the fact that many heart failure patients are not vaccinated, as they should be, against pneumonia – both pneumococcus and influenza vaccination,” Dr. McMurray said in an interview. “We wanted to document the frequency and consequences of pneumonia in patients with heart failure to help highlight this deficiency in care.”
Dr. McMurray said he believes this is the first study to document the incidence of pneumonia and pneumonia-related outcomes according to the two major ejection fraction phenotypes.
PARADIGM-HF and PARAGON-HF
The post hoc analysis consisted of 8,399 patients with HF with reduced ejection fraction (HFrEF) in PARADIGM-HF (Eur J Heart Fail. 2013 Sep;15[9]:1062-73) and 4,796 patients with HFpEF in PARAGON-HF (N Engl J Med. 2014 Sep 11;371[11]:993-1004). The analysis focused on the 528 and 510 patients in each study, respectively, who developed pneumonia. Those rates translated to an incidence rate of 29 per 1,000 patient-years (95% confidence interval, 27-31) in PARADIGM-HF and 39 per 1,000 patient-years (95% CI, 36-42) in PARAGON-HF.
After pneumonia, the risk of death in patients increased substantially. In PARADIGM-HF, the adjusted hazard ratio for the risk of death from any cause after pneumonia was 4.34 (95% CI, 3.73-5.05). In PARAGON-HF, it was 3.76 (95% CI, 3.09-4.58). HF patients who contracted pneumonia also tended to have HF longer than their counterparts who didn’t develop pneumonia, but the frequency of previous hospitalization for HF didn’t vary between the pneumonia and no-pneumonia groups.
Patients who developed pneumonia tended to be older (average age of 66.9 years vs. 64.6 years, P < .001) and male (83.9% vs. 77.8%, P < .001). The mean age of patients in PARADIGM-HF was almost a decade younger than those in PARAGON-HF, 64 vs. 73 years.
Pneumonia patients also had worse Kansas City Cardiomyopathy Questionnaire scores (76 vs. 80 on average), but no difference in New York Heart Association functional class. “In general, patients who developed pneumonia had more symptoms and signs and HF than those who did not develop pneumonia,” Dr. McMurray and colleagues wrote.
Pneumonia patients also had higher rates of chronic obstructive pulmonary disease (26% vs. 12%), diabetes (43% vs. 34%), and atrial fibrillation (46% vs. 36%).
Another reason for conducting the study, Dr. McMurray said, “was the prior findings in patients with coronary disease and acute myocardial infarction that the risk associated with an episode of pneumonia [e.g., in subsequent vascular events and deaths] persisted long after the acute event. We wanted to see if this was also the case for heart failure, and indeed it was.”
For example, the adjusted HR for cardiovascular death or hospitalization in the first month following an episode of pneumonia was 9.48 (range of 6.85-13.12, P < .001), leveling off to 1.59 after 3 months or more.
Vaccination crucial in HF patients
Dr. McMurray noted that this study emphasizes the importance of pneumonia vaccination for patients with HF. “Given that we have so few treatments to offer patients with HFpEF, this makes the potential value of vaccination in these patients all the greater,” he said.
The COVID-19 pandemic, Dr. McMurray said, is a “good reminder of the dangers of a respiratory infection and the importance of vaccination in these patients. COVID-19 has interesting parallels in being a systemic disease and one with postacute, persisting effects.”
The persistent risk for adverse cardiovascular events 3 months and later after pneumonia is a novel finding of the study, wrote Donna Mancini, MD, and Gregory Gibson, MD, in an invited commentary (J Am Coll Cardiol. 2021;77:1974-6). Both are with the Icahn School of Medicine at Mt. Sinai in New York. The post hoc study also “serves as an important reminder” of pneumonia risk in patients with HF, especially during the pandemic, they wrote.
“Although vaccination alone appears unlikely to be a panacea, it is a readily accessible tool for mitigating disease severity and improving outcomes,” Dr. Mancini and Dr. Gibson wrote. “After all, an ounce of prevention is worth a pound of cure.”
Novartis provided funding for the PARADIGM-HF and PARAGON-HF trials, and Dr. McMurray and coauthors disclosed financial relationships with Novartis. Dr. Mancini and Dr. Gibson have no relevant financial relationships to disclose.
Patients with heart failure get pneumonia at a rate almost three times greater than expected and, once they do get pneumonia, have about a fourfold greater risk of death, investigators for a retrospective analysis of 13,000 patients from two landmark randomized HF trials have found.
The investigators also found that HF patients with preserved ejection fraction (HFpEF) are at the highest risk of developing pneumonia. The findings underscore the importance of patients with HF getting a pneumonia vaccination, they found.
The analysis showed that 6.3% of patients in the PARADIGM-HF trial and 10.6% of those in the PARAGON-HF trial developed pneumonia, reported the study authors, led by John J.V. McMurray, MD, of the British Heart Foundation Cardiovascular Research Center at the University of Glasgow in Scotland (J Am Coll Cardiol. 2021;77:1961-73).
“The main reason for doing this study was the fact that many heart failure patients are not vaccinated, as they should be, against pneumonia – both pneumococcus and influenza vaccination,” Dr. McMurray said in an interview. “We wanted to document the frequency and consequences of pneumonia in patients with heart failure to help highlight this deficiency in care.”
Dr. McMurray said he believes this is the first study to document the incidence of pneumonia and pneumonia-related outcomes according to the two major ejection fraction phenotypes.
PARADIGM-HF and PARAGON-HF
The post hoc analysis consisted of 8,399 patients with HF with reduced ejection fraction (HFrEF) in PARADIGM-HF (Eur J Heart Fail. 2013 Sep;15[9]:1062-73) and 4,796 patients with HFpEF in PARAGON-HF (N Engl J Med. 2014 Sep 11;371[11]:993-1004). The analysis focused on the 528 and 510 patients in each study, respectively, who developed pneumonia. Those rates translated to an incidence rate of 29 per 1,000 patient-years (95% confidence interval, 27-31) in PARADIGM-HF and 39 per 1,000 patient-years (95% CI, 36-42) in PARAGON-HF.
After pneumonia, the risk of death in patients increased substantially. In PARADIGM-HF, the adjusted hazard ratio for the risk of death from any cause after pneumonia was 4.34 (95% CI, 3.73-5.05). In PARAGON-HF, it was 3.76 (95% CI, 3.09-4.58). HF patients who contracted pneumonia also tended to have HF longer than their counterparts who didn’t develop pneumonia, but the frequency of previous hospitalization for HF didn’t vary between the pneumonia and no-pneumonia groups.
Patients who developed pneumonia tended to be older (average age of 66.9 years vs. 64.6 years, P < .001) and male (83.9% vs. 77.8%, P < .001). The mean age of patients in PARADIGM-HF was almost a decade younger than those in PARAGON-HF, 64 vs. 73 years.
Pneumonia patients also had worse Kansas City Cardiomyopathy Questionnaire scores (76 vs. 80 on average), but no difference in New York Heart Association functional class. “In general, patients who developed pneumonia had more symptoms and signs and HF than those who did not develop pneumonia,” Dr. McMurray and colleagues wrote.
Pneumonia patients also had higher rates of chronic obstructive pulmonary disease (26% vs. 12%), diabetes (43% vs. 34%), and atrial fibrillation (46% vs. 36%).
Another reason for conducting the study, Dr. McMurray said, “was the prior findings in patients with coronary disease and acute myocardial infarction that the risk associated with an episode of pneumonia [e.g., in subsequent vascular events and deaths] persisted long after the acute event. We wanted to see if this was also the case for heart failure, and indeed it was.”
For example, the adjusted HR for cardiovascular death or hospitalization in the first month following an episode of pneumonia was 9.48 (range of 6.85-13.12, P < .001), leveling off to 1.59 after 3 months or more.
Vaccination crucial in HF patients
Dr. McMurray noted that this study emphasizes the importance of pneumonia vaccination for patients with HF. “Given that we have so few treatments to offer patients with HFpEF, this makes the potential value of vaccination in these patients all the greater,” he said.
The COVID-19 pandemic, Dr. McMurray said, is a “good reminder of the dangers of a respiratory infection and the importance of vaccination in these patients. COVID-19 has interesting parallels in being a systemic disease and one with postacute, persisting effects.”
The persistent risk for adverse cardiovascular events 3 months and later after pneumonia is a novel finding of the study, wrote Donna Mancini, MD, and Gregory Gibson, MD, in an invited commentary (J Am Coll Cardiol. 2021;77:1974-6). Both are with the Icahn School of Medicine at Mt. Sinai in New York. The post hoc study also “serves as an important reminder” of pneumonia risk in patients with HF, especially during the pandemic, they wrote.
“Although vaccination alone appears unlikely to be a panacea, it is a readily accessible tool for mitigating disease severity and improving outcomes,” Dr. Mancini and Dr. Gibson wrote. “After all, an ounce of prevention is worth a pound of cure.”
Novartis provided funding for the PARADIGM-HF and PARAGON-HF trials, and Dr. McMurray and coauthors disclosed financial relationships with Novartis. Dr. Mancini and Dr. Gibson have no relevant financial relationships to disclose.
FROM JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
How some COVID-19 vaccines could cause rare blood clots
on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.
This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.
According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.
On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.
In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.
“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness.
“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.
Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.
Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria.
This has experts questioning whether all vaccines of this type may cause these rare clots.
“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
Adenovirus vaccines scrutinized
Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.
Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses.
Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system.
The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.
There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.
The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.
Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans.
Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.
There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.
Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport.
But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.
The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1.
Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.
On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.
The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.
The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.
So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.
A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.
The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.
“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
Studies suggest possible mechanism
On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.
The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.
These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.
It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.
The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).
It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.
“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”
No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.
Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising.
Grappling with evidence
The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.
Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.
With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.
They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.
Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.
“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.
“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.
A version of this article first appeared on Medscape.com.
on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.
This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.
According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.
On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.
In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.
“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness.
“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.
Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.
Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria.
This has experts questioning whether all vaccines of this type may cause these rare clots.
“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
Adenovirus vaccines scrutinized
Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.
Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses.
Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system.
The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.
There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.
The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.
Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans.
Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.
There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.
Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport.
But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.
The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1.
Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.
On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.
The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.
The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.
So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.
A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.
The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.
“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
Studies suggest possible mechanism
On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.
The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.
These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.
It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.
The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).
It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.
“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”
No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.
Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising.
Grappling with evidence
The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.
Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.
With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.
They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.
Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.
“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.
“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.
A version of this article first appeared on Medscape.com.
on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.
This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.
According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.
On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.
In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.
“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness.
“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.
Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.
Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria.
This has experts questioning whether all vaccines of this type may cause these rare clots.
“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
Adenovirus vaccines scrutinized
Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.
Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses.
Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system.
The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.
There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.
The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.
Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans.
Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.
There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.
Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport.
But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.
The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1.
Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.
On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.
The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.
The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.
So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.
A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.
The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.
“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
Studies suggest possible mechanism
On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.
The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.
These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.
It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.
The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).
It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.
“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”
No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.
Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising.
Grappling with evidence
The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.
Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.
With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.
They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.
Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.
“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.
“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.
A version of this article first appeared on Medscape.com.
Sarcoidosis: An FP’s primer on an enigmatic disease
Sarcoidosis is a multisystem inflammatory disease of unclear etiology that primarily affects the lungs. It can occur at any age but usually develops before the age of 50 years, with an initial peak incidence at 20 to 29 years and a second peak incidence after 50 years of age, especially among women in Scandinavia and Japan.1 Sarcoidosis affects men and women of all racial and ethnic groups throughout the world, but differences based on race, sex, and geography are noted.1
The highest rates are reported in northern European and African-American individuals, particularly in women.1,2 The adjusted annual incidence of sarcoidosis among African Americans is approximately 3 times that among White Americans3 and is more likely to be chronic and fatal in African Americans.3 The disease can be familial with a possible recessive inheritance mode with incomplete penetrance.4 Risk of sarcoidosis in monozygotic twins appears to be 80 times greater than that in the general population, which supports genetic factors accounting for two-thirds of disease susceptibility.5
Likely factors in the development of sarcoidosis
The exact cause of sarcoidosis is unknown, but we have insights into its pathogenesis and potential triggers.1,6-9 Genes involved are being identified: class I and II human leukocyte antigen (HLA) molecules are most consistently associated with risk of sarcoidosis. Environmental exposures can activate the innate immune system and precondition a susceptible individual to react to potential causative antigens in a highly polarized, antigen-specific Th1 immune response. The epithelioid granulomatous response involves local proinflammatory cytokine production and enhanced T-cell immunity at sites of inflammation.10 Granulomas generally form to confine pathogens, restrict inflammation, and protect surrounding tissue.11-13
ACCESS (A Case Control Etiologic Study of Sarcoidosis) identified several environmental exposures such as chemicals used in the agriculture industry, mold or mildew, and musty odors at work.14 Tobacco use was not associated with sarcoidosis.14 Recent studies have shown positive associations with service in the US Navy,15 metal working,16 firefighting,17 the handling of building supplies,18 and onsite exposure while assisting in rescue efforts at the World Trade Center disaster.19 Other data support the likelihood that specific environmental exposures associated with microbe-rich environments modestly increase the risk of sarcoidosis.14 Mycobacterial and propionibacterial DNA and RNA are potentially associated with sarcoidosis.20
Clinical manifestations are nonspecific
The diagnosis of sarcoidosis can be difficult and delayed due to diverse organ involvement and nonspecific presentations. TABLE 121-31 shows the diverse manifestations in a patient with suspected sarcoidosis. Around 50% of the patients are asymptomatic.23,24 Sarcoidosis is a diagnosis of exclusion, starting with a detailed history to rule out infections, occupational or environmental exposures, malignancies, and other possible disorders (TABLE 2).22
Diagnostic work-up
Radiologic studies
Chest x-ray (CXR) provides diagnostic and prognostic information in the evaluation of sarcoidosis using the Scadding classification system (FIGURE 1).21,25,32,33 Interobserver variability, especially between stages II and III and III and IV is the major limitation of this system.32 At presentation, radiographs are abnormal in approximately 90% of patients.34 Lymphadenopathy is the most common radiographic abnormality, occurring in more than two-thirds of cases, and pulmonary opacities (nodules and reticulation) with a middle to upper lobe predilection are present in 20% to 50% of patients.1,31,35 The nodules vary in size and can coalesce and cause alveolar collapse, thus producing consolidation.36 Linear opacities radiating laterally from the hilum into the middle and upper zones are characteristic in fibrotic disease.
Continue to: High-resoluton computed tomography
High-resolution computed tomography (HRCT). Micronodules in a perilymphatic distribution with upper lobe predominance combined with subcarinal and symmetrical hilar lymph node enlargement is practically diagnostic of sarcoidosis in the right clinical context. TABLE 321,23,25,32 and FIGURE 221,23,25,32 summarize the common CT chest findings of sarcoidosis.
Advanced imaging such as (18)F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) are used in specialized settings for advanced pulmonary, cardiac, or neurosarcoidosis.
