Pulmonology

Longitudinal progression of parenchymal changes on CT images — also referred to as quantitative interstitial abnormalities (QIA) – is independently associated with decreased lung function and an increased all-cause mortality risk, an analysis of two cohorts of ever-smokers indicates. And among the main risk factors for QIA progression is smoking.

“These abnormalities have gone by a few different names but fundamentally, they are high density findings of chest CT that in some cases represent early or subtle evidence of pulmonary fibrosis,” Samuel Ash, MD, MPH, assistant professor of medicine, Brigham and Women’s Hospital, Boston, told this news organization.

“I think this just adds to the huge list of reasons why people should quit smoking. So when I see someone with visual evidence of this type of change on their chest CT, I make sure to emphasize that while they don’t have interstitial lung disease [ILD] yet, these findings suggest they may be susceptible to lung injury from tobacco smoke and that if they don’t stop smoking now, they are at risk for a disease like interstitial pulmonary fibrosis [IPF] which is a highly morbid disease with a high mortality risk,” he added.

The study was published online in the journal CHEST.
 

Ever-smoking cohorts

Analysis of QIA progression on CT chest scans was carried out on participants from the Genetic Epidemiology of COPD (COPDGene) study as well as those from the Pittsburgh Lung Screening Study (PLuSS). COPDGene was a prospective cohort of over 10,300 ever-smokers with at least a 10–pack-year smoking history between the ages of 45 and 80. Participants underwent a series of tests including chest CT scans at baseline between 2006 and 2011 and again approximately 5 years later.

Patients with a postbronchodilator forced expiratory volume in 1 second (FEV₁) of 80% or more of predicted and a FEV₁-to-FVC (forced vital capacity) ratio of at least 0.7 were defined to have GOLD stage 0 disease while those with a postbronchodilator FEV₁ of 80% or less than predicted and a FEV₁-to-FVC ratio of at least 0.7 were defined to have preserved ratio impaired spirometry (PRISm) disease.

PLuSS involved 3,642 ever-smokers between the ages of 50 years and 79 years with at least a 12.5–pack-year history with no prior history of lung cancer. Participants again underwent a series of tests including a CT scan on visit 1 between 2002 and 2005 and then a second CT scan at a second visit almost 9 years later. “In the COPDGene cohort, 4,635 participants had complete clinical data, CT scans and spirometry from visits 1 and 2 for analysis,” the authors reported.

At visit 1 almost 48% of participants were current smokers and the mean pack-year history of the cohort was 41.9 years. The mean time between visits 1 and 2 was 5.6 years. Both the mean prebronchodilator FEV₁ as well as the mean FVC decreased between visits 1 and 2. For example, the mean prebronchodilator FEV₁ dropped from 2.2 liters to 2.0 liters between visits 1 and 2 while the mean prebronchodilator FVC decreased from 3.2 liters to 3.0 liters between the first and second visits.

In the PLuSS cohort, 1,307 participants had complete imaging and spirometry data available for visits 1 and 2 for analysis. The mean time between visits 1 and 2 was 8.6 years. Over 59% of the cohort were current smokers with a mean pack-year history of 65. Again, the mean prebronchodilator FEV1 and FVC both dropped between visit 1 and 2, as the authors note.

The mean prebronchodilator FEV1, for example, decreased from 2.5 liters to 2.1 liters between visits 1 and 2 while the mean prebronchodilator FVC dropped from 3.6 liters to 3.2 liters during the same interval. Looking at risk factors associated with QIA progression, investigators note that each additional year of baseline age was associated with a higher annual increase in QIA by 0.01% per year (95% confidence interval, 0.01%-0.02%; P < .001) in the COPDGene cohort and a 0.02% increase (95% CI, 0.01%-0.02%; P < .001) in the PLuSS cohort.

Female sex in turn was associated with a 0.07% per year (95% CI, 0.02%-0.12%; P = .003) higher increase in the QIA, compared with men in the COPDGene cohort and a 0.14% (95% CI, 0.02%-0.26%; P = .025) per year higher increase in the QIA in the PLuSS cohort. Current smoking status was only associated with a higher rate of QIA progression in the COPDGene cohort at a rate of 0.10% per year (95% CI, 0.06%-0.15%; P < .001).

Lastly, every copy of the minor allele of the MUIC5B promoter polymorphism was associated with a 0.12% per year (95% CI, 0.07%-0.16%; P < .0001) increase in QIA in the COPDGene cohort as well.
 

Smoking cessation

Smoking cessation is the obvious first step for patients with evidence of QIA progression but physicians can probably do more for these patients sooner, Dr. Ash said. “If we use heart disease as an analogy, we don’t want to start treating someone until they have a heart attack or are in heart failure, we start by checking their cholesterol and blood pressure and treating them with medications to prevent progression.”

Similarly, physicians need to start thinking about IPF and other lung diseases in the same way. For IPF, medications such as pirfenidone (Esbriet) and nintedanib (Ofev) do not reverse prior lung damage but they do slow disease progression and physicians need to initiate treatment before patients are short of breath, not after. Meantime, Dr. Ash advised physicians that, if they have a patient who is getting a CT scan for whatever reason, they should keep a close eye on whether or not patients have any of these interstitial changes and, if they do, then if the changes are getting worse.

“These patients are likely to be the ones who are going to develop IPF and who may benefit from ongoing imaging surveillance,” he said. And while clinicians may not yet be ready to use a quantitative tool at the bedside, “this tool – or one like it – is coming and we have to start thinking about how to incorporate these types of devices into our clinical practice.”
 

Temporal changes

Asked to comment on the findings, Surya Bhatt, MD, associate professor of medicine at the University of Alabama at Birmingham, said that the study advances the community’s understanding of the relationship between temporal changes in objectively measured interstitial lung abnormalities and several important clinical outcomes, including lung function decline and mortality. “Several risk factors for progression were also identified,” he noted.

“And these results make a case for initiating clinical trials to determine whether early treatment with existing antifibrotic medications in these high risk individuals can decrease the perpetuation of these permanent lung changes,” Dr. Bhatt said.

The COPDGene study was supported in part by contributions made by an industry advisory board. Dr. Ash was supported in part by Quantitative Imaging Solutions. Dr. Bhatt declared that he has receiving consulting fees or has service on advisory boards for Boehringer Ingelheim and Sanofi/Regeneron. He ha also received fee for CME from IntegrityCE.

Longitudinal progression of parenchymal changes on CT images — also referred to as quantitative interstitial abnormalities (QIA) – is independently associated with decreased lung function and an increased all-cause mortality risk, an analysis of two cohorts of ever-smokers indicates. And among the main risk factors for QIA progression is smoking.

“These abnormalities have gone by a few different names but fundamentally, they are high density findings of chest CT that in some cases represent early or subtle evidence of pulmonary fibrosis,” Samuel Ash, MD, MPH, assistant professor of medicine, Brigham and Women’s Hospital, Boston, told this news organization.

“I think this just adds to the huge list of reasons why people should quit smoking. So when I see someone with visual evidence of this type of change on their chest CT, I make sure to emphasize that while they don’t have interstitial lung disease [ILD] yet, these findings suggest they may be susceptible to lung injury from tobacco smoke and that if they don’t stop smoking now, they are at risk for a disease like interstitial pulmonary fibrosis [IPF] which is a highly morbid disease with a high mortality risk,” he added.

The study was published online in the journal CHEST.
 

Ever-smoking cohorts

Analysis of QIA progression on CT chest scans was carried out on participants from the Genetic Epidemiology of COPD (COPDGene) study as well as those from the Pittsburgh Lung Screening Study (PLuSS). COPDGene was a prospective cohort of over 10,300 ever-smokers with at least a 10–pack-year smoking history between the ages of 45 and 80. Participants underwent a series of tests including chest CT scans at baseline between 2006 and 2011 and again approximately 5 years later.

Patients with a postbronchodilator forced expiratory volume in 1 second (FEV₁) of 80% or more of predicted and a FEV₁-to-FVC (forced vital capacity) ratio of at least 0.7 were defined to have GOLD stage 0 disease while those with a postbronchodilator FEV₁ of 80% or less than predicted and a FEV₁-to-FVC ratio of at least 0.7 were defined to have preserved ratio impaired spirometry (PRISm) disease.

PLuSS involved 3,642 ever-smokers between the ages of 50 years and 79 years with at least a 12.5–pack-year history with no prior history of lung cancer. Participants again underwent a series of tests including a CT scan on visit 1 between 2002 and 2005 and then a second CT scan at a second visit almost 9 years later. “In the COPDGene cohort, 4,635 participants had complete clinical data, CT scans and spirometry from visits 1 and 2 for analysis,” the authors reported.

At visit 1 almost 48% of participants were current smokers and the mean pack-year history of the cohort was 41.9 years. The mean time between visits 1 and 2 was 5.6 years. Both the mean prebronchodilator FEV₁ as well as the mean FVC decreased between visits 1 and 2. For example, the mean prebronchodilator FEV₁ dropped from 2.2 liters to 2.0 liters between visits 1 and 2 while the mean prebronchodilator FVC decreased from 3.2 liters to 3.0 liters between the first and second visits.

In the PLuSS cohort, 1,307 participants had complete imaging and spirometry data available for visits 1 and 2 for analysis. The mean time between visits 1 and 2 was 8.6 years. Over 59% of the cohort were current smokers with a mean pack-year history of 65. Again, the mean prebronchodilator FEV1 and FVC both dropped between visit 1 and 2, as the authors note.

The mean prebronchodilator FEV1, for example, decreased from 2.5 liters to 2.1 liters between visits 1 and 2 while the mean prebronchodilator FVC dropped from 3.6 liters to 3.2 liters during the same interval. Looking at risk factors associated with QIA progression, investigators note that each additional year of baseline age was associated with a higher annual increase in QIA by 0.01% per year (95% confidence interval, 0.01%-0.02%; P < .001) in the COPDGene cohort and a 0.02% increase (95% CI, 0.01%-0.02%; P < .001) in the PLuSS cohort.

Female sex in turn was associated with a 0.07% per year (95% CI, 0.02%-0.12%; P = .003) higher increase in the QIA, compared with men in the COPDGene cohort and a 0.14% (95% CI, 0.02%-0.26%; P = .025) per year higher increase in the QIA in the PLuSS cohort. Current smoking status was only associated with a higher rate of QIA progression in the COPDGene cohort at a rate of 0.10% per year (95% CI, 0.06%-0.15%; P < .001).

Lastly, every copy of the minor allele of the MUIC5B promoter polymorphism was associated with a 0.12% per year (95% CI, 0.07%-0.16%; P < .0001) increase in QIA in the COPDGene cohort as well.
 

Smoking cessation

Smoking cessation is the obvious first step for patients with evidence of QIA progression but physicians can probably do more for these patients sooner, Dr. Ash said. “If we use heart disease as an analogy, we don’t want to start treating someone until they have a heart attack or are in heart failure, we start by checking their cholesterol and blood pressure and treating them with medications to prevent progression.”

Similarly, physicians need to start thinking about IPF and other lung diseases in the same way. For IPF, medications such as pirfenidone (Esbriet) and nintedanib (Ofev) do not reverse prior lung damage but they do slow disease progression and physicians need to initiate treatment before patients are short of breath, not after. Meantime, Dr. Ash advised physicians that, if they have a patient who is getting a CT scan for whatever reason, they should keep a close eye on whether or not patients have any of these interstitial changes and, if they do, then if the changes are getting worse.

“These patients are likely to be the ones who are going to develop IPF and who may benefit from ongoing imaging surveillance,” he said. And while clinicians may not yet be ready to use a quantitative tool at the bedside, “this tool – or one like it – is coming and we have to start thinking about how to incorporate these types of devices into our clinical practice.”
 

Temporal changes

Asked to comment on the findings, Surya Bhatt, MD, associate professor of medicine at the University of Alabama at Birmingham, said that the study advances the community’s understanding of the relationship between temporal changes in objectively measured interstitial lung abnormalities and several important clinical outcomes, including lung function decline and mortality. “Several risk factors for progression were also identified,” he noted.

“And these results make a case for initiating clinical trials to determine whether early treatment with existing antifibrotic medications in these high risk individuals can decrease the perpetuation of these permanent lung changes,” Dr. Bhatt said.

The COPDGene study was supported in part by contributions made by an industry advisory board. Dr. Ash was supported in part by Quantitative Imaging Solutions. Dr. Bhatt declared that he has receiving consulting fees or has service on advisory boards for Boehringer Ingelheim and Sanofi/Regeneron. He ha also received fee for CME from IntegrityCE.

Longitudinal progression of parenchymal changes on CT images — also referred to as quantitative interstitial abnormalities (QIA) – is independently associated with decreased lung function and an increased all-cause mortality risk, an analysis of two cohorts of ever-smokers indicates. And among the main risk factors for QIA progression is smoking.

“These abnormalities have gone by a few different names but fundamentally, they are high density findings of chest CT that in some cases represent early or subtle evidence of pulmonary fibrosis,” Samuel Ash, MD, MPH, assistant professor of medicine, Brigham and Women’s Hospital, Boston, told this news organization.

“I think this just adds to the huge list of reasons why people should quit smoking. So when I see someone with visual evidence of this type of change on their chest CT, I make sure to emphasize that while they don’t have interstitial lung disease [ILD] yet, these findings suggest they may be susceptible to lung injury from tobacco smoke and that if they don’t stop smoking now, they are at risk for a disease like interstitial pulmonary fibrosis [IPF] which is a highly morbid disease with a high mortality risk,” he added.

The study was published online in the journal CHEST.
 

Ever-smoking cohorts

Analysis of QIA progression on CT chest scans was carried out on participants from the Genetic Epidemiology of COPD (COPDGene) study as well as those from the Pittsburgh Lung Screening Study (PLuSS). COPDGene was a prospective cohort of over 10,300 ever-smokers with at least a 10–pack-year smoking history between the ages of 45 and 80. Participants underwent a series of tests including chest CT scans at baseline between 2006 and 2011 and again approximately 5 years later.

Patients with a postbronchodilator forced expiratory volume in 1 second (FEV₁) of 80% or more of predicted and a FEV₁-to-FVC (forced vital capacity) ratio of at least 0.7 were defined to have GOLD stage 0 disease while those with a postbronchodilator FEV₁ of 80% or less than predicted and a FEV₁-to-FVC ratio of at least 0.7 were defined to have preserved ratio impaired spirometry (PRISm) disease.

PLuSS involved 3,642 ever-smokers between the ages of 50 years and 79 years with at least a 12.5–pack-year history with no prior history of lung cancer. Participants again underwent a series of tests including a CT scan on visit 1 between 2002 and 2005 and then a second CT scan at a second visit almost 9 years later. “In the COPDGene cohort, 4,635 participants had complete clinical data, CT scans and spirometry from visits 1 and 2 for analysis,” the authors reported.

At visit 1 almost 48% of participants were current smokers and the mean pack-year history of the cohort was 41.9 years. The mean time between visits 1 and 2 was 5.6 years. Both the mean prebronchodilator FEV₁ as well as the mean FVC decreased between visits 1 and 2. For example, the mean prebronchodilator FEV₁ dropped from 2.2 liters to 2.0 liters between visits 1 and 2 while the mean prebronchodilator FVC decreased from 3.2 liters to 3.0 liters between the first and second visits.

In the PLuSS cohort, 1,307 participants had complete imaging and spirometry data available for visits 1 and 2 for analysis. The mean time between visits 1 and 2 was 8.6 years. Over 59% of the cohort were current smokers with a mean pack-year history of 65. Again, the mean prebronchodilator FEV1 and FVC both dropped between visit 1 and 2, as the authors note.

The mean prebronchodilator FEV1, for example, decreased from 2.5 liters to 2.1 liters between visits 1 and 2 while the mean prebronchodilator FVC dropped from 3.6 liters to 3.2 liters during the same interval. Looking at risk factors associated with QIA progression, investigators note that each additional year of baseline age was associated with a higher annual increase in QIA by 0.01% per year (95% confidence interval, 0.01%-0.02%; P < .001) in the COPDGene cohort and a 0.02% increase (95% CI, 0.01%-0.02%; P < .001) in the PLuSS cohort.

Female sex in turn was associated with a 0.07% per year (95% CI, 0.02%-0.12%; P = .003) higher increase in the QIA, compared with men in the COPDGene cohort and a 0.14% (95% CI, 0.02%-0.26%; P = .025) per year higher increase in the QIA in the PLuSS cohort. Current smoking status was only associated with a higher rate of QIA progression in the COPDGene cohort at a rate of 0.10% per year (95% CI, 0.06%-0.15%; P < .001).

Lastly, every copy of the minor allele of the MUIC5B promoter polymorphism was associated with a 0.12% per year (95% CI, 0.07%-0.16%; P < .0001) increase in QIA in the COPDGene cohort as well.
 

Smoking cessation

Smoking cessation is the obvious first step for patients with evidence of QIA progression but physicians can probably do more for these patients sooner, Dr. Ash said. “If we use heart disease as an analogy, we don’t want to start treating someone until they have a heart attack or are in heart failure, we start by checking their cholesterol and blood pressure and treating them with medications to prevent progression.”

Similarly, physicians need to start thinking about IPF and other lung diseases in the same way. For IPF, medications such as pirfenidone (Esbriet) and nintedanib (Ofev) do not reverse prior lung damage but they do slow disease progression and physicians need to initiate treatment before patients are short of breath, not after. Meantime, Dr. Ash advised physicians that, if they have a patient who is getting a CT scan for whatever reason, they should keep a close eye on whether or not patients have any of these interstitial changes and, if they do, then if the changes are getting worse.

“These patients are likely to be the ones who are going to develop IPF and who may benefit from ongoing imaging surveillance,” he said. And while clinicians may not yet be ready to use a quantitative tool at the bedside, “this tool – or one like it – is coming and we have to start thinking about how to incorporate these types of devices into our clinical practice.”
 

Temporal changes

Asked to comment on the findings, Surya Bhatt, MD, associate professor of medicine at the University of Alabama at Birmingham, said that the study advances the community’s understanding of the relationship between temporal changes in objectively measured interstitial lung abnormalities and several important clinical outcomes, including lung function decline and mortality. “Several risk factors for progression were also identified,” he noted.

“And these results make a case for initiating clinical trials to determine whether early treatment with existing antifibrotic medications in these high risk individuals can decrease the perpetuation of these permanent lung changes,” Dr. Bhatt said.

The COPDGene study was supported in part by contributions made by an industry advisory board. Dr. Ash was supported in part by Quantitative Imaging Solutions. Dr. Bhatt declared that he has receiving consulting fees or has service on advisory boards for Boehringer Ingelheim and Sanofi/Regeneron. He ha also received fee for CME from IntegrityCE.

In 2021, in U.S. states far removed from one another, numerous cases of melioidosis (Whitmore’s disease) sprang up, some with a fatal outcome. What is the common factor linking all of those affected? So begins the search for evidence.

No relations or common journeys

Between March and July 2021, cases of the bacterial infectious disease sprang up in Georgia, Kansas, Minnesota, and Texas, with the disease being fatal for two of those affected. Usually, cases of melioidosis occur in the United States after traveling to regions where the pathogen is prevalent. However, none of the patients had undertaken any previous international travel.

When the genomes of the bacterial strains (Burkholderia pseudomallei) were sequenced, they showed a high level of concordance, suggesting a common source of infection. The bacterial strain is similar to those that are found in Southeast Asia above all. An imported product from there was taken into consideration as the trigger.

The Centers for Disease Control and Prevention examined blood samples from the patients, as well as samples from the soil, water, food, and household items around their homes.
 

Aroma spray as a trigger

In October, the cause of the melioidosis was finally identified in the house of the patient from Georgia: an aromatherapy spray. The genetic fingerprint of the bacterial strain matched with that from the other patients. The common trigger was thus discovered.

The contaminated spray, with a lavender-chamomile scent for room fragrancing, was sold between February and October in some branches of Walmart, as well as in their online store. The product was therefore recalled and it was checked whether the ingredients were also being used in other products.

The CDC requested physicians to also take melioidosis into account if they were presented with acute bacterial infections that did not respond to normal antibiotics and to inquire whether the affected room spray had been used.
 

More information about melioidosis

Melioidosis is an infectious disease affecting humans and animals. The trigger is the bacteria B pseudomallei. The disease appears predominantly in tropical regions, especially in Southeast Asia and northern Australia.

Transmission

The bacteria can be found in contaminated water and soil. It is disseminated between humans and animals through direct contact with the infectious source, such as through inhaling dust particles or water droplets, or through consuming contaminated water or food. Human-to-human transmission is extremely rare. Recently however, tropical saltwater fish were identified as potential carriers.

Symptoms

Melioidosis has a wide range of symptoms, which can lead to its being confused with other diseases such as tuberculosis or other forms of pneumonia. There are different forms of the disease, each with different symptoms.

• Localized infection: localized pain and swelling, fever, ulceration, and abscess.
• Pulmonary infection: cough, chest pain, high fever, headaches, and loss of appetite
• Bacteremia: fever, headaches, breathing problems, stomach discomfort, joint pain, and disorientation.
• Disseminated infection: fever, weight loss, stomach or chest pain, muscle or joint pain, headaches, central nervous system infections, and epileptic seizures.

The incubation time is not clearly defined and can be from 1 day to several years; however, the symptoms mostly emerge 2-4 weeks after exposure. The risk factors include diabetes, high alcohol consumption, chronic pulmonary or kidney disease, and immunodeficiencies.

Diagnosis based on the symptoms is often difficult since the clinical picture is similar to other, more common conditions.
 

Therapy

If the melioidosis is identified as such, it can be treated with only mildly effective antibiotics, since it has a natural resistance to many commonly used antibiotics. The type of infection and the course of treatment also affects the long-term outcome. Without treatment, 90% of the infections have a fatal outcome. With appropriate treatment, the mortality rate still lies at 40%.

Therapy generally begins with intravenous antibiotic therapy for at least 2-8 weeks (ceftazidime or meropenem). Oral antibiotic therapy then follows for 3-6 months (trimethoprim-sulfamethoxazole or amoxicillin/clavulanic acid). If the patient is allergic to penicillin, alternative antibiotics can be used.
 

Use as a bioweapon

The CDC classifies B. pseudomallei as a potential pathogen for biological attack (class-B candidate). The agency lists the potential reasons for use as a bioweapon as:

• The pathogen can be found naturally in certain regions.
• The triggered disease can take a serious course and ultimately be fatal without appropriate therapy.
• In the past, the United States has used similar pathogens in wars as bioweapons.

In a potential attack, the pathogen could be spread through air, water, or food, and by doing so, many people would be exposed. Any contact with the bacteria can result in melioidosis. As the bacteria cannot be seen, smelled, or tasted, the biological attack would not be recognized for some time. A certain amount of time can also pass until the pathogen is identified, once fever and respiratory diseases have developed.

In such an emergency, the CDC would collaborate with other federal and local authorities to supply specialized testing laboratories and provide the public with information.

This content was translated from Coliquio. A version appeared on Medscape.com.

In 2021, in U.S. states far removed from one another, numerous cases of melioidosis (Whitmore’s disease) sprang up, some with a fatal outcome. What is the common factor linking all of those affected? So begins the search for evidence.

No relations or common journeys

Between March and July 2021, cases of the bacterial infectious disease sprang up in Georgia, Kansas, Minnesota, and Texas, with the disease being fatal for two of those affected. Usually, cases of melioidosis occur in the United States after traveling to regions where the pathogen is prevalent. However, none of the patients had undertaken any previous international travel.

When the genomes of the bacterial strains (Burkholderia pseudomallei) were sequenced, they showed a high level of concordance, suggesting a common source of infection. The bacterial strain is similar to those that are found in Southeast Asia above all. An imported product from there was taken into consideration as the trigger.

The Centers for Disease Control and Prevention examined blood samples from the patients, as well as samples from the soil, water, food, and household items around their homes.
 

Aroma spray as a trigger

In October, the cause of the melioidosis was finally identified in the house of the patient from Georgia: an aromatherapy spray. The genetic fingerprint of the bacterial strain matched with that from the other patients. The common trigger was thus discovered.

