Pulmonology

ORLANDO, FLORIDA — Asthma is the most common cause of chronic cough in children, but it’s important to be aware of other differential diagnoses for those patients who have less common concerns, according to Rajeev Bhatia, MD, division chief of pulmonology at Phoenix Children’s in Phoenix, Arizona. Bhatia reviewed both the major causes of chronic cough as well as the rare zebras to watch out for in a presentation at the American Academy of Pediatrics (AAP) 2024 National Conference.

“When you see a patient for cough, the most important thing is, history, history, history,” Bhatia said. “There are many, many, many clues in the history, age of onset, and duration.” That includes starting at birth to ensure you don’t miss key details such as a preterm birth. It’s also important to discuss what the cough sounds like, how frequent it is, what makes it better, what makes it worse, and how it’s affecting the child and others around them — all of which can help narrow the diagnosis.

Jose Quijada, DO, a pediatrician with CommuniCare Pediatrics in San Antonio, found the session “incredibly useful” not only because of the specific pointers about each condition but also because of the realistic case studies he included throughout.

“Sometimes when you’re practicing, you focus on what’s most common,” Quijada said, so it was helpful to get a review of some of the key features and red flags that point to less common causes that may need to be considered. He particularly appreciated the discussion of habitual cough and potential treatments because those can be challenging patients and it can be tough to find a middle ground with how much workup to do.
 

Common Causes of Chronic Cough

The coughing from inadequately controlled asthma tends to be nonproductive and worse at night or in the early morning, Bhatia explained, and it’s often accompanied by wheezing, shortness of breath, and chest tightness. While fractional exhaled nitric oxide can be useful, “studies show that it is more useful for to monitor the symptoms rather than to diagnose the asthma,” Bhatia told attendees, but he also added that spirometry can be normal in patients with asthma. In young patients, the Asthma Predictive Index can be an invaluable tool, he also said.

Another common cause of chronic cough is a postinfectious cough, which lasts more than 3 weeks after resolution of acute upper respiratory infection. It occurs in about one in 10 children after a viral infection such as a rhinovirus or respiratory syncytial virus infection and results from extensive inflammation and disruption of the airway epithelial integrity. Chest x-rays are usually normal in these patients, and the cough will usually resolve on its own. Albuterol has not been shown to be any more effective than placebo for a postinfectious cough, and antibiotics similarly have no clinically useful role.

A wet cough that lasts for at least 4 weeks and appears to have no other specific cause may be protracted bacterial bronchitis (PBB). While the cause of PBB isn’t known, it could be due to frequent illnesses that cause airway inflammation and injury over time, thereby making it easier for bacteria to grow and cause infection. Risk factors include tracheomalacia/bronchomalacia and childcare attendance, and typical pathogens include Haemophilus influenzae, Streptococcus pneumonia, and Moraxella catarrhalis.

While an x-ray can be done, radiography is often normal in patients with PBB. Bronchoscopy will reveal purulent secretions. PBB should resolve with at least 2 weeks of antibiotics, including amoxicillin-clavulanate, but the course can be extended to 4 weeks if the cough persists. However, about 40% of patients will have recurrence, and those with recurrent PBB or with a chronic cough unresponsive to 4 weeks of antibiotics should be referred to a pediatric pulmonologist.

Upper airway cough syndrome is the updated name for postnasal drip, which can occur with both allergic and nonallergic rhinitis and chronic rhinosinusitis. This is often a dry, throat-clearing cough that can be accompanied by headaches, nasal congestion, and sinus or facial tenderness. An examination will reveal posterior pharynx cobblestoning, Bhatia said, and empirical use of intranasal steroids can be both diagnostic and therapeutic for upper airway cough syndrome. He also emphasized the importance of taking an environmental history and avoiding exposure of environmental triggers.
 

Uncommon Pulmonary Causes of Chronic Cough

After discussing frequent reasons patients may present with a chronic cough, Bhatia went on to discuss the less common things to consider if the provider has eliminated the other possibilities. These include both pulmonary causes as well as congenital malformations, gastrointestinal causes, and habit cough.

A child who presents with a sudden onset of cough or wheeze in the absence of an upper respiratory infection may have a retained foreign body. This cough can be mistaken for bronchiolitis, asthma, croup, and other infectious conditions, especially because a partial obstruction can make diagnosis confusing or challenging. Adding to the challenge is that most foreign bodies will be radiolucent. A decubitus chest x-ray could be useful, but bronchoscopy is necessary for diagnosis. Bhatia stressed that it’s easy to miss a foreign body in younger children and that the wheezing can be more prominent on one side or another.

Cystic fibrosis, another uncommon cause of chronic cough, is ideally diagnosed via newborn screening, but screening is imperfect and can involve missed diagnoses or false negatives. Over 75% of cystic fibrosis cases are diagnosed by age 2, but that means a substantial number of cases still are not diagnosed until older childhood or later. This cough will be a chronic productive/wet cough.

A family history of cystic fibrosis may be present but doesn’t have to be, so signs to look for include poor weight gain, sinusitis, nasal polyps, clubbing, and isolation of suspicious organisms from a respiratory culture, such as Pseudomonas aeruginosa or Burkholderia cepacia complex. Clubbing in the fingers is a particularly telltale symptom of undiagnosed cystic fibrosis, and bronchiectasis of unknown etiology will be present. Suspicion of cystic fibrosis should lead to a referral to a cystic fibrosis center for a sweat test.

Even rarer than cystic fibrosis is primary ciliary dyskinesia (PCD), an inherited autosomal recessive disease that occurs in about one in 20,000 live births and involves a structural or functional defect in the cilia. About half of all patients with PCD will have situs inversus — an arrangement of chest and abdominal organs that is a mirror image of typical human anatomical presentation — but most people with situs inversus do not have PCD. One type of PCD is Kartagener syndrome, identified by the triad of situs inversus totalis, chronic sinusitis, and bronchiectasis.

Children with PCD present with a chronic productive cough and recurrent pneumonias, and nearly all patients will have rhinosinusitis. About 60% of patients will develop respiratory symptoms such as mild distress or cough in their first month, and recurrent otitis media is common in these patients. PCD diagnosis is based on a combination of genetic testing, nasal nitric oxide, and evaluation of ciliary motion and structure. Clinical suspicion of PCD should lead to a specialist referral.

Nearly all people with PCD will eventually develop bronchiectasis, where the priority should be airway clearance using antibiotics for acute exacerbations and chronic azithromycin therapy for recurrent exacerbations. Patients with chronic rhinosinusitis, chronic otitis media, and nasal polyposis should be referred to an ENT specialist.
 

Other Uncommon Causes of Chronic Cough

A non-pulmonary, uncommon cause of chronic cough is a vascular ring, a congenital anomaly in which blood vessels encircle and potentially constrict the esophagus and/or trachea. The most common type is a double aortic arch, but a right aortic arch or pulmonary artery sling is also possible. These coughs sound harsh and are usually accompanied by stridor, dyspnea and feeding problems. Workup includes an echocardiogram, a CT angiogram, and possibly a bronchoscopy to determine the extent of the airway narrowing. In symptomatic patients, surgery is indicated for correction.

Another congenital malformation that can cause chronic cough is a tracheoesophageal fistula, which occurs in about one in 3500 live births, commonly linked to trisomy disorders and VACTERL. Several types of tracheoesophageal fistula exist, and H-type fistula is associated with late onset symptoms. The cough can be wet or dry and sometimes sounds like barking because of the associated airway collapse. Patients often have recurrent pneumonia, bronchitis, and cough or cyanosis with feeding. Workup should include an upper gastrointestinal series but not with barium, Bhatia said, because that can cause pneumonitis. Instead, the series should be done with a thickened water-soluble contrast material, and a bronchoscopy may be indicated as well.

Though common as a condition in adults, gastroesophageal reflux disease (GERD) is a rare, but possible, cause of chronic cough in children. More often, the reflux is the result of the cough rather than the cause. The most sensitive tool for assessing GERD is esophageal 24-hour pH/impedance reflux monitoring. However, treatment of the reflux for cough is not recommended unless the patient has clinical features of GERD, including dystonic neck posturing in infants, heartburn, regurgitation, or other symptoms. If the patient has clinical symptoms, then treatment is acid suppressive therapy for 4-8 weeks, followed by a clinical reassessment.

An uncommon cause of chronic cough with no biological mechanism is habit cough. Habit cough is most easily distinguished from other coughs by its sounds, a “large, loud, honking noise,” Bhatia said. It also lacks a clear trigger and is usually absent during sleep, but it can be continuous during the day. Frustratingly, the patients themselves often don’t seem bothered by the cough, but “it’s very disruptive in the school and everywhere else,” Bhatia said. Families and/providers will often have tried multiple treatments and seen no improvement with habit cough.

The first thing to do with habit cough is reassure the family that there’s nothing serious going on because they are often worried by this point. Several non-pharmaceutical treatments can be effective, such as suggestion therapy or the “warm water technique,” in which the patient takes a sip of warm water every time they feel the urge to cough. “If they’re able to break the cycle, most of the time, they are fine,” Bhatia said. In rarer cases, more involved behavioral interventions may be indicated, such as a psychology referral if an underlying anxiety or other behavioral disorder is contributing.
 

Newer Causes of Cough

Two more recent causes of cough to watch for are long COVID and e-cigarette or vaping product–associated lung injury (EVALI), Bhatia said. The clearest sign of EVALI is a history of e-cigarette/vaping exposure, but clinical symptoms include a dry cough that occurs with dyspnea and chest pain. A chest x-ray may show diffuse, hazy, or consolidative opacities. Sometimes antibiotics or steroids can be helpful, but the evidence isn’t strong, and the most effective treatment is stopping e-cigarette use. Less commonly, passive exposure to vaping can also be associated with EVALI.

The most recent research on long COVID suggests that about 10-20% of children with acute COVID develop long COVID, and about a quarter of these patients develop a chronic dry cough. It’s often associated with fatigue and shortness of breath, which can be assessed with cardiopulmonary exercise testing. Sometimes a short trial of inhaled steroids can help.