Tissue biopsy
Skin lesions (other than erythema nodosum), eye lesions, and peripheral lymph nodes are considered the safest extrapulmonary locations for biopsy.21,25 If pulmonary infiltrates or lymphadenopathy are present, or if extrapulmonary biopsy sites are not available, then flexible bronchoscopy with biopsy is the mainstay for tissue sampling.25
Bronchoalveolar lavage (BAL), transbronchial biopsy (TBB), endobronchial biopsy (EBB), and endobronchial ultrasound (EBUS) are invaluable modalities that have reduced the need for open lung biopsy. BAL in sarcoidosis can show lymphocytosis > 15% (nonspecific) and a CD4:CD8 lymphocyte ratio > 3.5 (specificity > 90%).21,22 TBB is more sensitive than EBB; however, sensitivity overall is heightened when both of them are combined. The advent of EBUS has increased the safety and efficiency of needle aspiration of mediastinal lymph nodes. Diagnostic yield of EBUS (~80%) is superior to that with TBB and EBB (~50%), especially in stage I and II sarcoidosis.37 The combination of EBUS with TBB improves the diagnostic yield to ~90%.37
The decision to obtain biopsy samples hinges on the nature of clinical and radiologic findings (FIGURE 3).22,25,26
Continue to: Laboratory studies
Laboratory studies
Multiple abnormalities may be seen in sarcoidosis, and specific lab tests may help support a diagnosis of sarcoidosis or detect organ-specific disease activity (TABLE 4).22,23,25,38 However, no consistently accurate biomarkers exist for use in clinical practice. An angiotensin-converting enzyme (ACE) level greater than 2 times the upper limit of normal may be helpful; however, sensitivity remains low, and genetic polymorphisms can influence the ACE level.25 Biomarkers sometimes used to assess disease activity are serum interleukin-2 receptor, neopterin, chitotriosidase, lysozyme, KL-6 glycoprotein, and amyloid A.21
Additional tests to assess specific features or organ involvement
Pulmonary function testing (PFT) is reviewed in detail below under “pulmonary sarcoidosis.”
Electrocardiogram (EKG)/transthoracic echocardiogram (TTE). EKG abnormalities—conduction disturbances, arrhythmias, or nonspecific ST segment and T-wave changes—are the most common nonspecific findings.30 TTE findings are also nonspecific but have value in assessing cardiac chamber size and function and myocardial involvement. TTE is indeed the most common screening modality for sarcoidosis-associated pulmonary hypertension (SAPH), which is definitively diagnosed by right heart catheterization (RHC). Further evaluation for cardiac sarcoidosis can be done with cardiac MRI or fluorodeoxyglucose PET in specialized settings.
Lumbar puncture (LP) may reveal lymphocytic infiltration in suspected neurosarcoidosis, but the finding is nonspecific and can reflect infection or malignancy. Oligoclonal bands may also be seen in about one-third of neurosarcoidosis cases, and it is imperative to rule out multiple sclerosis.28
Pulmonary sarcoidosis
Pulmonary sarcoidosis accounts for most of the morbidity, mortality, and health care use associated with sarcoidosis.39,40
Continue to: Pathology of early and advanced pulmonary sarcoidosis
Pathology of early and advanced pulmonary sarcoidosis
Sarcoidosis is characterized by coalescing, tightly clustered, nonnecrotizing granulomas in the lung (FIGURE 4), most often located along the lymphatic routes of the pleura, interlobular septa, and bronchovascular bundles.41 Granulomas contain epithelioid cells or multinucleated giant cells surrounded by a chronic lymphocytic infiltrate. Typically, intracytoplasmic inclusions, such as Schaumann bodies, asteroid bodies, and blue bodies of calcium oxalates are noted within giant cells.
In chronic disease, lymphocytic infiltrate vanishes and granulomas tend to become increasingly fibrotic and enlarge to form hyalinized nodules rich with densely eosinophilic collagen. In 10% to 30% of cases, the lungs undergo progressive fibrosis.40 Nonresolving inflammation appears to be the major cause of fibrosis and the peribronchovascular localization leading to marked bronchial distortion.
Clinical features, monitoring, and outcomes
Pulmonary involvement occurs in most patients with sarcoidosis, and subclinical pulmonary disease is generally present, even when extrathoracic manifestations predominate.23 Dry cough, dyspnea, and chest discomfort are the most common symptoms. Chest auscultation is usually unremarkable. Wheezing is more common in those with fibrosis and is attributed to airway-centric fibrosis.42 There is often a substantial delay between the onset of symptoms and the diagnosis of pulmonary sarcoidosis, as symptoms are nonspecific and might be mistaken for more common pulmonary diseases, such as asthma or chronic bronchitis.43
Since sarcoidosis can affect pulmonary parenchyma, interstitium, large and small airways, pulmonary vasculature, and respiratory muscles, the pattern of lung function impairment on PFT varies from normal to obstruction, restriction, isolated diffusion defect, or a combination of these. The typical physiologic abnormality is a restrictive ventilatory defect with a decreased diffusing capacity of the lung for carbon monoxide (DLCO). Extent of disease seen on HRCT correlates with level of restriction.44 Airway obstruction can be multifactorial and due to airway distortion (more likely to occur in fibrotic lung disease) and luminal disease.45-48 The 6-minute walk test and DLCO can also aid in the diagnosis of SAPH and advanced parenchymal lung disease.
While monitoring is done clinically and with testing (PFT and imaging) as needed, the optimal approach is unclear. Nevertheless, longitudinal monitoring with testing may provide useful management and prognostic information.40 Pulmonary function can remain stable in fibrotic sarcoidosis over extended periods and actually can improve in some patients.49 Serial spirometry, particularly forced vital capacity, is the most reliable tool for monitoring; when a decline in measurement occurs, chest radiography can elucidate the mechanism.50,51
Continue to: Because sarcoidosis is a multisystem disease...
Because sarcoidosis is a multisystem disease, caution needs to be exercised when evaluating a patient’s new or worsening respiratory symptoms to accurately determine the cause of symptoms and direct therapy accordingly. In addition to refractory inflammatory pulmonary disease, airway disease, infection, fibrosis, and SAPH, one needs to consider extrapulmonary involvement or complications such as cardiac or neurologic disease, musculoskeletal disease, depression, or fatigue. Adverse medication effects, deconditioning, or unrelated (or possibly related) disorders (eg pulmonary embolism) may be to blame.
Determining prognosis
Prognosis of sarcoidosis varies and depends on epidemiologic factors, clinical presentation, and course, as well as specific organ involvement. Patients may develop life-threatening pulmonary, cardiac, or neurologic complications. End-stage disease may require organ transplantation for eligible patients.
Most patients with pulmonary sarcoidosis experience clinical remission with minimal residual organ impairment and a favorable long-term outcome. Advanced pulmonary disease (known as APS) occurs in a small proportion of patients with sarcoidosis but accounts for most of the poor outcomes in sarcoidosis.40 APS is variably defined, but it generally includes pulmonary fibrosis, SAPH, and respiratory infection.
One percent to 5% of patients with sarcoidosis die from complications, and mortality is higher in women and African Americans.52 Mortality and morbidity may be increasing.53 The reasons behind these trends are unclear but could include true increases in disease incidence, better detection rates, greater severity of disease, or an aging population. Increased hospitalizations and health care use might be due to organ damage from granulomatous inflammation (and resultant fibrosis), complications associated with treatment, and psychosocial effects of the disease/treatment.
Management
Management consists primarily of anti-inflammatory or immunosuppressive therapies but can also include measures to address specific complications (such as fatigue) and organ transplant, as well as efforts to counter adverse medication effects. Other supportive and preventive measures may include, on a case-by-case basis, oxygen supplementation, vaccinations, or pulmonary rehabilitation. Details of these are found in other, more in-depth reviews on treatment; we will briefly review anti-inflammatory therapy, which forms the cornerstone of treatment in most patients with sarcoidosis.
Continue to: General approach to treatment decisions
General approach to treatment decisions. Anti-inflammatory therapy is used to reduce granulomatous inflammation, thereby preserving organ function and reducing symptoms. A decision to begin treatment is one shared with the patient and is based on symptoms and potential danger of organ system failure.54 Patients who are symptomatic or have progressive disease or physiologic impairment are generally candidates for treatment. Monitoring usually suffices for those who have minimal symptoms, stable disease, and preserved organ function.
Patients with pulmonary sarcoidosis at CXR stage 0 should not receive treatment, given that large, randomized trials have shown no meaningful benefit and that these patients have a high likelihood of spontaneous remission and excellent long-term prognosis.55-58 However, a subgroup of patients classified as stage 0/I on CXR may show parenchymal disease on HRCT,59 and, if more symptomatic, could be considered for treatment. For patients with stage II to IV pulmonary sarcoidosis with symptoms, there is good evidence that treatment may improve lung function and reduce dyspnea and fatigue.57,60-62
Corticosteroids are first-line treatment for most patients. Based on expert opinion, treatment of pulmonary sarcoidosis is generally started with oral prednisone (or an equivalent corticosteroid). A starting dose of 20 to 40 mg/d generally is sufficient for most patients. If the patient responds to initial treatment, prednisone dose is tapered over a period of months. If symptoms worsen during tapering, the minimum effective dose is maintained without further attempts at tapering. Treatment is continued for at least 3 to 6 months but it might be needed for longer durations; unfortunately, evidence-based guidelines are lacking.63 Once the patient goes into remission, close monitoring is done for possible relapses. Inhaled corticosteroids alone have not reduced symptoms or improved lung function in patients with pulmonary sarcoidosis.64-66
Steroid-sparing agents are added for many patients. For patients receiving chronic prednisone therapy (≥ 10 mg for > 6 months), steroid-sparing agents are considered to minimize the adverse effects of steroids or to better control the inflammatory activity of sarcoidosis. These agents must be carefully selected, and clinical and laboratory monitoring need to be done throughout therapy. TABLE 558,64,67-81
The management might be complicated for extrapulmonary, multi-organ, and advanced sarcoidosis (advanced pulmonary sarcoidosis, cardiac disease, neurosarcoidosis, lupus pernio, etc) when specialized testing, as well as a combination of corticosteroids and steroid-sparing agents (with higher doses or prolonged courses), might be needed. This should be performed at an expert sarcoidosis center, ideally in a multidisciplinary setting involving pulmonologists and/or rheumatologists, chest radiologists, and specialists as indicated, based on specific organ involvement.
Continue to: Research and future directions
Research and future directions
Key goals for research are identifying more accurate biomarkers of disease, improving diagnosis of multi-organ disease, determining validated endpoints of clinical trials in sarcoidosis, and developing treatments for refractory cases.
There is optimism and opportunity in the field of sarcoidosis overall. An example of an advancement is in the area of APS, as the severity and importance of this phenotype has been better understood. Worldwide registries and trials of pulmonary vasodilator therapy (bosentan, sildenafil, epoprostenol, and inhaled iloprost) in patients with SAPH without left ventricular dysfunction are promising.82-85 However, no benefit in survival has been shown.
RioSAPH is a double-blind, placebo-controlled trial of Riociguat (a stimulator of soluble guanylate cyclase) for SAPH (NCT02625558) that is closed to enrollment and undergoing data review. Similarly, results of the phase IV study of pirfenidone, an antifibrotic agent that was shown to decrease disease progression and deaths in idiopathic pulmonary fibrosis,86 are awaited in the near future.
Other potential directions being explored are multicenter patient registries and randomized controlled trials, analyses of existing databases, use of biobanking, and patient-centered outcome measures. Hopefully, the care of patients with sarcoidosis will become more evidence based with ongoing and upcoming research in this field.
CORRESPONDENCE
Rohit Gupta, MBBS, FCCP, 3401 North Broad Street, 7 Parkinson Pavilion, Philadelphia, PA 19140; [email protected]
1. Costabel U, Hunninghake G. ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis Statement Committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders. Eur Respir J. 1999;14:735-737.
2. Hillerdal G, Nöu E, Osterman K, et al. Sarcoidosis: epidemiology and prognosis. A 15-year European study. Am Rev Respir Dis. 1984;130:29-32.
3. Mirsaeidi M, Machado RF, Schraufnagel D, et al. Racial difference in sarcoidosis mortality in the United States. Chest. 2015;147:438-449.
4. Rybicki BA, Iannuzzi MC, Frederick MM, et al. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Resp Crit Care Med. 2001;164:2085-2091.
5. Sverrild A, Backer V, Kyvik KO, et al. Heredity in sarcoidosis:a registry-based twin study. Thorax. 2008;63:894.
6. Vuyst P, Dumortier P, Schandené L, et al. Sarcoidlike lung granulomatosis induced by aluminum dusts. Am Rev Respir Dis. 1987;135:493-497.
7. Werfel U, Schneider J, Rödelsperger K, et al. Sarcoid granulomatosis after zirconium exposure with multiple organ involvement. European Respir J. 1998;12:750.
8. Newman KL, Newman LS. Occupational causes of sarcoidosis. Curr Opin Allergy Clin Immunol. 2012;12:145-150.
9. Zissel G, Müller-Quernheim J. Specific antigen(s) in sarcoidosis:a link to autoimmunity? Eur Respir J. 2016;47:707-709.
10. Chen ES, Moller DR. Etiology of sarcoidosis. Clin Chest Med. 2008;29:365-377.
11. Agostini C, Adami F, Semenzato G. New pathogenetic insights into the sarcoid granuloma. Curr Opin Rheumatol. 2000;12:71-76.
12. Valentonyte R, Hampe J, Huse K, et al. Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet. 2005;37:357-364.
13. Rybicki BA, Walewski JL, Maliarik MJ, et al. The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites. Am J Hum Genet. 2005;77:491-499.
14. Newman LS, Rose CS, Bresnitz EA, et al. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med. 2004;170:1324-1330.
15. Gorham ED, Garland CF, Garland FC, et al. Trends and occupational associations in incidence of hospitalized pulmonary sarcoidosis and other lung diseases in Navy personnel: a 27-year historical prospective study, 1975-2001. Chest. 2004;126:1431-1438.
16. Kucera GP, Rybicki BA, Kirkey KL, et al. Occupational risk factors for sarcoidosis in African-American siblings. Chest. 2003;123:1527-1535.
17. Prezant DJ, Dhala A, Goldstein A, et al. The incidence, prevalence, and severity of sarcoidosis in New York City firefighters. Chest. 1999;116:1183-1193.
18. Barnard J, Rose C, Newman L, et al. Job and industry classifications associated with sarcoidosis in A Case–Control Etiologic Study of Sarcoidosis (ACCESS). J Occup Environ Med. 2005;47:226-234.
19. Izbicki G, Chavko R, Banauch GI, et al. World Trade Center “sarcoid-like” granulomatous pulmonary disease in New York City Fire Department rescue workers. Chest. 2007;131:1414-1423.
20. Eishi Y, Suga M, Ishige I, et al. Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol. 2002;40:198-204.
21. Valeyre D, Prasse A, Nunes H, et al. Sarcoidosis. Lancet. 2014;383:1155-1167.
22. Crouser ED, Maier LA, Wilson KC, et al. Diagnosis and detection of sarcoidosis. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;201:e26-51.