The contaminated spray, with a lavender-chamomile scent for room fragrancing, was sold between February and October in some branches of Walmart, as well as in their online store. The product was therefore recalled and it was checked whether the ingredients were also being used in other products.

The CDC requested physicians to also take melioidosis into account if they were presented with acute bacterial infections that did not respond to normal antibiotics and to inquire whether the affected room spray had been used.
 

More information about melioidosis

Melioidosis is an infectious disease affecting humans and animals. The trigger is the bacteria B pseudomallei. The disease appears predominantly in tropical regions, especially in Southeast Asia and northern Australia.

Transmission

The bacteria can be found in contaminated water and soil. It is disseminated between humans and animals through direct contact with the infectious source, such as through inhaling dust particles or water droplets, or through consuming contaminated water or food. Human-to-human transmission is extremely rare. Recently however, tropical saltwater fish were identified as potential carriers.

Symptoms

Melioidosis has a wide range of symptoms, which can lead to its being confused with other diseases such as tuberculosis or other forms of pneumonia. There are different forms of the disease, each with different symptoms.

• Localized infection: localized pain and swelling, fever, ulceration, and abscess.
• Pulmonary infection: cough, chest pain, high fever, headaches, and loss of appetite
• Bacteremia: fever, headaches, breathing problems, stomach discomfort, joint pain, and disorientation.
• Disseminated infection: fever, weight loss, stomach or chest pain, muscle or joint pain, headaches, central nervous system infections, and epileptic seizures.

The incubation time is not clearly defined and can be from 1 day to several years; however, the symptoms mostly emerge 2-4 weeks after exposure. The risk factors include diabetes, high alcohol consumption, chronic pulmonary or kidney disease, and immunodeficiencies.

Diagnosis based on the symptoms is often difficult since the clinical picture is similar to other, more common conditions.
 

Therapy

If the melioidosis is identified as such, it can be treated with only mildly effective antibiotics, since it has a natural resistance to many commonly used antibiotics. The type of infection and the course of treatment also affects the long-term outcome. Without treatment, 90% of the infections have a fatal outcome. With appropriate treatment, the mortality rate still lies at 40%.

Therapy generally begins with intravenous antibiotic therapy for at least 2-8 weeks (ceftazidime or meropenem). Oral antibiotic therapy then follows for 3-6 months (trimethoprim-sulfamethoxazole or amoxicillin/clavulanic acid). If the patient is allergic to penicillin, alternative antibiotics can be used.
 

Use as a bioweapon

The CDC classifies B. pseudomallei as a potential pathogen for biological attack (class-B candidate). The agency lists the potential reasons for use as a bioweapon as:

• The pathogen can be found naturally in certain regions.
• The triggered disease can take a serious course and ultimately be fatal without appropriate therapy.
• In the past, the United States has used similar pathogens in wars as bioweapons.

In a potential attack, the pathogen could be spread through air, water, or food, and by doing so, many people would be exposed. Any contact with the bacteria can result in melioidosis. As the bacteria cannot be seen, smelled, or tasted, the biological attack would not be recognized for some time. A certain amount of time can also pass until the pathogen is identified, once fever and respiratory diseases have developed.

In such an emergency, the CDC would collaborate with other federal and local authorities to supply specialized testing laboratories and provide the public with information.

This content was translated from Coliquio. A version appeared on Medscape.com.

In 2021, in U.S. states far removed from one another, numerous cases of melioidosis (Whitmore’s disease) sprang up, some with a fatal outcome. What is the common factor linking all of those affected? So begins the search for evidence.

No relations or common journeys

Between March and July 2021, cases of the bacterial infectious disease sprang up in Georgia, Kansas, Minnesota, and Texas, with the disease being fatal for two of those affected. Usually, cases of melioidosis occur in the United States after traveling to regions where the pathogen is prevalent. However, none of the patients had undertaken any previous international travel.

When the genomes of the bacterial strains (Burkholderia pseudomallei) were sequenced, they showed a high level of concordance, suggesting a common source of infection. The bacterial strain is similar to those that are found in Southeast Asia above all. An imported product from there was taken into consideration as the trigger.

The Centers for Disease Control and Prevention examined blood samples from the patients, as well as samples from the soil, water, food, and household items around their homes.
 

Aroma spray as a trigger

In October, the cause of the melioidosis was finally identified in the house of the patient from Georgia: an aromatherapy spray. The genetic fingerprint of the bacterial strain matched with that from the other patients. The common trigger was thus discovered.

The contaminated spray, with a lavender-chamomile scent for room fragrancing, was sold between February and October in some branches of Walmart, as well as in their online store. The product was therefore recalled and it was checked whether the ingredients were also being used in other products.

The CDC requested physicians to also take melioidosis into account if they were presented with acute bacterial infections that did not respond to normal antibiotics and to inquire whether the affected room spray had been used.
 

More information about melioidosis

Melioidosis is an infectious disease affecting humans and animals. The trigger is the bacteria B pseudomallei. The disease appears predominantly in tropical regions, especially in Southeast Asia and northern Australia.

Transmission

The bacteria can be found in contaminated water and soil. It is disseminated between humans and animals through direct contact with the infectious source, such as through inhaling dust particles or water droplets, or through consuming contaminated water or food. Human-to-human transmission is extremely rare. Recently however, tropical saltwater fish were identified as potential carriers.

Symptoms

Melioidosis has a wide range of symptoms, which can lead to its being confused with other diseases such as tuberculosis or other forms of pneumonia. There are different forms of the disease, each with different symptoms.

• Localized infection: localized pain and swelling, fever, ulceration, and abscess.
• Pulmonary infection: cough, chest pain, high fever, headaches, and loss of appetite
• Bacteremia: fever, headaches, breathing problems, stomach discomfort, joint pain, and disorientation.
• Disseminated infection: fever, weight loss, stomach or chest pain, muscle or joint pain, headaches, central nervous system infections, and epileptic seizures.

The incubation time is not clearly defined and can be from 1 day to several years; however, the symptoms mostly emerge 2-4 weeks after exposure. The risk factors include diabetes, high alcohol consumption, chronic pulmonary or kidney disease, and immunodeficiencies.

Diagnosis based on the symptoms is often difficult since the clinical picture is similar to other, more common conditions.
 

Therapy

If the melioidosis is identified as such, it can be treated with only mildly effective antibiotics, since it has a natural resistance to many commonly used antibiotics. The type of infection and the course of treatment also affects the long-term outcome. Without treatment, 90% of the infections have a fatal outcome. With appropriate treatment, the mortality rate still lies at 40%.

Therapy generally begins with intravenous antibiotic therapy for at least 2-8 weeks (ceftazidime or meropenem). Oral antibiotic therapy then follows for 3-6 months (trimethoprim-sulfamethoxazole or amoxicillin/clavulanic acid). If the patient is allergic to penicillin, alternative antibiotics can be used.
 

Use as a bioweapon

The CDC classifies B. pseudomallei as a potential pathogen for biological attack (class-B candidate). The agency lists the potential reasons for use as a bioweapon as:

• The pathogen can be found naturally in certain regions.
• The triggered disease can take a serious course and ultimately be fatal without appropriate therapy.
• In the past, the United States has used similar pathogens in wars as bioweapons.

In a potential attack, the pathogen could be spread through air, water, or food, and by doing so, many people would be exposed. Any contact with the bacteria can result in melioidosis. As the bacteria cannot be seen, smelled, or tasted, the biological attack would not be recognized for some time. A certain amount of time can also pass until the pathogen is identified, once fever and respiratory diseases have developed.

In such an emergency, the CDC would collaborate with other federal and local authorities to supply specialized testing laboratories and provide the public with information.

This content was translated from Coliquio. A version appeared on Medscape.com.

This column presents a sampling of new and still-recruiting trials of interest to pulmonologists and their patients.

Trials are selected based primarily on these conditions: idiopathic pulmonary fibrosis/interstitial lung disease; chronic obstructive pulmonary disease (COPD); asthma; cystic fibrosis; infectious lung diseases; pulmonary artery hypertension; and lung cancer. Links to the studies and contact information are provided for each.

Idiopathic pulmonary fibrosis/interstitial lung disease

A Study to Evaluate Long-term Safety of Nintedanib in Children and Adolescents With Interstitial Lung Disease (InPedILD™-ON): NCT05285982

This nonrandomized, phase 3 study is open to children and adolescents between 6 and 17 years old who have interstitial lung disease with lung fibrosis. It is designed to test how well long-term treatment with nintedanib (a drug already used to treat lung fibrosis in adults) is tolerated in children and adolescents.

A total of 60 study participants will take nintedanib capsules twice a day for at least 2 years or until nintedanib or other treatment options become available outside of the study. There will be 9-11 site visits during the first 2 years and site visits every 3 months afterward.

Study physicians will collect information on any health problems of the participants. The primary outcome measure will be the incidence of treatment-emergent adverse events.
 

Location: 26 locations in the United States and internationally

Sponsor: Boehringer Ingelheim

Contact: [email protected]

Study start date: April 2022

Expected completion Date: May 2026

Asthma

A Phase 2, Single-Dose, Randomized, Active and Placebo Controlled, Four-Period, Cross-Over Study of the Safety and Efficacy of Intranasal Epinephrine After Administration of ARS-1 or Albuterol in Subjects With Persistent Asthma: NCT05363670

ARS-1 is a novel aqueous formulation of epinephrine nasal spray. The primary outcomes of this study will be the effect of ARS-1 versus albuterol and placebo from baseline to 1 hour on the difference in forced expiratory volume in 1 second based on area under the curve.

A total of 30 study participants (ages 12-65 years) will be recruited.
 

Location: Three U.S. locations in Florida, Maryland, and Ohio.

Sponsor: ARS Pharmaceuticals

Contact: [email protected]

Study start date: July 2022

Expected completion Date: November 2022

COPD

Treatment of Pneumocystitis in COPD (the TOPIC Study): NCT05418777

In this randomized, double-blind, placebo-controlled study, the primary outcome will be to determine if treating Pneumocystis jirovecii in acute exacerbations of COPD with confirmed P. jirovecii colonization has a beneficial clinical impact. As a secondary goal of the study, it will be determined if the addition of trimethoprim-sulfamethoxazole (TMP-SMX) to standard of care can decolonize these patients and if the decolonization is durable for at least 3 months.
 

A total of 30 participants aged 40-89 years will be randomized to receive either a suspension with the equivalent of one double-strength TMP-SMX or a suspension with placebo by mouth every 12 hours. If the participant is discharged prior to completing the 10-day course of the medication, they will be sent home with the remaining study medication and a medication diary which will be collected.
 

Location: William Beaumont Hospital, Royal Oak, Mich.

Sponsor: William Beaumont Hospitals

Contact: [email protected]

Study start date: July 2022

Expected completion Date: August 2023

Inter-lobar Fissure Completion in Patients With Failed Bronchoscopic Lung Volume Reduction (SAVED-1): NCT05257681

This study is intended to be a pilot prospective controlled clinical trial to evaluate the potential role of a lung fissure completion with pleural adhesiolysis strategy (experimental intervention) in severe emphysema/COPD patients with failed bronchoscopic lung volume reduction via the use of endobronchial valves therapy.

In 20 select patients (ages 40-75 years), the lung fissure completion with adhesiolysis strategy will be performed by video-assisted thoracoscopic surgery guided stapling along the lung fissures to reduce collateral ventilation with adhesions removal. The primary outcomes will be to prove that interlobar fissures can be completed to at least 95% in severe emphysema patients with previously failed bronchoscopic lung volume reduction over a 2 year period and the occurrence of adverse events in that period. The surgery will be considered feasible if the target inter-lobar fissure can be completed in at least 90% of the patients enrolled. Secondary outcomes over 2 years will include quality of life improvement and the percentage of patients with significant changes in pulmonary function testing.
 

Location: Beth Deaconess Medical Center, Boston

Sponsor: Beth Israel Deaconess Medical Center

Contact: [email protected]

Study start date: May 2022

Expected completion Date: May 2024

This column presents a sampling of new and still-recruiting trials of interest to pulmonologists and their patients.

Trials are selected based primarily on these conditions: idiopathic pulmonary fibrosis/interstitial lung disease; chronic obstructive pulmonary disease (COPD); asthma; cystic fibrosis; infectious lung diseases; pulmonary artery hypertension; and lung cancer. Links to the studies and contact information are provided for each.

Idiopathic pulmonary fibrosis/interstitial lung disease

A Study to Evaluate Long-term Safety of Nintedanib in Children and Adolescents With Interstitial Lung Disease (InPedILD™-ON): NCT05285982

This nonrandomized, phase 3 study is open to children and adolescents between 6 and 17 years old who have interstitial lung disease with lung fibrosis. It is designed to test how well long-term treatment with nintedanib (a drug already used to treat lung fibrosis in adults) is tolerated in children and adolescents.

A total of 60 study participants will take nintedanib capsules twice a day for at least 2 years or until nintedanib or other treatment options become available outside of the study. There will be 9-11 site visits during the first 2 years and site visits every 3 months afterward.

Study physicians will collect information on any health problems of the participants. The primary outcome measure will be the incidence of treatment-emergent adverse events.
 

Location: 26 locations in the United States and internationally

Sponsor: Boehringer Ingelheim

Contact: [email protected]

Study start date: April 2022

Expected completion Date: May 2026

Asthma

A Phase 2, Single-Dose, Randomized, Active and Placebo Controlled, Four-Period, Cross-Over Study of the Safety and Efficacy of Intranasal Epinephrine After Administration of ARS-1 or Albuterol in Subjects With Persistent Asthma: NCT05363670

ARS-1 is a novel aqueous formulation of epinephrine nasal spray. The primary outcomes of this study will be the effect of ARS-1 versus albuterol and placebo from baseline to 1 hour on the difference in forced expiratory volume in 1 second based on area under the curve.

A total of 30 study participants (ages 12-65 years) will be recruited.
 

Location: Three U.S. locations in Florida, Maryland, and Ohio.

Sponsor: ARS Pharmaceuticals

Contact: [email protected]

Study start date: July 2022

Expected completion Date: November 2022

COPD

Treatment of Pneumocystitis in COPD (the TOPIC Study): NCT05418777

In this randomized, double-blind, placebo-controlled study, the primary outcome will be to determine if treating Pneumocystis jirovecii in acute exacerbations of COPD with confirmed P. jirovecii colonization has a beneficial clinical impact. As a secondary goal of the study, it will be determined if the addition of trimethoprim-sulfamethoxazole (TMP-SMX) to standard of care can decolonize these patients and if the decolonization is durable for at least 3 months.
 

A total of 30 participants aged 40-89 years will be randomized to receive either a suspension with the equivalent of one double-strength TMP-SMX or a suspension with placebo by mouth every 12 hours. If the participant is discharged prior to completing the 10-day course of the medication, they will be sent home with the remaining study medication and a medication diary which will be collected.
 

Location: William Beaumont Hospital, Royal Oak, Mich.

Sponsor: William Beaumont Hospitals

Contact: [email protected]

Study start date: July 2022

Expected completion Date: August 2023

Inter-lobar Fissure Completion in Patients With Failed Bronchoscopic Lung Volume Reduction (SAVED-1): NCT05257681

This study is intended to be a pilot prospective controlled clinical trial to evaluate the potential role of a lung fissure completion with pleural adhesiolysis strategy (experimental intervention) in severe emphysema/COPD patients with failed bronchoscopic lung volume reduction via the use of endobronchial valves therapy.

In 20 select patients (ages 40-75 years), the lung fissure completion with adhesiolysis strategy will be performed by video-assisted thoracoscopic surgery guided stapling along the lung fissures to reduce collateral ventilation with adhesions removal. The primary outcomes will be to prove that interlobar fissures can be completed to at least 95% in severe emphysema patients with previously failed bronchoscopic lung volume reduction over a 2 year period and the occurrence of adverse events in that period. The surgery will be considered feasible if the target inter-lobar fissure can be completed in at least 90% of the patients enrolled. Secondary outcomes over 2 years will include quality of life improvement and the percentage of patients with significant changes in pulmonary function testing.
 

Location: Beth Deaconess Medical Center, Boston

Sponsor: Beth Israel Deaconess Medical Center

Contact: [email protected]

Study start date: May 2022

Expected completion Date: May 2024

This column presents a sampling of new and still-recruiting trials of interest to pulmonologists and their patients.

Trials are selected based primarily on these conditions: idiopathic pulmonary fibrosis/interstitial lung disease; chronic obstructive pulmonary disease (COPD); asthma; cystic fibrosis; infectious lung diseases; pulmonary artery hypertension; and lung cancer. Links to the studies and contact information are provided for each.

Idiopathic pulmonary fibrosis/interstitial lung disease

A Study to Evaluate Long-term Safety of Nintedanib in Children and Adolescents With Interstitial Lung Disease (InPedILD™-ON): NCT05285982

This nonrandomized, phase 3 study is open to children and adolescents between 6 and 17 years old who have interstitial lung disease with lung fibrosis. It is designed to test how well long-term treatment with nintedanib (a drug already used to treat lung fibrosis in adults) is tolerated in children and adolescents.

A total of 60 study participants will take nintedanib capsules twice a day for at least 2 years or until nintedanib or other treatment options become available outside of the study. There will be 9-11 site visits during the first 2 years and site visits every 3 months afterward.

Study physicians will collect information on any health problems of the participants. The primary outcome measure will be the incidence of treatment-emergent adverse events.
 

Location: 26 locations in the United States and internationally

Sponsor: Boehringer Ingelheim

Contact: [email protected]

Study start date: April 2022

Expected completion Date: May 2026

Asthma

A Phase 2, Single-Dose, Randomized, Active and Placebo Controlled, Four-Period, Cross-Over Study of the Safety and Efficacy of Intranasal Epinephrine After Administration of ARS-1 or Albuterol in Subjects With Persistent Asthma: NCT05363670

ARS-1 is a novel aqueous formulation of epinephrine nasal spray. The primary outcomes of this study will be the effect of ARS-1 versus albuterol and placebo from baseline to 1 hour on the difference in forced expiratory volume in 1 second based on area under the curve.

A total of 30 study participants (ages 12-65 years) will be recruited.
 

Location: Three U.S. locations in Florida, Maryland, and Ohio.

Sponsor: ARS Pharmaceuticals

Contact: [email protected]

Study start date: July 2022

Expected completion Date: November 2022

COPD

Treatment of Pneumocystitis in COPD (the TOPIC Study): NCT05418777

In this randomized, double-blind, placebo-controlled study, the primary outcome will be to determine if treating Pneumocystis jirovecii in acute exacerbations of COPD with confirmed P. jirovecii colonization has a beneficial clinical impact. As a secondary goal of the study, it will be determined if the addition of trimethoprim-sulfamethoxazole (TMP-SMX) to standard of care can decolonize these patients and if the decolonization is durable for at least 3 months.
 

A total of 30 participants aged 40-89 years will be randomized to receive either a suspension with the equivalent of one double-strength TMP-SMX or a suspension with placebo by mouth every 12 hours. If the participant is discharged prior to completing the 10-day course of the medication, they will be sent home with the remaining study medication and a medication diary which will be collected.
 

Location: William Beaumont Hospital, Royal Oak, Mich.

Sponsor: William Beaumont Hospitals

Contact: [email protected]

Study start date: July 2022

Expected completion Date: August 2023

Inter-lobar Fissure Completion in Patients With Failed Bronchoscopic Lung Volume Reduction (SAVED-1): NCT05257681

This study is intended to be a pilot prospective controlled clinical trial to evaluate the potential role of a lung fissure completion with pleural adhesiolysis strategy (experimental intervention) in severe emphysema/COPD patients with failed bronchoscopic lung volume reduction via the use of endobronchial valves therapy.

In 20 select patients (ages 40-75 years), the lung fissure completion with adhesiolysis strategy will be performed by video-assisted thoracoscopic surgery guided stapling along the lung fissures to reduce collateral ventilation with adhesions removal. The primary outcomes will be to prove that interlobar fissures can be completed to at least 95% in severe emphysema patients with previously failed bronchoscopic lung volume reduction over a 2 year period and the occurrence of adverse events in that period. The surgery will be considered feasible if the target inter-lobar fissure can be completed in at least 90% of the patients enrolled. Secondary outcomes over 2 years will include quality of life improvement and the percentage of patients with significant changes in pulmonary function testing.
 

Location: Beth Deaconess Medical Center, Boston

Sponsor: Beth Israel Deaconess Medical Center

Contact: [email protected]

Study start date: May 2022

Expected completion Date: May 2024

Case Example

A 37-year-old female never smoker presents to your clinic with progressive dyspnea over the past 15 years. She reports dyspnea on exertion, wheezing, chronic nasal congestion, and difficulty sleeping that started a year after she returned from military deployment to Iraq. She has been unable to exercise, even at low intensity, for the past 5 years, despite being previously active. She has experienced some symptom improvement by taking an albuterol inhaler as needed, loratadine (10 mg), and fluticasone nasal spray (50 mcg). She occasionally uses famotidine for reflux (40 mg). She deployed to Southwest Asia for 12 months (2002-2003) and was primarily stationed in Qayyarah West, an Air Force base in the Mosul district in northern Iraq. She reports exposure during deployment to the fire in the Al-Mishraq sulfur mine, located approximately 25 km north of Qayyarah West, as well as dust storms and burn pits. She currently works as a medical assistant. Her examination is remarkable for normal bronchovesicular breath sounds without any wheezing or crackles on pulmonary evaluation. Her body mass index is 31. You obtain a chest radiograph and spirometry, which are both normal.

The veteran reports feeling frustrated as she has had multiple specialty evaluations in community clinics without receiving a diagnosis, despite worsening symptoms. She reports that she added her information to the Airborne Hazards and Open Burn Pit Registry (AHOBPR). She recently received a letter from the US Department of Veterans Affairs (VA) Post-Deployment Cardiopulmonary Evaluation Network (PDCEN) and is asking you whether she should participate in the PDCEN specialty evaluation. You are not familiar with the military experiences she has described or the programs she asks you about; however, you would like to know more to best care for your patient.

Background

The year 2021 marked the 20th anniversary of the September 11 attacks and the launch of the Global War on Terrorism. Almost 3 million US military personnel have been deployed in support of these operations along with about 300,000 US civilian contractors and thousands of troops from more than 40 nations.^1-3

Deployment after 2001 to Afghanistan and the Southwest Asia theater of operations, which includes but is not limited to Iraq, Kuwait, and Saudi Arabia, has been associated with increased prevalence of dyspnea and cough as well as diagnoses of asthma, chronic obstructive pulmonary disease (COPD), and other chronic respiratory diseases.^4-9 Expert committees convened by the National Academies of Sciences, Engineering, and Medicine concluded that deployment to the Southwest Asia region and Afghanistan was associated with respiratory symptoms of cough, wheeze, and shortness of breath and might be associated with long-term health effects, particularly in vulnerable (eg, individuals with asthma) or highly exposed populations (eg, those assigned to work at burn pits).^10,11 Several reports have found constrictive bronchiolitis, emphysema, granulomatous inflammation, and pigment deposition on lung biopsy in deployed persons with unexplained dyspnea and subtle, or normal, clinical findings.^12-14

Respiratory hazards associated with deployment to Southwest Asia and Afghanistan are unique and varied. These exposures include blast injuries and a variety of particulate matter sources, such as burn pit combustion byproducts, aeroallergens, and dust storms.^7,8,15,16 One air sampling study conducted at 15 deployment sites in Southwest Asia and Afghanistan found mean fine particulate matter (PM_2.5) levels were as much as 10 times greater than sampling sites in both rural and urban cities in the United States; all sites sampled exceeded military exposure guidelines (65 µg/m³ for 1 year).^17,18 Long-term exposure to PM_2.5 has been associated with the development of chronic respiratory and cardiovascular disease; therefore, there has been considerable attention to the respiratory (and nonrespiratory) health of deployed military personnel.¹⁹

Concerns regarding the association between deployment and lung disease led to the creation of the national VA Airborne Hazards and Open Burn Pit Registry (AHOBPR) in 2014 and consists of (1) an online questionnaire to document deployment and medical history, exposure concerns, and symptoms; and (2) an optional in-person or virtual clinical health evaluation at the individual’s local VA medical center or military treatment facility (MTF). As of March 2022, more than 300,000 individuals have completed the online questionnaire of which about 30% declined the optional clinical health evaluation.