Bhatia also mentioned a handful of other uncommon causes of chronic cough that most American pediatricians are unlikely to see: Childhood interstitial lung disease, tuberculosis, use of Angiotensin-Converting Enzyme inhibitors, and a build-up of ear wax via the Arnold’s nerve reflex.
 

Evaluation and Workup

Bhatia also discussed what to cover while taking a history and questions to ask. The history should include the type of cough, the onset timing (sudden vs gradual), associated symptoms, the cough trajectory, medications the patient is taking, and the patient’s past medical history and environmental exposures. Those attributes are included in this more comprehensive list of questions to consider during evaluation, adapted from a list provided in a 2019 article in Paediatric Respiratory Reviews:

• Age of onset and duration?
• Was the onset sudden or associate with an illness?
• Is the cough wet or dry?
• What does the cough sound like?
• How often does the cough occur?
• Is it progressive?
• Is it present during sleep?
• Are there any other associated symptoms, such as wheeze, dyspnea, vomiting, chest pain, etc?
• Are there any exacerbating factors or known triggers?
• Are there any relieving factors, including a trial of bronchodilators?
• Has there been exposure to auto-irritants, such as secondhand smoke?
• What is the cough’s effect on the child and on others around the child?
• Does the child have any other underlying conditions such as neuromuscular disease or asthma?
• What medications is the child taking or has recently taken?
• Is there a family history of atopy and/or respiratory disease?

Bhatia also recommended paying special attention to the following red flags or key features that may help more quickly narrow the diagnosis and often require a specialist referral:

• Digital clubbing, failure to thrive, or low tone
• An abnormal cardiac exam
• Tachypnea, hypoxemia, chest retractions, or hemoptysis
• Abnormal breath sounds such as unilateral wheezing or coarse crackles
• Abnormal spirometry in those aged 5 and older showing reversible obstruction, which often indicates asthma
• An abnormal chest x-ray with, for example, bilateral infiltrates, hyperinflation, right middle lobe syndrome, situs inversus, unilateral hyperlucency, a right aortic arch, etc.

No external funding was used for the presentation. Bhatia and Quijada had no disclosures.
 

A version of this article appeared on Medscape.com.

ORLANDO, FLORIDA — Asthma is the most common cause of chronic cough in children, but it’s important to be aware of other differential diagnoses for those patients who have less common concerns, according to Rajeev Bhatia, MD, division chief of pulmonology at Phoenix Children’s in Phoenix, Arizona. Bhatia reviewed both the major causes of chronic cough as well as the rare zebras to watch out for in a presentation at the American Academy of Pediatrics (AAP) 2024 National Conference.

“When you see a patient for cough, the most important thing is, history, history, history,” Bhatia said. “There are many, many, many clues in the history, age of onset, and duration.” That includes starting at birth to ensure you don’t miss key details such as a preterm birth. It’s also important to discuss what the cough sounds like, how frequent it is, what makes it better, what makes it worse, and how it’s affecting the child and others around them — all of which can help narrow the diagnosis.

Jose Quijada, DO, a pediatrician with CommuniCare Pediatrics in San Antonio, found the session “incredibly useful” not only because of the specific pointers about each condition but also because of the realistic case studies he included throughout.

“Sometimes when you’re practicing, you focus on what’s most common,” Quijada said, so it was helpful to get a review of some of the key features and red flags that point to less common causes that may need to be considered. He particularly appreciated the discussion of habitual cough and potential treatments because those can be challenging patients and it can be tough to find a middle ground with how much workup to do.
 

Common Causes of Chronic Cough

The coughing from inadequately controlled asthma tends to be nonproductive and worse at night or in the early morning, Bhatia explained, and it’s often accompanied by wheezing, shortness of breath, and chest tightness. While fractional exhaled nitric oxide can be useful, “studies show that it is more useful for to monitor the symptoms rather than to diagnose the asthma,” Bhatia told attendees, but he also added that spirometry can be normal in patients with asthma. In young patients, the Asthma Predictive Index can be an invaluable tool, he also said.

Another common cause of chronic cough is a postinfectious cough, which lasts more than 3 weeks after resolution of acute upper respiratory infection. It occurs in about one in 10 children after a viral infection such as a rhinovirus or respiratory syncytial virus infection and results from extensive inflammation and disruption of the airway epithelial integrity. Chest x-rays are usually normal in these patients, and the cough will usually resolve on its own. Albuterol has not been shown to be any more effective than placebo for a postinfectious cough, and antibiotics similarly have no clinically useful role.

A wet cough that lasts for at least 4 weeks and appears to have no other specific cause may be protracted bacterial bronchitis (PBB). While the cause of PBB isn’t known, it could be due to frequent illnesses that cause airway inflammation and injury over time, thereby making it easier for bacteria to grow and cause infection. Risk factors include tracheomalacia/bronchomalacia and childcare attendance, and typical pathogens include Haemophilus influenzae, Streptococcus pneumonia, and Moraxella catarrhalis.

While an x-ray can be done, radiography is often normal in patients with PBB. Bronchoscopy will reveal purulent secretions. PBB should resolve with at least 2 weeks of antibiotics, including amoxicillin-clavulanate, but the course can be extended to 4 weeks if the cough persists. However, about 40% of patients will have recurrence, and those with recurrent PBB or with a chronic cough unresponsive to 4 weeks of antibiotics should be referred to a pediatric pulmonologist.

Upper airway cough syndrome is the updated name for postnasal drip, which can occur with both allergic and nonallergic rhinitis and chronic rhinosinusitis. This is often a dry, throat-clearing cough that can be accompanied by headaches, nasal congestion, and sinus or facial tenderness. An examination will reveal posterior pharynx cobblestoning, Bhatia said, and empirical use of intranasal steroids can be both diagnostic and therapeutic for upper airway cough syndrome. He also emphasized the importance of taking an environmental history and avoiding exposure of environmental triggers.
 

Uncommon Pulmonary Causes of Chronic Cough

After discussing frequent reasons patients may present with a chronic cough, Bhatia went on to discuss the less common things to consider if the provider has eliminated the other possibilities. These include both pulmonary causes as well as congenital malformations, gastrointestinal causes, and habit cough.

A child who presents with a sudden onset of cough or wheeze in the absence of an upper respiratory infection may have a retained foreign body. This cough can be mistaken for bronchiolitis, asthma, croup, and other infectious conditions, especially because a partial obstruction can make diagnosis confusing or challenging. Adding to the challenge is that most foreign bodies will be radiolucent. A decubitus chest x-ray could be useful, but bronchoscopy is necessary for diagnosis. Bhatia stressed that it’s easy to miss a foreign body in younger children and that the wheezing can be more prominent on one side or another.

Cystic fibrosis, another uncommon cause of chronic cough, is ideally diagnosed via newborn screening, but screening is imperfect and can involve missed diagnoses or false negatives. Over 75% of cystic fibrosis cases are diagnosed by age 2, but that means a substantial number of cases still are not diagnosed until older childhood or later. This cough will be a chronic productive/wet cough.

A family history of cystic fibrosis may be present but doesn’t have to be, so signs to look for include poor weight gain, sinusitis, nasal polyps, clubbing, and isolation of suspicious organisms from a respiratory culture, such as Pseudomonas aeruginosa or Burkholderia cepacia complex. Clubbing in the fingers is a particularly telltale symptom of undiagnosed cystic fibrosis, and bronchiectasis of unknown etiology will be present. Suspicion of cystic fibrosis should lead to a referral to a cystic fibrosis center for a sweat test.

Even rarer than cystic fibrosis is primary ciliary dyskinesia (PCD), an inherited autosomal recessive disease that occurs in about one in 20,000 live births and involves a structural or functional defect in the cilia. About half of all patients with PCD will have situs inversus — an arrangement of chest and abdominal organs that is a mirror image of typical human anatomical presentation — but most people with situs inversus do not have PCD. One type of PCD is Kartagener syndrome, identified by the triad of situs inversus totalis, chronic sinusitis, and bronchiectasis.

Children with PCD present with a chronic productive cough and recurrent pneumonias, and nearly all patients will have rhinosinusitis. About 60% of patients will develop respiratory symptoms such as mild distress or cough in their first month, and recurrent otitis media is common in these patients. PCD diagnosis is based on a combination of genetic testing, nasal nitric oxide, and evaluation of ciliary motion and structure. Clinical suspicion of PCD should lead to a specialist referral.

Nearly all people with PCD will eventually develop bronchiectasis, where the priority should be airway clearance using antibiotics for acute exacerbations and chronic azithromycin therapy for recurrent exacerbations. Patients with chronic rhinosinusitis, chronic otitis media, and nasal polyposis should be referred to an ENT specialist.
 

Other Uncommon Causes of Chronic Cough

A non-pulmonary, uncommon cause of chronic cough is a vascular ring, a congenital anomaly in which blood vessels encircle and potentially constrict the esophagus and/or trachea. The most common type is a double aortic arch, but a right aortic arch or pulmonary artery sling is also possible. These coughs sound harsh and are usually accompanied by stridor, dyspnea and feeding problems. Workup includes an echocardiogram, a CT angiogram, and possibly a bronchoscopy to determine the extent of the airway narrowing. In symptomatic patients, surgery is indicated for correction.

Another congenital malformation that can cause chronic cough is a tracheoesophageal fistula, which occurs in about one in 3500 live births, commonly linked to trisomy disorders and VACTERL. Several types of tracheoesophageal fistula exist, and H-type fistula is associated with late onset symptoms. The cough can be wet or dry and sometimes sounds like barking because of the associated airway collapse. Patients often have recurrent pneumonia, bronchitis, and cough or cyanosis with feeding. Workup should include an upper gastrointestinal series but not with barium, Bhatia said, because that can cause pneumonitis. Instead, the series should be done with a thickened water-soluble contrast material, and a bronchoscopy may be indicated as well.

Though common as a condition in adults, gastroesophageal reflux disease (GERD) is a rare, but possible, cause of chronic cough in children. More often, the reflux is the result of the cough rather than the cause. The most sensitive tool for assessing GERD is esophageal 24-hour pH/impedance reflux monitoring. However, treatment of the reflux for cough is not recommended unless the patient has clinical features of GERD, including dystonic neck posturing in infants, heartburn, regurgitation, or other symptoms. If the patient has clinical symptoms, then treatment is acid suppressive therapy for 4-8 weeks, followed by a clinical reassessment.