23. Judson MA, ed. Pulmonary Sarcoidosis: A Guide for the Practicing Clinician. Springer; 2014.
24. Govender P, Berman JS. The diagnosis of sarcoidosis. Clin Chest Med. 2015;36:585-602.
25. Valeyre D, Bernaudin J-F, Uzunhan Y, et al. Clinical presentation of sarcoidosis and diagnostic work-up. Semin Resp Crit Care Med. 2014;35:336-351.
26. Judson MA. The clinical features of sarcoidosis: a comprehensive review. Clin Rev Allergy Immunol. 2015;49:63-78.
27. Wanat KA, Rosenbach M. Cutaneous sarcoidosis. Clin Chest Med. 2015;36:685-702.
28. Culver DA, Neto ML, Moss BP, et al. Neurosarcoidosis. Semin Resp Crit Care Med. 2017;38:499-513.
29. Pasadhika S, Rosenbaum JT. Ocular sarcoidosis. Clin Chest Med. 2015;36:669-683.
30. Sayah DM, Bradfield JS, Moriarty JM, et al. Cardiac involvement in sarcoidosis: evolving concepts in diagnosis and treatment. Semin Resp Crit Care Med. 2017;38:477-498.
31. Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Resp Crit Care. 2012;164:1885-1889.
32. Keijsers RG, Veltkamp M, Grutters JC. Chest imaging. Clin Chest Med. 2015;36:603-619.
33. Scadding J. Prognosis of intrathoracic sarcoidosis in England. A review of 136 cases after five years’ observation. Brit Med J. 1961;2:1165-1172.
34. Miller B, Putman C. The chest radiograph and sarcoidosis. Reevaluation of the chest radiograph in assessing activity of sarcoidosis: a preliminary communication. Sarcoidosis. 1985;2:85-90.
35. Loddenkemper R, Kloppenborg A, Schoenfeld N, et al. Clinical findings in 715 patients with newly detected pulmonary sarcoidosis--results of a cooperative study in former West Germany and Switzerland. WATL Study Group. Wissenschaftliche Arbeitsgemeinschaft für die Therapie von Lungenkrankheitan. Sarcoidosis Vasc Diffuse Lung Dis. 1998;15:178-182.
36. Calandriello L, Walsh SLF. Imaging for sarcoidosis. Semin Resp Crit Care Med. 2017;38:417-436.
37. Gupta D, Dadhwal DS, Agarwal R, et al. Endobronchial ultrasound-guided transbronchial needle aspiration vs conventional transbronchial needle aspiration in the diagnosis of sarcoidosis. Chest. 2014;146:547-556.
38. Baydur A. Recent developments in the physiological assessment of sarcoidosis: clinical implications. Curr Opin Pulm Med. 2012;18:499-505.
39. Jamilloux Y, Maucort-Boulch D, Kerever S, et al. Sarcoidosis-related mortality in France: a multiple-cause-of-death analysis. Eur Respir J. 2016;48:1700-1709.
40. Gupta R, Baughman RP. Advanced pulmonary sarcoidosis. Semin Respir Crit Care Med. 2020;41:700-715.
41. Rossi G, Cavazza A, Colby TV. Pathology of sarcoidosis. Clin Rev Allergy Immunol. 2015;49:36-44.
42. Hansell D, Milne D, Wilsher M, et al. Pulmonary sarcoidosis: morphologic associations of airflow obstruction at thin-section CT. Radiology. 1998;209:697-704.
43. Judson MA, Thompson BW, Rabin DL, et al. The diagnostic pathway to sarcoidosis. Chest. 2003;123:406-412.
44. Müller NL, Mawson JB, Mathieson JR, et al. Sarcoidosis: correlation of extent of disease at CT with clinical, functional, and radiographic findings. Radiology. 1989;171:613-618.
45. Harrison BDW, Shaylor JM, Stokes TC, et al. Airflow limitation in sarcoidosis—a study of pulmonary function in 107 patients with newly diagnosed disease. Resp Med. 1991;85:59-64.
46. Polychronopoulos VS, Prakash UBS. Airway Involvement in sarcoidosis. Chest. 2009;136:1371-1380.
47. Chambellan A, Turbie P, Nunes H, et al. Endoluminal stenosis of proximal bronchi in sarcoidosis: bronchoscopy, function, and evolution. Chest. 2005;127:472-481.
48. Handa T, Nagai S, Fushimi Y, et al. Clinical and radiographic indices associated with airflow limitation in patients with sarcoidosis. Chest. 2006;130:1851-1856.
49. Nardi A, Brillet P-Y, Letoumelin P, et al. Stage IV sarcoidosis: comparison of survival with the general population and causes of death. Eur Respir J. 2011;38:1368-1373.
50. Zappala CJ, Desai SR, Copley SJ, et al. Accuracy of individual variables in the monitoring of long-term change in pulmonary sarcoidosis as judged by serial high-resolution CT scan data. Chest. 2014;145:101-107.
51. Gafà G, Sverzellati N, Bonati E, et al. Follow-up in pulmonary sarcoidosis: comparison between HRCT and pulmonary function tests. Radiol Med. 2012;117:968-978.
52. Gerke AK. Morbidity and mortality in sarcoidosis. Curr Opin Pulm Med. 2014;20:472-478.
53. Kearney GD, Obi ON, Maddipati V, et al. Sarcoidosis deaths in the United States: 1999–2016. Respir Med. 2019;149:30-35.
54. Baughman RP, Judson M, Wells A. The indications for the treatment of sarcoidosis: Wells Law. Sarcoidosis Vasc Diffuse Lung Dis. 2017;34:280-282.
55. Nagai S, Shigematsu M, Hamada K, et al. Clinical courses and prognoses of pulmonary sarcoidosis. Curr Opin Pulm Med. 1999;5:293-298.
56. Neville E, Walker AN, James DG. Prognostic factors predicting the outcome of sarcoidosis: an analysis of 818 patients. Q J Med. 1983;52:525-533.
57. Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and the Irish Thoracic Society. Thorax. 2008;63(suppl 5):v1-v58.
58. Pietinalho A, Tukiainen P, Haahtela T, et al. Oral prednisolone followed by inhaled budesonide in newly diagnosed pulmonary sarcoidosis: a double-blind, placebo-controlled multicenter study. Finnish Pulmonary Sarcoidosis Group. Chest. 1999;116:424-431.
59. Oberstein A, von Zitzewitz H, Schweden F, et al. Non invasive evaluation of the inflammatory activity in sarcoidosis with high-resolution computed tomography. Sarcoidosis Vasc Diffuse Lung Dis. 1997;14:65-72.
60. Gibson G, Prescott RJ, Muers MF, et al. British Thoracic Society Sarcoidosis study: effects of long term corticosteroid treatment. Thorax. 1996;51:238-247.
61. Baughman RP, Nunes H. Therapy for sarcoidosis: evidence-based recommendations. Expert Rev Clin Immunol. 2012;8:95-103.
62. Pietinalho A, Tukiainen P, Haahtela T, et al. Early treatment of stage II sarcoidosis improves 5-year pulmonary function. Chest. 2002;121:24-31.
63. Rahaghi FF, Baughman RP, Saketkoo LA, et al. Delphi consensus recommendations for a treatment algorithm in pulmonary sarcoidosis. Eur Respir Rev. 2020;29:190146.
64. Baughman RP, Iannuzzi MC, Lower EE, et al. Use of fluticasone in acute symptomatic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2002;19:198-204.
65. du Bois RM, Greenhalgh PM, Southcott AM, et al. Randomized trial of inhaled fluticasone propionate in chronic stable pulmonary sarcoidosis: a pilot study. Eur Respir J. 1999;13:1345-1350.
66. Milman N, Graudal N, Grode G, Munch E. No effect of high‐dose inhaled steroids in pulmonary sarcoidosis: a double‐blind, placebo‐controlled study. J Intern Med. 1994;236:285-290.
67. Baughman RP, Winget DB, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis. 2000;17:60-66.
68. Vorselaars ADM, Wuyts WA, Vorselaars VMM, et al. Methotrexate vs azathioprine in second-line therapy of sarcoidosis. Chest. 2013;144:805-812.
69. Sahoo D, Bandyopadhyay D, Xu M, et al. Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis. Eur Respir J. 2011;38:1145-1150.
70. Baughman RP, Drent M, Kavuru M, et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Resp Crit Care Med . 2006;174:795-802.
71. Rossman MD, Newman LS, Baughman RP, et al. A double-blinded, randomized, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2006;23:201-208.
72. Selroos O, Sellergren T. Corticosteroid therapy of pulmonary sarcoidosis. A prospective evaluation of alternate day and daily dosage in stage II disease. Scand J Respir Dis . 1979;60:215-221.
73. Israel HL, Fouts DW, Beggs RA. A controlled trial of prednisone treatment of sarcoidosis. Am Rev Respir Dis . 1973;107:609-614.
74. Hamzeh N, Voelker A, Forssén A, et al. Efficacy of mycophenolate mofetil in sarcoidosis. Respir Med . 2014;108:1663-1669.
75. Brill A-K, Ott SR, Geiser T. Effect and safety of mycophenolate mofetil in chronic pulmonary sarcoidosis: a retrospective study. Respiration . 2013;86:376-383.
76. Baughman RP, Lower EE. Leflunomide for chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2004;21:43-48.
77. Sweiss NJ, Noth I, Mirsaeidi M, et al. Efficacy results of a 52-week trial of adalimumab in the treatment of refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2014;31:46-54.
78. Sweiss NJ, Lower EE, Mirsaeidi M, et al. Rituximab in the treatment of refractory pulmonary sarcoidosis. Eur Respir J . 2014;43:1525-1528.
79. Thatayatikom A, Thatayatikom S, White AJ. Infliximab treatment for severe granulomatous disease in common variable immunodeficiency: a case report and review of the literature. Ann Allergy Asthma Immunol . 2005;95:293-300.
80. Drake WP, Oswald-Richter K, Richmond BW, et al. Oral antimycobacterial therapy in chronic cutaneous sarcoidosis: a randomized, single-masked, placebo-controlled study. Jama Dermatol . 2013;149:1040-1049.
81. Drake WP, Richmond BW, Oswald-Richter K, et al. Effects of broad-spectrum antimycobacterial therapy on chronic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2013;30:201-211.
82. Baughman RP, Culver DA, Cordova FC, et al. Bosentan for sarcoidosis-associated pulmonary hypertension: a double-blind placebo controlled randomized trial. Chest . 2014;145:810-817.
83. Baughman RP, Shlobin OA, Wells AU, et al. Clinical features of sarcoidosis associated pulmonary hypertension: results of a multi-national registry. Respir Med . 2018;139:72-78.
84. Fisher KA, Serlin DM, Wilson KC, et al. Sarcoidosis-associated pulmonary hypertension outcome with long-term epoprostenol treatment. Chest . 2006;130:1481-1488.
85. Baughman RP, Judson MA, Lower EE, et al. Inhaled iloprost for sarcoidosis associated pulmonary hypertension. Sarcoidosis Vasc Diffuse Lung Dis . 2009;26:110-120.
86. King TE, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med . 2014;370:2083-2092.
Sarcoidosis is a multisystem inflammatory disease of unclear etiology that primarily affects the lungs. It can occur at any age but usually develops before the age of 50 years, with an initial peak incidence at 20 to 29 years and a second peak incidence after 50 years of age, especially among women in Scandinavia and Japan.1 Sarcoidosis affects men and women of all racial and ethnic groups throughout the world, but differences based on race, sex, and geography are noted.1
The highest rates are reported in northern European and African-American individuals, particularly in women.1,2 The adjusted annual incidence of sarcoidosis among African Americans is approximately 3 times that among White Americans3 and is more likely to be chronic and fatal in African Americans.3 The disease can be familial with a possible recessive inheritance mode with incomplete penetrance.4 Risk of sarcoidosis in monozygotic twins appears to be 80 times greater than that in the general population, which supports genetic factors accounting for two-thirds of disease susceptibility.5
Likely factors in the development of sarcoidosis
The exact cause of sarcoidosis is unknown, but we have insights into its pathogenesis and potential triggers.1,6-9 Genes involved are being identified: class I and II human leukocyte antigen (HLA) molecules are most consistently associated with risk of sarcoidosis. Environmental exposures can activate the innate immune system and precondition a susceptible individual to react to potential causative antigens in a highly polarized, antigen-specific Th1 immune response. The epithelioid granulomatous response involves local proinflammatory cytokine production and enhanced T-cell immunity at sites of inflammation.10 Granulomas generally form to confine pathogens, restrict inflammation, and protect surrounding tissue.11-13
ACCESS (A Case Control Etiologic Study of Sarcoidosis) identified several environmental exposures such as chemicals used in the agriculture industry, mold or mildew, and musty odors at work.14 Tobacco use was not associated with sarcoidosis.14 Recent studies have shown positive associations with service in the US Navy,15 metal working,16 firefighting,17 the handling of building supplies,18 and onsite exposure while assisting in rescue efforts at the World Trade Center disaster.19 Other data support the likelihood that specific environmental exposures associated with microbe-rich environments modestly increase the risk of sarcoidosis.14 Mycobacterial and propionibacterial DNA and RNA are potentially associated with sarcoidosis.20
Clinical manifestations are nonspecific
The diagnosis of sarcoidosis can be difficult and delayed due to diverse organ involvement and nonspecific presentations. TABLE 121-31 shows the diverse manifestations in a patient with suspected sarcoidosis. Around 50% of the patients are asymptomatic.23,24 Sarcoidosis is a diagnosis of exclusion, starting with a detailed history to rule out infections, occupational or environmental exposures, malignancies, and other possible disorders (TABLE 2).22
Diagnostic work-up
Radiologic studies
Chest x-ray (CXR) provides diagnostic and prognostic information in the evaluation of sarcoidosis using the Scadding classification system (FIGURE 1).21,25,32,33 Interobserver variability, especially between stages II and III and III and IV is the major limitation of this system.32 At presentation, radiographs are abnormal in approximately 90% of patients.34 Lymphadenopathy is the most common radiographic abnormality, occurring in more than two-thirds of cases, and pulmonary opacities (nodules and reticulation) with a middle to upper lobe predilection are present in 20% to 50% of patients.1,31,35 The nodules vary in size and can coalesce and cause alveolar collapse, thus producing consolidation.36 Linear opacities radiating laterally from the hilum into the middle and upper zones are characteristic in fibrotic disease.
Continue to: High-resoluton computed tomography
High-resolution computed tomography (HRCT). Micronodules in a perilymphatic distribution with upper lobe predominance combined with subcarinal and symmetrical hilar lymph node enlargement is practically diagnostic of sarcoidosis in the right clinical context. TABLE 321,23,25,32 and FIGURE 221,23,25,32 summarize the common CT chest findings of sarcoidosis.
Advanced imaging such as (18)F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) are used in specialized settings for advanced pulmonary, cardiac, or neurosarcoidosis.