The clinical evaluation available to AHOBPR participants has not yet been described in the literature. Therefore, our objectives are to examine AHOBPR clinical evaluation data and review its application throughout the VA. In addition, we will also describe a parallel effort by the VA PDCEN, which is to provide comprehensive multiday clinical evaluations for unique AHOBPR participants with unexplained dyspnea and self-reported respiratory disease. A secondary aim of this publication is to disseminate information to health care professionals (HCPs) within and outside of the VA to aid in the referral and evaluation of previously deployed veterans who experience unexplained dyspnea.

AHOBPR Overview

The AHOBPR is an online questionnaire and optional in-person health evaluation that includes 7 major categories targeting deployment history, symptoms, medical history, health concerns, residential history, nonmilitary occupational history, nonmilitary environmental exposures, and health care utilization. The VA Defense Information Repository is used to obtain service dates for the service member/veteran, conflict involvement, and primary location during deployment. The questionnaire portion of the AHOBPR is administered online. It currently is open to all veterans who served in the Southwest Asia theater of operations (including Iraq, Kuwait, and Egypt) any time after August 2, 1990, or Afghanistan, Djibouti, Syria, or Uzbekistan after September 11, 2001. Veterans are eligible for completing the AHOBPR and optional health evaluation at no cost to the veteran regardless of VA benefits or whether they are currently enrolled in VA health care. Though the focus of the present manuscript is to profile a VA program, it is important to note that the US Department of Defense (DoD) is an active partner with the VA in the promotion of the AHOBPR to service members and similarly provides health evaluations for active-duty service members (including activating Reserve and Guard) through their local MTF.

We reviewed and analyzed AHOBPR operations and VA data from 2014 to 2020. Our analyses were limited to veterans seeking evaluation as well as their corresponding symptoms and HCP’s clinical impression from the electronic health record. As of September 20, 2021, 267,125 individuals completed the AHOBPR. The mean age was 43 years (range, 19-84), and the majority were male (86%) and served in the Army (58%). Open-air burn pits (91%), engine maintenance (38.8%), and convoy operations (71.7%) were the most common deployment-related exposures.

The optional in-person AHOBPR health evaluation may be requested by the veteran after completing the online questionnaire and is performed at the veteran’s local VA facility. The evaluation is most often completed by an environmental health clinician or primary care practitioner (PCP). A variety of resources are available to providers for training on this topic, including fact sheets, webinars, monthly calls, conferences, and accredited e-learning.²⁰ As part of the clinical evaluation, the veteran’s chief concerns are assessed and evaluated. At the time of our analysis, 24,578 clinical examinations were performed across 126 VA medical facilities, with considerable geographic variation. Veterans receiving evaluations were predominantly male (89%) with a median age of 46.0 years (IQR, 15). Veterans’ major respiratory concerns included dyspnea (45.1%), decreased exercise ability (34.8%), and cough > 3 weeks (30.3%) (Table). After clinical evaluation by a VA or MTF HCP, 47.8% were found to have a respiratory diagnosis, including asthma (30.1%), COPD (12.8%), and bronchitis (11.9%).

Post-Deployment Cardiopulmonary Evaluation Network Clinical Evaluation

In May 2019, the VA established the Airborne Hazards and Burn Pits Center of Excellence (AHBPCE). One of the AHBPCE’s objectives is to deliver specialized care and consultation for veterans with concerns about their postdeployment health, including, but not limited to, unexplained dyspnea. To meet this objective, the AHBPCE developed the PDCEN, a national network consisting of specialty HCPs from 5 VA medical centers—located in San Francisco, California; Denver, Colorado; Baltimore, Maryland; Ann Arbor, Michigan; and East Orange, New Jersey. Collectively, the PDCEN has developed a standardized approach for the comprehensive clinical evaluation of unexplained dyspnea that is implemented uniformly across sites. Staff at the PDCEN screen the AHOBPR to identify veterans with features of respiratory disease and invite them to participate in an in-person evaluation at the nearest PDCEN site. Given the specialty expertise (detailed below) within the Network, the PDCEN focuses on complex cases that are resource intensive. To address complex cases of unexplained dyspnea, the PDCEN has developed a core clinical evaluation approach (Figure).

The first step in a veteran’s PDCEN evaluation entails a set of detailed questionnaires that request information about the veteran’s current respiratory, sleep, and mental health symptoms and any associated medical diagnoses. Questionnaires also identify potential exposures to military burn pits, sulfur mine and oil field fires, diesel exhaust fumes, dust storms, urban pollution, explosions/blasts, and chemical weapons. In addition, the questionnaires include deployment geographic location, which may inform future estimates of particulate matter exposure.²¹ Prior VA and non-VA evaluations and testing of their respiratory concerns are obtained for review. Exposure and health records from the DoD are also reviewed when available.

The next step in the PDCEN evaluation comprises comprehensive testing, including complete pulmonary function testing, methacholine challenge, cardiopulmonary exercise testing, forced oscillometry and exhaled nitric oxide testing, paired high-resolution inspiratory and expiratory chest computed tomography (CT) imaging, sinus CT imaging, direct flexible laryngoscopy, echocardiography, polysomnography, and laboratory blood testing. The testing process is managed by local site coordinators and varies by institution based on availability of each testing modality and subspecialist appointments.

Once testing is completed, the veteran is evaluated by a team of HCPs, including physicians from the disciplines of pulmonary medicine, environmental and occupational health, sleep medicine, otolaryngology and speech pathology, and mental health (when appropriate). After the clinical evaluation has been completed, this team of expert HCPs at each site convenes to provide a final summary review visit intended to be a comprehensive assessment of the veteran’s primary health concerns. The 3 primary objectives of this final review are to inform the veteran of (1) what respiratory and related conditions they have; (2) whether the conditions is/are deployment related; and (3) what treatments and/or follow-up care may enhance their current state of health in partnership with their local HCPs. The PDCEN does not provide ongoing management of any conditions identified during the veteran’s evaluation but communicates findings and recommendations to the veteran and their PCP for long-term care.

Discussion

The AHOBPR was established in response to mounting concerns that service members and veterans were experiencing adverse health effects that might be attributable to deployment-related exposures. Nearly half of all patients currently enrolled in the AHOBPR report dyspnea, and about one-third have decreased exercise tolerance and/or cough. Of those who completed the questionnaire and the subsequent in-person and generalized AHOBPR examination, our interim analysis showed that about half were assigned a respiratory diagnosis. Yet for many veterans, their breathing symptoms remained unexplained or did not respond to treatment.

While the AHOBPR and related examinations address the needs of many veterans, others may require more comprehensive examination. The PDCEN attends to the latter by providing more detailed and comprehensive clinical evaluations of veterans with deployment-related respiratory health concerns and seeks to learn from these evaluations by analyzing data obtained from veterans across sites. As such, the PDCEN hopes not only to improve the health of individual veterans, but also create standard practices for both VA and non-VA community evaluation of veterans exposed to respiratory hazards during deployment.

One of the major challenges in the field of postdeployment respiratory health is the lack of clear universal language or case definitions that encompass the veteran’s clinical concerns. In an influential case series published in 2011, 38 (77%) of 49 soldiers with history of airborne hazard exposure and unexplained exercise intolerance were reported to have histopathology consistent with constrictive bronchiolitis on surgical lung biopsy.¹⁴ Subsequent publications have described other histopathologic features in deployed military personnel, including granulomatous inflammation, interstitial lung disease, emphysema, and pleuritis.^12-14 Reconciling these findings from surgical lung biopsy with the clinical presentation and noninvasive studies has proved difficult. Therefore, several groups of investigators have proposed terms, including postdeployment respiratory syndrome, deployment-related distal lung disease, and Iraq/Afghanistan War lung injury to describe the increased respiratory symptoms and variety of histopathologic and imaging findings in this population.^9,12,22 At present, there remains a lack of consensus on terminology and case definitions as well as the role of military environmental exposures in exacerbating and/or causing these conditions. As HCPs, it is important to appreciate and acknowledge that the ambiguity and controversy pertaining to terminology, causation, and service connections are a common source of frustration experienced by veterans, which are increasingly reflected among reports in popular media and lay press.

A second and related challenge in the field of postdeployment respiratory health that contributes to veteran and HCP frustration is that many of the aforementioned abnormalities described on surgical lung biopsy are not readily identifiable on noninvasive tests, including traditional interpretation of pulmonary function tests or chest CT imaging.^12-14,22 Thus, underlying conditions could be overlooked and veterans’ concerns and symptoms may be dismissed or misattributed to other comorbid conditions. While surgical lung biopsies may offer diagnostic clarity in identifying lung disease, there are significant procedural risks of surgical and anesthetic complications. Furthermore, a definitive diagnosis does not necessarily guarantee a clear treatment plan. For example, there are no current therapies approved by the US Food and Drug Administration for the treatment of constrictive bronchiolitis.

Research efforts are underway, including within the PDCEN, to evaluate a more sensitive and noninvasive assessment of the small airways that may even reduce or eliminate the need for surgical lung biopsy. In contrast to traditional pulmonary function testing, which is helpful for evaluation of the larger airways, forced oscillation technique can be used noninvasively, using pressure oscillations to evaluate for diseases of the smaller airways and has been used in the veteran population and in those exposed to dust from the World Trade Center disaster.^23-25 Multiple breath washout technique provides a lung clearance index that is determined by the number of lung turnovers it takes to clear the lungs of an inert gas (eg, sulfur hexafluoride, nitrogen). Elevated lung clearance index values suggest ventilation heterogeneity and have been shown to be higher among deployed veterans with dyspnea.^26,27 Finally, advanced CT analytic techniques may help identify functional small airways disease and are higher in deployed service members with constrictive bronchiolitis on surgical lung biopsy.²⁸ These innovative noninvasive techniques are experimental but promising, especially as part of a broader evaluation of small airways disease.

AHOBPR clinical evaluations represent an initial step to better understand postdeployment health conditions available to all AHOBPR participants. The PDCEN clinical evaluation extends the AHOBPR evaluation by providing specialty care for certain veterans requiring more comprehensive evaluation while systematically collecting and analyzing clinical data to advance the field. The VA is committed to leveraging these data and all available expertise to provide a clear description of the spectrum of disease in this population and improve our ability to diagnose, follow, and treat respiratory health conditions occurring after deployment to Southwest Asia and Afghanistan.

Case Conclusion

The veteran was referred to a PDCEN site and underwent a comprehensive multidisciplinary evaluation. Pulmonary function testing showed lung volumes and vital capacity within the predicted normal range, mild air trapping, and a low diffusion capacity for carbon monoxide. Methacholine challenge testing was normal; however, forced oscillometry suggested small airways obstruction. A high-resolution CT showed air trapping without parenchymal changes. Cardiopulmonary exercise testing demonstrated a peak exercise capacity within the predicted normal range but low breathing reserve. Otolaryngology evaluation including laryngoscopy suggested chronic nonallergic rhinitis.

At the end of the veteran’s evaluation, a summary review reported nonallergic rhinitis and distal airway obstruction consistent with small airways disease. Both were reported as most likely related to deployment given her significant environmental exposures and the temporal relationship with her deployment and symptom onset as well as lack of other identifiable causes. A more precise histopathologic diagnosis could be firmly established with a surgical lung biopsy, but after shared decision making with a PDCEN HCP, the patient declined to undergo this invasive procedure. After you review the summary review and recommendations from the PDCEN group, you start the veteran on intranasal steroids and a combined inhaled corticosteroid/long-acting β agonist inhaler as well as refer the veteran to pulmonary rehabilitation. After several weeks, she reports an improvement in sleep and nasal symptoms but continues to experience residual exercise intolerance.

This case serves as an example of the significant limitations that a previously active and healthy patient can develop after deployment to Southwest Asia and Afghanistan. Encouraging this veteran to complete the AHOBPR allowed her to be considered for a PDCEN evaluation that provided the opportunity to undergo a comprehensive noninvasive evaluation of her chronic dyspnea. In doing so, she obtained 2 important diagnoses and data from her evaluation will help establish best practices for standardized evaluations of respiratory concerns following deployment. Through the AHOBPR and PDCEN, the VA seeks to better understand postdeployment health conditions, their relationship to military and environmental exposures, and how best to diagnose and treat these conditions.

Acknowledgments

This work was supported by the US Department of Veterans Affairs (VA) Airborne Hazards and Burn Pits Center of Excellence (Public Law 115-929). The authors acknowledge support and contributions from Dr. Eric Shuping and leadership at VA’s Health Outcomes Military Exposures office as well as the New Jersey War Related Illness and Injury Study Center. In addition, we thank Erin McRoberts and Rajeev Swarup for their contributions to the Post-Deployment Cardiopulmonary Evaluation Network. Post-Deployment Cardiopulmonary Evaluation Network members:

Mehrdad Arjomandi, Caroline Davis, Michelle DeLuca, Nancy Eager, Courtney A. Eberhardt, Michael J. Falvo, Timothy Foley, Fiona A.S. Graff, Deborah Heaney, Stella E. Hines, Rachel E. Howard, Nisha Jani, Sheena Kamineni, Silpa Krefft, Mary L. Langlois, Helen Lozier, Simran K. Matharu, Anisa Moore, Lydia Patrick-DeLuca, Edward Pickering, Alexander Rabin, Michelle Robertson, Samantha L. Rogers, Aaron H. Schneider, Anand Shah, Anays Sotolongo, Jennifer H. Therkorn, Rebecca I. Toczylowski, Matthew Watson, Alison D. Wilczynski, Ian W. Wilson, Romi A. Yount.

Case Example

A 37-year-old female never smoker presents to your clinic with progressive dyspnea over the past 15 years. She reports dyspnea on exertion, wheezing, chronic nasal congestion, and difficulty sleeping that started a year after she returned from military deployment to Iraq. She has been unable to exercise, even at low intensity, for the past 5 years, despite being previously active. She has experienced some symptom improvement by taking an albuterol inhaler as needed, loratadine (10 mg), and fluticasone nasal spray (50 mcg). She occasionally uses famotidine for reflux (40 mg). She deployed to Southwest Asia for 12 months (2002-2003) and was primarily stationed in Qayyarah West, an Air Force base in the Mosul district in northern Iraq. She reports exposure during deployment to the fire in the Al-Mishraq sulfur mine, located approximately 25 km north of Qayyarah West, as well as dust storms and burn pits. She currently works as a medical assistant. Her examination is remarkable for normal bronchovesicular breath sounds without any wheezing or crackles on pulmonary evaluation. Her body mass index is 31. You obtain a chest radiograph and spirometry, which are both normal.

The veteran reports feeling frustrated as she has had multiple specialty evaluations in community clinics without receiving a diagnosis, despite worsening symptoms. She reports that she added her information to the Airborne Hazards and Open Burn Pit Registry (AHOBPR). She recently received a letter from the US Department of Veterans Affairs (VA) Post-Deployment Cardiopulmonary Evaluation Network (PDCEN) and is asking you whether she should participate in the PDCEN specialty evaluation. You are not familiar with the military experiences she has described or the programs she asks you about; however, you would like to know more to best care for your patient.

Background

The year 2021 marked the 20th anniversary of the September 11 attacks and the launch of the Global War on Terrorism. Almost 3 million US military personnel have been deployed in support of these operations along with about 300,000 US civilian contractors and thousands of troops from more than 40 nations.^1-3

Deployment after 2001 to Afghanistan and the Southwest Asia theater of operations, which includes but is not limited to Iraq, Kuwait, and Saudi Arabia, has been associated with increased prevalence of dyspnea and cough as well as diagnoses of asthma, chronic obstructive pulmonary disease (COPD), and other chronic respiratory diseases.^4-9 Expert committees convened by the National Academies of Sciences, Engineering, and Medicine concluded that deployment to the Southwest Asia region and Afghanistan was associated with respiratory symptoms of cough, wheeze, and shortness of breath and might be associated with long-term health effects, particularly in vulnerable (eg, individuals with asthma) or highly exposed populations (eg, those assigned to work at burn pits).^10,11 Several reports have found constrictive bronchiolitis, emphysema, granulomatous inflammation, and pigment deposition on lung biopsy in deployed persons with unexplained dyspnea and subtle, or normal, clinical findings.^12-14

Respiratory hazards associated with deployment to Southwest Asia and Afghanistan are unique and varied. These exposures include blast injuries and a variety of particulate matter sources, such as burn pit combustion byproducts, aeroallergens, and dust storms.^7,8,15,16 One air sampling study conducted at 15 deployment sites in Southwest Asia and Afghanistan found mean fine particulate matter (PM_2.5) levels were as much as 10 times greater than sampling sites in both rural and urban cities in the United States; all sites sampled exceeded military exposure guidelines (65 µg/m³ for 1 year).^17,18 Long-term exposure to PM_2.5 has been associated with the development of chronic respiratory and cardiovascular disease; therefore, there has been considerable attention to the respiratory (and nonrespiratory) health of deployed military personnel.¹⁹

Concerns regarding the association between deployment and lung disease led to the creation of the national VA Airborne Hazards and Open Burn Pit Registry (AHOBPR) in 2014 and consists of (1) an online questionnaire to document deployment and medical history, exposure concerns, and symptoms; and (2) an optional in-person or virtual clinical health evaluation at the individual’s local VA medical center or military treatment facility (MTF). As of March 2022, more than 300,000 individuals have completed the online questionnaire of which about 30% declined the optional clinical health evaluation.

The clinical evaluation available to AHOBPR participants has not yet been described in the literature. Therefore, our objectives are to examine AHOBPR clinical evaluation data and review its application throughout the VA. In addition, we will also describe a parallel effort by the VA PDCEN, which is to provide comprehensive multiday clinical evaluations for unique AHOBPR participants with unexplained dyspnea and self-reported respiratory disease. A secondary aim of this publication is to disseminate information to health care professionals (HCPs) within and outside of the VA to aid in the referral and evaluation of previously deployed veterans who experience unexplained dyspnea.

AHOBPR Overview

The AHOBPR is an online questionnaire and optional in-person health evaluation that includes 7 major categories targeting deployment history, symptoms, medical history, health concerns, residential history, nonmilitary occupational history, nonmilitary environmental exposures, and health care utilization. The VA Defense Information Repository is used to obtain service dates for the service member/veteran, conflict involvement, and primary location during deployment. The questionnaire portion of the AHOBPR is administered online. It currently is open to all veterans who served in the Southwest Asia theater of operations (including Iraq, Kuwait, and Egypt) any time after August 2, 1990, or Afghanistan, Djibouti, Syria, or Uzbekistan after September 11, 2001. Veterans are eligible for completing the AHOBPR and optional health evaluation at no cost to the veteran regardless of VA benefits or whether they are currently enrolled in VA health care. Though the focus of the present manuscript is to profile a VA program, it is important to note that the US Department of Defense (DoD) is an active partner with the VA in the promotion of the AHOBPR to service members and similarly provides health evaluations for active-duty service members (including activating Reserve and Guard) through their local MTF.

We reviewed and analyzed AHOBPR operations and VA data from 2014 to 2020. Our analyses were limited to veterans seeking evaluation as well as their corresponding symptoms and HCP’s clinical impression from the electronic health record. As of September 20, 2021, 267,125 individuals completed the AHOBPR. The mean age was 43 years (range, 19-84), and the majority were male (86%) and served in the Army (58%). Open-air burn pits (91%), engine maintenance (38.8%), and convoy operations (71.7%) were the most common deployment-related exposures.

The optional in-person AHOBPR health evaluation may be requested by the veteran after completing the online questionnaire and is performed at the veteran’s local VA facility. The evaluation is most often completed by an environmental health clinician or primary care practitioner (PCP). A variety of resources are available to providers for training on this topic, including fact sheets, webinars, monthly calls, conferences, and accredited e-learning.²⁰ As part of the clinical evaluation, the veteran’s chief concerns are assessed and evaluated. At the time of our analysis, 24,578 clinical examinations were performed across 126 VA medical facilities, with considerable geographic variation. Veterans receiving evaluations were predominantly male (89%) with a median age of 46.0 years (IQR, 15). Veterans’ major respiratory concerns included dyspnea (45.1%), decreased exercise ability (34.8%), and cough > 3 weeks (30.3%) (Table). After clinical evaluation by a VA or MTF HCP, 47.8% were found to have a respiratory diagnosis, including asthma (30.1%), COPD (12.8%), and bronchitis (11.9%).

Post-Deployment Cardiopulmonary Evaluation Network Clinical Evaluation

In May 2019, the VA established the Airborne Hazards and Burn Pits Center of Excellence (AHBPCE). One of the AHBPCE’s objectives is to deliver specialized care and consultation for veterans with concerns about their postdeployment health, including, but not limited to, unexplained dyspnea. To meet this objective, the AHBPCE developed the PDCEN, a national network consisting of specialty HCPs from 5 VA medical centers—located in San Francisco, California; Denver, Colorado; Baltimore, Maryland; Ann Arbor, Michigan; and East Orange, New Jersey. Collectively, the PDCEN has developed a standardized approach for the comprehensive clinical evaluation of unexplained dyspnea that is implemented uniformly across sites. Staff at the PDCEN screen the AHOBPR to identify veterans with features of respiratory disease and invite them to participate in an in-person evaluation at the nearest PDCEN site. Given the specialty expertise (detailed below) within the Network, the PDCEN focuses on complex cases that are resource intensive. To address complex cases of unexplained dyspnea, the PDCEN has developed a core clinical evaluation approach (Figure).

The first step in a veteran’s PDCEN evaluation entails a set of detailed questionnaires that request information about the veteran’s current respiratory, sleep, and mental health symptoms and any associated medical diagnoses. Questionnaires also identify potential exposures to military burn pits, sulfur mine and oil field fires, diesel exhaust fumes, dust storms, urban pollution, explosions/blasts, and chemical weapons. In addition, the questionnaires include deployment geographic location, which may inform future estimates of particulate matter exposure.²¹ Prior VA and non-VA evaluations and testing of their respiratory concerns are obtained for review. Exposure and health records from the DoD are also reviewed when available.

The next step in the PDCEN evaluation comprises comprehensive testing, including complete pulmonary function testing, methacholine challenge, cardiopulmonary exercise testing, forced oscillometry and exhaled nitric oxide testing, paired high-resolution inspiratory and expiratory chest computed tomography (CT) imaging, sinus CT imaging, direct flexible laryngoscopy, echocardiography, polysomnography, and laboratory blood testing. The testing process is managed by local site coordinators and varies by institution based on availability of each testing modality and subspecialist appointments.

Once testing is completed, the veteran is evaluated by a team of HCPs, including physicians from the disciplines of pulmonary medicine, environmental and occupational health, sleep medicine, otolaryngology and speech pathology, and mental health (when appropriate). After the clinical evaluation has been completed, this team of expert HCPs at each site convenes to provide a final summary review visit intended to be a comprehensive assessment of the veteran’s primary health concerns. The 3 primary objectives of this final review are to inform the veteran of (1) what respiratory and related conditions they have; (2) whether the conditions is/are deployment related; and (3) what treatments and/or follow-up care may enhance their current state of health in partnership with their local HCPs. The PDCEN does not provide ongoing management of any conditions identified during the veteran’s evaluation but communicates findings and recommendations to the veteran and their PCP for long-term care.

Discussion

The AHOBPR was established in response to mounting concerns that service members and veterans were experiencing adverse health effects that might be attributable to deployment-related exposures. Nearly half of all patients currently enrolled in the AHOBPR report dyspnea, and about one-third have decreased exercise tolerance and/or cough. Of those who completed the questionnaire and the subsequent in-person and generalized AHOBPR examination, our interim analysis showed that about half were assigned a respiratory diagnosis. Yet for many veterans, their breathing symptoms remained unexplained or did not respond to treatment.