An uncommon cause of chronic cough with no biological mechanism is habit cough. Habit cough is most easily distinguished from other coughs by its sounds, a “large, loud, honking noise,” Bhatia said. It also lacks a clear trigger and is usually absent during sleep, but it can be continuous during the day. Frustratingly, the patients themselves often don’t seem bothered by the cough, but “it’s very disruptive in the school and everywhere else,” Bhatia said. Families and/providers will often have tried multiple treatments and seen no improvement with habit cough.

The first thing to do with habit cough is reassure the family that there’s nothing serious going on because they are often worried by this point. Several non-pharmaceutical treatments can be effective, such as suggestion therapy or the “warm water technique,” in which the patient takes a sip of warm water every time they feel the urge to cough. “If they’re able to break the cycle, most of the time, they are fine,” Bhatia said. In rarer cases, more involved behavioral interventions may be indicated, such as a psychology referral if an underlying anxiety or other behavioral disorder is contributing.
 

Newer Causes of Cough

Two more recent causes of cough to watch for are long COVID and e-cigarette or vaping product–associated lung injury (EVALI), Bhatia said. The clearest sign of EVALI is a history of e-cigarette/vaping exposure, but clinical symptoms include a dry cough that occurs with dyspnea and chest pain. A chest x-ray may show diffuse, hazy, or consolidative opacities. Sometimes antibiotics or steroids can be helpful, but the evidence isn’t strong, and the most effective treatment is stopping e-cigarette use. Less commonly, passive exposure to vaping can also be associated with EVALI.

The most recent research on long COVID suggests that about 10-20% of children with acute COVID develop long COVID, and about a quarter of these patients develop a chronic dry cough. It’s often associated with fatigue and shortness of breath, which can be assessed with cardiopulmonary exercise testing. Sometimes a short trial of inhaled steroids can help.

Bhatia also mentioned a handful of other uncommon causes of chronic cough that most American pediatricians are unlikely to see: Childhood interstitial lung disease, tuberculosis, use of Angiotensin-Converting Enzyme inhibitors, and a build-up of ear wax via the Arnold’s nerve reflex.
 

Evaluation and Workup

Bhatia also discussed what to cover while taking a history and questions to ask. The history should include the type of cough, the onset timing (sudden vs gradual), associated symptoms, the cough trajectory, medications the patient is taking, and the patient’s past medical history and environmental exposures. Those attributes are included in this more comprehensive list of questions to consider during evaluation, adapted from a list provided in a 2019 article in Paediatric Respiratory Reviews:

• Age of onset and duration?
• Was the onset sudden or associate with an illness?
• Is the cough wet or dry?
• What does the cough sound like?
• How often does the cough occur?
• Is it progressive?
• Is it present during sleep?
• Are there any other associated symptoms, such as wheeze, dyspnea, vomiting, chest pain, etc?
• Are there any exacerbating factors or known triggers?
• Are there any relieving factors, including a trial of bronchodilators?
• Has there been exposure to auto-irritants, such as secondhand smoke?
• What is the cough’s effect on the child and on others around the child?
• Does the child have any other underlying conditions such as neuromuscular disease or asthma?
• What medications is the child taking or has recently taken?
• Is there a family history of atopy and/or respiratory disease?

Bhatia also recommended paying special attention to the following red flags or key features that may help more quickly narrow the diagnosis and often require a specialist referral:

• Digital clubbing, failure to thrive, or low tone
• An abnormal cardiac exam
• Tachypnea, hypoxemia, chest retractions, or hemoptysis
• Abnormal breath sounds such as unilateral wheezing or coarse crackles
• Abnormal spirometry in those aged 5 and older showing reversible obstruction, which often indicates asthma
• An abnormal chest x-ray with, for example, bilateral infiltrates, hyperinflation, right middle lobe syndrome, situs inversus, unilateral hyperlucency, a right aortic arch, etc.

No external funding was used for the presentation. Bhatia and Quijada had no disclosures.
 

A version of this article appeared on Medscape.com.

ORLANDO, FLORIDA — Asthma is the most common cause of chronic cough in children, but it’s important to be aware of other differential diagnoses for those patients who have less common concerns, according to Rajeev Bhatia, MD, division chief of pulmonology at Phoenix Children’s in Phoenix, Arizona. Bhatia reviewed both the major causes of chronic cough as well as the rare zebras to watch out for in a presentation at the American Academy of Pediatrics (AAP) 2024 National Conference.

“When you see a patient for cough, the most important thing is, history, history, history,” Bhatia said. “There are many, many, many clues in the history, age of onset, and duration.” That includes starting at birth to ensure you don’t miss key details such as a preterm birth. It’s also important to discuss what the cough sounds like, how frequent it is, what makes it better, what makes it worse, and how it’s affecting the child and others around them — all of which can help narrow the diagnosis.

Jose Quijada, DO, a pediatrician with CommuniCare Pediatrics in San Antonio, found the session “incredibly useful” not only because of the specific pointers about each condition but also because of the realistic case studies he included throughout.

“Sometimes when you’re practicing, you focus on what’s most common,” Quijada said, so it was helpful to get a review of some of the key features and red flags that point to less common causes that may need to be considered. He particularly appreciated the discussion of habitual cough and potential treatments because those can be challenging patients and it can be tough to find a middle ground with how much workup to do.
 

Common Causes of Chronic Cough

The coughing from inadequately controlled asthma tends to be nonproductive and worse at night or in the early morning, Bhatia explained, and it’s often accompanied by wheezing, shortness of breath, and chest tightness. While fractional exhaled nitric oxide can be useful, “studies show that it is more useful for to monitor the symptoms rather than to diagnose the asthma,” Bhatia told attendees, but he also added that spirometry can be normal in patients with asthma. In young patients, the Asthma Predictive Index can be an invaluable tool, he also said.

Another common cause of chronic cough is a postinfectious cough, which lasts more than 3 weeks after resolution of acute upper respiratory infection. It occurs in about one in 10 children after a viral infection such as a rhinovirus or respiratory syncytial virus infection and results from extensive inflammation and disruption of the airway epithelial integrity. Chest x-rays are usually normal in these patients, and the cough will usually resolve on its own. Albuterol has not been shown to be any more effective than placebo for a postinfectious cough, and antibiotics similarly have no clinically useful role.

A wet cough that lasts for at least 4 weeks and appears to have no other specific cause may be protracted bacterial bronchitis (PBB). While the cause of PBB isn’t known, it could be due to frequent illnesses that cause airway inflammation and injury over time, thereby making it easier for bacteria to grow and cause infection. Risk factors include tracheomalacia/bronchomalacia and childcare attendance, and typical pathogens include Haemophilus influenzae, Streptococcus pneumonia, and Moraxella catarrhalis.

While an x-ray can be done, radiography is often normal in patients with PBB. Bronchoscopy will reveal purulent secretions. PBB should resolve with at least 2 weeks of antibiotics, including amoxicillin-clavulanate, but the course can be extended to 4 weeks if the cough persists. However, about 40% of patients will have recurrence, and those with recurrent PBB or with a chronic cough unresponsive to 4 weeks of antibiotics should be referred to a pediatric pulmonologist.

Upper airway cough syndrome is the updated name for postnasal drip, which can occur with both allergic and nonallergic rhinitis and chronic rhinosinusitis. This is often a dry, throat-clearing cough that can be accompanied by headaches, nasal congestion, and sinus or facial tenderness. An examination will reveal posterior pharynx cobblestoning, Bhatia said, and empirical use of intranasal steroids can be both diagnostic and therapeutic for upper airway cough syndrome. He also emphasized the importance of taking an environmental history and avoiding exposure of environmental triggers.
 

Uncommon Pulmonary Causes of Chronic Cough

After discussing frequent reasons patients may present with a chronic cough, Bhatia went on to discuss the less common things to consider if the provider has eliminated the other possibilities. These include both pulmonary causes as well as congenital malformations, gastrointestinal causes, and habit cough.

A child who presents with a sudden onset of cough or wheeze in the absence of an upper respiratory infection may have a retained foreign body. This cough can be mistaken for bronchiolitis, asthma, croup, and other infectious conditions, especially because a partial obstruction can make diagnosis confusing or challenging. Adding to the challenge is that most foreign bodies will be radiolucent. A decubitus chest x-ray could be useful, but bronchoscopy is necessary for diagnosis. Bhatia stressed that it’s easy to miss a foreign body in younger children and that the wheezing can be more prominent on one side or another.

Cystic fibrosis, another uncommon cause of chronic cough, is ideally diagnosed via newborn screening, but screening is imperfect and can involve missed diagnoses or false negatives. Over 75% of cystic fibrosis cases are diagnosed by age 2, but that means a substantial number of cases still are not diagnosed until older childhood or later. This cough will be a chronic productive/wet cough.

A family history of cystic fibrosis may be present but doesn’t have to be, so signs to look for include poor weight gain, sinusitis, nasal polyps, clubbing, and isolation of suspicious organisms from a respiratory culture, such as Pseudomonas aeruginosa or Burkholderia cepacia complex. Clubbing in the fingers is a particularly telltale symptom of undiagnosed cystic fibrosis, and bronchiectasis of unknown etiology will be present. Suspicion of cystic fibrosis should lead to a referral to a cystic fibrosis center for a sweat test.

Even rarer than cystic fibrosis is primary ciliary dyskinesia (PCD), an inherited autosomal recessive disease that occurs in about one in 20,000 live births and involves a structural or functional defect in the cilia. About half of all patients with PCD will have situs inversus — an arrangement of chest and abdominal organs that is a mirror image of typical human anatomical presentation — but most people with situs inversus do not have PCD. One type of PCD is Kartagener syndrome, identified by the triad of situs inversus totalis, chronic sinusitis, and bronchiectasis.

Children with PCD present with a chronic productive cough and recurrent pneumonias, and nearly all patients will have rhinosinusitis. About 60% of patients will develop respiratory symptoms such as mild distress or cough in their first month, and recurrent otitis media is common in these patients. PCD diagnosis is based on a combination of genetic testing, nasal nitric oxide, and evaluation of ciliary motion and structure. Clinical suspicion of PCD should lead to a specialist referral.