Tissue biopsy
Skin lesions (other than erythema nodosum), eye lesions, and peripheral lymph nodes are considered the safest extrapulmonary locations for biopsy.21,25 If pulmonary infiltrates or lymphadenopathy are present, or if extrapulmonary biopsy sites are not available, then flexible bronchoscopy with biopsy is the mainstay for tissue sampling.25
Bronchoalveolar lavage (BAL), transbronchial biopsy (TBB), endobronchial biopsy (EBB), and endobronchial ultrasound (EBUS) are invaluable modalities that have reduced the need for open lung biopsy. BAL in sarcoidosis can show lymphocytosis > 15% (nonspecific) and a CD4:CD8 lymphocyte ratio > 3.5 (specificity > 90%).21,22 TBB is more sensitive than EBB; however, sensitivity overall is heightened when both of them are combined. The advent of EBUS has increased the safety and efficiency of needle aspiration of mediastinal lymph nodes. Diagnostic yield of EBUS (~80%) is superior to that with TBB and EBB (~50%), especially in stage I and II sarcoidosis.37 The combination of EBUS with TBB improves the diagnostic yield to ~90%.37
The decision to obtain biopsy samples hinges on the nature of clinical and radiologic findings (FIGURE 3).22,25,26
Continue to: Laboratory studies
Laboratory studies
Multiple abnormalities may be seen in sarcoidosis, and specific lab tests may help support a diagnosis of sarcoidosis or detect organ-specific disease activity (TABLE 4).22,23,25,38 However, no consistently accurate biomarkers exist for use in clinical practice. An angiotensin-converting enzyme (ACE) level greater than 2 times the upper limit of normal may be helpful; however, sensitivity remains low, and genetic polymorphisms can influence the ACE level.25 Biomarkers sometimes used to assess disease activity are serum interleukin-2 receptor, neopterin, chitotriosidase, lysozyme, KL-6 glycoprotein, and amyloid A.21
Additional tests to assess specific features or organ involvement
Pulmonary function testing (PFT) is reviewed in detail below under “pulmonary sarcoidosis.”
Electrocardiogram (EKG)/transthoracic echocardiogram (TTE). EKG abnormalities—conduction disturbances, arrhythmias, or nonspecific ST segment and T-wave changes—are the most common nonspecific findings.30 TTE findings are also nonspecific but have value in assessing cardiac chamber size and function and myocardial involvement. TTE is indeed the most common screening modality for sarcoidosis-associated pulmonary hypertension (SAPH), which is definitively diagnosed by right heart catheterization (RHC). Further evaluation for cardiac sarcoidosis can be done with cardiac MRI or fluorodeoxyglucose PET in specialized settings.
Lumbar puncture (LP) may reveal lymphocytic infiltration in suspected neurosarcoidosis, but the finding is nonspecific and can reflect infection or malignancy. Oligoclonal bands may also be seen in about one-third of neurosarcoidosis cases, and it is imperative to rule out multiple sclerosis.28
Pulmonary sarcoidosis
Pulmonary sarcoidosis accounts for most of the morbidity, mortality, and health care use associated with sarcoidosis.39,40
Continue to: Pathology of early and advanced pulmonary sarcoidosis
Pathology of early and advanced pulmonary sarcoidosis
Sarcoidosis is characterized by coalescing, tightly clustered, nonnecrotizing granulomas in the lung (FIGURE 4), most often located along the lymphatic routes of the pleura, interlobular septa, and bronchovascular bundles.41 Granulomas contain epithelioid cells or multinucleated giant cells surrounded by a chronic lymphocytic infiltrate. Typically, intracytoplasmic inclusions, such as Schaumann bodies, asteroid bodies, and blue bodies of calcium oxalates are noted within giant cells.
In chronic disease, lymphocytic infiltrate vanishes and granulomas tend to become increasingly fibrotic and enlarge to form hyalinized nodules rich with densely eosinophilic collagen. In 10% to 30% of cases, the lungs undergo progressive fibrosis.40 Nonresolving inflammation appears to be the major cause of fibrosis and the peribronchovascular localization leading to marked bronchial distortion.
Clinical features, monitoring, and outcomes
Pulmonary involvement occurs in most patients with sarcoidosis, and subclinical pulmonary disease is generally present, even when extrathoracic manifestations predominate.23 Dry cough, dyspnea, and chest discomfort are the most common symptoms. Chest auscultation is usually unremarkable. Wheezing is more common in those with fibrosis and is attributed to airway-centric fibrosis.42 There is often a substantial delay between the onset of symptoms and the diagnosis of pulmonary sarcoidosis, as symptoms are nonspecific and might be mistaken for more common pulmonary diseases, such as asthma or chronic bronchitis.43
Since sarcoidosis can affect pulmonary parenchyma, interstitium, large and small airways, pulmonary vasculature, and respiratory muscles, the pattern of lung function impairment on PFT varies from normal to obstruction, restriction, isolated diffusion defect, or a combination of these. The typical physiologic abnormality is a restrictive ventilatory defect with a decreased diffusing capacity of the lung for carbon monoxide (DLCO). Extent of disease seen on HRCT correlates with level of restriction.44 Airway obstruction can be multifactorial and due to airway distortion (more likely to occur in fibrotic lung disease) and luminal disease.45-48 The 6-minute walk test and DLCO can also aid in the diagnosis of SAPH and advanced parenchymal lung disease.
While monitoring is done clinically and with testing (PFT and imaging) as needed, the optimal approach is unclear. Nevertheless, longitudinal monitoring with testing may provide useful management and prognostic information.40 Pulmonary function can remain stable in fibrotic sarcoidosis over extended periods and actually can improve in some patients.49 Serial spirometry, particularly forced vital capacity, is the most reliable tool for monitoring; when a decline in measurement occurs, chest radiography can elucidate the mechanism.50,51
Continue to: Because sarcoidosis is a multisystem disease...
Because sarcoidosis is a multisystem disease, caution needs to be exercised when evaluating a patient’s new or worsening respiratory symptoms to accurately determine the cause of symptoms and direct therapy accordingly. In addition to refractory inflammatory pulmonary disease, airway disease, infection, fibrosis, and SAPH, one needs to consider extrapulmonary involvement or complications such as cardiac or neurologic disease, musculoskeletal disease, depression, or fatigue. Adverse medication effects, deconditioning, or unrelated (or possibly related) disorders (eg pulmonary embolism) may be to blame.
Determining prognosis
Prognosis of sarcoidosis varies and depends on epidemiologic factors, clinical presentation, and course, as well as specific organ involvement. Patients may develop life-threatening pulmonary, cardiac, or neurologic complications. End-stage disease may require organ transplantation for eligible patients.
Most patients with pulmonary sarcoidosis experience clinical remission with minimal residual organ impairment and a favorable long-term outcome. Advanced pulmonary disease (known as APS) occurs in a small proportion of patients with sarcoidosis but accounts for most of the poor outcomes in sarcoidosis.40 APS is variably defined, but it generally includes pulmonary fibrosis, SAPH, and respiratory infection.
One percent to 5% of patients with sarcoidosis die from complications, and mortality is higher in women and African Americans.52 Mortality and morbidity may be increasing.53 The reasons behind these trends are unclear but could include true increases in disease incidence, better detection rates, greater severity of disease, or an aging population. Increased hospitalizations and health care use might be due to organ damage from granulomatous inflammation (and resultant fibrosis), complications associated with treatment, and psychosocial effects of the disease/treatment.
Management
Management consists primarily of anti-inflammatory or immunosuppressive therapies but can also include measures to address specific complications (such as fatigue) and organ transplant, as well as efforts to counter adverse medication effects. Other supportive and preventive measures may include, on a case-by-case basis, oxygen supplementation, vaccinations, or pulmonary rehabilitation. Details of these are found in other, more in-depth reviews on treatment; we will briefly review anti-inflammatory therapy, which forms the cornerstone of treatment in most patients with sarcoidosis.
Continue to: General approach to treatment decisions
General approach to treatment decisions. Anti-inflammatory therapy is used to reduce granulomatous inflammation, thereby preserving organ function and reducing symptoms. A decision to begin treatment is one shared with the patient and is based on symptoms and potential danger of organ system failure.54 Patients who are symptomatic or have progressive disease or physiologic impairment are generally candidates for treatment. Monitoring usually suffices for those who have minimal symptoms, stable disease, and preserved organ function.
Patients with pulmonary sarcoidosis at CXR stage 0 should not receive treatment, given that large, randomized trials have shown no meaningful benefit and that these patients have a high likelihood of spontaneous remission and excellent long-term prognosis.55-58 However, a subgroup of patients classified as stage 0/I on CXR may show parenchymal disease on HRCT,59 and, if more symptomatic, could be considered for treatment. For patients with stage II to IV pulmonary sarcoidosis with symptoms, there is good evidence that treatment may improve lung function and reduce dyspnea and fatigue.57,60-62
Corticosteroids are first-line treatment for most patients. Based on expert opinion, treatment of pulmonary sarcoidosis is generally started with oral prednisone (or an equivalent corticosteroid). A starting dose of 20 to 40 mg/d generally is sufficient for most patients. If the patient responds to initial treatment, prednisone dose is tapered over a period of months. If symptoms worsen during tapering, the minimum effective dose is maintained without further attempts at tapering. Treatment is continued for at least 3 to 6 months but it might be needed for longer durations; unfortunately, evidence-based guidelines are lacking.63 Once the patient goes into remission, close monitoring is done for possible relapses. Inhaled corticosteroids alone have not reduced symptoms or improved lung function in patients with pulmonary sarcoidosis.64-66
Steroid-sparing agents are added for many patients. For patients receiving chronic prednisone therapy (≥ 10 mg for > 6 months), steroid-sparing agents are considered to minimize the adverse effects of steroids or to better control the inflammatory activity of sarcoidosis. These agents must be carefully selected, and clinical and laboratory monitoring need to be done throughout therapy. TABLE 558,64,67-81
The management might be complicated for extrapulmonary, multi-organ, and advanced sarcoidosis (advanced pulmonary sarcoidosis, cardiac disease, neurosarcoidosis, lupus pernio, etc) when specialized testing, as well as a combination of corticosteroids and steroid-sparing agents (with higher doses or prolonged courses), might be needed. This should be performed at an expert sarcoidosis center, ideally in a multidisciplinary setting involving pulmonologists and/or rheumatologists, chest radiologists, and specialists as indicated, based on specific organ involvement.
Continue to: Research and future directions
Research and future directions
Key goals for research are identifying more accurate biomarkers of disease, improving diagnosis of multi-organ disease, determining validated endpoints of clinical trials in sarcoidosis, and developing treatments for refractory cases.
There is optimism and opportunity in the field of sarcoidosis overall. An example of an advancement is in the area of APS, as the severity and importance of this phenotype has been better understood. Worldwide registries and trials of pulmonary vasodilator therapy (bosentan, sildenafil, epoprostenol, and inhaled iloprost) in patients with SAPH without left ventricular dysfunction are promising.82-85 However, no benefit in survival has been shown.
RioSAPH is a double-blind, placebo-controlled trial of Riociguat (a stimulator of soluble guanylate cyclase) for SAPH (NCT02625558) that is closed to enrollment and undergoing data review. Similarly, results of the phase IV study of pirfenidone, an antifibrotic agent that was shown to decrease disease progression and deaths in idiopathic pulmonary fibrosis,86 are awaited in the near future.
Other potential directions being explored are multicenter patient registries and randomized controlled trials, analyses of existing databases, use of biobanking, and patient-centered outcome measures. Hopefully, the care of patients with sarcoidosis will become more evidence based with ongoing and upcoming research in this field.
CORRESPONDENCE
Rohit Gupta, MBBS, FCCP, 3401 North Broad Street, 7 Parkinson Pavilion, Philadelphia, PA 19140; [email protected]
Sarcoidosis is a multisystem inflammatory disease of unclear etiology that primarily affects the lungs. It can occur at any age but usually develops before the age of 50 years, with an initial peak incidence at 20 to 29 years and a second peak incidence after 50 years of age, especially among women in Scandinavia and Japan.1 Sarcoidosis affects men and women of all racial and ethnic groups throughout the world, but differences based on race, sex, and geography are noted.1
The highest rates are reported in northern European and African-American individuals, particularly in women.1,2 The adjusted annual incidence of sarcoidosis among African Americans is approximately 3 times that among White Americans3 and is more likely to be chronic and fatal in African Americans.3 The disease can be familial with a possible recessive inheritance mode with incomplete penetrance.4 Risk of sarcoidosis in monozygotic twins appears to be 80 times greater than that in the general population, which supports genetic factors accounting for two-thirds of disease susceptibility.5
Likely factors in the development of sarcoidosis
The exact cause of sarcoidosis is unknown, but we have insights into its pathogenesis and potential triggers.1,6-9 Genes involved are being identified: class I and II human leukocyte antigen (HLA) molecules are most consistently associated with risk of sarcoidosis. Environmental exposures can activate the innate immune system and precondition a susceptible individual to react to potential causative antigens in a highly polarized, antigen-specific Th1 immune response. The epithelioid granulomatous response involves local proinflammatory cytokine production and enhanced T-cell immunity at sites of inflammation.10 Granulomas generally form to confine pathogens, restrict inflammation, and protect surrounding tissue.11-13
ACCESS (A Case Control Etiologic Study of Sarcoidosis) identified several environmental exposures such as chemicals used in the agriculture industry, mold or mildew, and musty odors at work.14 Tobacco use was not associated with sarcoidosis.14 Recent studies have shown positive associations with service in the US Navy,15 metal working,16 firefighting,17 the handling of building supplies,18 and onsite exposure while assisting in rescue efforts at the World Trade Center disaster.19 Other data support the likelihood that specific environmental exposures associated with microbe-rich environments modestly increase the risk of sarcoidosis.14 Mycobacterial and propionibacterial DNA and RNA are potentially associated with sarcoidosis.20
Clinical manifestations are nonspecific
The diagnosis of sarcoidosis can be difficult and delayed due to diverse organ involvement and nonspecific presentations. TABLE 121-31 shows the diverse manifestations in a patient with suspected sarcoidosis. Around 50% of the patients are asymptomatic.23,24 Sarcoidosis is a diagnosis of exclusion, starting with a detailed history to rule out infections, occupational or environmental exposures, malignancies, and other possible disorders (TABLE 2).22
Diagnostic work-up
Radiologic studies
Chest x-ray (CXR) provides diagnostic and prognostic information in the evaluation of sarcoidosis using the Scadding classification system (FIGURE 1).21,25,32,33 Interobserver variability, especially between stages II and III and III and IV is the major limitation of this system.32 At presentation, radiographs are abnormal in approximately 90% of patients.34 Lymphadenopathy is the most common radiographic abnormality, occurring in more than two-thirds of cases, and pulmonary opacities (nodules and reticulation) with a middle to upper lobe predilection are present in 20% to 50% of patients.1,31,35 The nodules vary in size and can coalesce and cause alveolar collapse, thus producing consolidation.36 Linear opacities radiating laterally from the hilum into the middle and upper zones are characteristic in fibrotic disease.