While the AHOBPR and related examinations address the needs of many veterans, others may require more comprehensive examination. The PDCEN attends to the latter by providing more detailed and comprehensive clinical evaluations of veterans with deployment-related respiratory health concerns and seeks to learn from these evaluations by analyzing data obtained from veterans across sites. As such, the PDCEN hopes not only to improve the health of individual veterans, but also create standard practices for both VA and non-VA community evaluation of veterans exposed to respiratory hazards during deployment.

One of the major challenges in the field of postdeployment respiratory health is the lack of clear universal language or case definitions that encompass the veteran’s clinical concerns. In an influential case series published in 2011, 38 (77%) of 49 soldiers with history of airborne hazard exposure and unexplained exercise intolerance were reported to have histopathology consistent with constrictive bronchiolitis on surgical lung biopsy.¹⁴ Subsequent publications have described other histopathologic features in deployed military personnel, including granulomatous inflammation, interstitial lung disease, emphysema, and pleuritis.^12-14 Reconciling these findings from surgical lung biopsy with the clinical presentation and noninvasive studies has proved difficult. Therefore, several groups of investigators have proposed terms, including postdeployment respiratory syndrome, deployment-related distal lung disease, and Iraq/Afghanistan War lung injury to describe the increased respiratory symptoms and variety of histopathologic and imaging findings in this population.^9,12,22 At present, there remains a lack of consensus on terminology and case definitions as well as the role of military environmental exposures in exacerbating and/or causing these conditions. As HCPs, it is important to appreciate and acknowledge that the ambiguity and controversy pertaining to terminology, causation, and service connections are a common source of frustration experienced by veterans, which are increasingly reflected among reports in popular media and lay press.

A second and related challenge in the field of postdeployment respiratory health that contributes to veteran and HCP frustration is that many of the aforementioned abnormalities described on surgical lung biopsy are not readily identifiable on noninvasive tests, including traditional interpretation of pulmonary function tests or chest CT imaging.^12-14,22 Thus, underlying conditions could be overlooked and veterans’ concerns and symptoms may be dismissed or misattributed to other comorbid conditions. While surgical lung biopsies may offer diagnostic clarity in identifying lung disease, there are significant procedural risks of surgical and anesthetic complications. Furthermore, a definitive diagnosis does not necessarily guarantee a clear treatment plan. For example, there are no current therapies approved by the US Food and Drug Administration for the treatment of constrictive bronchiolitis.

Research efforts are underway, including within the PDCEN, to evaluate a more sensitive and noninvasive assessment of the small airways that may even reduce or eliminate the need for surgical lung biopsy. In contrast to traditional pulmonary function testing, which is helpful for evaluation of the larger airways, forced oscillation technique can be used noninvasively, using pressure oscillations to evaluate for diseases of the smaller airways and has been used in the veteran population and in those exposed to dust from the World Trade Center disaster.^23-25 Multiple breath washout technique provides a lung clearance index that is determined by the number of lung turnovers it takes to clear the lungs of an inert gas (eg, sulfur hexafluoride, nitrogen). Elevated lung clearance index values suggest ventilation heterogeneity and have been shown to be higher among deployed veterans with dyspnea.^26,27 Finally, advanced CT analytic techniques may help identify functional small airways disease and are higher in deployed service members with constrictive bronchiolitis on surgical lung biopsy.²⁸ These innovative noninvasive techniques are experimental but promising, especially as part of a broader evaluation of small airways disease.

AHOBPR clinical evaluations represent an initial step to better understand postdeployment health conditions available to all AHOBPR participants. The PDCEN clinical evaluation extends the AHOBPR evaluation by providing specialty care for certain veterans requiring more comprehensive evaluation while systematically collecting and analyzing clinical data to advance the field. The VA is committed to leveraging these data and all available expertise to provide a clear description of the spectrum of disease in this population and improve our ability to diagnose, follow, and treat respiratory health conditions occurring after deployment to Southwest Asia and Afghanistan.

Case Conclusion

The veteran was referred to a PDCEN site and underwent a comprehensive multidisciplinary evaluation. Pulmonary function testing showed lung volumes and vital capacity within the predicted normal range, mild air trapping, and a low diffusion capacity for carbon monoxide. Methacholine challenge testing was normal; however, forced oscillometry suggested small airways obstruction. A high-resolution CT showed air trapping without parenchymal changes. Cardiopulmonary exercise testing demonstrated a peak exercise capacity within the predicted normal range but low breathing reserve. Otolaryngology evaluation including laryngoscopy suggested chronic nonallergic rhinitis.

At the end of the veteran’s evaluation, a summary review reported nonallergic rhinitis and distal airway obstruction consistent with small airways disease. Both were reported as most likely related to deployment given her significant environmental exposures and the temporal relationship with her deployment and symptom onset as well as lack of other identifiable causes. A more precise histopathologic diagnosis could be firmly established with a surgical lung biopsy, but after shared decision making with a PDCEN HCP, the patient declined to undergo this invasive procedure. After you review the summary review and recommendations from the PDCEN group, you start the veteran on intranasal steroids and a combined inhaled corticosteroid/long-acting β agonist inhaler as well as refer the veteran to pulmonary rehabilitation. After several weeks, she reports an improvement in sleep and nasal symptoms but continues to experience residual exercise intolerance.

This case serves as an example of the significant limitations that a previously active and healthy patient can develop after deployment to Southwest Asia and Afghanistan. Encouraging this veteran to complete the AHOBPR allowed her to be considered for a PDCEN evaluation that provided the opportunity to undergo a comprehensive noninvasive evaluation of her chronic dyspnea. In doing so, she obtained 2 important diagnoses and data from her evaluation will help establish best practices for standardized evaluations of respiratory concerns following deployment. Through the AHOBPR and PDCEN, the VA seeks to better understand postdeployment health conditions, their relationship to military and environmental exposures, and how best to diagnose and treat these conditions.

Acknowledgments

This work was supported by the US Department of Veterans Affairs (VA) Airborne Hazards and Burn Pits Center of Excellence (Public Law 115-929). The authors acknowledge support and contributions from Dr. Eric Shuping and leadership at VA’s Health Outcomes Military Exposures office as well as the New Jersey War Related Illness and Injury Study Center. In addition, we thank Erin McRoberts and Rajeev Swarup for their contributions to the Post-Deployment Cardiopulmonary Evaluation Network. Post-Deployment Cardiopulmonary Evaluation Network members:

Mehrdad Arjomandi, Caroline Davis, Michelle DeLuca, Nancy Eager, Courtney A. Eberhardt, Michael J. Falvo, Timothy Foley, Fiona A.S. Graff, Deborah Heaney, Stella E. Hines, Rachel E. Howard, Nisha Jani, Sheena Kamineni, Silpa Krefft, Mary L. Langlois, Helen Lozier, Simran K. Matharu, Anisa Moore, Lydia Patrick-DeLuca, Edward Pickering, Alexander Rabin, Michelle Robertson, Samantha L. Rogers, Aaron H. Schneider, Anand Shah, Anays Sotolongo, Jennifer H. Therkorn, Rebecca I. Toczylowski, Matthew Watson, Alison D. Wilczynski, Ian W. Wilson, Romi A. Yount.

Case Example

A 37-year-old female never smoker presents to your clinic with progressive dyspnea over the past 15 years. She reports dyspnea on exertion, wheezing, chronic nasal congestion, and difficulty sleeping that started a year after she returned from military deployment to Iraq. She has been unable to exercise, even at low intensity, for the past 5 years, despite being previously active. She has experienced some symptom improvement by taking an albuterol inhaler as needed, loratadine (10 mg), and fluticasone nasal spray (50 mcg). She occasionally uses famotidine for reflux (40 mg). She deployed to Southwest Asia for 12 months (2002-2003) and was primarily stationed in Qayyarah West, an Air Force base in the Mosul district in northern Iraq. She reports exposure during deployment to the fire in the Al-Mishraq sulfur mine, located approximately 25 km north of Qayyarah West, as well as dust storms and burn pits. She currently works as a medical assistant. Her examination is remarkable for normal bronchovesicular breath sounds without any wheezing or crackles on pulmonary evaluation. Her body mass index is 31. You obtain a chest radiograph and spirometry, which are both normal.

The veteran reports feeling frustrated as she has had multiple specialty evaluations in community clinics without receiving a diagnosis, despite worsening symptoms. She reports that she added her information to the Airborne Hazards and Open Burn Pit Registry (AHOBPR). She recently received a letter from the US Department of Veterans Affairs (VA) Post-Deployment Cardiopulmonary Evaluation Network (PDCEN) and is asking you whether she should participate in the PDCEN specialty evaluation. You are not familiar with the military experiences she has described or the programs she asks you about; however, you would like to know more to best care for your patient.

Background

The year 2021 marked the 20th anniversary of the September 11 attacks and the launch of the Global War on Terrorism. Almost 3 million US military personnel have been deployed in support of these operations along with about 300,000 US civilian contractors and thousands of troops from more than 40 nations.^1-3

Deployment after 2001 to Afghanistan and the Southwest Asia theater of operations, which includes but is not limited to Iraq, Kuwait, and Saudi Arabia, has been associated with increased prevalence of dyspnea and cough as well as diagnoses of asthma, chronic obstructive pulmonary disease (COPD), and other chronic respiratory diseases.^4-9 Expert committees convened by the National Academies of Sciences, Engineering, and Medicine concluded that deployment to the Southwest Asia region and Afghanistan was associated with respiratory symptoms of cough, wheeze, and shortness of breath and might be associated with long-term health effects, particularly in vulnerable (eg, individuals with asthma) or highly exposed populations (eg, those assigned to work at burn pits).^10,11 Several reports have found constrictive bronchiolitis, emphysema, granulomatous inflammation, and pigment deposition on lung biopsy in deployed persons with unexplained dyspnea and subtle, or normal, clinical findings.^12-14

Respiratory hazards associated with deployment to Southwest Asia and Afghanistan are unique and varied. These exposures include blast injuries and a variety of particulate matter sources, such as burn pit combustion byproducts, aeroallergens, and dust storms.^7,8,15,16 One air sampling study conducted at 15 deployment sites in Southwest Asia and Afghanistan found mean fine particulate matter (PM_2.5) levels were as much as 10 times greater than sampling sites in both rural and urban cities in the United States; all sites sampled exceeded military exposure guidelines (65 µg/m³ for 1 year).^17,18 Long-term exposure to PM_2.5 has been associated with the development of chronic respiratory and cardiovascular disease; therefore, there has been considerable attention to the respiratory (and nonrespiratory) health of deployed military personnel.¹⁹

Concerns regarding the association between deployment and lung disease led to the creation of the national VA Airborne Hazards and Open Burn Pit Registry (AHOBPR) in 2014 and consists of (1) an online questionnaire to document deployment and medical history, exposure concerns, and symptoms; and (2) an optional in-person or virtual clinical health evaluation at the individual’s local VA medical center or military treatment facility (MTF). As of March 2022, more than 300,000 individuals have completed the online questionnaire of which about 30% declined the optional clinical health evaluation.

The clinical evaluation available to AHOBPR participants has not yet been described in the literature. Therefore, our objectives are to examine AHOBPR clinical evaluation data and review its application throughout the VA. In addition, we will also describe a parallel effort by the VA PDCEN, which is to provide comprehensive multiday clinical evaluations for unique AHOBPR participants with unexplained dyspnea and self-reported respiratory disease. A secondary aim of this publication is to disseminate information to health care professionals (HCPs) within and outside of the VA to aid in the referral and evaluation of previously deployed veterans who experience unexplained dyspnea.

AHOBPR Overview

The AHOBPR is an online questionnaire and optional in-person health evaluation that includes 7 major categories targeting deployment history, symptoms, medical history, health concerns, residential history, nonmilitary occupational history, nonmilitary environmental exposures, and health care utilization. The VA Defense Information Repository is used to obtain service dates for the service member/veteran, conflict involvement, and primary location during deployment. The questionnaire portion of the AHOBPR is administered online. It currently is open to all veterans who served in the Southwest Asia theater of operations (including Iraq, Kuwait, and Egypt) any time after August 2, 1990, or Afghanistan, Djibouti, Syria, or Uzbekistan after September 11, 2001. Veterans are eligible for completing the AHOBPR and optional health evaluation at no cost to the veteran regardless of VA benefits or whether they are currently enrolled in VA health care. Though the focus of the present manuscript is to profile a VA program, it is important to note that the US Department of Defense (DoD) is an active partner with the VA in the promotion of the AHOBPR to service members and similarly provides health evaluations for active-duty service members (including activating Reserve and Guard) through their local MTF.

We reviewed and analyzed AHOBPR operations and VA data from 2014 to 2020. Our analyses were limited to veterans seeking evaluation as well as their corresponding symptoms and HCP’s clinical impression from the electronic health record. As of September 20, 2021, 267,125 individuals completed the AHOBPR. The mean age was 43 years (range, 19-84), and the majority were male (86%) and served in the Army (58%). Open-air burn pits (91%), engine maintenance (38.8%), and convoy operations (71.7%) were the most common deployment-related exposures.

The optional in-person AHOBPR health evaluation may be requested by the veteran after completing the online questionnaire and is performed at the veteran’s local VA facility. The evaluation is most often completed by an environmental health clinician or primary care practitioner (PCP). A variety of resources are available to providers for training on this topic, including fact sheets, webinars, monthly calls, conferences, and accredited e-learning.²⁰ As part of the clinical evaluation, the veteran’s chief concerns are assessed and evaluated. At the time of our analysis, 24,578 clinical examinations were performed across 126 VA medical facilities, with considerable geographic variation. Veterans receiving evaluations were predominantly male (89%) with a median age of 46.0 years (IQR, 15). Veterans’ major respiratory concerns included dyspnea (45.1%), decreased exercise ability (34.8%), and cough > 3 weeks (30.3%) (Table). After clinical evaluation by a VA or MTF HCP, 47.8% were found to have a respiratory diagnosis, including asthma (30.1%), COPD (12.8%), and bronchitis (11.9%).

Post-Deployment Cardiopulmonary Evaluation Network Clinical Evaluation

In May 2019, the VA established the Airborne Hazards and Burn Pits Center of Excellence (AHBPCE). One of the AHBPCE’s objectives is to deliver specialized care and consultation for veterans with concerns about their postdeployment health, including, but not limited to, unexplained dyspnea. To meet this objective, the AHBPCE developed the PDCEN, a national network consisting of specialty HCPs from 5 VA medical centers—located in San Francisco, California; Denver, Colorado; Baltimore, Maryland; Ann Arbor, Michigan; and East Orange, New Jersey. Collectively, the PDCEN has developed a standardized approach for the comprehensive clinical evaluation of unexplained dyspnea that is implemented uniformly across sites. Staff at the PDCEN screen the AHOBPR to identify veterans with features of respiratory disease and invite them to participate in an in-person evaluation at the nearest PDCEN site. Given the specialty expertise (detailed below) within the Network, the PDCEN focuses on complex cases that are resource intensive. To address complex cases of unexplained dyspnea, the PDCEN has developed a core clinical evaluation approach (Figure).

The first step in a veteran’s PDCEN evaluation entails a set of detailed questionnaires that request information about the veteran’s current respiratory, sleep, and mental health symptoms and any associated medical diagnoses. Questionnaires also identify potential exposures to military burn pits, sulfur mine and oil field fires, diesel exhaust fumes, dust storms, urban pollution, explosions/blasts, and chemical weapons. In addition, the questionnaires include deployment geographic location, which may inform future estimates of particulate matter exposure.²¹ Prior VA and non-VA evaluations and testing of their respiratory concerns are obtained for review. Exposure and health records from the DoD are also reviewed when available.

The next step in the PDCEN evaluation comprises comprehensive testing, including complete pulmonary function testing, methacholine challenge, cardiopulmonary exercise testing, forced oscillometry and exhaled nitric oxide testing, paired high-resolution inspiratory and expiratory chest computed tomography (CT) imaging, sinus CT imaging, direct flexible laryngoscopy, echocardiography, polysomnography, and laboratory blood testing. The testing process is managed by local site coordinators and varies by institution based on availability of each testing modality and subspecialist appointments.

Once testing is completed, the veteran is evaluated by a team of HCPs, including physicians from the disciplines of pulmonary medicine, environmental and occupational health, sleep medicine, otolaryngology and speech pathology, and mental health (when appropriate). After the clinical evaluation has been completed, this team of expert HCPs at each site convenes to provide a final summary review visit intended to be a comprehensive assessment of the veteran’s primary health concerns. The 3 primary objectives of this final review are to inform the veteran of (1) what respiratory and related conditions they have; (2) whether the conditions is/are deployment related; and (3) what treatments and/or follow-up care may enhance their current state of health in partnership with their local HCPs. The PDCEN does not provide ongoing management of any conditions identified during the veteran’s evaluation but communicates findings and recommendations to the veteran and their PCP for long-term care.

Discussion

The AHOBPR was established in response to mounting concerns that service members and veterans were experiencing adverse health effects that might be attributable to deployment-related exposures. Nearly half of all patients currently enrolled in the AHOBPR report dyspnea, and about one-third have decreased exercise tolerance and/or cough. Of those who completed the questionnaire and the subsequent in-person and generalized AHOBPR examination, our interim analysis showed that about half were assigned a respiratory diagnosis. Yet for many veterans, their breathing symptoms remained unexplained or did not respond to treatment.

While the AHOBPR and related examinations address the needs of many veterans, others may require more comprehensive examination. The PDCEN attends to the latter by providing more detailed and comprehensive clinical evaluations of veterans with deployment-related respiratory health concerns and seeks to learn from these evaluations by analyzing data obtained from veterans across sites. As such, the PDCEN hopes not only to improve the health of individual veterans, but also create standard practices for both VA and non-VA community evaluation of veterans exposed to respiratory hazards during deployment.

One of the major challenges in the field of postdeployment respiratory health is the lack of clear universal language or case definitions that encompass the veteran’s clinical concerns. In an influential case series published in 2011, 38 (77%) of 49 soldiers with history of airborne hazard exposure and unexplained exercise intolerance were reported to have histopathology consistent with constrictive bronchiolitis on surgical lung biopsy.¹⁴ Subsequent publications have described other histopathologic features in deployed military personnel, including granulomatous inflammation, interstitial lung disease, emphysema, and pleuritis.^12-14 Reconciling these findings from surgical lung biopsy with the clinical presentation and noninvasive studies has proved difficult. Therefore, several groups of investigators have proposed terms, including postdeployment respiratory syndrome, deployment-related distal lung disease, and Iraq/Afghanistan War lung injury to describe the increased respiratory symptoms and variety of histopathologic and imaging findings in this population.^9,12,22 At present, there remains a lack of consensus on terminology and case definitions as well as the role of military environmental exposures in exacerbating and/or causing these conditions. As HCPs, it is important to appreciate and acknowledge that the ambiguity and controversy pertaining to terminology, causation, and service connections are a common source of frustration experienced by veterans, which are increasingly reflected among reports in popular media and lay press.

A second and related challenge in the field of postdeployment respiratory health that contributes to veteran and HCP frustration is that many of the aforementioned abnormalities described on surgical lung biopsy are not readily identifiable on noninvasive tests, including traditional interpretation of pulmonary function tests or chest CT imaging.^12-14,22 Thus, underlying conditions could be overlooked and veterans’ concerns and symptoms may be dismissed or misattributed to other comorbid conditions. While surgical lung biopsies may offer diagnostic clarity in identifying lung disease, there are significant procedural risks of surgical and anesthetic complications. Furthermore, a definitive diagnosis does not necessarily guarantee a clear treatment plan. For example, there are no current therapies approved by the US Food and Drug Administration for the treatment of constrictive bronchiolitis.

Research efforts are underway, including within the PDCEN, to evaluate a more sensitive and noninvasive assessment of the small airways that may even reduce or eliminate the need for surgical lung biopsy. In contrast to traditional pulmonary function testing, which is helpful for evaluation of the larger airways, forced oscillation technique can be used noninvasively, using pressure oscillations to evaluate for diseases of the smaller airways and has been used in the veteran population and in those exposed to dust from the World Trade Center disaster.^23-25 Multiple breath washout technique provides a lung clearance index that is determined by the number of lung turnovers it takes to clear the lungs of an inert gas (eg, sulfur hexafluoride, nitrogen). Elevated lung clearance index values suggest ventilation heterogeneity and have been shown to be higher among deployed veterans with dyspnea.^26,27 Finally, advanced CT analytic techniques may help identify functional small airways disease and are higher in deployed service members with constrictive bronchiolitis on surgical lung biopsy.²⁸ These innovative noninvasive techniques are experimental but promising, especially as part of a broader evaluation of small airways disease.

AHOBPR clinical evaluations represent an initial step to better understand postdeployment health conditions available to all AHOBPR participants. The PDCEN clinical evaluation extends the AHOBPR evaluation by providing specialty care for certain veterans requiring more comprehensive evaluation while systematically collecting and analyzing clinical data to advance the field. The VA is committed to leveraging these data and all available expertise to provide a clear description of the spectrum of disease in this population and improve our ability to diagnose, follow, and treat respiratory health conditions occurring after deployment to Southwest Asia and Afghanistan.

Case Conclusion

The veteran was referred to a PDCEN site and underwent a comprehensive multidisciplinary evaluation. Pulmonary function testing showed lung volumes and vital capacity within the predicted normal range, mild air trapping, and a low diffusion capacity for carbon monoxide. Methacholine challenge testing was normal; however, forced oscillometry suggested small airways obstruction. A high-resolution CT showed air trapping without parenchymal changes. Cardiopulmonary exercise testing demonstrated a peak exercise capacity within the predicted normal range but low breathing reserve. Otolaryngology evaluation including laryngoscopy suggested chronic nonallergic rhinitis.

At the end of the veteran’s evaluation, a summary review reported nonallergic rhinitis and distal airway obstruction consistent with small airways disease. Both were reported as most likely related to deployment given her significant environmental exposures and the temporal relationship with her deployment and symptom onset as well as lack of other identifiable causes. A more precise histopathologic diagnosis could be firmly established with a surgical lung biopsy, but after shared decision making with a PDCEN HCP, the patient declined to undergo this invasive procedure. After you review the summary review and recommendations from the PDCEN group, you start the veteran on intranasal steroids and a combined inhaled corticosteroid/long-acting β agonist inhaler as well as refer the veteran to pulmonary rehabilitation. After several weeks, she reports an improvement in sleep and nasal symptoms but continues to experience residual exercise intolerance.

This case serves as an example of the significant limitations that a previously active and healthy patient can develop after deployment to Southwest Asia and Afghanistan. Encouraging this veteran to complete the AHOBPR allowed her to be considered for a PDCEN evaluation that provided the opportunity to undergo a comprehensive noninvasive evaluation of her chronic dyspnea. In doing so, she obtained 2 important diagnoses and data from her evaluation will help establish best practices for standardized evaluations of respiratory concerns following deployment. Through the AHOBPR and PDCEN, the VA seeks to better understand postdeployment health conditions, their relationship to military and environmental exposures, and how best to diagnose and treat these conditions.

Acknowledgments

This work was supported by the US Department of Veterans Affairs (VA) Airborne Hazards and Burn Pits Center of Excellence (Public Law 115-929). The authors acknowledge support and contributions from Dr. Eric Shuping and leadership at VA’s Health Outcomes Military Exposures office as well as the New Jersey War Related Illness and Injury Study Center. In addition, we thank Erin McRoberts and Rajeev Swarup for their contributions to the Post-Deployment Cardiopulmonary Evaluation Network. Post-Deployment Cardiopulmonary Evaluation Network members:

Mehrdad Arjomandi, Caroline Davis, Michelle DeLuca, Nancy Eager, Courtney A. Eberhardt, Michael J. Falvo, Timothy Foley, Fiona A.S. Graff, Deborah Heaney, Stella E. Hines, Rachel E. Howard, Nisha Jani, Sheena Kamineni, Silpa Krefft, Mary L. Langlois, Helen Lozier, Simran K. Matharu, Anisa Moore, Lydia Patrick-DeLuca, Edward Pickering, Alexander Rabin, Michelle Robertson, Samantha L. Rogers, Aaron H. Schneider, Anand Shah, Anays Sotolongo, Jennifer H. Therkorn, Rebecca I. Toczylowski, Matthew Watson, Alison D. Wilczynski, Ian W. Wilson, Romi A. Yount.