Nearly all people with PCD will eventually develop bronchiectasis, where the priority should be airway clearance using antibiotics for acute exacerbations and chronic azithromycin therapy for recurrent exacerbations. Patients with chronic rhinosinusitis, chronic otitis media, and nasal polyposis should be referred to an ENT specialist.
 

Other Uncommon Causes of Chronic Cough

A non-pulmonary, uncommon cause of chronic cough is a vascular ring, a congenital anomaly in which blood vessels encircle and potentially constrict the esophagus and/or trachea. The most common type is a double aortic arch, but a right aortic arch or pulmonary artery sling is also possible. These coughs sound harsh and are usually accompanied by stridor, dyspnea and feeding problems. Workup includes an echocardiogram, a CT angiogram, and possibly a bronchoscopy to determine the extent of the airway narrowing. In symptomatic patients, surgery is indicated for correction.

Another congenital malformation that can cause chronic cough is a tracheoesophageal fistula, which occurs in about one in 3500 live births, commonly linked to trisomy disorders and VACTERL. Several types of tracheoesophageal fistula exist, and H-type fistula is associated with late onset symptoms. The cough can be wet or dry and sometimes sounds like barking because of the associated airway collapse. Patients often have recurrent pneumonia, bronchitis, and cough or cyanosis with feeding. Workup should include an upper gastrointestinal series but not with barium, Bhatia said, because that can cause pneumonitis. Instead, the series should be done with a thickened water-soluble contrast material, and a bronchoscopy may be indicated as well.

Though common as a condition in adults, gastroesophageal reflux disease (GERD) is a rare, but possible, cause of chronic cough in children. More often, the reflux is the result of the cough rather than the cause. The most sensitive tool for assessing GERD is esophageal 24-hour pH/impedance reflux monitoring. However, treatment of the reflux for cough is not recommended unless the patient has clinical features of GERD, including dystonic neck posturing in infants, heartburn, regurgitation, or other symptoms. If the patient has clinical symptoms, then treatment is acid suppressive therapy for 4-8 weeks, followed by a clinical reassessment.

An uncommon cause of chronic cough with no biological mechanism is habit cough. Habit cough is most easily distinguished from other coughs by its sounds, a “large, loud, honking noise,” Bhatia said. It also lacks a clear trigger and is usually absent during sleep, but it can be continuous during the day. Frustratingly, the patients themselves often don’t seem bothered by the cough, but “it’s very disruptive in the school and everywhere else,” Bhatia said. Families and/providers will often have tried multiple treatments and seen no improvement with habit cough.

The first thing to do with habit cough is reassure the family that there’s nothing serious going on because they are often worried by this point. Several non-pharmaceutical treatments can be effective, such as suggestion therapy or the “warm water technique,” in which the patient takes a sip of warm water every time they feel the urge to cough. “If they’re able to break the cycle, most of the time, they are fine,” Bhatia said. In rarer cases, more involved behavioral interventions may be indicated, such as a psychology referral if an underlying anxiety or other behavioral disorder is contributing.
 

Newer Causes of Cough

Two more recent causes of cough to watch for are long COVID and e-cigarette or vaping product–associated lung injury (EVALI), Bhatia said. The clearest sign of EVALI is a history of e-cigarette/vaping exposure, but clinical symptoms include a dry cough that occurs with dyspnea and chest pain. A chest x-ray may show diffuse, hazy, or consolidative opacities. Sometimes antibiotics or steroids can be helpful, but the evidence isn’t strong, and the most effective treatment is stopping e-cigarette use. Less commonly, passive exposure to vaping can also be associated with EVALI.

The most recent research on long COVID suggests that about 10-20% of children with acute COVID develop long COVID, and about a quarter of these patients develop a chronic dry cough. It’s often associated with fatigue and shortness of breath, which can be assessed with cardiopulmonary exercise testing. Sometimes a short trial of inhaled steroids can help.

Bhatia also mentioned a handful of other uncommon causes of chronic cough that most American pediatricians are unlikely to see: Childhood interstitial lung disease, tuberculosis, use of Angiotensin-Converting Enzyme inhibitors, and a build-up of ear wax via the Arnold’s nerve reflex.
 

Evaluation and Workup

Bhatia also discussed what to cover while taking a history and questions to ask. The history should include the type of cough, the onset timing (sudden vs gradual), associated symptoms, the cough trajectory, medications the patient is taking, and the patient’s past medical history and environmental exposures. Those attributes are included in this more comprehensive list of questions to consider during evaluation, adapted from a list provided in a 2019 article in Paediatric Respiratory Reviews:

• Age of onset and duration?
• Was the onset sudden or associate with an illness?
• Is the cough wet or dry?
• What does the cough sound like?
• How often does the cough occur?
• Is it progressive?
• Is it present during sleep?
• Are there any other associated symptoms, such as wheeze, dyspnea, vomiting, chest pain, etc?
• Are there any exacerbating factors or known triggers?
• Are there any relieving factors, including a trial of bronchodilators?
• Has there been exposure to auto-irritants, such as secondhand smoke?
• What is the cough’s effect on the child and on others around the child?
• Does the child have any other underlying conditions such as neuromuscular disease or asthma?
• What medications is the child taking or has recently taken?
• Is there a family history of atopy and/or respiratory disease?

Bhatia also recommended paying special attention to the following red flags or key features that may help more quickly narrow the diagnosis and often require a specialist referral:

• Digital clubbing, failure to thrive, or low tone
• An abnormal cardiac exam
• Tachypnea, hypoxemia, chest retractions, or hemoptysis
• Abnormal breath sounds such as unilateral wheezing or coarse crackles
• Abnormal spirometry in those aged 5 and older showing reversible obstruction, which often indicates asthma
• An abnormal chest x-ray with, for example, bilateral infiltrates, hyperinflation, right middle lobe syndrome, situs inversus, unilateral hyperlucency, a right aortic arch, etc.

No external funding was used for the presentation. Bhatia and Quijada had no disclosures.
 

A version of this article appeared on Medscape.com.

Cancer is becoming more common in younger generations. Data show that people under 50 are experiencing higher rates of cancer than any generation before them. As a genetic counselor, I hoped these upward trends in early-onset malignancies would slow with a better understanding of risk factors and prevention strategies. Unfortunately, the opposite is happening. Recent findings from the American Cancer Society reveal that the incidence of at least 17 of 34 cancer types is rising among GenX and Millennials. 

These statistics are alarming. I appreciate how easy it is for patients to get lost in the headlines about cancer, which may shape how they approach their healthcare. Each year, millions of Americans miss critical cancer screenings, with many citing fear of a positive test result as a leading reason. Others believe, despite the statistics, that cancer is not something they need to worry about until they are older. And then, of course, getting screened is not as easy as it should be. 

In my work, I meet with people from both younger and older generations who have either faced cancer themselves or witnessed a loved one experience the disease. One of the most common sentiments I hear from these patients is the desire to catch cancer earlier. My answer is always this: The first and most important step everyone can take is understanding their risk. 

For some, knowing they are at increased risk for cancer means starting screenings earlier — sometimes as early as age 25 — or getting screened with a more sensitive test. 

This proactive approach is the right one. Early detection can dramatically increase survival rates, sometimes by up to eightfold, depending on the type of cancer. It also significantly reduces the burden of total and cancer-specific healthcare costs. While screening may carry some potential risks, clinicians can minimize these risks by adhering to evidence-based guidelines, such as those from the American Cancer Society, and ensuring there is appropriate discussion of treatment options when a diagnosis is made.
 

Normalizing Cancer Risk Assessment and Screening 

A detailed cancer risk assessment and education about signs and symptoms should be part of every preventive care visit, regardless of someone’s age. Further, that cancer risk assessment should lead to clear recommendations and support for taking the next steps. 

This is where care advocacy and patient navigation come in. Care advocacy can improve outcomes at every stage of the cancer journey, from increasing screening rates to improving quality of life for survivors. I’ve seen first-hand how care advocates help patients overcome hurdles like long wait times for appointments they need, making both screening and diagnostic care easier to access. 

Now, with the finalization of a new rule from the Centers for Medicare & Medicaid Services, providers can bill for oncology navigation services that occur under their supervision. This formal recognition of care navigation affirms the value of these services not just clinically but financially as well. It will be through methods like care navigation, targeted outreach, and engaging educational resources — built into and covered by health plans — that patients will feel more in control over their health and have tools to help minimize the effects of cancer on the rest of their lives. 

These services benefit healthcare providers as well. Care navigation supports clinical care teams, from primary care providers to oncologists, by ensuring patients are seen before their cancer progresses to a more advanced stage. And even if patients follow screening recommendations for the rest of their lives and never get a positive result, they’ve still gained something invaluable: peace of mind, knowing they’ve taken an active role in their health. 
 

Fighting Fear With Routine

Treating cancer as a normal part of young people’s healthcare means helping them envision the disease as a condition that can be treated, much like a diagnosis of diabetes or high cholesterol. This mindset shift means quickly following up on a concerning symptom or screening result and reducing the time to start treatment if needed. And with treatment options and success rates for some cancers being better than ever, survivorship support must be built into every treatment plan from the start. Before treatment begins, healthcare providers should make time to talk about sometimes-overlooked key topics, such as reproductive options for people whose fertility may be affected by their cancer treatment, about plans for returning to work during or after treatment, and finding the right mental health support. 

Where we can’t prevent cancer, both primary care providers and oncologists can work together to help patients receive the right diagnosis and treatment as quickly as possible. Knowing insurance coverage has a direct effect on how early cancer is caught, for example, younger people need support in understanding and accessing benefits and resources that may be available through their existing healthcare channels, like some employer-sponsored health plans. Even if getting treated for cancer is inevitable for some, taking immediate action to get screened when it’s appropriate is the best thing we can do to lessen the impact of these rising cancer incidences across the country. At the end of the day, being afraid of cancer doesn’t decrease the chances of getting sick or dying from it. Proactive screening and early detection do. 
 