Continue to: High-resoluton computed tomography
High-resolution computed tomography (HRCT). Micronodules in a perilymphatic distribution with upper lobe predominance combined with subcarinal and symmetrical hilar lymph node enlargement is practically diagnostic of sarcoidosis in the right clinical context. TABLE 321,23,25,32 and FIGURE 221,23,25,32 summarize the common CT chest findings of sarcoidosis.
Advanced imaging such as (18)F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) are used in specialized settings for advanced pulmonary, cardiac, or neurosarcoidosis.
Tissue biopsy
Skin lesions (other than erythema nodosum), eye lesions, and peripheral lymph nodes are considered the safest extrapulmonary locations for biopsy.21,25 If pulmonary infiltrates or lymphadenopathy are present, or if extrapulmonary biopsy sites are not available, then flexible bronchoscopy with biopsy is the mainstay for tissue sampling.25
Bronchoalveolar lavage (BAL), transbronchial biopsy (TBB), endobronchial biopsy (EBB), and endobronchial ultrasound (EBUS) are invaluable modalities that have reduced the need for open lung biopsy. BAL in sarcoidosis can show lymphocytosis > 15% (nonspecific) and a CD4:CD8 lymphocyte ratio > 3.5 (specificity > 90%).21,22 TBB is more sensitive than EBB; however, sensitivity overall is heightened when both of them are combined. The advent of EBUS has increased the safety and efficiency of needle aspiration of mediastinal lymph nodes. Diagnostic yield of EBUS (~80%) is superior to that with TBB and EBB (~50%), especially in stage I and II sarcoidosis.37 The combination of EBUS with TBB improves the diagnostic yield to ~90%.37
The decision to obtain biopsy samples hinges on the nature of clinical and radiologic findings (FIGURE 3).22,25,26
Continue to: Laboratory studies
Laboratory studies
Multiple abnormalities may be seen in sarcoidosis, and specific lab tests may help support a diagnosis of sarcoidosis or detect organ-specific disease activity (TABLE 4).22,23,25,38 However, no consistently accurate biomarkers exist for use in clinical practice. An angiotensin-converting enzyme (ACE) level greater than 2 times the upper limit of normal may be helpful; however, sensitivity remains low, and genetic polymorphisms can influence the ACE level.25 Biomarkers sometimes used to assess disease activity are serum interleukin-2 receptor, neopterin, chitotriosidase, lysozyme, KL-6 glycoprotein, and amyloid A.21
Additional tests to assess specific features or organ involvement
Pulmonary function testing (PFT) is reviewed in detail below under “pulmonary sarcoidosis.”
Electrocardiogram (EKG)/transthoracic echocardiogram (TTE). EKG abnormalities—conduction disturbances, arrhythmias, or nonspecific ST segment and T-wave changes—are the most common nonspecific findings.30 TTE findings are also nonspecific but have value in assessing cardiac chamber size and function and myocardial involvement. TTE is indeed the most common screening modality for sarcoidosis-associated pulmonary hypertension (SAPH), which is definitively diagnosed by right heart catheterization (RHC). Further evaluation for cardiac sarcoidosis can be done with cardiac MRI or fluorodeoxyglucose PET in specialized settings.
Lumbar puncture (LP) may reveal lymphocytic infiltration in suspected neurosarcoidosis, but the finding is nonspecific and can reflect infection or malignancy. Oligoclonal bands may also be seen in about one-third of neurosarcoidosis cases, and it is imperative to rule out multiple sclerosis.28
Pulmonary sarcoidosis
Pulmonary sarcoidosis accounts for most of the morbidity, mortality, and health care use associated with sarcoidosis.39,40
Continue to: Pathology of early and advanced pulmonary sarcoidosis
Pathology of early and advanced pulmonary sarcoidosis
Sarcoidosis is characterized by coalescing, tightly clustered, nonnecrotizing granulomas in the lung (FIGURE 4), most often located along the lymphatic routes of the pleura, interlobular septa, and bronchovascular bundles.41 Granulomas contain epithelioid cells or multinucleated giant cells surrounded by a chronic lymphocytic infiltrate. Typically, intracytoplasmic inclusions, such as Schaumann bodies, asteroid bodies, and blue bodies of calcium oxalates are noted within giant cells.
In chronic disease, lymphocytic infiltrate vanishes and granulomas tend to become increasingly fibrotic and enlarge to form hyalinized nodules rich with densely eosinophilic collagen. In 10% to 30% of cases, the lungs undergo progressive fibrosis.40 Nonresolving inflammation appears to be the major cause of fibrosis and the peribronchovascular localization leading to marked bronchial distortion.
Clinical features, monitoring, and outcomes
Pulmonary involvement occurs in most patients with sarcoidosis, and subclinical pulmonary disease is generally present, even when extrathoracic manifestations predominate.23 Dry cough, dyspnea, and chest discomfort are the most common symptoms. Chest auscultation is usually unremarkable. Wheezing is more common in those with fibrosis and is attributed to airway-centric fibrosis.42 There is often a substantial delay between the onset of symptoms and the diagnosis of pulmonary sarcoidosis, as symptoms are nonspecific and might be mistaken for more common pulmonary diseases, such as asthma or chronic bronchitis.43
Since sarcoidosis can affect pulmonary parenchyma, interstitium, large and small airways, pulmonary vasculature, and respiratory muscles, the pattern of lung function impairment on PFT varies from normal to obstruction, restriction, isolated diffusion defect, or a combination of these. The typical physiologic abnormality is a restrictive ventilatory defect with a decreased diffusing capacity of the lung for carbon monoxide (DLCO). Extent of disease seen on HRCT correlates with level of restriction.44 Airway obstruction can be multifactorial and due to airway distortion (more likely to occur in fibrotic lung disease) and luminal disease.45-48 The 6-minute walk test and DLCO can also aid in the diagnosis of SAPH and advanced parenchymal lung disease.
While monitoring is done clinically and with testing (PFT and imaging) as needed, the optimal approach is unclear. Nevertheless, longitudinal monitoring with testing may provide useful management and prognostic information.40 Pulmonary function can remain stable in fibrotic sarcoidosis over extended periods and actually can improve in some patients.49 Serial spirometry, particularly forced vital capacity, is the most reliable tool for monitoring; when a decline in measurement occurs, chest radiography can elucidate the mechanism.50,51
Continue to: Because sarcoidosis is a multisystem disease...
Because sarcoidosis is a multisystem disease, caution needs to be exercised when evaluating a patient’s new or worsening respiratory symptoms to accurately determine the cause of symptoms and direct therapy accordingly. In addition to refractory inflammatory pulmonary disease, airway disease, infection, fibrosis, and SAPH, one needs to consider extrapulmonary involvement or complications such as cardiac or neurologic disease, musculoskeletal disease, depression, or fatigue. Adverse medication effects, deconditioning, or unrelated (or possibly related) disorders (eg pulmonary embolism) may be to blame.
Determining prognosis
Prognosis of sarcoidosis varies and depends on epidemiologic factors, clinical presentation, and course, as well as specific organ involvement. Patients may develop life-threatening pulmonary, cardiac, or neurologic complications. End-stage disease may require organ transplantation for eligible patients.
Most patients with pulmonary sarcoidosis experience clinical remission with minimal residual organ impairment and a favorable long-term outcome. Advanced pulmonary disease (known as APS) occurs in a small proportion of patients with sarcoidosis but accounts for most of the poor outcomes in sarcoidosis.40 APS is variably defined, but it generally includes pulmonary fibrosis, SAPH, and respiratory infection.
One percent to 5% of patients with sarcoidosis die from complications, and mortality is higher in women and African Americans.52 Mortality and morbidity may be increasing.53 The reasons behind these trends are unclear but could include true increases in disease incidence, better detection rates, greater severity of disease, or an aging population. Increased hospitalizations and health care use might be due to organ damage from granulomatous inflammation (and resultant fibrosis), complications associated with treatment, and psychosocial effects of the disease/treatment.
Management
Management consists primarily of anti-inflammatory or immunosuppressive therapies but can also include measures to address specific complications (such as fatigue) and organ transplant, as well as efforts to counter adverse medication effects. Other supportive and preventive measures may include, on a case-by-case basis, oxygen supplementation, vaccinations, or pulmonary rehabilitation. Details of these are found in other, more in-depth reviews on treatment; we will briefly review anti-inflammatory therapy, which forms the cornerstone of treatment in most patients with sarcoidosis.
Continue to: General approach to treatment decisions
General approach to treatment decisions. Anti-inflammatory therapy is used to reduce granulomatous inflammation, thereby preserving organ function and reducing symptoms. A decision to begin treatment is one shared with the patient and is based on symptoms and potential danger of organ system failure.54 Patients who are symptomatic or have progressive disease or physiologic impairment are generally candidates for treatment. Monitoring usually suffices for those who have minimal symptoms, stable disease, and preserved organ function.
Patients with pulmonary sarcoidosis at CXR stage 0 should not receive treatment, given that large, randomized trials have shown no meaningful benefit and that these patients have a high likelihood of spontaneous remission and excellent long-term prognosis.55-58 However, a subgroup of patients classified as stage 0/I on CXR may show parenchymal disease on HRCT,59 and, if more symptomatic, could be considered for treatment. For patients with stage II to IV pulmonary sarcoidosis with symptoms, there is good evidence that treatment may improve lung function and reduce dyspnea and fatigue.57,60-62
Corticosteroids are first-line treatment for most patients. Based on expert opinion, treatment of pulmonary sarcoidosis is generally started with oral prednisone (or an equivalent corticosteroid). A starting dose of 20 to 40 mg/d generally is sufficient for most patients. If the patient responds to initial treatment, prednisone dose is tapered over a period of months. If symptoms worsen during tapering, the minimum effective dose is maintained without further attempts at tapering. Treatment is continued for at least 3 to 6 months but it might be needed for longer durations; unfortunately, evidence-based guidelines are lacking.63 Once the patient goes into remission, close monitoring is done for possible relapses. Inhaled corticosteroids alone have not reduced symptoms or improved lung function in patients with pulmonary sarcoidosis.64-66
Steroid-sparing agents are added for many patients. For patients receiving chronic prednisone therapy (≥ 10 mg for > 6 months), steroid-sparing agents are considered to minimize the adverse effects of steroids or to better control the inflammatory activity of sarcoidosis. These agents must be carefully selected, and clinical and laboratory monitoring need to be done throughout therapy. TABLE 558,64,67-81
The management might be complicated for extrapulmonary, multi-organ, and advanced sarcoidosis (advanced pulmonary sarcoidosis, cardiac disease, neurosarcoidosis, lupus pernio, etc) when specialized testing, as well as a combination of corticosteroids and steroid-sparing agents (with higher doses or prolonged courses), might be needed. This should be performed at an expert sarcoidosis center, ideally in a multidisciplinary setting involving pulmonologists and/or rheumatologists, chest radiologists, and specialists as indicated, based on specific organ involvement.
Continue to: Research and future directions
Research and future directions
Key goals for research are identifying more accurate biomarkers of disease, improving diagnosis of multi-organ disease, determining validated endpoints of clinical trials in sarcoidosis, and developing treatments for refractory cases.
There is optimism and opportunity in the field of sarcoidosis overall. An example of an advancement is in the area of APS, as the severity and importance of this phenotype has been better understood. Worldwide registries and trials of pulmonary vasodilator therapy (bosentan, sildenafil, epoprostenol, and inhaled iloprost) in patients with SAPH without left ventricular dysfunction are promising.82-85 However, no benefit in survival has been shown.
RioSAPH is a double-blind, placebo-controlled trial of Riociguat (a stimulator of soluble guanylate cyclase) for SAPH (NCT02625558) that is closed to enrollment and undergoing data review. Similarly, results of the phase IV study of pirfenidone, an antifibrotic agent that was shown to decrease disease progression and deaths in idiopathic pulmonary fibrosis,86 are awaited in the near future.
Other potential directions being explored are multicenter patient registries and randomized controlled trials, analyses of existing databases, use of biobanking, and patient-centered outcome measures. Hopefully, the care of patients with sarcoidosis will become more evidence based with ongoing and upcoming research in this field.
CORRESPONDENCE
Rohit Gupta, MBBS, FCCP, 3401 North Broad Street, 7 Parkinson Pavilion, Philadelphia, PA 19140; [email protected]
1. Costabel U, Hunninghake G. ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis Statement Committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders. Eur Respir J. 1999;14:735-737.
2. Hillerdal G, Nöu E, Osterman K, et al. Sarcoidosis: epidemiology and prognosis. A 15-year European study. Am Rev Respir Dis. 1984;130:29-32.
3. Mirsaeidi M, Machado RF, Schraufnagel D, et al. Racial difference in sarcoidosis mortality in the United States. Chest. 2015;147:438-449.
4. Rybicki BA, Iannuzzi MC, Frederick MM, et al. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Resp Crit Care Med. 2001;164:2085-2091.
5. Sverrild A, Backer V, Kyvik KO, et al. Heredity in sarcoidosis:a registry-based twin study. Thorax. 2008;63:894.
6. Vuyst P, Dumortier P, Schandené L, et al. Sarcoidlike lung granulomatosis induced by aluminum dusts. Am Rev Respir Dis. 1987;135:493-497.
7. Werfel U, Schneider J, Rödelsperger K, et al. Sarcoid granulomatosis after zirconium exposure with multiple organ involvement. European Respir J. 1998;12:750.
8. Newman KL, Newman LS. Occupational causes of sarcoidosis. Curr Opin Allergy Clin Immunol. 2012;12:145-150.
9. Zissel G, Müller-Quernheim J. Specific antigen(s) in sarcoidosis:a link to autoimmunity? Eur Respir J. 2016;47:707-709.
10. Chen ES, Moller DR. Etiology of sarcoidosis. Clin Chest Med. 2008;29:365-377.
11. Agostini C, Adami F, Semenzato G. New pathogenetic insights into the sarcoid granuloma. Curr Opin Rheumatol. 2000;12:71-76.
12. Valentonyte R, Hampe J, Huse K, et al. Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet. 2005;37:357-364.
13. Rybicki BA, Walewski JL, Maliarik MJ, et al. The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites. Am J Hum Genet. 2005;77:491-499.
14. Newman LS, Rose CS, Bresnitz EA, et al. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med. 2004;170:1324-1330.
15. Gorham ED, Garland CF, Garland FC, et al. Trends and occupational associations in incidence of hospitalized pulmonary sarcoidosis and other lung diseases in Navy personnel: a 27-year historical prospective study, 1975-2001. Chest. 2004;126:1431-1438.
16. Kucera GP, Rybicki BA, Kirkey KL, et al. Occupational risk factors for sarcoidosis in African-American siblings. Chest. 2003;123:1527-1535.
17. Prezant DJ, Dhala A, Goldstein A, et al. The incidence, prevalence, and severity of sarcoidosis in New York City firefighters. Chest. 1999;116:1183-1193.