Pulse oximetry is a vital monitoring tool in the ICU and in pulmonary medicine. Regrettably, re-emerging data show that pulse oximeters do not accurately measure blood oxygen levels in Black patients, presumably due to their skin tone. Patients with darker skin are, therefore, more likely to experience occult hypoxemia (i.e., low arterial oxygen saturation despite a seemingly normal pulse oximetry reading). While inaccuracy of pulse oximeter measurements in patients with darker skin has been recognized for decades, recent studies have highlighted this as an ongoing problem with potentially severe consequences for Black patients and other patients of color.

One recent study found that Black patients had almost three times the likelihood of occult hypoxemia compared with White patients (Sjoding, MW, et al. N Engl J Med. 2020;383[25]:2477-8).

Subsequent studies have confirmed this to be a widespread problem across various clinical settings in hundreds of hospitals (Wong AI, et al. JAMA Netw Open. 2021;4[11]:e2131674; Valbuena VS, et al. Chest. 2022;161[4]:971-8). A recent retrospective cohort study of patients with COVID-19 found that occult hypoxemia in Black and Hispanic patients was associated with delayed eligibility for potentially lifesaving COVID-19 therapies (Fawzy AF, et al. JAMA Intern Med. 2022; published online May 31, 2022).

Now that numerous studies have demonstrated the inaccuracy of pulse oximetry with the potential to cause harm to historically marginalized racial and ethnic groups, must we abandon the use of pulse oximetry? We would argue that pulse oximeters remain valuable tools, but for now, we must adapt our practice until better devices are widely adopted.

First, it is crucial that health professionals are aware that pulse oximeters may underestimate the true extent of hypoxemia for all patients, but particularly for patients with darker skin. Acknowledging this device flaw is essential to avoid harm to our patients.

Second, clinicians must have heightened skepticism for seemingly normal pulse oximetry values when caring for symptomatic patients at risk of occult hypoxemia.

Until better pulse oximeters are widely available, clinicians must consider workarounds aimed at ensuring timely identification of hypoxemia in Black patients and other patients of color.

These patients may need invasive monitoring of arterial oxygenation, including arterial blood gas checks or an arterial catheter. However, invasive monitoring comes at the cost of discomfort to patients and potential complications, such as vessel or nerve damage.

Invasive monitoring of patients at risk for occult hypoxemia is not an equitable or acceptable long-term solution for this problem. As advocates for patients, clinicians and professional organizations should lobby regulatory bodies to ensure pulse oximeters are accurate for all patients.

We must also call on government leaders to move this process forward. For example, in response to efforts by the United Kingdom’s Intensive Care Society, the Health Secretary of the UK, Sajid Javid, has called for a review of pulse oximeters as part of a larger review assessing structural issues in health care that lead to worse outcomes in racial and ethnic minorities (BBC News. https://www.bbc.com/news/uk-59363544. Published online Nov. 21, 2021).

Device companies are largely for-profit corporations with obligations to their shareholders. It seems that existing incentives are insufficient to motivate investment in less biased technology and real-world evaluations of their devices.

We previously called for buyers of pulse oximeters to change the incentives of device companies – that is, for “hospitals to commit to only purchasing pulse oximeters that have been shown to work equally well in patients of colour.” (Hidalgo DC, et al. Lancet Respir Med. 2021;9[4]:E37). And, indeed, we worry that hospitals are putting themselves at medicolegal risk by not raising their purchasing standards. Since it is now widely known that pulse oximeters are inaccurate in certain patients, could there be liability for hospitals that continue to use devices we know to be disproportionately inaccurate by race?

Pulse oximetry is a vital monitoring tool in the ICU and in pulmonary medicine. Regrettably, re-emerging data show that pulse oximeters do not accurately measure blood oxygen levels in Black patients, presumably due to their skin tone. Patients with darker skin are, therefore, more likely to experience occult hypoxemia (i.e., low arterial oxygen saturation despite a seemingly normal pulse oximetry reading). While inaccuracy of pulse oximeter measurements in patients with darker skin has been recognized for decades, recent studies have highlighted this as an ongoing problem with potentially severe consequences for Black patients and other patients of color.

One recent study found that Black patients had almost three times the likelihood of occult hypoxemia compared with White patients (Sjoding, MW, et al. N Engl J Med. 2020;383[25]:2477-8).

Subsequent studies have confirmed this to be a widespread problem across various clinical settings in hundreds of hospitals (Wong AI, et al. JAMA Netw Open. 2021;4[11]:e2131674; Valbuena VS, et al. Chest. 2022;161[4]:971-8). A recent retrospective cohort study of patients with COVID-19 found that occult hypoxemia in Black and Hispanic patients was associated with delayed eligibility for potentially lifesaving COVID-19 therapies (Fawzy AF, et al. JAMA Intern Med. 2022; published online May 31, 2022).

Now that numerous studies have demonstrated the inaccuracy of pulse oximetry with the potential to cause harm to historically marginalized racial and ethnic groups, must we abandon the use of pulse oximetry? We would argue that pulse oximeters remain valuable tools, but for now, we must adapt our practice until better devices are widely adopted.

First, it is crucial that health professionals are aware that pulse oximeters may underestimate the true extent of hypoxemia for all patients, but particularly for patients with darker skin. Acknowledging this device flaw is essential to avoid harm to our patients.

Second, clinicians must have heightened skepticism for seemingly normal pulse oximetry values when caring for symptomatic patients at risk of occult hypoxemia.

Until better pulse oximeters are widely available, clinicians must consider workarounds aimed at ensuring timely identification of hypoxemia in Black patients and other patients of color.

These patients may need invasive monitoring of arterial oxygenation, including arterial blood gas checks or an arterial catheter. However, invasive monitoring comes at the cost of discomfort to patients and potential complications, such as vessel or nerve damage.

Invasive monitoring of patients at risk for occult hypoxemia is not an equitable or acceptable long-term solution for this problem. As advocates for patients, clinicians and professional organizations should lobby regulatory bodies to ensure pulse oximeters are accurate for all patients.

We must also call on government leaders to move this process forward. For example, in response to efforts by the United Kingdom’s Intensive Care Society, the Health Secretary of the UK, Sajid Javid, has called for a review of pulse oximeters as part of a larger review assessing structural issues in health care that lead to worse outcomes in racial and ethnic minorities (BBC News. https://www.bbc.com/news/uk-59363544. Published online Nov. 21, 2021).

Device companies are largely for-profit corporations with obligations to their shareholders. It seems that existing incentives are insufficient to motivate investment in less biased technology and real-world evaluations of their devices.

We previously called for buyers of pulse oximeters to change the incentives of device companies – that is, for “hospitals to commit to only purchasing pulse oximeters that have been shown to work equally well in patients of colour.” (Hidalgo DC, et al. Lancet Respir Med. 2021;9[4]:E37). And, indeed, we worry that hospitals are putting themselves at medicolegal risk by not raising their purchasing standards. Since it is now widely known that pulse oximeters are inaccurate in certain patients, could there be liability for hospitals that continue to use devices we know to be disproportionately inaccurate by race?

Pulse oximetry is a vital monitoring tool in the ICU and in pulmonary medicine. Regrettably, re-emerging data show that pulse oximeters do not accurately measure blood oxygen levels in Black patients, presumably due to their skin tone. Patients with darker skin are, therefore, more likely to experience occult hypoxemia (i.e., low arterial oxygen saturation despite a seemingly normal pulse oximetry reading). While inaccuracy of pulse oximeter measurements in patients with darker skin has been recognized for decades, recent studies have highlighted this as an ongoing problem with potentially severe consequences for Black patients and other patients of color.

One recent study found that Black patients had almost three times the likelihood of occult hypoxemia compared with White patients (Sjoding, MW, et al. N Engl J Med. 2020;383[25]:2477-8).

Subsequent studies have confirmed this to be a widespread problem across various clinical settings in hundreds of hospitals (Wong AI, et al. JAMA Netw Open. 2021;4[11]:e2131674; Valbuena VS, et al. Chest. 2022;161[4]:971-8). A recent retrospective cohort study of patients with COVID-19 found that occult hypoxemia in Black and Hispanic patients was associated with delayed eligibility for potentially lifesaving COVID-19 therapies (Fawzy AF, et al. JAMA Intern Med. 2022; published online May 31, 2022).

Now that numerous studies have demonstrated the inaccuracy of pulse oximetry with the potential to cause harm to historically marginalized racial and ethnic groups, must we abandon the use of pulse oximetry? We would argue that pulse oximeters remain valuable tools, but for now, we must adapt our practice until better devices are widely adopted.

First, it is crucial that health professionals are aware that pulse oximeters may underestimate the true extent of hypoxemia for all patients, but particularly for patients with darker skin. Acknowledging this device flaw is essential to avoid harm to our patients.

Second, clinicians must have heightened skepticism for seemingly normal pulse oximetry values when caring for symptomatic patients at risk of occult hypoxemia.

Until better pulse oximeters are widely available, clinicians must consider workarounds aimed at ensuring timely identification of hypoxemia in Black patients and other patients of color.

These patients may need invasive monitoring of arterial oxygenation, including arterial blood gas checks or an arterial catheter. However, invasive monitoring comes at the cost of discomfort to patients and potential complications, such as vessel or nerve damage.

Invasive monitoring of patients at risk for occult hypoxemia is not an equitable or acceptable long-term solution for this problem. As advocates for patients, clinicians and professional organizations should lobby regulatory bodies to ensure pulse oximeters are accurate for all patients.

We must also call on government leaders to move this process forward. For example, in response to efforts by the United Kingdom’s Intensive Care Society, the Health Secretary of the UK, Sajid Javid, has called for a review of pulse oximeters as part of a larger review assessing structural issues in health care that lead to worse outcomes in racial and ethnic minorities (BBC News. https://www.bbc.com/news/uk-59363544. Published online Nov. 21, 2021).

Device companies are largely for-profit corporations with obligations to their shareholders. It seems that existing incentives are insufficient to motivate investment in less biased technology and real-world evaluations of their devices.

We previously called for buyers of pulse oximeters to change the incentives of device companies – that is, for “hospitals to commit to only purchasing pulse oximeters that have been shown to work equally well in patients of colour.” (Hidalgo DC, et al. Lancet Respir Med. 2021;9[4]:E37). And, indeed, we worry that hospitals are putting themselves at medicolegal risk by not raising their purchasing standards. Since it is now widely known that pulse oximeters are inaccurate in certain patients, could there be liability for hospitals that continue to use devices we know to be disproportionately inaccurate by race?

The Pulmonary Fibrosis Foundation (PFF) has launched a new initiative in which they hope to capture a far more diverse representation of patients with pulmonary fibrosis (PF) than the current registry allows them to do, a press release from the PFF indicated.

“The existing registry we have – the PFF Patient Registry – is limited to our care centers, which are primarily academic clinical institutions and we have only a few thousand patients within that registry,” Junelle Speller, MBA, vice president of the PFF Registry, told this news organization.

“We wanted to go beyond these care centers and capture patients in community centers, and in rural settings to provide a more complete understanding of patients with this disease and, of course, have a larger sample size,” she added.

“So, the major impetus behind the PFF Community Registry was to gather a more diverse representative sample of PF patients across all parts of the United States and, most importantly, accelerate the research on PF toward improving earlier diagnosis, treatment, and outcomes for these patients,” Ms. Speller said.
 

Passive versus active

The PFF Community Registry differs in its structure and purpose from the PFF Patient Registry, as Ms. Speller explained. First, the PFF Patient Registry, established in 2016, is “passive” in its nature in that whatever information is entered into a patient’s electronic medical record or clinical chart on a routine office visit is abstracted and captured in the registry. By contrast, the PFF Community Registry is asking for self-reported data from patients, “so it’s more of an ‘active’ registry and will give us a chance to have a bidirectional connection with participants, provide email updates and newsletters, and give patients an opportunity to participate in future studies within the registry as well as in clinical trials,” she noted.

The two registries still overlap in that both capture demographic data on patients’ medical and family histories as well as any medications patients may be taking, but the Community Registry will also capture information with respect to education, employment, patient-reported outcomes, and quality of life metrics. “It will also let us know how patients feel about continued education on the disease itself and patient participation in support groups,” Ms. Speller observed.

The Community Registry will also collect information from lung transplant recipients who have had PF or any other form of interstitial lung disease (ILD) as well as information from caregivers and family members affected by the patient’s disease. As Ms. Speller noted, both PF and other forms of ILD (of which there are more than 200 types) are all characterized by inflammation or scarring in the lung. “Patients are often misdiagnosed, and it can take months, even years, to identify the disease,” Ms. Speller said.

From there, it can be a very long and difficult road ahead, with no cure in sight, although several antifibrotic drugs do help slow disease progression. Typically, onset is around the age of 60 and symptoms include chronic dry cough, fatigue, shortness of breath, weakness, discomfort in the chest, and sometimes unexplained weight loss. Some patients do have a history of smoking, but not all, Ms. Speller noted. So far, registry data suggest PF largely occurs in White patients.

“We’re very excited about the Community Registry, particularly about reaching into communities that we haven’t been able to reach with our existing registry,” Ms. Speller noted. “The rural population in particular is often underserved, so we are really looking forward to capturing data from these patients as well as those from community centers within smaller and larger cities,” she observed.

“A powerful aspect of the Community Registry is that we can use the information gained from it to understand the experience of individuals living with PF, and how it impacts their lives and those of their families and caregivers,” Kevin Flaherty, MD, steering committee chair, PFF Registry, said in a statement.

“Researchers can also look at the data to better understand fibrotic lung diseases and learn about effective approaches to improve patient care,” he added.

Patients who wish to join the PFF Community Registry can sign up at pffregistry.org. To learn more about PF and its risk factors, readers are invited to visit www.AboutPF.org. More than 250,000 patients in the United States are living with either PF or other types of ILD.

Ms. Speller and Dr. Flaherty disclosed no financial conflicts of interest. The PFF Registry is supported by its founding partner, Genentech, Visionary Partner, United Therapeutics, and its sustaining partner, Boehringer Ingelheim, as well as many donors.

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

This article was updated 8/8/22.

The Pulmonary Fibrosis Foundation (PFF) has launched a new initiative in which they hope to capture a far more diverse representation of patients with pulmonary fibrosis (PF) than the current registry allows them to do, a press release from the PFF indicated.

“The existing registry we have – the PFF Patient Registry – is limited to our care centers, which are primarily academic clinical institutions and we have only a few thousand patients within that registry,” Junelle Speller, MBA, vice president of the PFF Registry, told this news organization.

“We wanted to go beyond these care centers and capture patients in community centers, and in rural settings to provide a more complete understanding of patients with this disease and, of course, have a larger sample size,” she added.

“So, the major impetus behind the PFF Community Registry was to gather a more diverse representative sample of PF patients across all parts of the United States and, most importantly, accelerate the research on PF toward improving earlier diagnosis, treatment, and outcomes for these patients,” Ms. Speller said.
 

Passive versus active

The PFF Community Registry differs in its structure and purpose from the PFF Patient Registry, as Ms. Speller explained. First, the PFF Patient Registry, established in 2016, is “passive” in its nature in that whatever information is entered into a patient’s electronic medical record or clinical chart on a routine office visit is abstracted and captured in the registry. By contrast, the PFF Community Registry is asking for self-reported data from patients, “so it’s more of an ‘active’ registry and will give us a chance to have a bidirectional connection with participants, provide email updates and newsletters, and give patients an opportunity to participate in future studies within the registry as well as in clinical trials,” she noted.

The two registries still overlap in that both capture demographic data on patients’ medical and family histories as well as any medications patients may be taking, but the Community Registry will also capture information with respect to education, employment, patient-reported outcomes, and quality of life metrics. “It will also let us know how patients feel about continued education on the disease itself and patient participation in support groups,” Ms. Speller observed.

The Community Registry will also collect information from lung transplant recipients who have had PF or any other form of interstitial lung disease (ILD) as well as information from caregivers and family members affected by the patient’s disease. As Ms. Speller noted, both PF and other forms of ILD (of which there are more than 200 types) are all characterized by inflammation or scarring in the lung. “Patients are often misdiagnosed, and it can take months, even years, to identify the disease,” Ms. Speller said.

From there, it can be a very long and difficult road ahead, with no cure in sight, although several antifibrotic drugs do help slow disease progression. Typically, onset is around the age of 60 and symptoms include chronic dry cough, fatigue, shortness of breath, weakness, discomfort in the chest, and sometimes unexplained weight loss. Some patients do have a history of smoking, but not all, Ms. Speller noted. So far, registry data suggest PF largely occurs in White patients.

“We’re very excited about the Community Registry, particularly about reaching into communities that we haven’t been able to reach with our existing registry,” Ms. Speller noted. “The rural population in particular is often underserved, so we are really looking forward to capturing data from these patients as well as those from community centers within smaller and larger cities,” she observed.

“A powerful aspect of the Community Registry is that we can use the information gained from it to understand the experience of individuals living with PF, and how it impacts their lives and those of their families and caregivers,” Kevin Flaherty, MD, steering committee chair, PFF Registry, said in a statement.

“Researchers can also look at the data to better understand fibrotic lung diseases and learn about effective approaches to improve patient care,” he added.

Patients who wish to join the PFF Community Registry can sign up at pffregistry.org. To learn more about PF and its risk factors, readers are invited to visit www.AboutPF.org. More than 250,000 patients in the United States are living with either PF or other types of ILD.

Ms. Speller and Dr. Flaherty disclosed no financial conflicts of interest. The PFF Registry is supported by its founding partner, Genentech, Visionary Partner, United Therapeutics, and its sustaining partner, Boehringer Ingelheim, as well as many donors.

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

This article was updated 8/8/22.

The Pulmonary Fibrosis Foundation (PFF) has launched a new initiative in which they hope to capture a far more diverse representation of patients with pulmonary fibrosis (PF) than the current registry allows them to do, a press release from the PFF indicated.

“The existing registry we have – the PFF Patient Registry – is limited to our care centers, which are primarily academic clinical institutions and we have only a few thousand patients within that registry,” Junelle Speller, MBA, vice president of the PFF Registry, told this news organization.

“We wanted to go beyond these care centers and capture patients in community centers, and in rural settings to provide a more complete understanding of patients with this disease and, of course, have a larger sample size,” she added.

“So, the major impetus behind the PFF Community Registry was to gather a more diverse representative sample of PF patients across all parts of the United States and, most importantly, accelerate the research on PF toward improving earlier diagnosis, treatment, and outcomes for these patients,” Ms. Speller said.
 

Passive versus active

The PFF Community Registry differs in its structure and purpose from the PFF Patient Registry, as Ms. Speller explained. First, the PFF Patient Registry, established in 2016, is “passive” in its nature in that whatever information is entered into a patient’s electronic medical record or clinical chart on a routine office visit is abstracted and captured in the registry. By contrast, the PFF Community Registry is asking for self-reported data from patients, “so it’s more of an ‘active’ registry and will give us a chance to have a bidirectional connection with participants, provide email updates and newsletters, and give patients an opportunity to participate in future studies within the registry as well as in clinical trials,” she noted.

The two registries still overlap in that both capture demographic data on patients’ medical and family histories as well as any medications patients may be taking, but the Community Registry will also capture information with respect to education, employment, patient-reported outcomes, and quality of life metrics. “It will also let us know how patients feel about continued education on the disease itself and patient participation in support groups,” Ms. Speller observed.

The Community Registry will also collect information from lung transplant recipients who have had PF or any other form of interstitial lung disease (ILD) as well as information from caregivers and family members affected by the patient’s disease. As Ms. Speller noted, both PF and other forms of ILD (of which there are more than 200 types) are all characterized by inflammation or scarring in the lung. “Patients are often misdiagnosed, and it can take months, even years, to identify the disease,” Ms. Speller said.

From there, it can be a very long and difficult road ahead, with no cure in sight, although several antifibrotic drugs do help slow disease progression. Typically, onset is around the age of 60 and symptoms include chronic dry cough, fatigue, shortness of breath, weakness, discomfort in the chest, and sometimes unexplained weight loss. Some patients do have a history of smoking, but not all, Ms. Speller noted. So far, registry data suggest PF largely occurs in White patients.

“We’re very excited about the Community Registry, particularly about reaching into communities that we haven’t been able to reach with our existing registry,” Ms. Speller noted. “The rural population in particular is often underserved, so we are really looking forward to capturing data from these patients as well as those from community centers within smaller and larger cities,” she observed.

“A powerful aspect of the Community Registry is that we can use the information gained from it to understand the experience of individuals living with PF, and how it impacts their lives and those of their families and caregivers,” Kevin Flaherty, MD, steering committee chair, PFF Registry, said in a statement.

“Researchers can also look at the data to better understand fibrotic lung diseases and learn about effective approaches to improve patient care,” he added.

Patients who wish to join the PFF Community Registry can sign up at pffregistry.org. To learn more about PF and its risk factors, readers are invited to visit www.AboutPF.org. More than 250,000 patients in the United States are living with either PF or other types of ILD.

Ms. Speller and Dr. Flaherty disclosed no financial conflicts of interest. The PFF Registry is supported by its founding partner, Genentech, Visionary Partner, United Therapeutics, and its sustaining partner, Boehringer Ingelheim, as well as many donors.

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

This article was updated 8/8/22.

Over the last several years, hundreds of millions of dollars have been spent on robotic bronchoscopy systems in the United States. The release of robotic scopes was made to great fanfare, translating into the market being infiltrated with these systems. With base costs in the hundreds of thousands of dollars, robotic bronchoscope systems are easily the most expensive singular capital investment in the bronchoscopy suite. I frequently get asked questions from those who have not yet made that purchase: “Should I buy a robot?” “How could I justify a new robot purchase to my hospital?” “Is the hype real?” These are complex questions to answer. Before one can answer, I think it’s best to look back on the last 2 decades of bronchoscopy for peripheral lung nodules to get a better understanding of the value proposition robotic bronchoscopes may offer.

Guided bronchoscopy for lung nodules has significantly evolved over the past 2 decades, shifting diagnostic procedures from interventional radiologist to the pulmonologist. Some of these advances were based in redesigns of the bronchoscope (ultrathin bronchoscopy) or application of technology to the bronchoscope (radial EBUS, virtual bronchoscopy); but, these were not broadly applicable to the pulmonology community at large. It was not until the development of electromagnetic navigational bronchoscopy (ENB) that widespread adoption of bronchoscopy for lung nodules occurred. By and large, ENB fueled a rapid expansion of nodule bronchoscopy, mainly due to its ease of use and novel approach. Initial studies of ENB had impressive results; however, studies were criticized for having small numbers, inadequate follow-up, spurious definitions of yield, and that they were being done at highly specialized centers. The NAVIGATE trial was launched to address these criticisms among “real world” conditions. Sponsored by Medtronic, it studied ENB (superDimension platform, v6.0 or higher) across 29 academic and medical centers in the United States, enrolling over 1,000 patients (Folch EE, et al. J Thorac Oncol. 2019;14[3]:445-58. Epub 2018 Nov 23), and reported a diagnostic yield of 73%.

This led to a drive to improve upon yield, resulting in development of new technologies specifically designed to address some of the factors thought associated with diminished yield, and, out of this, robotic bronchoscopy was born. These factors included CT scan-body registration divergence, deflection of the extended working channel (EWC) by rigid biopsy tools, and inability to accurately “aim” the EWC-biopsy tool at the nodule; these were especially problematic in nodules not associated with airways. Robotic scopes were specifically designed to reach into the peripheral lung airways similar to an EWC, but with better structural integrity and steerability. This tip integrity would resist tool-related displacement, and steerability would allow for improved targeting of nodules during the biopsy.