Brockman, Genetic Counselor, Color Health, Buffalo, New York, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Cancer is becoming more common in younger generations. Data show that people under 50 are experiencing higher rates of cancer than any generation before them. As a genetic counselor, I hoped these upward trends in early-onset malignancies would slow with a better understanding of risk factors and prevention strategies. Unfortunately, the opposite is happening. Recent findings from the American Cancer Society reveal that the incidence of at least 17 of 34 cancer types is rising among GenX and Millennials. 

These statistics are alarming. I appreciate how easy it is for patients to get lost in the headlines about cancer, which may shape how they approach their healthcare. Each year, millions of Americans miss critical cancer screenings, with many citing fear of a positive test result as a leading reason. Others believe, despite the statistics, that cancer is not something they need to worry about until they are older. And then, of course, getting screened is not as easy as it should be. 

In my work, I meet with people from both younger and older generations who have either faced cancer themselves or witnessed a loved one experience the disease. One of the most common sentiments I hear from these patients is the desire to catch cancer earlier. My answer is always this: The first and most important step everyone can take is understanding their risk. 

For some, knowing they are at increased risk for cancer means starting screenings earlier — sometimes as early as age 25 — or getting screened with a more sensitive test. 

This proactive approach is the right one. Early detection can dramatically increase survival rates, sometimes by up to eightfold, depending on the type of cancer. It also significantly reduces the burden of total and cancer-specific healthcare costs. While screening may carry some potential risks, clinicians can minimize these risks by adhering to evidence-based guidelines, such as those from the American Cancer Society, and ensuring there is appropriate discussion of treatment options when a diagnosis is made.
 

Normalizing Cancer Risk Assessment and Screening 

A detailed cancer risk assessment and education about signs and symptoms should be part of every preventive care visit, regardless of someone’s age. Further, that cancer risk assessment should lead to clear recommendations and support for taking the next steps. 

This is where care advocacy and patient navigation come in. Care advocacy can improve outcomes at every stage of the cancer journey, from increasing screening rates to improving quality of life for survivors. I’ve seen first-hand how care advocates help patients overcome hurdles like long wait times for appointments they need, making both screening and diagnostic care easier to access. 

Now, with the finalization of a new rule from the Centers for Medicare & Medicaid Services, providers can bill for oncology navigation services that occur under their supervision. This formal recognition of care navigation affirms the value of these services not just clinically but financially as well. It will be through methods like care navigation, targeted outreach, and engaging educational resources — built into and covered by health plans — that patients will feel more in control over their health and have tools to help minimize the effects of cancer on the rest of their lives. 

These services benefit healthcare providers as well. Care navigation supports clinical care teams, from primary care providers to oncologists, by ensuring patients are seen before their cancer progresses to a more advanced stage. And even if patients follow screening recommendations for the rest of their lives and never get a positive result, they’ve still gained something invaluable: peace of mind, knowing they’ve taken an active role in their health. 
 

Fighting Fear With Routine

Treating cancer as a normal part of young people’s healthcare means helping them envision the disease as a condition that can be treated, much like a diagnosis of diabetes or high cholesterol. This mindset shift means quickly following up on a concerning symptom or screening result and reducing the time to start treatment if needed. And with treatment options and success rates for some cancers being better than ever, survivorship support must be built into every treatment plan from the start. Before treatment begins, healthcare providers should make time to talk about sometimes-overlooked key topics, such as reproductive options for people whose fertility may be affected by their cancer treatment, about plans for returning to work during or after treatment, and finding the right mental health support. 

Where we can’t prevent cancer, both primary care providers and oncologists can work together to help patients receive the right diagnosis and treatment as quickly as possible. Knowing insurance coverage has a direct effect on how early cancer is caught, for example, younger people need support in understanding and accessing benefits and resources that may be available through their existing healthcare channels, like some employer-sponsored health plans. Even if getting treated for cancer is inevitable for some, taking immediate action to get screened when it’s appropriate is the best thing we can do to lessen the impact of these rising cancer incidences across the country. At the end of the day, being afraid of cancer doesn’t decrease the chances of getting sick or dying from it. Proactive screening and early detection do. 
 

Brockman, Genetic Counselor, Color Health, Buffalo, New York, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Cancer is becoming more common in younger generations. Data show that people under 50 are experiencing higher rates of cancer than any generation before them. As a genetic counselor, I hoped these upward trends in early-onset malignancies would slow with a better understanding of risk factors and prevention strategies. Unfortunately, the opposite is happening. Recent findings from the American Cancer Society reveal that the incidence of at least 17 of 34 cancer types is rising among GenX and Millennials. 

These statistics are alarming. I appreciate how easy it is for patients to get lost in the headlines about cancer, which may shape how they approach their healthcare. Each year, millions of Americans miss critical cancer screenings, with many citing fear of a positive test result as a leading reason. Others believe, despite the statistics, that cancer is not something they need to worry about until they are older. And then, of course, getting screened is not as easy as it should be. 

In my work, I meet with people from both younger and older generations who have either faced cancer themselves or witnessed a loved one experience the disease. One of the most common sentiments I hear from these patients is the desire to catch cancer earlier. My answer is always this: The first and most important step everyone can take is understanding their risk. 

For some, knowing they are at increased risk for cancer means starting screenings earlier — sometimes as early as age 25 — or getting screened with a more sensitive test. 

This proactive approach is the right one. Early detection can dramatically increase survival rates, sometimes by up to eightfold, depending on the type of cancer. It also significantly reduces the burden of total and cancer-specific healthcare costs. While screening may carry some potential risks, clinicians can minimize these risks by adhering to evidence-based guidelines, such as those from the American Cancer Society, and ensuring there is appropriate discussion of treatment options when a diagnosis is made.
 

Normalizing Cancer Risk Assessment and Screening 

A detailed cancer risk assessment and education about signs and symptoms should be part of every preventive care visit, regardless of someone’s age. Further, that cancer risk assessment should lead to clear recommendations and support for taking the next steps. 

This is where care advocacy and patient navigation come in. Care advocacy can improve outcomes at every stage of the cancer journey, from increasing screening rates to improving quality of life for survivors. I’ve seen first-hand how care advocates help patients overcome hurdles like long wait times for appointments they need, making both screening and diagnostic care easier to access. 

Now, with the finalization of a new rule from the Centers for Medicare & Medicaid Services, providers can bill for oncology navigation services that occur under their supervision. This formal recognition of care navigation affirms the value of these services not just clinically but financially as well. It will be through methods like care navigation, targeted outreach, and engaging educational resources — built into and covered by health plans — that patients will feel more in control over their health and have tools to help minimize the effects of cancer on the rest of their lives. 

These services benefit healthcare providers as well. Care navigation supports clinical care teams, from primary care providers to oncologists, by ensuring patients are seen before their cancer progresses to a more advanced stage. And even if patients follow screening recommendations for the rest of their lives and never get a positive result, they’ve still gained something invaluable: peace of mind, knowing they’ve taken an active role in their health. 
 

Fighting Fear With Routine

Treating cancer as a normal part of young people’s healthcare means helping them envision the disease as a condition that can be treated, much like a diagnosis of diabetes or high cholesterol. This mindset shift means quickly following up on a concerning symptom or screening result and reducing the time to start treatment if needed. And with treatment options and success rates for some cancers being better than ever, survivorship support must be built into every treatment plan from the start. Before treatment begins, healthcare providers should make time to talk about sometimes-overlooked key topics, such as reproductive options for people whose fertility may be affected by their cancer treatment, about plans for returning to work during or after treatment, and finding the right mental health support. 

Where we can’t prevent cancer, both primary care providers and oncologists can work together to help patients receive the right diagnosis and treatment as quickly as possible. Knowing insurance coverage has a direct effect on how early cancer is caught, for example, younger people need support in understanding and accessing benefits and resources that may be available through their existing healthcare channels, like some employer-sponsored health plans. Even if getting treated for cancer is inevitable for some, taking immediate action to get screened when it’s appropriate is the best thing we can do to lessen the impact of these rising cancer incidences across the country. At the end of the day, being afraid of cancer doesn’t decrease the chances of getting sick or dying from it. Proactive screening and early detection do. 
 

Brockman, Genetic Counselor, Color Health, Buffalo, New York, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Primary care doctors and specialists should advise patients who have already experienced a heart attack or stroke that they are at a higher risk for long COVID and need to take steps to avoid contracting the virus, according to new research.

The study, led by researchers at Columbia University, New York City, suggests that anyone with cardiovascular disease (CVD) — defined as having experienced a heart attack or stroke — should consider getting the updated COVID vaccine boosters. They also suggest patients with CVD take other steps to avoid an acute infection, such as avoiding crowded indoor spaces.

There is no specific test or treatment for long COVID, which can become disabling and chronic. Long COVID is defined by the failure to recover from acute COVID-19 in 90 days.

The scientists used data from nearly 5000 people enrolled in 14 established, ongoing research programs, including the 76-year-old Framingham Heart Study. The results of the analysis of the “mega-cohort” were published in JAMA Network Open.

Most of the 14 studies already had 10-20 years of data on the cardiac health of thousands of enrollees, said Norrina B. Allen, one of the authors and a cardiac epidemiologist at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“This is a particularly strong study that looked at risk factors — or individual health — prior to developing COVID and their impact on the likely of recovering from COVID,” she said.

In addition to those with CVD, women and adults with preexisting chronic illnesses took longer to recover.

More than 20% of those in the large, racially and ethnically diverse US population–based study did not recover from COVID in 90 days. The researchers found that the median self-reported time to recovery from acute infection was 20 days.

While women and those with chronic illness had a higher risk for long COVID, vaccination and infection with the Omicron variant wave were associated with shorter recovery times.

These findings make sense, said Ziyad Al-Aly, MD, chief of research at Veterans Affairs St. Louis Health Care System and clinical epidemiologist at Washington University in St. Louis, Missouri.

“We also see that COVID-19 can lead to new-onset cardiovascular disease,” said Al-Aly, who was not involved in the study. “There is clearly a (link) between COVID and cardiovascular disease. These two seem to be intimately intertwined. In my view, this emphasizes the importance of targeting these individuals for vaccination and potentially antivirals (when they get infected) to help reduce their risk of adverse events and ameliorate their chance of full and fast recovery.”