18. Barnard J, Rose C, Newman L, et al. Job and industry classifications associated with sarcoidosis in A Case–Control Etiologic Study of Sarcoidosis (ACCESS). J Occup Environ Med. 2005;47:226-234.
19. Izbicki G, Chavko R, Banauch GI, et al. World Trade Center “sarcoid-like” granulomatous pulmonary disease in New York City Fire Department rescue workers. Chest. 2007;131:1414-1423.
20. Eishi Y, Suga M, Ishige I, et al. Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol. 2002;40:198-204.
21. Valeyre D, Prasse A, Nunes H, et al. Sarcoidosis. Lancet. 2014;383:1155-1167.
22. Crouser ED, Maier LA, Wilson KC, et al. Diagnosis and detection of sarcoidosis. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;201:e26-51.
23. Judson MA, ed. Pulmonary Sarcoidosis: A Guide for the Practicing Clinician. Springer; 2014.
24. Govender P, Berman JS. The diagnosis of sarcoidosis. Clin Chest Med. 2015;36:585-602.
25. Valeyre D, Bernaudin J-F, Uzunhan Y, et al. Clinical presentation of sarcoidosis and diagnostic work-up. Semin Resp Crit Care Med. 2014;35:336-351.
26. Judson MA. The clinical features of sarcoidosis: a comprehensive review. Clin Rev Allergy Immunol. 2015;49:63-78.
27. Wanat KA, Rosenbach M. Cutaneous sarcoidosis. Clin Chest Med. 2015;36:685-702.
28. Culver DA, Neto ML, Moss BP, et al. Neurosarcoidosis. Semin Resp Crit Care Med. 2017;38:499-513.
29. Pasadhika S, Rosenbaum JT. Ocular sarcoidosis. Clin Chest Med. 2015;36:669-683.
30. Sayah DM, Bradfield JS, Moriarty JM, et al. Cardiac involvement in sarcoidosis: evolving concepts in diagnosis and treatment. Semin Resp Crit Care Med. 2017;38:477-498.
31. Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Resp Crit Care. 2012;164:1885-1889.
32. Keijsers RG, Veltkamp M, Grutters JC. Chest imaging. Clin Chest Med. 2015;36:603-619.
33. Scadding J. Prognosis of intrathoracic sarcoidosis in England. A review of 136 cases after five years’ observation. Brit Med J. 1961;2:1165-1172.
34. Miller B, Putman C. The chest radiograph and sarcoidosis. Reevaluation of the chest radiograph in assessing activity of sarcoidosis: a preliminary communication. Sarcoidosis. 1985;2:85-90.
35. Loddenkemper R, Kloppenborg A, Schoenfeld N, et al. Clinical findings in 715 patients with newly detected pulmonary sarcoidosis--results of a cooperative study in former West Germany and Switzerland. WATL Study Group. Wissenschaftliche Arbeitsgemeinschaft für die Therapie von Lungenkrankheitan. Sarcoidosis Vasc Diffuse Lung Dis. 1998;15:178-182.
36. Calandriello L, Walsh SLF. Imaging for sarcoidosis. Semin Resp Crit Care Med. 2017;38:417-436.
37. Gupta D, Dadhwal DS, Agarwal R, et al. Endobronchial ultrasound-guided transbronchial needle aspiration vs conventional transbronchial needle aspiration in the diagnosis of sarcoidosis. Chest. 2014;146:547-556.
38. Baydur A. Recent developments in the physiological assessment of sarcoidosis: clinical implications. Curr Opin Pulm Med. 2012;18:499-505.
39. Jamilloux Y, Maucort-Boulch D, Kerever S, et al. Sarcoidosis-related mortality in France: a multiple-cause-of-death analysis. Eur Respir J. 2016;48:1700-1709.
40. Gupta R, Baughman RP. Advanced pulmonary sarcoidosis. Semin Respir Crit Care Med. 2020;41:700-715.
41. Rossi G, Cavazza A, Colby TV. Pathology of sarcoidosis. Clin Rev Allergy Immunol. 2015;49:36-44.
42. Hansell D, Milne D, Wilsher M, et al. Pulmonary sarcoidosis: morphologic associations of airflow obstruction at thin-section CT. Radiology. 1998;209:697-704.
43. Judson MA, Thompson BW, Rabin DL, et al. The diagnostic pathway to sarcoidosis. Chest. 2003;123:406-412.
44. Müller NL, Mawson JB, Mathieson JR, et al. Sarcoidosis: correlation of extent of disease at CT with clinical, functional, and radiographic findings. Radiology. 1989;171:613-618.
45. Harrison BDW, Shaylor JM, Stokes TC, et al. Airflow limitation in sarcoidosis—a study of pulmonary function in 107 patients with newly diagnosed disease. Resp Med. 1991;85:59-64.
46. Polychronopoulos VS, Prakash UBS. Airway Involvement in sarcoidosis. Chest. 2009;136:1371-1380.
47. Chambellan A, Turbie P, Nunes H, et al. Endoluminal stenosis of proximal bronchi in sarcoidosis: bronchoscopy, function, and evolution. Chest. 2005;127:472-481.
48. Handa T, Nagai S, Fushimi Y, et al. Clinical and radiographic indices associated with airflow limitation in patients with sarcoidosis. Chest. 2006;130:1851-1856.
49. Nardi A, Brillet P-Y, Letoumelin P, et al. Stage IV sarcoidosis: comparison of survival with the general population and causes of death. Eur Respir J. 2011;38:1368-1373.
50. Zappala CJ, Desai SR, Copley SJ, et al. Accuracy of individual variables in the monitoring of long-term change in pulmonary sarcoidosis as judged by serial high-resolution CT scan data. Chest. 2014;145:101-107.
51. Gafà G, Sverzellati N, Bonati E, et al. Follow-up in pulmonary sarcoidosis: comparison between HRCT and pulmonary function tests. Radiol Med. 2012;117:968-978.
52. Gerke AK. Morbidity and mortality in sarcoidosis. Curr Opin Pulm Med. 2014;20:472-478.
53. Kearney GD, Obi ON, Maddipati V, et al. Sarcoidosis deaths in the United States: 1999–2016. Respir Med. 2019;149:30-35.
54. Baughman RP, Judson M, Wells A. The indications for the treatment of sarcoidosis: Wells Law. Sarcoidosis Vasc Diffuse Lung Dis. 2017;34:280-282.
55. Nagai S, Shigematsu M, Hamada K, et al. Clinical courses and prognoses of pulmonary sarcoidosis. Curr Opin Pulm Med. 1999;5:293-298.
56. Neville E, Walker AN, James DG. Prognostic factors predicting the outcome of sarcoidosis: an analysis of 818 patients. Q J Med. 1983;52:525-533.
57. Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and the Irish Thoracic Society. Thorax. 2008;63(suppl 5):v1-v58.
58. Pietinalho A, Tukiainen P, Haahtela T, et al. Oral prednisolone followed by inhaled budesonide in newly diagnosed pulmonary sarcoidosis: a double-blind, placebo-controlled multicenter study. Finnish Pulmonary Sarcoidosis Group. Chest. 1999;116:424-431.
59. Oberstein A, von Zitzewitz H, Schweden F, et al. Non invasive evaluation of the inflammatory activity in sarcoidosis with high-resolution computed tomography. Sarcoidosis Vasc Diffuse Lung Dis. 1997;14:65-72.
60. Gibson G, Prescott RJ, Muers MF, et al. British Thoracic Society Sarcoidosis study: effects of long term corticosteroid treatment. Thorax. 1996;51:238-247.
61. Baughman RP, Nunes H. Therapy for sarcoidosis: evidence-based recommendations. Expert Rev Clin Immunol. 2012;8:95-103.
62. Pietinalho A, Tukiainen P, Haahtela T, et al. Early treatment of stage II sarcoidosis improves 5-year pulmonary function. Chest. 2002;121:24-31.
63. Rahaghi FF, Baughman RP, Saketkoo LA, et al. Delphi consensus recommendations for a treatment algorithm in pulmonary sarcoidosis. Eur Respir Rev. 2020;29:190146.
64. Baughman RP, Iannuzzi MC, Lower EE, et al. Use of fluticasone in acute symptomatic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2002;19:198-204.
65. du Bois RM, Greenhalgh PM, Southcott AM, et al. Randomized trial of inhaled fluticasone propionate in chronic stable pulmonary sarcoidosis: a pilot study. Eur Respir J. 1999;13:1345-1350.
66. Milman N, Graudal N, Grode G, Munch E. No effect of high‐dose inhaled steroids in pulmonary sarcoidosis: a double‐blind, placebo‐controlled study. J Intern Med. 1994;236:285-290.
67. Baughman RP, Winget DB, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis. 2000;17:60-66.
68. Vorselaars ADM, Wuyts WA, Vorselaars VMM, et al. Methotrexate vs azathioprine in second-line therapy of sarcoidosis. Chest. 2013;144:805-812.
69. Sahoo D, Bandyopadhyay D, Xu M, et al. Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis. Eur Respir J. 2011;38:1145-1150.
70. Baughman RP, Drent M, Kavuru M, et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Resp Crit Care Med . 2006;174:795-802.
71. Rossman MD, Newman LS, Baughman RP, et al. A double-blinded, randomized, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2006;23:201-208.
72. Selroos O, Sellergren T. Corticosteroid therapy of pulmonary sarcoidosis. A prospective evaluation of alternate day and daily dosage in stage II disease. Scand J Respir Dis . 1979;60:215-221.
73. Israel HL, Fouts DW, Beggs RA. A controlled trial of prednisone treatment of sarcoidosis. Am Rev Respir Dis . 1973;107:609-614.
74. Hamzeh N, Voelker A, Forssén A, et al. Efficacy of mycophenolate mofetil in sarcoidosis. Respir Med . 2014;108:1663-1669.
75. Brill A-K, Ott SR, Geiser T. Effect and safety of mycophenolate mofetil in chronic pulmonary sarcoidosis: a retrospective study. Respiration . 2013;86:376-383.
76. Baughman RP, Lower EE. Leflunomide for chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2004;21:43-48.
77. Sweiss NJ, Noth I, Mirsaeidi M, et al. Efficacy results of a 52-week trial of adalimumab in the treatment of refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2014;31:46-54.
78. Sweiss NJ, Lower EE, Mirsaeidi M, et al. Rituximab in the treatment of refractory pulmonary sarcoidosis. Eur Respir J . 2014;43:1525-1528.
79. Thatayatikom A, Thatayatikom S, White AJ. Infliximab treatment for severe granulomatous disease in common variable immunodeficiency: a case report and review of the literature. Ann Allergy Asthma Immunol . 2005;95:293-300.
80. Drake WP, Oswald-Richter K, Richmond BW, et al. Oral antimycobacterial therapy in chronic cutaneous sarcoidosis: a randomized, single-masked, placebo-controlled study. Jama Dermatol . 2013;149:1040-1049.
81. Drake WP, Richmond BW, Oswald-Richter K, et al. Effects of broad-spectrum antimycobacterial therapy on chronic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2013;30:201-211.
82. Baughman RP, Culver DA, Cordova FC, et al. Bosentan for sarcoidosis-associated pulmonary hypertension: a double-blind placebo controlled randomized trial. Chest . 2014;145:810-817.
83. Baughman RP, Shlobin OA, Wells AU, et al. Clinical features of sarcoidosis associated pulmonary hypertension: results of a multi-national registry. Respir Med . 2018;139:72-78.
84. Fisher KA, Serlin DM, Wilson KC, et al. Sarcoidosis-associated pulmonary hypertension outcome with long-term epoprostenol treatment. Chest . 2006;130:1481-1488.
85. Baughman RP, Judson MA, Lower EE, et al. Inhaled iloprost for sarcoidosis associated pulmonary hypertension. Sarcoidosis Vasc Diffuse Lung Dis . 2009;26:110-120.
86. King TE, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med . 2014;370:2083-2092.
1. Costabel U, Hunninghake G. ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis Statement Committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders. Eur Respir J. 1999;14:735-737.
2. Hillerdal G, Nöu E, Osterman K, et al. Sarcoidosis: epidemiology and prognosis. A 15-year European study. Am Rev Respir Dis. 1984;130:29-32.
3. Mirsaeidi M, Machado RF, Schraufnagel D, et al. Racial difference in sarcoidosis mortality in the United States. Chest. 2015;147:438-449.
4. Rybicki BA, Iannuzzi MC, Frederick MM, et al. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Resp Crit Care Med. 2001;164:2085-2091.
5. Sverrild A, Backer V, Kyvik KO, et al. Heredity in sarcoidosis:a registry-based twin study. Thorax. 2008;63:894.
6. Vuyst P, Dumortier P, Schandené L, et al. Sarcoidlike lung granulomatosis induced by aluminum dusts. Am Rev Respir Dis. 1987;135:493-497.
7. Werfel U, Schneider J, Rödelsperger K, et al. Sarcoid granulomatosis after zirconium exposure with multiple organ involvement. European Respir J. 1998;12:750.
8. Newman KL, Newman LS. Occupational causes of sarcoidosis. Curr Opin Allergy Clin Immunol. 2012;12:145-150.
9. Zissel G, Müller-Quernheim J. Specific antigen(s) in sarcoidosis:a link to autoimmunity? Eur Respir J. 2016;47:707-709.
10. Chen ES, Moller DR. Etiology of sarcoidosis. Clin Chest Med. 2008;29:365-377.
11. Agostini C, Adami F, Semenzato G. New pathogenetic insights into the sarcoid granuloma. Curr Opin Rheumatol. 2000;12:71-76.
12. Valentonyte R, Hampe J, Huse K, et al. Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet. 2005;37:357-364.
13. Rybicki BA, Walewski JL, Maliarik MJ, et al. The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites. Am J Hum Genet. 2005;77:491-499.
14. Newman LS, Rose CS, Bresnitz EA, et al. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med. 2004;170:1324-1330.
15. Gorham ED, Garland CF, Garland FC, et al. Trends and occupational associations in incidence of hospitalized pulmonary sarcoidosis and other lung diseases in Navy personnel: a 27-year historical prospective study, 1975-2001. Chest. 2004;126:1431-1438.
16. Kucera GP, Rybicki BA, Kirkey KL, et al. Occupational risk factors for sarcoidosis in African-American siblings. Chest. 2003;123:1527-1535.
17. Prezant DJ, Dhala A, Goldstein A, et al. The incidence, prevalence, and severity of sarcoidosis in New York City firefighters. Chest. 1999;116:1183-1193.
18. Barnard J, Rose C, Newman L, et al. Job and industry classifications associated with sarcoidosis in A Case–Control Etiologic Study of Sarcoidosis (ACCESS). J Occup Environ Med. 2005;47:226-234.
19. Izbicki G, Chavko R, Banauch GI, et al. World Trade Center “sarcoid-like” granulomatous pulmonary disease in New York City Fire Department rescue workers. Chest. 2007;131:1414-1423.