There are two robots approved by the FDA at the time of this writing (Auris Monarch, Intuitive Ion), with a third awaiting FDA clearance (Noah Galaxy). In general, though the engineering of the robotic scopes to improve structural tip integrity are similar, the approach to navigation and targeting vary significantly. The Monarch platform uses electromagnetic guidance, similar to other traditional ENB platforms. The Ion platform does not use ENB; instead, it uses fiberoptic shape sensing technology, which analyzes the shape and orientation of the scope to provide location information. There are potential advantages to shape sensing, the most notable being the absence of electromagnetics; this allows for use of fluoroscopy during the procedure, which otherwise would have interfered with ENB-based navigation. There are other subtle differences between the two robots. The Monarch uses a scope-in-scope design, with a robotic scope contained within a robotic sheath; the Ion uses a single robotic scope. The Ion scope diameter is 3.5 mm, whereas the Monarch diameter is 4.4 mm; this may be a potential advantage when having to navigate through smaller airways.

So, which robot is better suited to reach peripheral nodules more consistently and accurately? I get asked this question a lot, since I have both platforms at my institution. But, answering with my own opinion based on my institution’s anecdotal experience would be irresponsible. I’m more of a “what does the data show?” person. Luckily, we do have clinical trials in both robot technologies. It should be noted here that there will likely never be a head-to-head randomized trial, so evaluating published studies with each platform is going to be the best method we have for comparison going forward, albeit an imperfect one. It should also be noted that many of the early robotic bronchoscopy trials have to be looked at with caution, as yield definitions tended not to be conservative and/or the follow-up of non-malignant was not robust. With that in mind, let’s review representative high-quality studies for each platform.

The best study to date using the Ion platform came out of Memorial Sloan Kettering Cancer Center (Kalchiem-Dekel O, et al. Chest. 2022;161[2];572-82). This single-site study reported on 159 nodule biopsies, with the primary outcome being diagnostic yield. The patients had 1 year of follow-up, and the definition of yield was conservative. The average lesion size was 18 mm, and nodule locations and characteristics were representative of real-world conditions. Overall diagnostic yield was 81.7%; however, it dropped to under 70% for nodules under 20 mm in size.

The largest study to date using the Monarch platform was also a single center study, this from the University of Chicago (Agrawal, et al. Ann Thorac Surg. 2022 Jan 17;S0003-4975(22)00042-X. Online ahead of print). This study included 124 nodules with at least 12 months of follow-up; diagnostic yield definition was conservative. Median nodule size was 20.5 mm, with distribution and characteristics representative of real-world conditions. Overall accuracy was 77%, and, similar to the Ion study, dropped to under 70% when nodule size was smaller than 20 mm.

Overall, both robot studies seemed to show a modest improvement in diagnostic yield when compared with ENB, and their outcomes were overall similar. It is important to remember that these were studies of each center’s first experiences with early versions of each technology; over time, the technology will continue to improve, as will operator skill and experience, and with that, perhaps improvements in yield will be seen, as well.

Interestingly, both studies evaluated target localization using radial EBUS (rEBUS), which also allowed for airway-nodule relationships to be reported. In Kalchiem-Dekel’s study, 85% of cases used rEBUS to determine localization, and, of these, 91.2% of cases showed accurate localization. In Agrawal’s study, rEBUS was used in all cases with a reported localization of 94%. In both, yield did not seem to be affected by airway-nodule relationships, perhaps explained by more robust tip control of the robotic scope. However, localization did not equate to yield in all cases, which brings up a very important question: Can the yield of robotic bronchoscopy be further improved with better real-time on-board imaging, such as CBCT scanning or C-arm based tomography? Currently, there is a study using 3D technology (Cios 3D Mobile Spin) in conjunction with the Ion platform to evaluate this.

So, let’s circle back to where we started. I think if you look at the totality of the data, it is clear that the robotic platforms currently offer a modest improvement in diagnostic yield over traditional ENB, with individual performances that are somewhat equivalent despite differences in design and operation. But does this improvement in yield justify the cost? Individual hospitals will have to make that decision. The capital cost and per-use price of the scope is significant, which has to be balanced against each center’s current performance with non-robotic bronchoscopy.

To date, there have been over 25,000 robotic procedures performed in the United States, so enthusiasm across diverse centers is being maintained. Whether this enthusiasm is driven by yield or novelty, or both, I’m not sure. With other nonrobotic platforms having reached, or soon to reach, the market, this is a good time to be in the business of bronchoscopy.

Dr. Cicenia is in the Section of Bronchoscopy at Cleveland Clinic’s Respiratory Institute, Cleveland, Ohio.

Over the last several years, hundreds of millions of dollars have been spent on robotic bronchoscopy systems in the United States. The release of robotic scopes was made to great fanfare, translating into the market being infiltrated with these systems. With base costs in the hundreds of thousands of dollars, robotic bronchoscope systems are easily the most expensive singular capital investment in the bronchoscopy suite. I frequently get asked questions from those who have not yet made that purchase: “Should I buy a robot?” “How could I justify a new robot purchase to my hospital?” “Is the hype real?” These are complex questions to answer. Before one can answer, I think it’s best to look back on the last 2 decades of bronchoscopy for peripheral lung nodules to get a better understanding of the value proposition robotic bronchoscopes may offer.

Guided bronchoscopy for lung nodules has significantly evolved over the past 2 decades, shifting diagnostic procedures from interventional radiologist to the pulmonologist. Some of these advances were based in redesigns of the bronchoscope (ultrathin bronchoscopy) or application of technology to the bronchoscope (radial EBUS, virtual bronchoscopy); but, these were not broadly applicable to the pulmonology community at large. It was not until the development of electromagnetic navigational bronchoscopy (ENB) that widespread adoption of bronchoscopy for lung nodules occurred. By and large, ENB fueled a rapid expansion of nodule bronchoscopy, mainly due to its ease of use and novel approach. Initial studies of ENB had impressive results; however, studies were criticized for having small numbers, inadequate follow-up, spurious definitions of yield, and that they were being done at highly specialized centers. The NAVIGATE trial was launched to address these criticisms among “real world” conditions. Sponsored by Medtronic, it studied ENB (superDimension platform, v6.0 or higher) across 29 academic and medical centers in the United States, enrolling over 1,000 patients (Folch EE, et al. J Thorac Oncol. 2019;14[3]:445-58. Epub 2018 Nov 23), and reported a diagnostic yield of 73%.

This led to a drive to improve upon yield, resulting in development of new technologies specifically designed to address some of the factors thought associated with diminished yield, and, out of this, robotic bronchoscopy was born. These factors included CT scan-body registration divergence, deflection of the extended working channel (EWC) by rigid biopsy tools, and inability to accurately “aim” the EWC-biopsy tool at the nodule; these were especially problematic in nodules not associated with airways. Robotic scopes were specifically designed to reach into the peripheral lung airways similar to an EWC, but with better structural integrity and steerability. This tip integrity would resist tool-related displacement, and steerability would allow for improved targeting of nodules during the biopsy.

There are two robots approved by the FDA at the time of this writing (Auris Monarch, Intuitive Ion), with a third awaiting FDA clearance (Noah Galaxy). In general, though the engineering of the robotic scopes to improve structural tip integrity are similar, the approach to navigation and targeting vary significantly. The Monarch platform uses electromagnetic guidance, similar to other traditional ENB platforms. The Ion platform does not use ENB; instead, it uses fiberoptic shape sensing technology, which analyzes the shape and orientation of the scope to provide location information. There are potential advantages to shape sensing, the most notable being the absence of electromagnetics; this allows for use of fluoroscopy during the procedure, which otherwise would have interfered with ENB-based navigation. There are other subtle differences between the two robots. The Monarch uses a scope-in-scope design, with a robotic scope contained within a robotic sheath; the Ion uses a single robotic scope. The Ion scope diameter is 3.5 mm, whereas the Monarch diameter is 4.4 mm; this may be a potential advantage when having to navigate through smaller airways.

So, which robot is better suited to reach peripheral nodules more consistently and accurately? I get asked this question a lot, since I have both platforms at my institution. But, answering with my own opinion based on my institution’s anecdotal experience would be irresponsible. I’m more of a “what does the data show?” person. Luckily, we do have clinical trials in both robot technologies. It should be noted here that there will likely never be a head-to-head randomized trial, so evaluating published studies with each platform is going to be the best method we have for comparison going forward, albeit an imperfect one. It should also be noted that many of the early robotic bronchoscopy trials have to be looked at with caution, as yield definitions tended not to be conservative and/or the follow-up of non-malignant was not robust. With that in mind, let’s review representative high-quality studies for each platform.

The best study to date using the Ion platform came out of Memorial Sloan Kettering Cancer Center (Kalchiem-Dekel O, et al. Chest. 2022;161[2];572-82). This single-site study reported on 159 nodule biopsies, with the primary outcome being diagnostic yield. The patients had 1 year of follow-up, and the definition of yield was conservative. The average lesion size was 18 mm, and nodule locations and characteristics were representative of real-world conditions. Overall diagnostic yield was 81.7%; however, it dropped to under 70% for nodules under 20 mm in size.

The largest study to date using the Monarch platform was also a single center study, this from the University of Chicago (Agrawal, et al. Ann Thorac Surg. 2022 Jan 17;S0003-4975(22)00042-X. Online ahead of print). This study included 124 nodules with at least 12 months of follow-up; diagnostic yield definition was conservative. Median nodule size was 20.5 mm, with distribution and characteristics representative of real-world conditions. Overall accuracy was 77%, and, similar to the Ion study, dropped to under 70% when nodule size was smaller than 20 mm.

Overall, both robot studies seemed to show a modest improvement in diagnostic yield when compared with ENB, and their outcomes were overall similar. It is important to remember that these were studies of each center’s first experiences with early versions of each technology; over time, the technology will continue to improve, as will operator skill and experience, and with that, perhaps improvements in yield will be seen, as well.

Interestingly, both studies evaluated target localization using radial EBUS (rEBUS), which also allowed for airway-nodule relationships to be reported. In Kalchiem-Dekel’s study, 85% of cases used rEBUS to determine localization, and, of these, 91.2% of cases showed accurate localization. In Agrawal’s study, rEBUS was used in all cases with a reported localization of 94%. In both, yield did not seem to be affected by airway-nodule relationships, perhaps explained by more robust tip control of the robotic scope. However, localization did not equate to yield in all cases, which brings up a very important question: Can the yield of robotic bronchoscopy be further improved with better real-time on-board imaging, such as CBCT scanning or C-arm based tomography? Currently, there is a study using 3D technology (Cios 3D Mobile Spin) in conjunction with the Ion platform to evaluate this.

So, let’s circle back to where we started. I think if you look at the totality of the data, it is clear that the robotic platforms currently offer a modest improvement in diagnostic yield over traditional ENB, with individual performances that are somewhat equivalent despite differences in design and operation. But does this improvement in yield justify the cost? Individual hospitals will have to make that decision. The capital cost and per-use price of the scope is significant, which has to be balanced against each center’s current performance with non-robotic bronchoscopy.

To date, there have been over 25,000 robotic procedures performed in the United States, so enthusiasm across diverse centers is being maintained. Whether this enthusiasm is driven by yield or novelty, or both, I’m not sure. With other nonrobotic platforms having reached, or soon to reach, the market, this is a good time to be in the business of bronchoscopy.

Dr. Cicenia is in the Section of Bronchoscopy at Cleveland Clinic’s Respiratory Institute, Cleveland, Ohio.

Over the last several years, hundreds of millions of dollars have been spent on robotic bronchoscopy systems in the United States. The release of robotic scopes was made to great fanfare, translating into the market being infiltrated with these systems. With base costs in the hundreds of thousands of dollars, robotic bronchoscope systems are easily the most expensive singular capital investment in the bronchoscopy suite. I frequently get asked questions from those who have not yet made that purchase: “Should I buy a robot?” “How could I justify a new robot purchase to my hospital?” “Is the hype real?” These are complex questions to answer. Before one can answer, I think it’s best to look back on the last 2 decades of bronchoscopy for peripheral lung nodules to get a better understanding of the value proposition robotic bronchoscopes may offer.

Guided bronchoscopy for lung nodules has significantly evolved over the past 2 decades, shifting diagnostic procedures from interventional radiologist to the pulmonologist. Some of these advances were based in redesigns of the bronchoscope (ultrathin bronchoscopy) or application of technology to the bronchoscope (radial EBUS, virtual bronchoscopy); but, these were not broadly applicable to the pulmonology community at large. It was not until the development of electromagnetic navigational bronchoscopy (ENB) that widespread adoption of bronchoscopy for lung nodules occurred. By and large, ENB fueled a rapid expansion of nodule bronchoscopy, mainly due to its ease of use and novel approach. Initial studies of ENB had impressive results; however, studies were criticized for having small numbers, inadequate follow-up, spurious definitions of yield, and that they were being done at highly specialized centers. The NAVIGATE trial was launched to address these criticisms among “real world” conditions. Sponsored by Medtronic, it studied ENB (superDimension platform, v6.0 or higher) across 29 academic and medical centers in the United States, enrolling over 1,000 patients (Folch EE, et al. J Thorac Oncol. 2019;14[3]:445-58. Epub 2018 Nov 23), and reported a diagnostic yield of 73%.

This led to a drive to improve upon yield, resulting in development of new technologies specifically designed to address some of the factors thought associated with diminished yield, and, out of this, robotic bronchoscopy was born. These factors included CT scan-body registration divergence, deflection of the extended working channel (EWC) by rigid biopsy tools, and inability to accurately “aim” the EWC-biopsy tool at the nodule; these were especially problematic in nodules not associated with airways. Robotic scopes were specifically designed to reach into the peripheral lung airways similar to an EWC, but with better structural integrity and steerability. This tip integrity would resist tool-related displacement, and steerability would allow for improved targeting of nodules during the biopsy.

There are two robots approved by the FDA at the time of this writing (Auris Monarch, Intuitive Ion), with a third awaiting FDA clearance (Noah Galaxy). In general, though the engineering of the robotic scopes to improve structural tip integrity are similar, the approach to navigation and targeting vary significantly. The Monarch platform uses electromagnetic guidance, similar to other traditional ENB platforms. The Ion platform does not use ENB; instead, it uses fiberoptic shape sensing technology, which analyzes the shape and orientation of the scope to provide location information. There are potential advantages to shape sensing, the most notable being the absence of electromagnetics; this allows for use of fluoroscopy during the procedure, which otherwise would have interfered with ENB-based navigation. There are other subtle differences between the two robots. The Monarch uses a scope-in-scope design, with a robotic scope contained within a robotic sheath; the Ion uses a single robotic scope. The Ion scope diameter is 3.5 mm, whereas the Monarch diameter is 4.4 mm; this may be a potential advantage when having to navigate through smaller airways.

So, which robot is better suited to reach peripheral nodules more consistently and accurately? I get asked this question a lot, since I have both platforms at my institution. But, answering with my own opinion based on my institution’s anecdotal experience would be irresponsible. I’m more of a “what does the data show?” person. Luckily, we do have clinical trials in both robot technologies. It should be noted here that there will likely never be a head-to-head randomized trial, so evaluating published studies with each platform is going to be the best method we have for comparison going forward, albeit an imperfect one. It should also be noted that many of the early robotic bronchoscopy trials have to be looked at with caution, as yield definitions tended not to be conservative and/or the follow-up of non-malignant was not robust. With that in mind, let’s review representative high-quality studies for each platform.

The best study to date using the Ion platform came out of Memorial Sloan Kettering Cancer Center (Kalchiem-Dekel O, et al. Chest. 2022;161[2];572-82). This single-site study reported on 159 nodule biopsies, with the primary outcome being diagnostic yield. The patients had 1 year of follow-up, and the definition of yield was conservative. The average lesion size was 18 mm, and nodule locations and characteristics were representative of real-world conditions. Overall diagnostic yield was 81.7%; however, it dropped to under 70% for nodules under 20 mm in size.

The largest study to date using the Monarch platform was also a single center study, this from the University of Chicago (Agrawal, et al. Ann Thorac Surg. 2022 Jan 17;S0003-4975(22)00042-X. Online ahead of print). This study included 124 nodules with at least 12 months of follow-up; diagnostic yield definition was conservative. Median nodule size was 20.5 mm, with distribution and characteristics representative of real-world conditions. Overall accuracy was 77%, and, similar to the Ion study, dropped to under 70% when nodule size was smaller than 20 mm.

Overall, both robot studies seemed to show a modest improvement in diagnostic yield when compared with ENB, and their outcomes were overall similar. It is important to remember that these were studies of each center’s first experiences with early versions of each technology; over time, the technology will continue to improve, as will operator skill and experience, and with that, perhaps improvements in yield will be seen, as well.

Interestingly, both studies evaluated target localization using radial EBUS (rEBUS), which also allowed for airway-nodule relationships to be reported. In Kalchiem-Dekel’s study, 85% of cases used rEBUS to determine localization, and, of these, 91.2% of cases showed accurate localization. In Agrawal’s study, rEBUS was used in all cases with a reported localization of 94%. In both, yield did not seem to be affected by airway-nodule relationships, perhaps explained by more robust tip control of the robotic scope. However, localization did not equate to yield in all cases, which brings up a very important question: Can the yield of robotic bronchoscopy be further improved with better real-time on-board imaging, such as CBCT scanning or C-arm based tomography? Currently, there is a study using 3D technology (Cios 3D Mobile Spin) in conjunction with the Ion platform to evaluate this.

So, let’s circle back to where we started. I think if you look at the totality of the data, it is clear that the robotic platforms currently offer a modest improvement in diagnostic yield over traditional ENB, with individual performances that are somewhat equivalent despite differences in design and operation. But does this improvement in yield justify the cost? Individual hospitals will have to make that decision. The capital cost and per-use price of the scope is significant, which has to be balanced against each center’s current performance with non-robotic bronchoscopy.

To date, there have been over 25,000 robotic procedures performed in the United States, so enthusiasm across diverse centers is being maintained. Whether this enthusiasm is driven by yield or novelty, or both, I’m not sure. With other nonrobotic platforms having reached, or soon to reach, the market, this is a good time to be in the business of bronchoscopy.

Dr. Cicenia is in the Section of Bronchoscopy at Cleveland Clinic’s Respiratory Institute, Cleveland, Ohio.

New COVID-19 vaccine boosters, targeting new Omicron strains of the virus, are expected to roll out across the United States in September – a month ahead of schedule, the Biden administration announced this week.

Moderna has signed a $1.74 billion federal contract to supply 66 million initial doses of the “bivalent” booster, which includes the original “ancestral” virus strain and elements of the Omicron BA.4 and BA.5 variants. Pfizer also announced a $3.2 billion U.S. agreement for another 105 million shots. Both vaccine suppliers have signed options to provide millions more boosters in the months ahead.

About 83.5% of Americans have received at least one COVID-19 shot, with 71.5% fully vaccinated with the initial series, 48% receiving one booster shot, and 31% two boosters, according to the CDC. With about 130,000 new COVID cases per day, and about 440 deaths, officials say the updated boosters may help rein in those figures by targeting the highly transmissible and widely circulating Omicron strains.

Federal health officials are still hammering out details of guidelines and recommendations of who should get the boosters, which are expected to come from the CDC and FDA. For now, authorities have decided not to expand eligibility for second boosters of the existing vaccines – now recommended only for adults over 50 and those 12 and older with immune deficiencies. Children 5 through 11 are advised to receive a single booster, 5 months after their initial vaccine series.

For a preview of what to expect from the CDC and FDA, this news organization spoke with Keri Althoff, PhD, an epidemiologist at Johns Hopkins University, Baltimore.
 

Q: Based on what we know now, who should be getting one of these new bivalent boosters?A: Of course, there is a process here regarding the specific recommendations, but it appears there will likely be a recommendation for all individuals to get this bivalent booster, similar to the first booster. And there will likely be a recommended time frame as to time since the last booster.

Right now, we have a recommendation for adults over the age of 50 or adults who are at higher risk for severe COVID-related illness [to get] a second booster. For them, there will probably be a timeline that says you should get the booster if you’re X amount of months or more from your second booster; or X amount of months or more from your first booster, if you’ve only had one.

Q: What about pregnant women or those being treated for chronic health conditions?A: I would imagine that once this bivalent booster becomes available, it will be recommended for all adults.

Q: And for children?A: That’s a good question. It’s something I have been digging into, [and] I think parents are really interested in this. Most kids, 5 and above, are supposed to be boosted with one shot right now, if they’re X amount of days from their primary vaccine series. Of course those 6 months to 4.99 years are not yet eligible [for boosters].

As a parent, I would love to see my children become eligible for the bivalent booster. It would be great if these boosters are conveying some additional protection that the kids could get access to before we send them off to school this fall. But there are questions as to whether or not that is going to happen.

Q: If you never received a booster, but only the preliminary vaccine series, do you need to get those earlier boosters before having the new bivalent booster shot?A: I don’t think they will likely make that a requirement – to restrict the bivalent booster only to those who are already boosted or up to date on their vaccines at the time the bivalent booster becomes available. But that will be up to the [CDC] vaccine recommendation committee to decide.

Q: Are there any new risks associated with these boosters, since they were developed so rapidly?A: No. We continue to monitor this technology, and with all the mRNA vaccines that have been delivered, you have seen all that monitoring play out with the detection, for example, of different forms of inflammation of the heart tissue and who that may impact. So, those monitoring systems work, and they work really, really well, so we can detect those things. And we know these vaccines are definitely safe.

Q: Some health experts are concerned “vaccine fatigue” will have an impact on the booster campaign. What’s your take?A: We have seen this fatigue in the proportion of individuals who are boosted with a first booster and even boosted with a second. But having those earlier boosters along with this new bivalent booster is important, because essentially, what we’re doing is really priming the immune system.

We’re trying to expedite the process of getting people’s immune system up to speed so that when the virus comes our way – as we know it will, because [of] these Omicron strains that are highly infectious and really whipping through our communities – we’re able to get the highest level of population immunity, you don’t end up in the hospital.

Q: What other challenges do you see in persuading Americans to get another round of boosters?A: One of the things that I’ve been hearing a lot, which I get very nervous about, is people saying: “Oh, I got fully vaccinated, I did or did not get the booster, and I had COVID anyway and it was really nothing, it didn’t feel like much to me, and so I’m not going to be boosted anymore.” We are not in a place quite yet where those guidelines are being rolled back in any way, shape, or form. We still have highly vulnerable people to severe disease and death in our communities, and we’re seeing hundreds of deaths every day.

There are consequences, even if it isn’t in severity of disease, meaning hospitalization and death. And let’s not let the actual quality of the vaccine being so successful that it can keep you out of the hospital. Don’t mistake that for “I don’t need another one.”

Q: Unlike the flu shot, which is reformulated each year to match circulating strains, the new COVID boosters offer protection against older strains as well as the newer ones. Why?A: It’s all about creating a broader immune response in individuals so that as more strains emerge, which they likely will, we can create a broader population immune response [to all strains]. Our individual bodies are seeing differences in these strains through vaccination that helps everyone stay healthy.

Q: There haven’t been clinical trials of these new mRNA boosters. How strong is the evidence that they will be effective against the emerging Omicron variants?A: There have been some studies – some great studies – looking at things like neutralizing antibodies, which we use as a surrogate for clinical trials. But that is not the same as studying the outcome of interest, which would be hospitalizations. So, part of the challenge is to be able to say: “Okay, this is what we know about the safety and effectiveness of the prior vaccines ... and how can we relate that to outcomes with these new boosters at an earlier stage [before] clinical data is available?”

Q: How long will the new boosters’ protections last – do we know yet?A: That timing is still a question, but of course what plays a big role in that is what COVID strains are circulating. If we prep these boosters that are Omicron specific, and then we have something totally new emerge ... we have to be more nimble because the variants are outpacing what we’re able to do.

This turns out to be a bit of a game of probability – the more infection we have, the more replication of the virus; the more replication, the more opportunity for mutations and subsequent variants.

Q: What about a combined flu-COVID vaccine; is that on the horizon?A: My children, who like most children do not like vaccines, always tell me: “Mom, why can’t they just put the influenza vaccine and the COVID vaccine into the same shot?” And I’m like: “Oh, from your lips to some scientist’s ears.”