The study used data from the Collaborative Cohort of Cohorts for COVID-19 Research. The long list of researchers contributing to this study includes epidemiologists, biostatisticians, neurologists, pulmonologists, and cardiologists. The data come from a list of cohorts like the Framingham Heart Study, which identified key risk factors for CVD, including cholesterol levels. Other studies include the Atherosclerosis Risk in Communities study, which began in the mid-1980s. Researchers there recruited a cohort of 15,792 men and women in rural North Carolina and Mississippi and suburban Minneapolis. They enrolled a high number of African American participants, who have been underrepresented in past studies. Other cohorts focused on young adults with CVD and Hispanics, while another focused on people with chronic obstructive pulmonary disease.

Lead author Elizabeth C. Oelsner, MD, of Columbia University Irving Medical Center in New York City, said she was not surprised by the CVD-long COVID link.

“We were aware that individuals with CVD were at higher risk of a more severe acute infection,” she said. “We were also seeing evidence that long and severe infection led to persistent symptoms.”

Oelsner noted that many patients still take more than 3 months to recover, even during the Omicron wave.

“While that has improved over the course of the pandemic, many individuals are taking a very long time to recover, and that can have a huge burden on the patient,” she said.

She encourages healthcare providers to tell patients at higher risk to take steps to avoid the virus, including vaccination and boosters.

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

Primary care doctors and specialists should advise patients who have already experienced a heart attack or stroke that they are at a higher risk for long COVID and need to take steps to avoid contracting the virus, according to new research.

The study, led by researchers at Columbia University, New York City, suggests that anyone with cardiovascular disease (CVD) — defined as having experienced a heart attack or stroke — should consider getting the updated COVID vaccine boosters. They also suggest patients with CVD take other steps to avoid an acute infection, such as avoiding crowded indoor spaces.

There is no specific test or treatment for long COVID, which can become disabling and chronic. Long COVID is defined by the failure to recover from acute COVID-19 in 90 days.

The scientists used data from nearly 5000 people enrolled in 14 established, ongoing research programs, including the 76-year-old Framingham Heart Study. The results of the analysis of the “mega-cohort” were published in JAMA Network Open.

Most of the 14 studies already had 10-20 years of data on the cardiac health of thousands of enrollees, said Norrina B. Allen, one of the authors and a cardiac epidemiologist at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“This is a particularly strong study that looked at risk factors — or individual health — prior to developing COVID and their impact on the likely of recovering from COVID,” she said.

In addition to those with CVD, women and adults with preexisting chronic illnesses took longer to recover.

More than 20% of those in the large, racially and ethnically diverse US population–based study did not recover from COVID in 90 days. The researchers found that the median self-reported time to recovery from acute infection was 20 days.

While women and those with chronic illness had a higher risk for long COVID, vaccination and infection with the Omicron variant wave were associated with shorter recovery times.

These findings make sense, said Ziyad Al-Aly, MD, chief of research at Veterans Affairs St. Louis Health Care System and clinical epidemiologist at Washington University in St. Louis, Missouri.

“We also see that COVID-19 can lead to new-onset cardiovascular disease,” said Al-Aly, who was not involved in the study. “There is clearly a (link) between COVID and cardiovascular disease. These two seem to be intimately intertwined. In my view, this emphasizes the importance of targeting these individuals for vaccination and potentially antivirals (when they get infected) to help reduce their risk of adverse events and ameliorate their chance of full and fast recovery.”

The study used data from the Collaborative Cohort of Cohorts for COVID-19 Research. The long list of researchers contributing to this study includes epidemiologists, biostatisticians, neurologists, pulmonologists, and cardiologists. The data come from a list of cohorts like the Framingham Heart Study, which identified key risk factors for CVD, including cholesterol levels. Other studies include the Atherosclerosis Risk in Communities study, which began in the mid-1980s. Researchers there recruited a cohort of 15,792 men and women in rural North Carolina and Mississippi and suburban Minneapolis. They enrolled a high number of African American participants, who have been underrepresented in past studies. Other cohorts focused on young adults with CVD and Hispanics, while another focused on people with chronic obstructive pulmonary disease.

Lead author Elizabeth C. Oelsner, MD, of Columbia University Irving Medical Center in New York City, said she was not surprised by the CVD-long COVID link.

“We were aware that individuals with CVD were at higher risk of a more severe acute infection,” she said. “We were also seeing evidence that long and severe infection led to persistent symptoms.”

Oelsner noted that many patients still take more than 3 months to recover, even during the Omicron wave.

“While that has improved over the course of the pandemic, many individuals are taking a very long time to recover, and that can have a huge burden on the patient,” she said.

She encourages healthcare providers to tell patients at higher risk to take steps to avoid the virus, including vaccination and boosters.

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

Primary care doctors and specialists should advise patients who have already experienced a heart attack or stroke that they are at a higher risk for long COVID and need to take steps to avoid contracting the virus, according to new research.

The study, led by researchers at Columbia University, New York City, suggests that anyone with cardiovascular disease (CVD) — defined as having experienced a heart attack or stroke — should consider getting the updated COVID vaccine boosters. They also suggest patients with CVD take other steps to avoid an acute infection, such as avoiding crowded indoor spaces.

There is no specific test or treatment for long COVID, which can become disabling and chronic. Long COVID is defined by the failure to recover from acute COVID-19 in 90 days.

The scientists used data from nearly 5000 people enrolled in 14 established, ongoing research programs, including the 76-year-old Framingham Heart Study. The results of the analysis of the “mega-cohort” were published in JAMA Network Open.

Most of the 14 studies already had 10-20 years of data on the cardiac health of thousands of enrollees, said Norrina B. Allen, one of the authors and a cardiac epidemiologist at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“This is a particularly strong study that looked at risk factors — or individual health — prior to developing COVID and their impact on the likely of recovering from COVID,” she said.

In addition to those with CVD, women and adults with preexisting chronic illnesses took longer to recover.

More than 20% of those in the large, racially and ethnically diverse US population–based study did not recover from COVID in 90 days. The researchers found that the median self-reported time to recovery from acute infection was 20 days.

While women and those with chronic illness had a higher risk for long COVID, vaccination and infection with the Omicron variant wave were associated with shorter recovery times.

These findings make sense, said Ziyad Al-Aly, MD, chief of research at Veterans Affairs St. Louis Health Care System and clinical epidemiologist at Washington University in St. Louis, Missouri.

“We also see that COVID-19 can lead to new-onset cardiovascular disease,” said Al-Aly, who was not involved in the study. “There is clearly a (link) between COVID and cardiovascular disease. These two seem to be intimately intertwined. In my view, this emphasizes the importance of targeting these individuals for vaccination and potentially antivirals (when they get infected) to help reduce their risk of adverse events and ameliorate their chance of full and fast recovery.”

The study used data from the Collaborative Cohort of Cohorts for COVID-19 Research. The long list of researchers contributing to this study includes epidemiologists, biostatisticians, neurologists, pulmonologists, and cardiologists. The data come from a list of cohorts like the Framingham Heart Study, which identified key risk factors for CVD, including cholesterol levels. Other studies include the Atherosclerosis Risk in Communities study, which began in the mid-1980s. Researchers there recruited a cohort of 15,792 men and women in rural North Carolina and Mississippi and suburban Minneapolis. They enrolled a high number of African American participants, who have been underrepresented in past studies. Other cohorts focused on young adults with CVD and Hispanics, while another focused on people with chronic obstructive pulmonary disease.

Lead author Elizabeth C. Oelsner, MD, of Columbia University Irving Medical Center in New York City, said she was not surprised by the CVD-long COVID link.

“We were aware that individuals with CVD were at higher risk of a more severe acute infection,” she said. “We were also seeing evidence that long and severe infection led to persistent symptoms.”

Oelsner noted that many patients still take more than 3 months to recover, even during the Omicron wave.

“While that has improved over the course of the pandemic, many individuals are taking a very long time to recover, and that can have a huge burden on the patient,” she said.

She encourages healthcare providers to tell patients at higher risk to take steps to avoid the virus, including vaccination and boosters.

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

Depending on one’s perspective, “mast cell activation syndrome (MCAS)” is either a relatively rare, narrowly defined severe allergic condition or a vastly underrecognized underlying cause of multiple chronic inflammatory conditions that affect roughly 17% of the entire population. 

Inappropriate activation of mast cells — now termed mast cell activation disease (MCAD) — has long been known to underlie allergic symptoms and inflammation, and far less commonly, neoplasias such as mastocytosis. The concept of chronic, persistent MCAS associated with aberrant growth and dystrophism is more recent, emerging only in the last couple of decades as a separate entity under the MCAD heading. 

Observational studies and clinical experience have linked signs and symptoms of MCAS with other inflammatory chronic conditions such as hypermobile Ehlers-Danlos Syndrome (EDS), postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and recently, long COVID. However, those conditions themselves are diagnostically challenging, and as yet there is no proof of causation.

The idea that MCAS is the entity — or at least, a key one — at the center of “a confoundingly, extraordinarily heterogeneous chronic multisystem polymorbidity” was the theme of a recent 4-day meeting of a professional group informally dubbed “Masterminds.” Since their first meeting in 2018, the group has grown from about 35 to nearly 650 multidisciplinary professionals. 

Stephanie L. Grach, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minnesota, gave an introductory talk about the importance of changing “the medical paradigm around complex chronic illness.” Much of the rest of the meeting was devoted to sharing approaches for managing MCAS comorbidities, including dysautonomia, hypermobility, and associated craniocervical dysfunction, and various other multi-system conditions characterized by chronic pain and/or fatigue. Several talks covered the use of agents that block mast cell activity as potential treatment. 

In an interview, Grach said “the meeting was an exciting example of how not only research, but also medicine, is moving forward, and it’s really cool to see that people are independently coming to very similar conclusions about shared pathologies, and because of that, the importance of overlap amongst complex medical conditions that historically have really been poorly addressed.”

She added, “mast cell activation, or mast cell hyperactivity, is one part of the greater picture. What’s important about the mast cell component is that of the multiple different targetable pathologies, it’s one that currently has potential available therapies that can be explored, some of them relatively easily.”