20. Eishi Y, Suga M, Ishige I, et al. Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol. 2002;40:198-204.
21. Valeyre D, Prasse A, Nunes H, et al. Sarcoidosis. Lancet. 2014;383:1155-1167.
22. Crouser ED, Maier LA, Wilson KC, et al. Diagnosis and detection of sarcoidosis. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;201:e26-51.
23. Judson MA, ed. Pulmonary Sarcoidosis: A Guide for the Practicing Clinician. Springer; 2014.
24. Govender P, Berman JS. The diagnosis of sarcoidosis. Clin Chest Med. 2015;36:585-602.
25. Valeyre D, Bernaudin J-F, Uzunhan Y, et al. Clinical presentation of sarcoidosis and diagnostic work-up. Semin Resp Crit Care Med. 2014;35:336-351.
26. Judson MA. The clinical features of sarcoidosis: a comprehensive review. Clin Rev Allergy Immunol. 2015;49:63-78.
27. Wanat KA, Rosenbach M. Cutaneous sarcoidosis. Clin Chest Med. 2015;36:685-702.
28. Culver DA, Neto ML, Moss BP, et al. Neurosarcoidosis. Semin Resp Crit Care Med. 2017;38:499-513.
29. Pasadhika S, Rosenbaum JT. Ocular sarcoidosis. Clin Chest Med. 2015;36:669-683.
30. Sayah DM, Bradfield JS, Moriarty JM, et al. Cardiac involvement in sarcoidosis: evolving concepts in diagnosis and treatment. Semin Resp Crit Care Med. 2017;38:477-498.
31. Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Resp Crit Care. 2012;164:1885-1889.
32. Keijsers RG, Veltkamp M, Grutters JC. Chest imaging. Clin Chest Med. 2015;36:603-619.
33. Scadding J. Prognosis of intrathoracic sarcoidosis in England. A review of 136 cases after five years’ observation. Brit Med J. 1961;2:1165-1172.
34. Miller B, Putman C. The chest radiograph and sarcoidosis. Reevaluation of the chest radiograph in assessing activity of sarcoidosis: a preliminary communication. Sarcoidosis. 1985;2:85-90.
35. Loddenkemper R, Kloppenborg A, Schoenfeld N, et al. Clinical findings in 715 patients with newly detected pulmonary sarcoidosis--results of a cooperative study in former West Germany and Switzerland. WATL Study Group. Wissenschaftliche Arbeitsgemeinschaft für die Therapie von Lungenkrankheitan. Sarcoidosis Vasc Diffuse Lung Dis. 1998;15:178-182.
36. Calandriello L, Walsh SLF. Imaging for sarcoidosis. Semin Resp Crit Care Med. 2017;38:417-436.
37. Gupta D, Dadhwal DS, Agarwal R, et al. Endobronchial ultrasound-guided transbronchial needle aspiration vs conventional transbronchial needle aspiration in the diagnosis of sarcoidosis. Chest. 2014;146:547-556.
38. Baydur A. Recent developments in the physiological assessment of sarcoidosis: clinical implications. Curr Opin Pulm Med. 2012;18:499-505.
39. Jamilloux Y, Maucort-Boulch D, Kerever S, et al. Sarcoidosis-related mortality in France: a multiple-cause-of-death analysis. Eur Respir J. 2016;48:1700-1709.
40. Gupta R, Baughman RP. Advanced pulmonary sarcoidosis. Semin Respir Crit Care Med. 2020;41:700-715.
41. Rossi G, Cavazza A, Colby TV. Pathology of sarcoidosis. Clin Rev Allergy Immunol. 2015;49:36-44.
42. Hansell D, Milne D, Wilsher M, et al. Pulmonary sarcoidosis: morphologic associations of airflow obstruction at thin-section CT. Radiology. 1998;209:697-704.
43. Judson MA, Thompson BW, Rabin DL, et al. The diagnostic pathway to sarcoidosis. Chest. 2003;123:406-412.
44. Müller NL, Mawson JB, Mathieson JR, et al. Sarcoidosis: correlation of extent of disease at CT with clinical, functional, and radiographic findings. Radiology. 1989;171:613-618.
45. Harrison BDW, Shaylor JM, Stokes TC, et al. Airflow limitation in sarcoidosis—a study of pulmonary function in 107 patients with newly diagnosed disease. Resp Med. 1991;85:59-64.
46. Polychronopoulos VS, Prakash UBS. Airway Involvement in sarcoidosis. Chest. 2009;136:1371-1380.
47. Chambellan A, Turbie P, Nunes H, et al. Endoluminal stenosis of proximal bronchi in sarcoidosis: bronchoscopy, function, and evolution. Chest. 2005;127:472-481.
48. Handa T, Nagai S, Fushimi Y, et al. Clinical and radiographic indices associated with airflow limitation in patients with sarcoidosis. Chest. 2006;130:1851-1856.
49. Nardi A, Brillet P-Y, Letoumelin P, et al. Stage IV sarcoidosis: comparison of survival with the general population and causes of death. Eur Respir J. 2011;38:1368-1373.
50. Zappala CJ, Desai SR, Copley SJ, et al. Accuracy of individual variables in the monitoring of long-term change in pulmonary sarcoidosis as judged by serial high-resolution CT scan data. Chest. 2014;145:101-107.
51. Gafà G, Sverzellati N, Bonati E, et al. Follow-up in pulmonary sarcoidosis: comparison between HRCT and pulmonary function tests. Radiol Med. 2012;117:968-978.
52. Gerke AK. Morbidity and mortality in sarcoidosis. Curr Opin Pulm Med. 2014;20:472-478.
53. Kearney GD, Obi ON, Maddipati V, et al. Sarcoidosis deaths in the United States: 1999–2016. Respir Med. 2019;149:30-35.
54. Baughman RP, Judson M, Wells A. The indications for the treatment of sarcoidosis: Wells Law. Sarcoidosis Vasc Diffuse Lung Dis. 2017;34:280-282.
55. Nagai S, Shigematsu M, Hamada K, et al. Clinical courses and prognoses of pulmonary sarcoidosis. Curr Opin Pulm Med. 1999;5:293-298.
56. Neville E, Walker AN, James DG. Prognostic factors predicting the outcome of sarcoidosis: an analysis of 818 patients. Q J Med. 1983;52:525-533.
57. Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and the Irish Thoracic Society. Thorax. 2008;63(suppl 5):v1-v58.
58. Pietinalho A, Tukiainen P, Haahtela T, et al. Oral prednisolone followed by inhaled budesonide in newly diagnosed pulmonary sarcoidosis: a double-blind, placebo-controlled multicenter study. Finnish Pulmonary Sarcoidosis Group. Chest. 1999;116:424-431.
59. Oberstein A, von Zitzewitz H, Schweden F, et al. Non invasive evaluation of the inflammatory activity in sarcoidosis with high-resolution computed tomography. Sarcoidosis Vasc Diffuse Lung Dis. 1997;14:65-72.
60. Gibson G, Prescott RJ, Muers MF, et al. British Thoracic Society Sarcoidosis study: effects of long term corticosteroid treatment. Thorax. 1996;51:238-247.
61. Baughman RP, Nunes H. Therapy for sarcoidosis: evidence-based recommendations. Expert Rev Clin Immunol. 2012;8:95-103.
62. Pietinalho A, Tukiainen P, Haahtela T, et al. Early treatment of stage II sarcoidosis improves 5-year pulmonary function. Chest. 2002;121:24-31.
63. Rahaghi FF, Baughman RP, Saketkoo LA, et al. Delphi consensus recommendations for a treatment algorithm in pulmonary sarcoidosis. Eur Respir Rev. 2020;29:190146.
64. Baughman RP, Iannuzzi MC, Lower EE, et al. Use of fluticasone in acute symptomatic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2002;19:198-204.
65. du Bois RM, Greenhalgh PM, Southcott AM, et al. Randomized trial of inhaled fluticasone propionate in chronic stable pulmonary sarcoidosis: a pilot study. Eur Respir J. 1999;13:1345-1350.
66. Milman N, Graudal N, Grode G, Munch E. No effect of high‐dose inhaled steroids in pulmonary sarcoidosis: a double‐blind, placebo‐controlled study. J Intern Med. 1994;236:285-290.
67. Baughman RP, Winget DB, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis. 2000;17:60-66.
68. Vorselaars ADM, Wuyts WA, Vorselaars VMM, et al. Methotrexate vs azathioprine in second-line therapy of sarcoidosis. Chest. 2013;144:805-812.
69. Sahoo D, Bandyopadhyay D, Xu M, et al. Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis. Eur Respir J. 2011;38:1145-1150.
70. Baughman RP, Drent M, Kavuru M, et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Resp Crit Care Med . 2006;174:795-802.
71. Rossman MD, Newman LS, Baughman RP, et al. A double-blinded, randomized, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2006;23:201-208.
72. Selroos O, Sellergren T. Corticosteroid therapy of pulmonary sarcoidosis. A prospective evaluation of alternate day and daily dosage in stage II disease. Scand J Respir Dis . 1979;60:215-221.
73. Israel HL, Fouts DW, Beggs RA. A controlled trial of prednisone treatment of sarcoidosis. Am Rev Respir Dis . 1973;107:609-614.
74. Hamzeh N, Voelker A, Forssén A, et al. Efficacy of mycophenolate mofetil in sarcoidosis. Respir Med . 2014;108:1663-1669.
75. Brill A-K, Ott SR, Geiser T. Effect and safety of mycophenolate mofetil in chronic pulmonary sarcoidosis: a retrospective study. Respiration . 2013;86:376-383.
76. Baughman RP, Lower EE. Leflunomide for chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2004;21:43-48.
77. Sweiss NJ, Noth I, Mirsaeidi M, et al. Efficacy results of a 52-week trial of adalimumab in the treatment of refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2014;31:46-54.
78. Sweiss NJ, Lower EE, Mirsaeidi M, et al. Rituximab in the treatment of refractory pulmonary sarcoidosis. Eur Respir J . 2014;43:1525-1528.
79. Thatayatikom A, Thatayatikom S, White AJ. Infliximab treatment for severe granulomatous disease in common variable immunodeficiency: a case report and review of the literature. Ann Allergy Asthma Immunol . 2005;95:293-300.
80. Drake WP, Oswald-Richter K, Richmond BW, et al. Oral antimycobacterial therapy in chronic cutaneous sarcoidosis: a randomized, single-masked, placebo-controlled study. Jama Dermatol . 2013;149:1040-1049.
81. Drake WP, Richmond BW, Oswald-Richter K, et al. Effects of broad-spectrum antimycobacterial therapy on chronic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2013;30:201-211.
82. Baughman RP, Culver DA, Cordova FC, et al. Bosentan for sarcoidosis-associated pulmonary hypertension: a double-blind placebo controlled randomized trial. Chest . 2014;145:810-817.
83. Baughman RP, Shlobin OA, Wells AU, et al. Clinical features of sarcoidosis associated pulmonary hypertension: results of a multi-national registry. Respir Med . 2018;139:72-78.
84. Fisher KA, Serlin DM, Wilson KC, et al. Sarcoidosis-associated pulmonary hypertension outcome with long-term epoprostenol treatment. Chest . 2006;130:1481-1488.
85. Baughman RP, Judson MA, Lower EE, et al. Inhaled iloprost for sarcoidosis associated pulmonary hypertension. Sarcoidosis Vasc Diffuse Lung Dis . 2009;26:110-120.
86. King TE, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med . 2014;370:2083-2092.
PRACTICE RECOMMENDATIONS
› Consider biopsy to aid in diagnosing sarcoidosis; it may be avoided with a high clinical suspicion for sarcoidosis (eg, Löfgren syndrome, lupus pernio, or Heerfordt syndrome). C
› Rule out alternative diagnoses such as infection, malignancy, collagen vascular disease, and vasculitis. C
› Identify extra-pulmonary organ involvement, as clinically indicated, by screening with a baseline eye examination; complete blood count; creatinine, alkaline phosphatase, and calcium levels; electrocardiogram, and other organ-specific studies. C
› Make a patient-centered decision whether to begin antiinflammatory treatment based on symptomatology and risk of organ failure or death. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
2020 Focused Updates to the Asthma Management Guidelines
National Asthma Education and Prevention Program (NAEPP) published its last Expert Panel Report in 2007. Since that time, substantial progress has been made in understanding the pathophysiology and treatment of asthma. A new report has provided a much-needed update in the evaluation and management of asthma. It focuses on several priority topics jointly decided upon by the National Heart, Lung, and Blood Institute (NHLBI) Advisory Council Asthma Expert Working Group, the National Asthma Education and Prevention Program (NAEPP) participant organizations, and the public in 2015. These topics include the role of fractional exhaled nitric oxide (FeNO), allergen mitigation, intermittent inhaled corticosteroids (ICS), long-acting muscarinic agents (LAMA), immunotherapy, and bronchial thermoplasty (BT) in asthma management. This document did not include the subsequent new developments in the role of biologics in asthma. The following is a summary of the recommendations made in the 2020 Focused Updates to the Asthma Management Guidelines.1
FeNO measurement is recommended to aid in asthma diagnosis and monitoring and to assist in ICS medication titration in individuals with asthma who are 5 years and older. The panel recommends that clinicians use FeNO levels, in conjunction with other relevant clinical data such as spirometry and asthma control questionnaires, for medical decision making. Similarly, when using FeNO to guide therapeutic changes in the ICS dose, the panel advises making changes based upon frequent measurements as a part of longitudinal assessment rather than one single measurement, as several factors can influence an FeNO measurement. Studies have demonstrated that a strategy that incorporates FeNO measurements into a treatment algorithm can reduce the risk of exacerbations; however, this has not been shown to reduce hospitalizations or quality of life.2
Allergen mitigation interventions, which can be used in individuals of all ages, are only recommended for those who have symptoms related to specific indoor aeroallergens exposure. This can be confirmed by skin testing or specific IgE in the appropriate clinical setting if specific allergen testing is not readily available. While most recommendations focus on using a multicomponent approach to allergen mitigation (ie, dust mite covers, HEPA filters, air purifiers, carpet removal, mold remediation, pest or pest removal, etc), pest removal was the only single-component approach that was deemed effective. Dust mite covers alone are unlikely to lead to significant improvement if not paired with additional mitigation strategies; however, note that there was low certainty about these recommendations. Ultimately, allergen mitigation should focus on addressing those identified triggers resulting in poor control of asthma. Simultaneously, the clinician should consider the resources and costs associated with some of these interventions.