At a time like this, where mRNA technology has totally disrupted what we can do with vaccines, in such a good way, I think we should push for the limits, because that would be incredible.

Q: If you’ve received a non-mRNA COVID vaccine, like those produced by Johnson & Johnson and Novavax, should you also get an mRNA booster?A: Right now, the CDC guidelines do state that if your primary vaccine series was not with an mRNA vaccine then being boosted with an mRNA is a fine thing to do, and it’s actually encouraged. So that’s not going to change with the bivalent booster.

Q: Is it okay to get a flu shot and a COVID booster at the same time, as the Centers for Disease Control and Prevention has recommended with past vaccines?A: I don’t anticipate there being recommendations against that. But I would also say watch for the recommendations that come out this fall on the bivalent boosters.

I do hope in the recommendations the CDC makes about the COVID boosters, they will say think about also getting your influenza vaccine, too. You could also get your COVID booster first, then by October get your influenza vaccine.

Q: Once you’re fully boosted, is it safe to stop wearing a mask, social distancing, avoiding crowded indoor spaces, and taking other precautions to avoid COVID-19?A: The virus is going to do what it does, which is infect whomever it can, and make them sick. So, if you see a lot of community transmission – you know who is ill with COVID in your kids’ schools, you know in your workplace and when people go out – that still signals there’s some increases in the circulation of virus. So, look at that to understand what your risk is.

If you know someone or have a colleague who is currently pregnant or immune suppressed, think about how you can protect them with mask-wearing, even if it’s just when you’re in one-on-one closed-door meetings with that individual.

So, your masking question is an important one, and it’s important for people to continue to hang onto those masks and wear them the week before you go see Grandma, for instance, to further reduce your risk so you don’t bring anything to here.

The high-level community risk nationwide is high right now. COVID is here.

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

New COVID-19 vaccine boosters, targeting new Omicron strains of the virus, are expected to roll out across the United States in September – a month ahead of schedule, the Biden administration announced this week.

Moderna has signed a $1.74 billion federal contract to supply 66 million initial doses of the “bivalent” booster, which includes the original “ancestral” virus strain and elements of the Omicron BA.4 and BA.5 variants. Pfizer also announced a $3.2 billion U.S. agreement for another 105 million shots. Both vaccine suppliers have signed options to provide millions more boosters in the months ahead.

About 83.5% of Americans have received at least one COVID-19 shot, with 71.5% fully vaccinated with the initial series, 48% receiving one booster shot, and 31% two boosters, according to the CDC. With about 130,000 new COVID cases per day, and about 440 deaths, officials say the updated boosters may help rein in those figures by targeting the highly transmissible and widely circulating Omicron strains.

Federal health officials are still hammering out details of guidelines and recommendations of who should get the boosters, which are expected to come from the CDC and FDA. For now, authorities have decided not to expand eligibility for second boosters of the existing vaccines – now recommended only for adults over 50 and those 12 and older with immune deficiencies. Children 5 through 11 are advised to receive a single booster, 5 months after their initial vaccine series.

For a preview of what to expect from the CDC and FDA, this news organization spoke with Keri Althoff, PhD, an epidemiologist at Johns Hopkins University, Baltimore.
 

Q: Based on what we know now, who should be getting one of these new bivalent boosters?A: Of course, there is a process here regarding the specific recommendations, but it appears there will likely be a recommendation for all individuals to get this bivalent booster, similar to the first booster. And there will likely be a recommended time frame as to time since the last booster.

Right now, we have a recommendation for adults over the age of 50 or adults who are at higher risk for severe COVID-related illness [to get] a second booster. For them, there will probably be a timeline that says you should get the booster if you’re X amount of months or more from your second booster; or X amount of months or more from your first booster, if you’ve only had one.

Q: What about pregnant women or those being treated for chronic health conditions?A: I would imagine that once this bivalent booster becomes available, it will be recommended for all adults.

Q: And for children?A: That’s a good question. It’s something I have been digging into, [and] I think parents are really interested in this. Most kids, 5 and above, are supposed to be boosted with one shot right now, if they’re X amount of days from their primary vaccine series. Of course those 6 months to 4.99 years are not yet eligible [for boosters].

As a parent, I would love to see my children become eligible for the bivalent booster. It would be great if these boosters are conveying some additional protection that the kids could get access to before we send them off to school this fall. But there are questions as to whether or not that is going to happen.

Q: If you never received a booster, but only the preliminary vaccine series, do you need to get those earlier boosters before having the new bivalent booster shot?A: I don’t think they will likely make that a requirement – to restrict the bivalent booster only to those who are already boosted or up to date on their vaccines at the time the bivalent booster becomes available. But that will be up to the [CDC] vaccine recommendation committee to decide.

Q: Are there any new risks associated with these boosters, since they were developed so rapidly?A: No. We continue to monitor this technology, and with all the mRNA vaccines that have been delivered, you have seen all that monitoring play out with the detection, for example, of different forms of inflammation of the heart tissue and who that may impact. So, those monitoring systems work, and they work really, really well, so we can detect those things. And we know these vaccines are definitely safe.

Q: Some health experts are concerned “vaccine fatigue” will have an impact on the booster campaign. What’s your take?A: We have seen this fatigue in the proportion of individuals who are boosted with a first booster and even boosted with a second. But having those earlier boosters along with this new bivalent booster is important, because essentially, what we’re doing is really priming the immune system.

We’re trying to expedite the process of getting people’s immune system up to speed so that when the virus comes our way – as we know it will, because [of] these Omicron strains that are highly infectious and really whipping through our communities – we’re able to get the highest level of population immunity, you don’t end up in the hospital.

Q: What other challenges do you see in persuading Americans to get another round of boosters?A: One of the things that I’ve been hearing a lot, which I get very nervous about, is people saying: “Oh, I got fully vaccinated, I did or did not get the booster, and I had COVID anyway and it was really nothing, it didn’t feel like much to me, and so I’m not going to be boosted anymore.” We are not in a place quite yet where those guidelines are being rolled back in any way, shape, or form. We still have highly vulnerable people to severe disease and death in our communities, and we’re seeing hundreds of deaths every day.

There are consequences, even if it isn’t in severity of disease, meaning hospitalization and death. And let’s not let the actual quality of the vaccine being so successful that it can keep you out of the hospital. Don’t mistake that for “I don’t need another one.”

Q: Unlike the flu shot, which is reformulated each year to match circulating strains, the new COVID boosters offer protection against older strains as well as the newer ones. Why?A: It’s all about creating a broader immune response in individuals so that as more strains emerge, which they likely will, we can create a broader population immune response [to all strains]. Our individual bodies are seeing differences in these strains through vaccination that helps everyone stay healthy.

Q: There haven’t been clinical trials of these new mRNA boosters. How strong is the evidence that they will be effective against the emerging Omicron variants?A: There have been some studies – some great studies – looking at things like neutralizing antibodies, which we use as a surrogate for clinical trials. But that is not the same as studying the outcome of interest, which would be hospitalizations. So, part of the challenge is to be able to say: “Okay, this is what we know about the safety and effectiveness of the prior vaccines ... and how can we relate that to outcomes with these new boosters at an earlier stage [before] clinical data is available?”

Q: How long will the new boosters’ protections last – do we know yet?A: That timing is still a question, but of course what plays a big role in that is what COVID strains are circulating. If we prep these boosters that are Omicron specific, and then we have something totally new emerge ... we have to be more nimble because the variants are outpacing what we’re able to do.

This turns out to be a bit of a game of probability – the more infection we have, the more replication of the virus; the more replication, the more opportunity for mutations and subsequent variants.

Q: What about a combined flu-COVID vaccine; is that on the horizon?A: My children, who like most children do not like vaccines, always tell me: “Mom, why can’t they just put the influenza vaccine and the COVID vaccine into the same shot?” And I’m like: “Oh, from your lips to some scientist’s ears.”

At a time like this, where mRNA technology has totally disrupted what we can do with vaccines, in such a good way, I think we should push for the limits, because that would be incredible.

Q: If you’ve received a non-mRNA COVID vaccine, like those produced by Johnson & Johnson and Novavax, should you also get an mRNA booster?A: Right now, the CDC guidelines do state that if your primary vaccine series was not with an mRNA vaccine then being boosted with an mRNA is a fine thing to do, and it’s actually encouraged. So that’s not going to change with the bivalent booster.

Q: Is it okay to get a flu shot and a COVID booster at the same time, as the Centers for Disease Control and Prevention has recommended with past vaccines?A: I don’t anticipate there being recommendations against that. But I would also say watch for the recommendations that come out this fall on the bivalent boosters.

I do hope in the recommendations the CDC makes about the COVID boosters, they will say think about also getting your influenza vaccine, too. You could also get your COVID booster first, then by October get your influenza vaccine.

Q: Once you’re fully boosted, is it safe to stop wearing a mask, social distancing, avoiding crowded indoor spaces, and taking other precautions to avoid COVID-19?A: The virus is going to do what it does, which is infect whomever it can, and make them sick. So, if you see a lot of community transmission – you know who is ill with COVID in your kids’ schools, you know in your workplace and when people go out – that still signals there’s some increases in the circulation of virus. So, look at that to understand what your risk is.

If you know someone or have a colleague who is currently pregnant or immune suppressed, think about how you can protect them with mask-wearing, even if it’s just when you’re in one-on-one closed-door meetings with that individual.

So, your masking question is an important one, and it’s important for people to continue to hang onto those masks and wear them the week before you go see Grandma, for instance, to further reduce your risk so you don’t bring anything to here.

The high-level community risk nationwide is high right now. COVID is here.

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

New COVID-19 vaccine boosters, targeting new Omicron strains of the virus, are expected to roll out across the United States in September – a month ahead of schedule, the Biden administration announced this week.

Moderna has signed a $1.74 billion federal contract to supply 66 million initial doses of the “bivalent” booster, which includes the original “ancestral” virus strain and elements of the Omicron BA.4 and BA.5 variants. Pfizer also announced a $3.2 billion U.S. agreement for another 105 million shots. Both vaccine suppliers have signed options to provide millions more boosters in the months ahead.

About 83.5% of Americans have received at least one COVID-19 shot, with 71.5% fully vaccinated with the initial series, 48% receiving one booster shot, and 31% two boosters, according to the CDC. With about 130,000 new COVID cases per day, and about 440 deaths, officials say the updated boosters may help rein in those figures by targeting the highly transmissible and widely circulating Omicron strains.

Federal health officials are still hammering out details of guidelines and recommendations of who should get the boosters, which are expected to come from the CDC and FDA. For now, authorities have decided not to expand eligibility for second boosters of the existing vaccines – now recommended only for adults over 50 and those 12 and older with immune deficiencies. Children 5 through 11 are advised to receive a single booster, 5 months after their initial vaccine series.

For a preview of what to expect from the CDC and FDA, this news organization spoke with Keri Althoff, PhD, an epidemiologist at Johns Hopkins University, Baltimore.
 

Q: Based on what we know now, who should be getting one of these new bivalent boosters?A: Of course, there is a process here regarding the specific recommendations, but it appears there will likely be a recommendation for all individuals to get this bivalent booster, similar to the first booster. And there will likely be a recommended time frame as to time since the last booster.

Right now, we have a recommendation for adults over the age of 50 or adults who are at higher risk for severe COVID-related illness [to get] a second booster. For them, there will probably be a timeline that says you should get the booster if you’re X amount of months or more from your second booster; or X amount of months or more from your first booster, if you’ve only had one.

Q: What about pregnant women or those being treated for chronic health conditions?A: I would imagine that once this bivalent booster becomes available, it will be recommended for all adults.

Q: And for children?A: That’s a good question. It’s something I have been digging into, [and] I think parents are really interested in this. Most kids, 5 and above, are supposed to be boosted with one shot right now, if they’re X amount of days from their primary vaccine series. Of course those 6 months to 4.99 years are not yet eligible [for boosters].

As a parent, I would love to see my children become eligible for the bivalent booster. It would be great if these boosters are conveying some additional protection that the kids could get access to before we send them off to school this fall. But there are questions as to whether or not that is going to happen.

Q: If you never received a booster, but only the preliminary vaccine series, do you need to get those earlier boosters before having the new bivalent booster shot?A: I don’t think they will likely make that a requirement – to restrict the bivalent booster only to those who are already boosted or up to date on their vaccines at the time the bivalent booster becomes available. But that will be up to the [CDC] vaccine recommendation committee to decide.

Q: Are there any new risks associated with these boosters, since they were developed so rapidly?A: No. We continue to monitor this technology, and with all the mRNA vaccines that have been delivered, you have seen all that monitoring play out with the detection, for example, of different forms of inflammation of the heart tissue and who that may impact. So, those monitoring systems work, and they work really, really well, so we can detect those things. And we know these vaccines are definitely safe.

Q: Some health experts are concerned “vaccine fatigue” will have an impact on the booster campaign. What’s your take?A: We have seen this fatigue in the proportion of individuals who are boosted with a first booster and even boosted with a second. But having those earlier boosters along with this new bivalent booster is important, because essentially, what we’re doing is really priming the immune system.

We’re trying to expedite the process of getting people’s immune system up to speed so that when the virus comes our way – as we know it will, because [of] these Omicron strains that are highly infectious and really whipping through our communities – we’re able to get the highest level of population immunity, you don’t end up in the hospital.

Q: What other challenges do you see in persuading Americans to get another round of boosters?A: One of the things that I’ve been hearing a lot, which I get very nervous about, is people saying: “Oh, I got fully vaccinated, I did or did not get the booster, and I had COVID anyway and it was really nothing, it didn’t feel like much to me, and so I’m not going to be boosted anymore.” We are not in a place quite yet where those guidelines are being rolled back in any way, shape, or form. We still have highly vulnerable people to severe disease and death in our communities, and we’re seeing hundreds of deaths every day.

There are consequences, even if it isn’t in severity of disease, meaning hospitalization and death. And let’s not let the actual quality of the vaccine being so successful that it can keep you out of the hospital. Don’t mistake that for “I don’t need another one.”

Q: Unlike the flu shot, which is reformulated each year to match circulating strains, the new COVID boosters offer protection against older strains as well as the newer ones. Why?A: It’s all about creating a broader immune response in individuals so that as more strains emerge, which they likely will, we can create a broader population immune response [to all strains]. Our individual bodies are seeing differences in these strains through vaccination that helps everyone stay healthy.

Q: There haven’t been clinical trials of these new mRNA boosters. How strong is the evidence that they will be effective against the emerging Omicron variants?A: There have been some studies – some great studies – looking at things like neutralizing antibodies, which we use as a surrogate for clinical trials. But that is not the same as studying the outcome of interest, which would be hospitalizations. So, part of the challenge is to be able to say: “Okay, this is what we know about the safety and effectiveness of the prior vaccines ... and how can we relate that to outcomes with these new boosters at an earlier stage [before] clinical data is available?”

Q: How long will the new boosters’ protections last – do we know yet?A: That timing is still a question, but of course what plays a big role in that is what COVID strains are circulating. If we prep these boosters that are Omicron specific, and then we have something totally new emerge ... we have to be more nimble because the variants are outpacing what we’re able to do.

This turns out to be a bit of a game of probability – the more infection we have, the more replication of the virus; the more replication, the more opportunity for mutations and subsequent variants.

Q: What about a combined flu-COVID vaccine; is that on the horizon?A: My children, who like most children do not like vaccines, always tell me: “Mom, why can’t they just put the influenza vaccine and the COVID vaccine into the same shot?” And I’m like: “Oh, from your lips to some scientist’s ears.”

At a time like this, where mRNA technology has totally disrupted what we can do with vaccines, in such a good way, I think we should push for the limits, because that would be incredible.

Q: If you’ve received a non-mRNA COVID vaccine, like those produced by Johnson & Johnson and Novavax, should you also get an mRNA booster?A: Right now, the CDC guidelines do state that if your primary vaccine series was not with an mRNA vaccine then being boosted with an mRNA is a fine thing to do, and it’s actually encouraged. So that’s not going to change with the bivalent booster.

Q: Is it okay to get a flu shot and a COVID booster at the same time, as the Centers for Disease Control and Prevention has recommended with past vaccines?A: I don’t anticipate there being recommendations against that. But I would also say watch for the recommendations that come out this fall on the bivalent boosters.

I do hope in the recommendations the CDC makes about the COVID boosters, they will say think about also getting your influenza vaccine, too. You could also get your COVID booster first, then by October get your influenza vaccine.

Q: Once you’re fully boosted, is it safe to stop wearing a mask, social distancing, avoiding crowded indoor spaces, and taking other precautions to avoid COVID-19?A: The virus is going to do what it does, which is infect whomever it can, and make them sick. So, if you see a lot of community transmission – you know who is ill with COVID in your kids’ schools, you know in your workplace and when people go out – that still signals there’s some increases in the circulation of virus. So, look at that to understand what your risk is.

If you know someone or have a colleague who is currently pregnant or immune suppressed, think about how you can protect them with mask-wearing, even if it’s just when you’re in one-on-one closed-door meetings with that individual.

So, your masking question is an important one, and it’s important for people to continue to hang onto those masks and wear them the week before you go see Grandma, for instance, to further reduce your risk so you don’t bring anything to here.

The high-level community risk nationwide is high right now. COVID is here.

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

An AI-guided analysis of more than 1,000 human lung transcriptomic datasets found that COVID-19 resembles idiopathic pulmonary fibrosis (IPF) at a fundamental level, according to a study published in eBiomedicine, part of The Lancet Discovery Science.

In the aftermath of COVID-19, a significant number of patients develop a fibrotic lung disease, for which insights into pathogenesis, disease models, or treatment options are lacking, according to researchers Dr. Sinha and colleagues. This long-haul form of the disease culminates in a fibrotic type of interstitial lung disease (ILD). While the actual prevalence of post–COVID-19 ILD (PCLD) is still emerging, early analysis indicates that more than a third of COVID-19 survivors develop fibrotic abnormalities, according to the authors.

Previous research has shown that one of the important determinants for PCLD is the duration of disease. Among patients who developed fibrosis, approximately 4% of patients had a disease duration of less than 1 week; approximately 24% had a disease duration between 1 and 3 weeks; and around 61% had a disease duration longer than 3 weeks, the authors stated.

The lung transcriptomic datasets compared in their study were associated with various lung conditions. The researchers used two viral pandemic signatures (ViP and sViP) and one COVID lung-derived signature. They found that the resemblances included that COVID-19 recapitulates the gene expression patterns (ViP and IPF signatures), cytokine storm (IL15-centric), and the AT2 cytopathic changes, for example, injury, DNA damage, arrest in a transient, damage-induced progenitor state, and senescence-associated secretory phenotype (SASP).

In laboratory experiments, Dr. Sinha and colleagues were able to induce these same immunocytopathic features in preclinical COVID-19 models (human adult lung organoid and hamster) and to reverse them in the hamster model with effective anti–CoV-2 therapeutics.

PPI-network analyses pinpointed endoplasmic reticulum (ER) stress as one of the shared early triggers of both IPF and COVID-19, and immunohistochemistry studies validated the same in the lungs of deceased subjects with COVID-19 and the SARS-CoV-2–challenged hamster lungs. Additionally, lungs from transgenic mice, in which ER stress was induced specifically in the AT2 cells, faithfully recapitulated the host immune response and alveolar cytopathic changes that are induced by SARS-CoV-2.

“In this work, we found that a blood-based gene expression biomarker, which works for prognostication in COVID, also works for IPF,” stated corresponding author Pradipta Ghosh, MD, professor in the departments of medicine and cellular and molecular medicine, University of California, San Diego. “If proven in prospective studies, this biomarker could indicate who is at greatest risk for progressive fibrosis and may require lung transplantation,” she said in an interview.

Dr. Ghosh stated further, “When it comes to therapeutics in COVID lung or IPF, we also found that shared fundamental pathogenic mechanisms present excellent opportunities for developing therapeutics that can arrest the fibrogenic drivers in both diseases. One clue that emerged is a specific cytokine that is at the heart of the smoldering inflammation which is invariably associated with fibrosis. That is interleukin 15 [IL-15] and its receptor.” Dr. Ghosh observed that there are two Food and Drug Administration–approved drugs for IPF. “None are very effective in arresting this invariably fatal disease. Hence, finding better options to treat IPF is an urgent and an unmet need.”

Preclinical testing of hypotheses, Dr. Ghosh said, is next on the path to clinical trials. “We have the advantage of using human lung organoids (mini-lungs grown using stem cells) in a dish, adding additional cells to the system (like fibroblasts and immune cells), infecting them with the virus, or subjecting them to the IL-15 cytokine and monitoring lung fibrosis progression in a dish. Anti–IL-15 therapy can then be initiated to observe reversal of the fibrogenic cascade.” Hamsters have also been shown to provide appropriate models for mimicking lung fibrosis, Dr. Ghosh said. 

“The report by Sinha and colleagues describes the fascinating similarities between drivers of post-COVID lung disease and idiopathic pulmonary fibrosis,” stated David Bowton, MD, professor emeritus, section on critical care, department of anesthesiology, Wake Forest University, Winston-Salem, N.C., in an interview. He added that, “Central to the mechanisms of induction of fibrosis in both disorders appears to be endoplasmic reticulum stress in alveolar type II cells (AT2). ER stress induces the unfolded protein response (UPR) that halts protein translation and promotes the degradation of misfolded proteins. Prolonged UPR can reprogram the cell or trigger apoptosis pathways. ER stress in the lung has been reported in a variety of cell lines including AT2 in IPF, bronchial and alveolar epithelial cells in asthma and [chronic obstructive pulmonary disease], and endothelial cells in pulmonary hypertension.”

Dr. Bowton commented further, including a caution, “Sinha and colleagues suggest that the identification of these gene signatures and mechanisms will be a fruitful avenue for developing effective therapeutics for IPF and other fibrotic lung diseases. I am hopeful that these data may offer clues that expedite this process.  However, the redundancy of triggers for effector pathways in biologic systems argues that, even if successful, this will be [a] long and fraught process.”

The research study was supported by National Institutes of Health grants and funding from the Tobacco-Related Disease Research Program.

Dr. Sinha, Dr. Ghosh, and Dr. Bowton reported no relevant disclosures.

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

An AI-guided analysis of more than 1,000 human lung transcriptomic datasets found that COVID-19 resembles idiopathic pulmonary fibrosis (IPF) at a fundamental level, according to a study published in eBiomedicine, part of The Lancet Discovery Science.

In the aftermath of COVID-19, a significant number of patients develop a fibrotic lung disease, for which insights into pathogenesis, disease models, or treatment options are lacking, according to researchers Dr. Sinha and colleagues. This long-haul form of the disease culminates in a fibrotic type of interstitial lung disease (ILD). While the actual prevalence of post–COVID-19 ILD (PCLD) is still emerging, early analysis indicates that more than a third of COVID-19 survivors develop fibrotic abnormalities, according to the authors.

Previous research has shown that one of the important determinants for PCLD is the duration of disease. Among patients who developed fibrosis, approximately 4% of patients had a disease duration of less than 1 week; approximately 24% had a disease duration between 1 and 3 weeks; and around 61% had a disease duration longer than 3 weeks, the authors stated.

The lung transcriptomic datasets compared in their study were associated with various lung conditions. The researchers used two viral pandemic signatures (ViP and sViP) and one COVID lung-derived signature. They found that the resemblances included that COVID-19 recapitulates the gene expression patterns (ViP and IPF signatures), cytokine storm (IL15-centric), and the AT2 cytopathic changes, for example, injury, DNA damage, arrest in a transient, damage-induced progenitor state, and senescence-associated secretory phenotype (SASP).

In laboratory experiments, Dr. Sinha and colleagues were able to induce these same immunocytopathic features in preclinical COVID-19 models (human adult lung organoid and hamster) and to reverse them in the hamster model with effective anti–CoV-2 therapeutics.

PPI-network analyses pinpointed endoplasmic reticulum (ER) stress as one of the shared early triggers of both IPF and COVID-19, and immunohistochemistry studies validated the same in the lungs of deceased subjects with COVID-19 and the SARS-CoV-2–challenged hamster lungs. Additionally, lungs from transgenic mice, in which ER stress was induced specifically in the AT2 cells, faithfully recapitulated the host immune response and alveolar cytopathic changes that are induced by SARS-CoV-2.