But Christopher Chang, MD, PhD, chief of the Pediatric Allergy and Immunology program, Joe DiMaggio Children’s Hospital, Hollywood, Florida, sees it differently. In an interview, he noted that the reason for disagreement over what constitutes MCAS is that “it doesn’t have a lot of objective findings that we can identify. ... We know that mast cells are important immune cells, just like all immune cells are important. It seems like whenever someone has unexplained symptoms, people try to blame it on mast cells. But it’s very hard to prove that.” 
 

Two Definitions Characterize the Illness Differently

One proposed “consensus” MCAS definition was first published in 2011 by a group led by hematologist Peter Valent, MD, of the Medical University of Vienna in Austria. It has been revised since, and similar versions adopted by medical societies, including the American Academy of Allergy, Asthma & Immunology (AAAAI). The most recent versions propose three core MCAS criteria: 

• Typical clinical signs of severe, recurrent (episodic) systemic (at least two organ systems) MCA are present (often in the form of anaphylaxis).
• The involvement of mast cells (MCs) is documented by biochemical studies, preferably an increase in serum tryptase levels from the individual’s baseline to plus 20% + 2 ng/mL.
• Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production, or drugs blocking mediator release or effects of MC-derived mediators.

The following year, a separate publication authored by Gerhard J. Molderings, MD, University of Bonn in Germany, and colleagues proposed a much broader MCAS definition. Also revised since, the latest “consensus-2” was published in 2020. This definition consists of one major criterion: “A constellation of clinical complaints attributable to pathologically increased MC activity, ie, MC mediator release syndrome.” This “constellation” involves conditions of nearly every organ system that, taken together, are estimated to affect up to 17% of the entire population. These are just a few examples: 

• Constitutional: Chronic fatigue, flushing, or sweats
• Dermatologic: Rashes or lesions
• Ophthalmologic: dry eyes
• Oral: Burning or itching in mouth
• Pulmonary: Airway inflammation at any/all levels
• Cardiovascular: Blood pressure lability or codiagnosis of POTS is common
• Gastrointestinal: Reflux, dysphagia, or malabsorption
• Genitourinary: Endometriosis, dysmenorrhea, or dyspareunia
• Musculoskeletal/connective tissue: Fibromyalgia or diagnosis of hypermobile EDS is common
• Neurologic: Headaches or sensory neuropathies
• Psychiatric: Depression or anxiety
• Endocrinologic: Thyroid disease or dyslipidemia
• Hematologic: Polycythemia or anemia (after ruling out other causes)

The diagnosis is made by fulfilling that major criterion, plus at least one objective assessment of pathologically increased release of MC mediators, including infiltrates, abnormal MC morphology, or MC genetic changes shown to increase MC activity. Other alternatives include evidence of above-normal levels of MC mediators, including tryptase, histamine or its metabolites, heparin, or chromatin A, in whole blood, serum, plasma, or urine. Symptomatic response to MC activation inhibitors can also be used but isn’t required as it is in the other definition. 
 

Underdiagnosis vs Overdiagnosis

Lawrence B. Afrin, MD, senior consultant in hematology/oncology at the AIM Center for Personalized Medicine, Westchester, New York, and lead author of the 2020 update of the broader “consensus-2” criteria, said in an interview, “we now know MCAS exists, and it’s prevalent, even though, for understandable and forgivable reasons, we’ve been missing it all along. ... If you see a patient who has this chronic, multisystem unwellness with general themes of inflammation plus or minus allergic issues and you can’t find some other rational explanation that better accounts for what’s going on ... then it’s reasonable to think to include MCAS in the differential diagnosis. If the patient happens not to fit the diagnostic criteria being advanced by one group, that doesn’t necessarily rule out the possibility that this is still going on.”

Afrin, along with his coauthors, faulted the narrower “consensus-1” definition for lacking data to support the “20% + 2” criteria for requiring the difficult determination of a patient’s “baseline” and for requiring evidence of response to treatment prior to making the diagnosis. Not all patients will respond to a given histamine blocker, he noted. 

But Lawrence B. Schwartz, MD, PhD, an author on both the Valent and AAAAI criteria, disagreed, noting that the narrower criteria “appear to have a high degree of specificity and sensitivity when the reaction is systemic and involves hypotension. Less severe clinical events, particularly involving the gastrointestinal or central nervous systems, do not have precise clinical or biomarker criteria for identifying mast cell involvement.” 

Added Schwartz, who is professor of medicine and chair of the Division of Rheumatology, Allergy, and Immunology and program director of Allergy and Immunology, Virginia Commonwealth University (VCU), Richmond, “when mast cell activation events occur only in the skin, we refer to it as chronic urticaria and in the airways or conjunctiva of allergic individuals as allergic asthma, rhinitis, and/or conjunctivitis. The absence of specific criteria for mast cell activation in the GI [gastrointestinal] tract or CNS [central nervous system] neither rules in mast cell involvement nor does it rule out mast cell involvement. Thus, more research is needed to find better diagnostic criteria.”

Schwartz also pointed to a recent paper reporting the use of artificial intelligence models to “quantify diagnostic precision and specificity” of “alternative” MCAS definitions. The conclusion was a “lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.”

During the meeting, Afrin acknowledged that the broader view risks overdiagnosis of MCAS. However, he also referenced Occam’s razor, the principle that the simplest explanation is probably the best one. “Which scenario is more likely? Multiple diagnoses and problems that are all independent of each other vs one diagnosis that’s biologically capable of causing most or all of the findings, ie, the simplest solution even if it’s not the most immediately obvious solution?”

He said in an interview: “Do we have any proof that MCAS is what’s underlying hypermobile Ehlers-Danlos or POTS or chronic fatigue? No, we don’t have any proof, not because anybody has done studies that have shown there to be no connection but simply because we’re so early in our awareness that the disease even exists that the necessary studies haven’t even been done yet.”

At the meeting, Afrin introduced proposals to turn the “Masterminds” group into a formal professional society and to launch a journal. He also gave an update on progress in developing a symptom assessment tool both for clinical use and to enable clinical trials of new drugs to target mast cells or their mediators. The plan is to field test the tool in 2025 and publish those results in 2026. 

Grach, Afrin, and Chang had no disclosures. Schwartz discovered tryptase and invented the Thermo Fisher tryptase assay, for which his institution (VCU) receives royalties that are shared with him. He also invented monoclonal antibodies used for detecting mast cells or basophils, for which VCU receives royalties from several companies, including Millipore, Santa Cruz, BioLegend, and Hycult Biotech, that are also shared with him. He is a paid consultant for Blueprint Medicines, Celldex Therapeutics, Invea, Third Harmonic Bio, HYCOR Biomedical, Jasper, TerSera Therapeutics, and GLG. He also serves on an AstraZeneca data safety monitoring board for a clinical trial involving benralizumab treatment of hypereosinophilic syndrome and receives royalties from UpToDate (biomarkers for anaphylaxis) and Goldman-Cecil Medicine (anaphylaxis).

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

Depending on one’s perspective, “mast cell activation syndrome (MCAS)” is either a relatively rare, narrowly defined severe allergic condition or a vastly underrecognized underlying cause of multiple chronic inflammatory conditions that affect roughly 17% of the entire population. 

Inappropriate activation of mast cells — now termed mast cell activation disease (MCAD) — has long been known to underlie allergic symptoms and inflammation, and far less commonly, neoplasias such as mastocytosis. The concept of chronic, persistent MCAS associated with aberrant growth and dystrophism is more recent, emerging only in the last couple of decades as a separate entity under the MCAD heading. 

Observational studies and clinical experience have linked signs and symptoms of MCAS with other inflammatory chronic conditions such as hypermobile Ehlers-Danlos Syndrome (EDS), postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and recently, long COVID. However, those conditions themselves are diagnostically challenging, and as yet there is no proof of causation.

The idea that MCAS is the entity — or at least, a key one — at the center of “a confoundingly, extraordinarily heterogeneous chronic multisystem polymorbidity” was the theme of a recent 4-day meeting of a professional group informally dubbed “Masterminds.” Since their first meeting in 2018, the group has grown from about 35 to nearly 650 multidisciplinary professionals. 

Stephanie L. Grach, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minnesota, gave an introductory talk about the importance of changing “the medical paradigm around complex chronic illness.” Much of the rest of the meeting was devoted to sharing approaches for managing MCAS comorbidities, including dysautonomia, hypermobility, and associated craniocervical dysfunction, and various other multi-system conditions characterized by chronic pain and/or fatigue. Several talks covered the use of agents that block mast cell activity as potential treatment. 

In an interview, Grach said “the meeting was an exciting example of how not only research, but also medicine, is moving forward, and it’s really cool to see that people are independently coming to very similar conclusions about shared pathologies, and because of that, the importance of overlap amongst complex medical conditions that historically have really been poorly addressed.”

She added, “mast cell activation, or mast cell hyperactivity, is one part of the greater picture. What’s important about the mast cell component is that of the multiple different targetable pathologies, it’s one that currently has potential available therapies that can be explored, some of them relatively easily.”

But Christopher Chang, MD, PhD, chief of the Pediatric Allergy and Immunology program, Joe DiMaggio Children’s Hospital, Hollywood, Florida, sees it differently. In an interview, he noted that the reason for disagreement over what constitutes MCAS is that “it doesn’t have a lot of objective findings that we can identify. ... We know that mast cells are important immune cells, just like all immune cells are important. It seems like whenever someone has unexplained symptoms, people try to blame it on mast cells. But it’s very hard to prove that.” 
 

Two Definitions Characterize the Illness Differently

One proposed “consensus” MCAS definition was first published in 2011 by a group led by hematologist Peter Valent, MD, of the Medical University of Vienna in Austria. It has been revised since, and similar versions adopted by medical societies, including the American Academy of Allergy, Asthma & Immunology (AAAAI). The most recent versions propose three core MCAS criteria: 

• Typical clinical signs of severe, recurrent (episodic) systemic (at least two organ systems) MCA are present (often in the form of anaphylaxis).
• The involvement of mast cells (MCs) is documented by biochemical studies, preferably an increase in serum tryptase levels from the individual’s baseline to plus 20% + 2 ng/mL.
• Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production, or drugs blocking mediator release or effects of MC-derived mediators.