The panel has recommended using ICS therapy for on-demand (prn) usage, even in those with mild persistent asthma, recognizing that earlier and more frequent on-demand ICS usage results in fewer exacerbations. While the recommendations slightly differ based upon the age group, in those >12 years with mild persistent asthma, recommendations are for either daily ICS + as-needed short-acting beta-agonist (SABA), or as-needed ICS and SABA use. As in the Global Initiative for Asthma (GINA) guidelines, the panel also recommends single maintenance and rescue therapy (SMART) using ICS-formoterol inhalers for moderate to severe asthma. SMART has also been shown to reduce the risk of exacerbation. The clinician needs to use ICS-LABA medications where formoterol is the LABA component due to its quick onset of action (within 5 minutes, hence allowing it to be used as a rescue). Shared decision-making must be utilized when considering cost, insurance formulary restrictions, and perhaps delayed insurer and pharmacy adoption of these guidelines, as patients are likely to use more than one canister in a month when utilizing SMART.3,4
LAMA is a pharmacologic class of long-acting inhaled bronchodilators. Guidelines addressed the role of LAMA in individuals aged 12 years and older. Three recommendations are made regarding the role of LAMA in this age group. In individuals with persistent, uncontrolled asthma while using ICS therapy, the guidelines recommend the addition of a LABA over LAMA therapy.5 LAMA can be added to ICS in individuals with uncontrolled asthma who cannot use LABA or are already on ICS-LABA maintenance therapy.
For those patients with mild to moderate allergic asthma, as defined by allergic sensitization via skin testing or in-vitro elevated serum IgE levels, the expert panel conditionally recommends subcutaneous immunotherapy (SCIT) as an adjunct treatment to standard pharmacotherapy. It is recommended only in those patients whose asthma remains controlled throughout initiation, build-up, and maintenance phases. SCIT should not be used for patients with severe asthma, and all attempts should be made to optimize asthma with standard therapy first. The risks and benefits of SCIT should be discussed with the specialist before starting therapy. Sublingual immunotherapy (SLIT) is not recommended for the treatment of asthma.
Regarding BT, the Expert Panel conditionally recommends against BT in individuals age 18 years and older with persistent asthma because of the small benefit to risk ratio and uncertain outcomes. Because there is a risk of worsening asthma control or inducing an exacerbation, it is advised that BT not be performed in individuals with an FEV <50%-60% or those with a history of life-threatening asthma. If BT is considered, it should be performed by an experienced specialist and should be done in conjunction with a clinical trial or registry to track its long-term safety and effectiveness.6 All efforts should be made to optimize asthma therapy and address comorbidities before pursuing BT.
This Expert Panel report provides a robust systematic review of the evidence that addresses key questions in the management of asthma. However, not providing any recommendations regarding the use of biologics was a significant gap. Further guidance regarding their role can be found in the GINA guidelines, and by the European Respiratory Society and American Thoracic Society, both of which were also published in 2020.7,8Dr. Adrish is Clinical Assistant Professor, Bronx Care Health System, New York; Dr. Patil is Assistant Professor, Department of Respiratory Sleep and Critical Care Medicine, Maharashtra University of Health Sciences (MUHS), India; Dr. Oberle is Assistant Professor of Medicine, Associate Medical Director, Duke Asthma, Allergy and Airway Center, Durham, NC.
References
1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. doi: 10.1016/j.jaci.2020.10.003. PMID: 33280709; PMCID: PMC7924476.
2. Zeiger RS, Schatz M, Zhang F, et al. Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma. 2011;48:8-17.
3. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122:1127-35.e8.
4. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001.
5. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting beta-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015;314:1720-30.
6. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. 2011;11:8.
7. Global strategy for asthma management and prevention. 2020.
8. Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55:1900588.
National Asthma Education and Prevention Program (NAEPP) published its last Expert Panel Report in 2007. Since that time, substantial progress has been made in understanding the pathophysiology and treatment of asthma. A new report has provided a much-needed update in the evaluation and management of asthma. It focuses on several priority topics jointly decided upon by the National Heart, Lung, and Blood Institute (NHLBI) Advisory Council Asthma Expert Working Group, the National Asthma Education and Prevention Program (NAEPP) participant organizations, and the public in 2015. These topics include the role of fractional exhaled nitric oxide (FeNO), allergen mitigation, intermittent inhaled corticosteroids (ICS), long-acting muscarinic agents (LAMA), immunotherapy, and bronchial thermoplasty (BT) in asthma management. This document did not include the subsequent new developments in the role of biologics in asthma. The following is a summary of the recommendations made in the 2020 Focused Updates to the Asthma Management Guidelines.1
FeNO measurement is recommended to aid in asthma diagnosis and monitoring and to assist in ICS medication titration in individuals with asthma who are 5 years and older. The panel recommends that clinicians use FeNO levels, in conjunction with other relevant clinical data such as spirometry and asthma control questionnaires, for medical decision making. Similarly, when using FeNO to guide therapeutic changes in the ICS dose, the panel advises making changes based upon frequent measurements as a part of longitudinal assessment rather than one single measurement, as several factors can influence an FeNO measurement. Studies have demonstrated that a strategy that incorporates FeNO measurements into a treatment algorithm can reduce the risk of exacerbations; however, this has not been shown to reduce hospitalizations or quality of life.2
Allergen mitigation interventions, which can be used in individuals of all ages, are only recommended for those who have symptoms related to specific indoor aeroallergens exposure. This can be confirmed by skin testing or specific IgE in the appropriate clinical setting if specific allergen testing is not readily available. While most recommendations focus on using a multicomponent approach to allergen mitigation (ie, dust mite covers, HEPA filters, air purifiers, carpet removal, mold remediation, pest or pest removal, etc), pest removal was the only single-component approach that was deemed effective. Dust mite covers alone are unlikely to lead to significant improvement if not paired with additional mitigation strategies; however, note that there was low certainty about these recommendations. Ultimately, allergen mitigation should focus on addressing those identified triggers resulting in poor control of asthma. Simultaneously, the clinician should consider the resources and costs associated with some of these interventions.
The panel has recommended using ICS therapy for on-demand (prn) usage, even in those with mild persistent asthma, recognizing that earlier and more frequent on-demand ICS usage results in fewer exacerbations. While the recommendations slightly differ based upon the age group, in those >12 years with mild persistent asthma, recommendations are for either daily ICS + as-needed short-acting beta-agonist (SABA), or as-needed ICS and SABA use. As in the Global Initiative for Asthma (GINA) guidelines, the panel also recommends single maintenance and rescue therapy (SMART) using ICS-formoterol inhalers for moderate to severe asthma. SMART has also been shown to reduce the risk of exacerbation. The clinician needs to use ICS-LABA medications where formoterol is the LABA component due to its quick onset of action (within 5 minutes, hence allowing it to be used as a rescue). Shared decision-making must be utilized when considering cost, insurance formulary restrictions, and perhaps delayed insurer and pharmacy adoption of these guidelines, as patients are likely to use more than one canister in a month when utilizing SMART.3,4
LAMA is a pharmacologic class of long-acting inhaled bronchodilators. Guidelines addressed the role of LAMA in individuals aged 12 years and older. Three recommendations are made regarding the role of LAMA in this age group. In individuals with persistent, uncontrolled asthma while using ICS therapy, the guidelines recommend the addition of a LABA over LAMA therapy.5 LAMA can be added to ICS in individuals with uncontrolled asthma who cannot use LABA or are already on ICS-LABA maintenance therapy.
For those patients with mild to moderate allergic asthma, as defined by allergic sensitization via skin testing or in-vitro elevated serum IgE levels, the expert panel conditionally recommends subcutaneous immunotherapy (SCIT) as an adjunct treatment to standard pharmacotherapy. It is recommended only in those patients whose asthma remains controlled throughout initiation, build-up, and maintenance phases. SCIT should not be used for patients with severe asthma, and all attempts should be made to optimize asthma with standard therapy first. The risks and benefits of SCIT should be discussed with the specialist before starting therapy. Sublingual immunotherapy (SLIT) is not recommended for the treatment of asthma.
Regarding BT, the Expert Panel conditionally recommends against BT in individuals age 18 years and older with persistent asthma because of the small benefit to risk ratio and uncertain outcomes. Because there is a risk of worsening asthma control or inducing an exacerbation, it is advised that BT not be performed in individuals with an FEV <50%-60% or those with a history of life-threatening asthma. If BT is considered, it should be performed by an experienced specialist and should be done in conjunction with a clinical trial or registry to track its long-term safety and effectiveness.6 All efforts should be made to optimize asthma therapy and address comorbidities before pursuing BT.
This Expert Panel report provides a robust systematic review of the evidence that addresses key questions in the management of asthma. However, not providing any recommendations regarding the use of biologics was a significant gap. Further guidance regarding their role can be found in the GINA guidelines, and by the European Respiratory Society and American Thoracic Society, both of which were also published in 2020.7,8Dr. Adrish is Clinical Assistant Professor, Bronx Care Health System, New York; Dr. Patil is Assistant Professor, Department of Respiratory Sleep and Critical Care Medicine, Maharashtra University of Health Sciences (MUHS), India; Dr. Oberle is Assistant Professor of Medicine, Associate Medical Director, Duke Asthma, Allergy and Airway Center, Durham, NC.
References
1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. doi: 10.1016/j.jaci.2020.10.003. PMID: 33280709; PMCID: PMC7924476.
2. Zeiger RS, Schatz M, Zhang F, et al. Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma. 2011;48:8-17.
3. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122:1127-35.e8.
4. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001.
5. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting beta-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015;314:1720-30.
6. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. 2011;11:8.
7. Global strategy for asthma management and prevention. 2020.
8. Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55:1900588.
National Asthma Education and Prevention Program (NAEPP) published its last Expert Panel Report in 2007. Since that time, substantial progress has been made in understanding the pathophysiology and treatment of asthma. A new report has provided a much-needed update in the evaluation and management of asthma. It focuses on several priority topics jointly decided upon by the National Heart, Lung, and Blood Institute (NHLBI) Advisory Council Asthma Expert Working Group, the National Asthma Education and Prevention Program (NAEPP) participant organizations, and the public in 2015. These topics include the role of fractional exhaled nitric oxide (FeNO), allergen mitigation, intermittent inhaled corticosteroids (ICS), long-acting muscarinic agents (LAMA), immunotherapy, and bronchial thermoplasty (BT) in asthma management. This document did not include the subsequent new developments in the role of biologics in asthma. The following is a summary of the recommendations made in the 2020 Focused Updates to the Asthma Management Guidelines.1
FeNO measurement is recommended to aid in asthma diagnosis and monitoring and to assist in ICS medication titration in individuals with asthma who are 5 years and older. The panel recommends that clinicians use FeNO levels, in conjunction with other relevant clinical data such as spirometry and asthma control questionnaires, for medical decision making. Similarly, when using FeNO to guide therapeutic changes in the ICS dose, the panel advises making changes based upon frequent measurements as a part of longitudinal assessment rather than one single measurement, as several factors can influence an FeNO measurement. Studies have demonstrated that a strategy that incorporates FeNO measurements into a treatment algorithm can reduce the risk of exacerbations; however, this has not been shown to reduce hospitalizations or quality of life.2
Allergen mitigation interventions, which can be used in individuals of all ages, are only recommended for those who have symptoms related to specific indoor aeroallergens exposure. This can be confirmed by skin testing or specific IgE in the appropriate clinical setting if specific allergen testing is not readily available. While most recommendations focus on using a multicomponent approach to allergen mitigation (ie, dust mite covers, HEPA filters, air purifiers, carpet removal, mold remediation, pest or pest removal, etc), pest removal was the only single-component approach that was deemed effective. Dust mite covers alone are unlikely to lead to significant improvement if not paired with additional mitigation strategies; however, note that there was low certainty about these recommendations. Ultimately, allergen mitigation should focus on addressing those identified triggers resulting in poor control of asthma. Simultaneously, the clinician should consider the resources and costs associated with some of these interventions.
The panel has recommended using ICS therapy for on-demand (prn) usage, even in those with mild persistent asthma, recognizing that earlier and more frequent on-demand ICS usage results in fewer exacerbations. While the recommendations slightly differ based upon the age group, in those >12 years with mild persistent asthma, recommendations are for either daily ICS + as-needed short-acting beta-agonist (SABA), or as-needed ICS and SABA use. As in the Global Initiative for Asthma (GINA) guidelines, the panel also recommends single maintenance and rescue therapy (SMART) using ICS-formoterol inhalers for moderate to severe asthma. SMART has also been shown to reduce the risk of exacerbation. The clinician needs to use ICS-LABA medications where formoterol is the LABA component due to its quick onset of action (within 5 minutes, hence allowing it to be used as a rescue). Shared decision-making must be utilized when considering cost, insurance formulary restrictions, and perhaps delayed insurer and pharmacy adoption of these guidelines, as patients are likely to use more than one canister in a month when utilizing SMART.3,4
LAMA is a pharmacologic class of long-acting inhaled bronchodilators. Guidelines addressed the role of LAMA in individuals aged 12 years and older. Three recommendations are made regarding the role of LAMA in this age group. In individuals with persistent, uncontrolled asthma while using ICS therapy, the guidelines recommend the addition of a LABA over LAMA therapy.5 LAMA can be added to ICS in individuals with uncontrolled asthma who cannot use LABA or are already on ICS-LABA maintenance therapy.
For those patients with mild to moderate allergic asthma, as defined by allergic sensitization via skin testing or in-vitro elevated serum IgE levels, the expert panel conditionally recommends subcutaneous immunotherapy (SCIT) as an adjunct treatment to standard pharmacotherapy. It is recommended only in those patients whose asthma remains controlled throughout initiation, build-up, and maintenance phases. SCIT should not be used for patients with severe asthma, and all attempts should be made to optimize asthma with standard therapy first. The risks and benefits of SCIT should be discussed with the specialist before starting therapy. Sublingual immunotherapy (SLIT) is not recommended for the treatment of asthma.
Regarding BT, the Expert Panel conditionally recommends against BT in individuals age 18 years and older with persistent asthma because of the small benefit to risk ratio and uncertain outcomes. Because there is a risk of worsening asthma control or inducing an exacerbation, it is advised that BT not be performed in individuals with an FEV <50%-60% or those with a history of life-threatening asthma. If BT is considered, it should be performed by an experienced specialist and should be done in conjunction with a clinical trial or registry to track its long-term safety and effectiveness.6 All efforts should be made to optimize asthma therapy and address comorbidities before pursuing BT.
This Expert Panel report provides a robust systematic review of the evidence that addresses key questions in the management of asthma. However, not providing any recommendations regarding the use of biologics was a significant gap. Further guidance regarding their role can be found in the GINA guidelines, and by the European Respiratory Society and American Thoracic Society, both of which were also published in 2020.7,8Dr. Adrish is Clinical Assistant Professor, Bronx Care Health System, New York; Dr. Patil is Assistant Professor, Department of Respiratory Sleep and Critical Care Medicine, Maharashtra University of Health Sciences (MUHS), India; Dr. Oberle is Assistant Professor of Medicine, Associate Medical Director, Duke Asthma, Allergy and Airway Center, Durham, NC.
References
1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. doi: 10.1016/j.jaci.2020.10.003. PMID: 33280709; PMCID: PMC7924476.
2. Zeiger RS, Schatz M, Zhang F, et al. Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma. 2011;48:8-17.
3. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122:1127-35.e8.
4. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001.
5. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting beta-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015;314:1720-30.
6. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. 2011;11:8.
7. Global strategy for asthma management and prevention. 2020.
8. Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55:1900588.