“In this work, we found that a blood-based gene expression biomarker, which works for prognostication in COVID, also works for IPF,” stated corresponding author Pradipta Ghosh, MD, professor in the departments of medicine and cellular and molecular medicine, University of California, San Diego. “If proven in prospective studies, this biomarker could indicate who is at greatest risk for progressive fibrosis and may require lung transplantation,” she said in an interview.

Dr. Ghosh stated further, “When it comes to therapeutics in COVID lung or IPF, we also found that shared fundamental pathogenic mechanisms present excellent opportunities for developing therapeutics that can arrest the fibrogenic drivers in both diseases. One clue that emerged is a specific cytokine that is at the heart of the smoldering inflammation which is invariably associated with fibrosis. That is interleukin 15 [IL-15] and its receptor.” Dr. Ghosh observed that there are two Food and Drug Administration–approved drugs for IPF. “None are very effective in arresting this invariably fatal disease. Hence, finding better options to treat IPF is an urgent and an unmet need.”

Preclinical testing of hypotheses, Dr. Ghosh said, is next on the path to clinical trials. “We have the advantage of using human lung organoids (mini-lungs grown using stem cells) in a dish, adding additional cells to the system (like fibroblasts and immune cells), infecting them with the virus, or subjecting them to the IL-15 cytokine and monitoring lung fibrosis progression in a dish. Anti–IL-15 therapy can then be initiated to observe reversal of the fibrogenic cascade.” Hamsters have also been shown to provide appropriate models for mimicking lung fibrosis, Dr. Ghosh said. 

“The report by Sinha and colleagues describes the fascinating similarities between drivers of post-COVID lung disease and idiopathic pulmonary fibrosis,” stated David Bowton, MD, professor emeritus, section on critical care, department of anesthesiology, Wake Forest University, Winston-Salem, N.C., in an interview. He added that, “Central to the mechanisms of induction of fibrosis in both disorders appears to be endoplasmic reticulum stress in alveolar type II cells (AT2). ER stress induces the unfolded protein response (UPR) that halts protein translation and promotes the degradation of misfolded proteins. Prolonged UPR can reprogram the cell or trigger apoptosis pathways. ER stress in the lung has been reported in a variety of cell lines including AT2 in IPF, bronchial and alveolar epithelial cells in asthma and [chronic obstructive pulmonary disease], and endothelial cells in pulmonary hypertension.”

Dr. Bowton commented further, including a caution, “Sinha and colleagues suggest that the identification of these gene signatures and mechanisms will be a fruitful avenue for developing effective therapeutics for IPF and other fibrotic lung diseases. I am hopeful that these data may offer clues that expedite this process.  However, the redundancy of triggers for effector pathways in biologic systems argues that, even if successful, this will be [a] long and fraught process.”

The research study was supported by National Institutes of Health grants and funding from the Tobacco-Related Disease Research Program.

Dr. Sinha, Dr. Ghosh, and Dr. Bowton reported no relevant disclosures.

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

An AI-guided analysis of more than 1,000 human lung transcriptomic datasets found that COVID-19 resembles idiopathic pulmonary fibrosis (IPF) at a fundamental level, according to a study published in eBiomedicine, part of The Lancet Discovery Science.

In the aftermath of COVID-19, a significant number of patients develop a fibrotic lung disease, for which insights into pathogenesis, disease models, or treatment options are lacking, according to researchers Dr. Sinha and colleagues. This long-haul form of the disease culminates in a fibrotic type of interstitial lung disease (ILD). While the actual prevalence of post–COVID-19 ILD (PCLD) is still emerging, early analysis indicates that more than a third of COVID-19 survivors develop fibrotic abnormalities, according to the authors.

Previous research has shown that one of the important determinants for PCLD is the duration of disease. Among patients who developed fibrosis, approximately 4% of patients had a disease duration of less than 1 week; approximately 24% had a disease duration between 1 and 3 weeks; and around 61% had a disease duration longer than 3 weeks, the authors stated.

The lung transcriptomic datasets compared in their study were associated with various lung conditions. The researchers used two viral pandemic signatures (ViP and sViP) and one COVID lung-derived signature. They found that the resemblances included that COVID-19 recapitulates the gene expression patterns (ViP and IPF signatures), cytokine storm (IL15-centric), and the AT2 cytopathic changes, for example, injury, DNA damage, arrest in a transient, damage-induced progenitor state, and senescence-associated secretory phenotype (SASP).

In laboratory experiments, Dr. Sinha and colleagues were able to induce these same immunocytopathic features in preclinical COVID-19 models (human adult lung organoid and hamster) and to reverse them in the hamster model with effective anti–CoV-2 therapeutics.

PPI-network analyses pinpointed endoplasmic reticulum (ER) stress as one of the shared early triggers of both IPF and COVID-19, and immunohistochemistry studies validated the same in the lungs of deceased subjects with COVID-19 and the SARS-CoV-2–challenged hamster lungs. Additionally, lungs from transgenic mice, in which ER stress was induced specifically in the AT2 cells, faithfully recapitulated the host immune response and alveolar cytopathic changes that are induced by SARS-CoV-2.

“In this work, we found that a blood-based gene expression biomarker, which works for prognostication in COVID, also works for IPF,” stated corresponding author Pradipta Ghosh, MD, professor in the departments of medicine and cellular and molecular medicine, University of California, San Diego. “If proven in prospective studies, this biomarker could indicate who is at greatest risk for progressive fibrosis and may require lung transplantation,” she said in an interview.

Dr. Ghosh stated further, “When it comes to therapeutics in COVID lung or IPF, we also found that shared fundamental pathogenic mechanisms present excellent opportunities for developing therapeutics that can arrest the fibrogenic drivers in both diseases. One clue that emerged is a specific cytokine that is at the heart of the smoldering inflammation which is invariably associated with fibrosis. That is interleukin 15 [IL-15] and its receptor.” Dr. Ghosh observed that there are two Food and Drug Administration–approved drugs for IPF. “None are very effective in arresting this invariably fatal disease. Hence, finding better options to treat IPF is an urgent and an unmet need.”

Preclinical testing of hypotheses, Dr. Ghosh said, is next on the path to clinical trials. “We have the advantage of using human lung organoids (mini-lungs grown using stem cells) in a dish, adding additional cells to the system (like fibroblasts and immune cells), infecting them with the virus, or subjecting them to the IL-15 cytokine and monitoring lung fibrosis progression in a dish. Anti–IL-15 therapy can then be initiated to observe reversal of the fibrogenic cascade.” Hamsters have also been shown to provide appropriate models for mimicking lung fibrosis, Dr. Ghosh said. 

“The report by Sinha and colleagues describes the fascinating similarities between drivers of post-COVID lung disease and idiopathic pulmonary fibrosis,” stated David Bowton, MD, professor emeritus, section on critical care, department of anesthesiology, Wake Forest University, Winston-Salem, N.C., in an interview. He added that, “Central to the mechanisms of induction of fibrosis in both disorders appears to be endoplasmic reticulum stress in alveolar type II cells (AT2). ER stress induces the unfolded protein response (UPR) that halts protein translation and promotes the degradation of misfolded proteins. Prolonged UPR can reprogram the cell or trigger apoptosis pathways. ER stress in the lung has been reported in a variety of cell lines including AT2 in IPF, bronchial and alveolar epithelial cells in asthma and [chronic obstructive pulmonary disease], and endothelial cells in pulmonary hypertension.”

Dr. Bowton commented further, including a caution, “Sinha and colleagues suggest that the identification of these gene signatures and mechanisms will be a fruitful avenue for developing effective therapeutics for IPF and other fibrotic lung diseases. I am hopeful that these data may offer clues that expedite this process.  However, the redundancy of triggers for effector pathways in biologic systems argues that, even if successful, this will be [a] long and fraught process.”

The research study was supported by National Institutes of Health grants and funding from the Tobacco-Related Disease Research Program.

Dr. Sinha, Dr. Ghosh, and Dr. Bowton reported no relevant disclosures.

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

Infants with bronchopulmonary dysplasia (BPD) who were born to Black mothers were significantly more likely to die or to have a longer hospital stay than infants of other ethnicities, based on data from more than 800 infants.

The overall incidence of BPD is rising, in part because of improved survival for extremely preterm infants, wrote Tamorah R. Lewis, MD, of the University of Missouri, Kansas City, and colleagues.

Previous studies suggest that racial disparities may affect outcomes for preterm infants with a range of neonatal morbidities during neonatal ICU (NICU) hospitalization, including respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis. However, the association of racial disparities with outcomes for preterm infants with BPD remains unclear, they said.

In a study published in JAMA Pediatrics, the researchers, on behalf of the Bronchopulmonary Dysplasia Collaborative, reviewed data from 834 preterm infants enrolled in the BPD Collaborative registry from Jan. 1, 2015, to July 19, 2021, at eight centers in the United States.

The study infants were born at less than 32 weeks’ gestation and were diagnosed with severe BPD according to the 2001 National Institutes of Health Consensus Criteria. The study population included 276 Black infants and 558 white infants. The median gestational age was 24 weeks, and 41% of the infants were female.

The primary outcomes were infant death and length of hospital stay.

Although death was infrequent (4% overall), Black maternal race was significantly associated with an increased risk of death from BPD (adjusted odds ratio, 2.1). Black maternal race also was significantly associated with a longer hospital stay for the infants, with an adjusted between-group difference of 10 days.

Infants of Black mothers also were more likely than those with White mothers to receive invasive respiratory support at the time of delivery. Black infants were more likely than White infants to have lower gestational age, lower birth weight and length, and smaller head circumference.

However, the proportions of cesarean deliveries, gender distribution, and infants small for gestational age were similar between Black and White infant groups. Medication exposure at 36 weeks postmenstrual age (PMA) also was similar for Black and White infants, and 50% of patients overall were treated with nasal continuous positive airway pressure at 36 weeks’ PMA. Awareness of the increased risk of death and longer hospital stay for Black infants is critical, “given the highly variable outcomes for patients with BPD and the uncertainty regarding demographic factors that contribute to late respiratory morbidity in severe BPD,” the researchers wrote.

The study findings were limited by several factors including variations among study centers in the identification and recording of maternal race, lack of data on paternal race, and the focus specifically on Black maternal race and not other ethnicities. Given the documented health disparities for Black individuals in the United States, “we restricted our cohort to only those patients born to Black or White mothers to estimate the association of Black maternal race and adverse in-hospital outcomes in infants with severe BPD,” the researchers wrote

Other limitations include the lack of data surrounding infant death and inability to adjust for all potential modifiers of BPD pathogenesis and progression, such as BPD comorbidities.

Prospective studies are needed to identify the sociodemographic mechanisms that may contribute to health outcome disparities for Black infants with severe BPD, the researchers emphasized.

In the meantime, the results highlight the need for more attention to variations in care for infants with BPD of different races, and approaches to family-centered care should consider “the precise needs of high-risk, structurally disadvantaged families while informing the design of prospective trials that improve outcomes for high-risk subgroups of children with severe BPD,” they concluded.
 

Data raise questions about the origin of disparities

The current study findings contribute to the knowledge and awareness of disparities in the high-risk NICU population, Nicolas A. Bamat, MD, and colleagues wrote in an accompanying editorial. “Further, their findings oppose the central tendency in the literature: that infants of Black mothers have less severe lung disease of prematurity during the birth hospitalization.”

The editorial authors noted that the study’s inclusion of racial characteristics as confounding variables to assess the effect of race on health “can imply questionable assumptions about where in a causal pathway racism begins to exert an effect,” whether after a diagnosis of BPD, during pregnancy in response to inequitable obstetric care, or “centuries ago, propagating forward through the shared experience of communities oppressed by the legacy of racism and its ongoing contemporary manifestations.”

The editorial authors added that, “in lung disease of prematurity, few variables are reliable antecedents to race as an exposure. Complex adjustment is necessary to reduce bias in targeted research questions.” However, the current study findings highlight the need to move toward more equitable neonatal care, and to prioritize interventions to reduce racial health disparities at the level of the NICU as well as at the hospital and government policy levels.
 

Consider range of contributing factors and confounders

The current study is important because “it is imperative to measure racial outcomes in health care in order to highlight and address disparities and biases,” Tim Joos, MD, said in an interview. However, “it can be difficult to determine how much race is a factor in itself versus a proxy for other important characteristics, such as socioeconomic status and level of education, that can confound the results.”

In the current study, the twofold-increased death rate in the premature infants of Black mothers is concerning and deserves further attention, Dr. Joos said. “The 10-day longer length of stay for infants of Black mothers seems quite shocking at first glance, but because of the long hospital stays for these extremely premature infants in general, it is about 7% longer than the infants born to White mothers.”

The take-home message is that this difference is still significant, and can reflect many factors including disease severity and complications, need for feeding assistance, teaching, and setting up home supports, said Dr. Joos.

As for additional research, “it would be useful for hospitals to break down why the differences exist, although I worry a provider or institution will feel they need to discharge Black families sooner to avoid being biased. Family preference and comfort level should be given high priority,” he emphasized.

The study received no outside funding, but lead author Dr. Lewis was supported by the National Institute on Child Health and Development and the Robert Wood Johnson Foundation. Several coauthors were supported by other grants from the National Institutes of Health. Dr. Barnat and one coauthor were supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Joos had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.


 

Infants with bronchopulmonary dysplasia (BPD) who were born to Black mothers were significantly more likely to die or to have a longer hospital stay than infants of other ethnicities, based on data from more than 800 infants.

The overall incidence of BPD is rising, in part because of improved survival for extremely preterm infants, wrote Tamorah R. Lewis, MD, of the University of Missouri, Kansas City, and colleagues.

Previous studies suggest that racial disparities may affect outcomes for preterm infants with a range of neonatal morbidities during neonatal ICU (NICU) hospitalization, including respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis. However, the association of racial disparities with outcomes for preterm infants with BPD remains unclear, they said.

In a study published in JAMA Pediatrics, the researchers, on behalf of the Bronchopulmonary Dysplasia Collaborative, reviewed data from 834 preterm infants enrolled in the BPD Collaborative registry from Jan. 1, 2015, to July 19, 2021, at eight centers in the United States.

The study infants were born at less than 32 weeks’ gestation and were diagnosed with severe BPD according to the 2001 National Institutes of Health Consensus Criteria. The study population included 276 Black infants and 558 white infants. The median gestational age was 24 weeks, and 41% of the infants were female.

The primary outcomes were infant death and length of hospital stay.

Although death was infrequent (4% overall), Black maternal race was significantly associated with an increased risk of death from BPD (adjusted odds ratio, 2.1). Black maternal race also was significantly associated with a longer hospital stay for the infants, with an adjusted between-group difference of 10 days.

Infants of Black mothers also were more likely than those with White mothers to receive invasive respiratory support at the time of delivery. Black infants were more likely than White infants to have lower gestational age, lower birth weight and length, and smaller head circumference.

However, the proportions of cesarean deliveries, gender distribution, and infants small for gestational age were similar between Black and White infant groups. Medication exposure at 36 weeks postmenstrual age (PMA) also was similar for Black and White infants, and 50% of patients overall were treated with nasal continuous positive airway pressure at 36 weeks’ PMA. Awareness of the increased risk of death and longer hospital stay for Black infants is critical, “given the highly variable outcomes for patients with BPD and the uncertainty regarding demographic factors that contribute to late respiratory morbidity in severe BPD,” the researchers wrote.

The study findings were limited by several factors including variations among study centers in the identification and recording of maternal race, lack of data on paternal race, and the focus specifically on Black maternal race and not other ethnicities. Given the documented health disparities for Black individuals in the United States, “we restricted our cohort to only those patients born to Black or White mothers to estimate the association of Black maternal race and adverse in-hospital outcomes in infants with severe BPD,” the researchers wrote

Other limitations include the lack of data surrounding infant death and inability to adjust for all potential modifiers of BPD pathogenesis and progression, such as BPD comorbidities.

Prospective studies are needed to identify the sociodemographic mechanisms that may contribute to health outcome disparities for Black infants with severe BPD, the researchers emphasized.

In the meantime, the results highlight the need for more attention to variations in care for infants with BPD of different races, and approaches to family-centered care should consider “the precise needs of high-risk, structurally disadvantaged families while informing the design of prospective trials that improve outcomes for high-risk subgroups of children with severe BPD,” they concluded.
 

Data raise questions about the origin of disparities

The current study findings contribute to the knowledge and awareness of disparities in the high-risk NICU population, Nicolas A. Bamat, MD, and colleagues wrote in an accompanying editorial. “Further, their findings oppose the central tendency in the literature: that infants of Black mothers have less severe lung disease of prematurity during the birth hospitalization.”

The editorial authors noted that the study’s inclusion of racial characteristics as confounding variables to assess the effect of race on health “can imply questionable assumptions about where in a causal pathway racism begins to exert an effect,” whether after a diagnosis of BPD, during pregnancy in response to inequitable obstetric care, or “centuries ago, propagating forward through the shared experience of communities oppressed by the legacy of racism and its ongoing contemporary manifestations.”

The editorial authors added that, “in lung disease of prematurity, few variables are reliable antecedents to race as an exposure. Complex adjustment is necessary to reduce bias in targeted research questions.” However, the current study findings highlight the need to move toward more equitable neonatal care, and to prioritize interventions to reduce racial health disparities at the level of the NICU as well as at the hospital and government policy levels.
 

Consider range of contributing factors and confounders

The current study is important because “it is imperative to measure racial outcomes in health care in order to highlight and address disparities and biases,” Tim Joos, MD, said in an interview. However, “it can be difficult to determine how much race is a factor in itself versus a proxy for other important characteristics, such as socioeconomic status and level of education, that can confound the results.”

In the current study, the twofold-increased death rate in the premature infants of Black mothers is concerning and deserves further attention, Dr. Joos said. “The 10-day longer length of stay for infants of Black mothers seems quite shocking at first glance, but because of the long hospital stays for these extremely premature infants in general, it is about 7% longer than the infants born to White mothers.”

The take-home message is that this difference is still significant, and can reflect many factors including disease severity and complications, need for feeding assistance, teaching, and setting up home supports, said Dr. Joos.

As for additional research, “it would be useful for hospitals to break down why the differences exist, although I worry a provider or institution will feel they need to discharge Black families sooner to avoid being biased. Family preference and comfort level should be given high priority,” he emphasized.

The study received no outside funding, but lead author Dr. Lewis was supported by the National Institute on Child Health and Development and the Robert Wood Johnson Foundation. Several coauthors were supported by other grants from the National Institutes of Health. Dr. Barnat and one coauthor were supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Joos had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.


 

Infants with bronchopulmonary dysplasia (BPD) who were born to Black mothers were significantly more likely to die or to have a longer hospital stay than infants of other ethnicities, based on data from more than 800 infants.

The overall incidence of BPD is rising, in part because of improved survival for extremely preterm infants, wrote Tamorah R. Lewis, MD, of the University of Missouri, Kansas City, and colleagues.

Previous studies suggest that racial disparities may affect outcomes for preterm infants with a range of neonatal morbidities during neonatal ICU (NICU) hospitalization, including respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis. However, the association of racial disparities with outcomes for preterm infants with BPD remains unclear, they said.

In a study published in JAMA Pediatrics, the researchers, on behalf of the Bronchopulmonary Dysplasia Collaborative, reviewed data from 834 preterm infants enrolled in the BPD Collaborative registry from Jan. 1, 2015, to July 19, 2021, at eight centers in the United States.

The study infants were born at less than 32 weeks’ gestation and were diagnosed with severe BPD according to the 2001 National Institutes of Health Consensus Criteria. The study population included 276 Black infants and 558 white infants. The median gestational age was 24 weeks, and 41% of the infants were female.

The primary outcomes were infant death and length of hospital stay.

Although death was infrequent (4% overall), Black maternal race was significantly associated with an increased risk of death from BPD (adjusted odds ratio, 2.1). Black maternal race also was significantly associated with a longer hospital stay for the infants, with an adjusted between-group difference of 10 days.

Infants of Black mothers also were more likely than those with White mothers to receive invasive respiratory support at the time of delivery. Black infants were more likely than White infants to have lower gestational age, lower birth weight and length, and smaller head circumference.

However, the proportions of cesarean deliveries, gender distribution, and infants small for gestational age were similar between Black and White infant groups. Medication exposure at 36 weeks postmenstrual age (PMA) also was similar for Black and White infants, and 50% of patients overall were treated with nasal continuous positive airway pressure at 36 weeks’ PMA. Awareness of the increased risk of death and longer hospital stay for Black infants is critical, “given the highly variable outcomes for patients with BPD and the uncertainty regarding demographic factors that contribute to late respiratory morbidity in severe BPD,” the researchers wrote.

The study findings were limited by several factors including variations among study centers in the identification and recording of maternal race, lack of data on paternal race, and the focus specifically on Black maternal race and not other ethnicities. Given the documented health disparities for Black individuals in the United States, “we restricted our cohort to only those patients born to Black or White mothers to estimate the association of Black maternal race and adverse in-hospital outcomes in infants with severe BPD,” the researchers wrote

Other limitations include the lack of data surrounding infant death and inability to adjust for all potential modifiers of BPD pathogenesis and progression, such as BPD comorbidities.

Prospective studies are needed to identify the sociodemographic mechanisms that may contribute to health outcome disparities for Black infants with severe BPD, the researchers emphasized.

In the meantime, the results highlight the need for more attention to variations in care for infants with BPD of different races, and approaches to family-centered care should consider “the precise needs of high-risk, structurally disadvantaged families while informing the design of prospective trials that improve outcomes for high-risk subgroups of children with severe BPD,” they concluded.
 

Data raise questions about the origin of disparities

The current study findings contribute to the knowledge and awareness of disparities in the high-risk NICU population, Nicolas A. Bamat, MD, and colleagues wrote in an accompanying editorial. “Further, their findings oppose the central tendency in the literature: that infants of Black mothers have less severe lung disease of prematurity during the birth hospitalization.”

The editorial authors noted that the study’s inclusion of racial characteristics as confounding variables to assess the effect of race on health “can imply questionable assumptions about where in a causal pathway racism begins to exert an effect,” whether after a diagnosis of BPD, during pregnancy in response to inequitable obstetric care, or “centuries ago, propagating forward through the shared experience of communities oppressed by the legacy of racism and its ongoing contemporary manifestations.”

The editorial authors added that, “in lung disease of prematurity, few variables are reliable antecedents to race as an exposure. Complex adjustment is necessary to reduce bias in targeted research questions.” However, the current study findings highlight the need to move toward more equitable neonatal care, and to prioritize interventions to reduce racial health disparities at the level of the NICU as well as at the hospital and government policy levels.
 

Consider range of contributing factors and confounders

The current study is important because “it is imperative to measure racial outcomes in health care in order to highlight and address disparities and biases,” Tim Joos, MD, said in an interview. However, “it can be difficult to determine how much race is a factor in itself versus a proxy for other important characteristics, such as socioeconomic status and level of education, that can confound the results.”

In the current study, the twofold-increased death rate in the premature infants of Black mothers is concerning and deserves further attention, Dr. Joos said. “The 10-day longer length of stay for infants of Black mothers seems quite shocking at first glance, but because of the long hospital stays for these extremely premature infants in general, it is about 7% longer than the infants born to White mothers.”

The take-home message is that this difference is still significant, and can reflect many factors including disease severity and complications, need for feeding assistance, teaching, and setting up home supports, said Dr. Joos.

As for additional research, “it would be useful for hospitals to break down why the differences exist, although I worry a provider or institution will feel they need to discharge Black families sooner to avoid being biased. Family preference and comfort level should be given high priority,” he emphasized.

The study received no outside funding, but lead author Dr. Lewis was supported by the National Institute on Child Health and Development and the Robert Wood Johnson Foundation. Several coauthors were supported by other grants from the National Institutes of Health. Dr. Barnat and one coauthor were supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Joos had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.