The following year, a separate publication authored by Gerhard J. Molderings, MD, University of Bonn in Germany, and colleagues proposed a much broader MCAS definition. Also revised since, the latest “consensus-2” was published in 2020. This definition consists of one major criterion: “A constellation of clinical complaints attributable to pathologically increased MC activity, ie, MC mediator release syndrome.” This “constellation” involves conditions of nearly every organ system that, taken together, are estimated to affect up to 17% of the entire population. These are just a few examples: 

• Constitutional: Chronic fatigue, flushing, or sweats
• Dermatologic: Rashes or lesions
• Ophthalmologic: dry eyes
• Oral: Burning or itching in mouth
• Pulmonary: Airway inflammation at any/all levels
• Cardiovascular: Blood pressure lability or codiagnosis of POTS is common
• Gastrointestinal: Reflux, dysphagia, or malabsorption
• Genitourinary: Endometriosis, dysmenorrhea, or dyspareunia
• Musculoskeletal/connective tissue: Fibromyalgia or diagnosis of hypermobile EDS is common
• Neurologic: Headaches or sensory neuropathies
• Psychiatric: Depression or anxiety
• Endocrinologic: Thyroid disease or dyslipidemia
• Hematologic: Polycythemia or anemia (after ruling out other causes)

The diagnosis is made by fulfilling that major criterion, plus at least one objective assessment of pathologically increased release of MC mediators, including infiltrates, abnormal MC morphology, or MC genetic changes shown to increase MC activity. Other alternatives include evidence of above-normal levels of MC mediators, including tryptase, histamine or its metabolites, heparin, or chromatin A, in whole blood, serum, plasma, or urine. Symptomatic response to MC activation inhibitors can also be used but isn’t required as it is in the other definition. 
 

Underdiagnosis vs Overdiagnosis

Lawrence B. Afrin, MD, senior consultant in hematology/oncology at the AIM Center for Personalized Medicine, Westchester, New York, and lead author of the 2020 update of the broader “consensus-2” criteria, said in an interview, “we now know MCAS exists, and it’s prevalent, even though, for understandable and forgivable reasons, we’ve been missing it all along. ... If you see a patient who has this chronic, multisystem unwellness with general themes of inflammation plus or minus allergic issues and you can’t find some other rational explanation that better accounts for what’s going on ... then it’s reasonable to think to include MCAS in the differential diagnosis. If the patient happens not to fit the diagnostic criteria being advanced by one group, that doesn’t necessarily rule out the possibility that this is still going on.”

Afrin, along with his coauthors, faulted the narrower “consensus-1” definition for lacking data to support the “20% + 2” criteria for requiring the difficult determination of a patient’s “baseline” and for requiring evidence of response to treatment prior to making the diagnosis. Not all patients will respond to a given histamine blocker, he noted. 

But Lawrence B. Schwartz, MD, PhD, an author on both the Valent and AAAAI criteria, disagreed, noting that the narrower criteria “appear to have a high degree of specificity and sensitivity when the reaction is systemic and involves hypotension. Less severe clinical events, particularly involving the gastrointestinal or central nervous systems, do not have precise clinical or biomarker criteria for identifying mast cell involvement.” 

Added Schwartz, who is professor of medicine and chair of the Division of Rheumatology, Allergy, and Immunology and program director of Allergy and Immunology, Virginia Commonwealth University (VCU), Richmond, “when mast cell activation events occur only in the skin, we refer to it as chronic urticaria and in the airways or conjunctiva of allergic individuals as allergic asthma, rhinitis, and/or conjunctivitis. The absence of specific criteria for mast cell activation in the GI [gastrointestinal] tract or CNS [central nervous system] neither rules in mast cell involvement nor does it rule out mast cell involvement. Thus, more research is needed to find better diagnostic criteria.”

Schwartz also pointed to a recent paper reporting the use of artificial intelligence models to “quantify diagnostic precision and specificity” of “alternative” MCAS definitions. The conclusion was a “lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.”

During the meeting, Afrin acknowledged that the broader view risks overdiagnosis of MCAS. However, he also referenced Occam’s razor, the principle that the simplest explanation is probably the best one. “Which scenario is more likely? Multiple diagnoses and problems that are all independent of each other vs one diagnosis that’s biologically capable of causing most or all of the findings, ie, the simplest solution even if it’s not the most immediately obvious solution?”

He said in an interview: “Do we have any proof that MCAS is what’s underlying hypermobile Ehlers-Danlos or POTS or chronic fatigue? No, we don’t have any proof, not because anybody has done studies that have shown there to be no connection but simply because we’re so early in our awareness that the disease even exists that the necessary studies haven’t even been done yet.”

At the meeting, Afrin introduced proposals to turn the “Masterminds” group into a formal professional society and to launch a journal. He also gave an update on progress in developing a symptom assessment tool both for clinical use and to enable clinical trials of new drugs to target mast cells or their mediators. The plan is to field test the tool in 2025 and publish those results in 2026. 

Grach, Afrin, and Chang had no disclosures. Schwartz discovered tryptase and invented the Thermo Fisher tryptase assay, for which his institution (VCU) receives royalties that are shared with him. He also invented monoclonal antibodies used for detecting mast cells or basophils, for which VCU receives royalties from several companies, including Millipore, Santa Cruz, BioLegend, and Hycult Biotech, that are also shared with him. He is a paid consultant for Blueprint Medicines, Celldex Therapeutics, Invea, Third Harmonic Bio, HYCOR Biomedical, Jasper, TerSera Therapeutics, and GLG. He also serves on an AstraZeneca data safety monitoring board for a clinical trial involving benralizumab treatment of hypereosinophilic syndrome and receives royalties from UpToDate (biomarkers for anaphylaxis) and Goldman-Cecil Medicine (anaphylaxis).

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

Depending on one’s perspective, “mast cell activation syndrome (MCAS)” is either a relatively rare, narrowly defined severe allergic condition or a vastly underrecognized underlying cause of multiple chronic inflammatory conditions that affect roughly 17% of the entire population. 

Inappropriate activation of mast cells — now termed mast cell activation disease (MCAD) — has long been known to underlie allergic symptoms and inflammation, and far less commonly, neoplasias such as mastocytosis. The concept of chronic, persistent MCAS associated with aberrant growth and dystrophism is more recent, emerging only in the last couple of decades as a separate entity under the MCAD heading. 

Observational studies and clinical experience have linked signs and symptoms of MCAS with other inflammatory chronic conditions such as hypermobile Ehlers-Danlos Syndrome (EDS), postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and recently, long COVID. However, those conditions themselves are diagnostically challenging, and as yet there is no proof of causation.

The idea that MCAS is the entity — or at least, a key one — at the center of “a confoundingly, extraordinarily heterogeneous chronic multisystem polymorbidity” was the theme of a recent 4-day meeting of a professional group informally dubbed “Masterminds.” Since their first meeting in 2018, the group has grown from about 35 to nearly 650 multidisciplinary professionals. 

Stephanie L. Grach, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minnesota, gave an introductory talk about the importance of changing “the medical paradigm around complex chronic illness.” Much of the rest of the meeting was devoted to sharing approaches for managing MCAS comorbidities, including dysautonomia, hypermobility, and associated craniocervical dysfunction, and various other multi-system conditions characterized by chronic pain and/or fatigue. Several talks covered the use of agents that block mast cell activity as potential treatment. 

In an interview, Grach said “the meeting was an exciting example of how not only research, but also medicine, is moving forward, and it’s really cool to see that people are independently coming to very similar conclusions about shared pathologies, and because of that, the importance of overlap amongst complex medical conditions that historically have really been poorly addressed.”

She added, “mast cell activation, or mast cell hyperactivity, is one part of the greater picture. What’s important about the mast cell component is that of the multiple different targetable pathologies, it’s one that currently has potential available therapies that can be explored, some of them relatively easily.”

But Christopher Chang, MD, PhD, chief of the Pediatric Allergy and Immunology program, Joe DiMaggio Children’s Hospital, Hollywood, Florida, sees it differently. In an interview, he noted that the reason for disagreement over what constitutes MCAS is that “it doesn’t have a lot of objective findings that we can identify. ... We know that mast cells are important immune cells, just like all immune cells are important. It seems like whenever someone has unexplained symptoms, people try to blame it on mast cells. But it’s very hard to prove that.” 
 

Two Definitions Characterize the Illness Differently

One proposed “consensus” MCAS definition was first published in 2011 by a group led by hematologist Peter Valent, MD, of the Medical University of Vienna in Austria. It has been revised since, and similar versions adopted by medical societies, including the American Academy of Allergy, Asthma & Immunology (AAAAI). The most recent versions propose three core MCAS criteria: 

• Typical clinical signs of severe, recurrent (episodic) systemic (at least two organ systems) MCA are present (often in the form of anaphylaxis).
• The involvement of mast cells (MCs) is documented by biochemical studies, preferably an increase in serum tryptase levels from the individual’s baseline to plus 20% + 2 ng/mL.
• Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production, or drugs blocking mediator release or effects of MC-derived mediators.

The following year, a separate publication authored by Gerhard J. Molderings, MD, University of Bonn in Germany, and colleagues proposed a much broader MCAS definition. Also revised since, the latest “consensus-2” was published in 2020. This definition consists of one major criterion: “A constellation of clinical complaints attributable to pathologically increased MC activity, ie, MC mediator release syndrome.” This “constellation” involves conditions of nearly every organ system that, taken together, are estimated to affect up to 17% of the entire population. These are just a few examples: 

• Constitutional: Chronic fatigue, flushing, or sweats
• Dermatologic: Rashes or lesions
• Ophthalmologic: dry eyes
• Oral: Burning or itching in mouth
• Pulmonary: Airway inflammation at any/all levels
• Cardiovascular: Blood pressure lability or codiagnosis of POTS is common
• Gastrointestinal: Reflux, dysphagia, or malabsorption
• Genitourinary: Endometriosis, dysmenorrhea, or dyspareunia
• Musculoskeletal/connective tissue: Fibromyalgia or diagnosis of hypermobile EDS is common
• Neurologic: Headaches or sensory neuropathies
• Psychiatric: Depression or anxiety
• Endocrinologic: Thyroid disease or dyslipidemia
• Hematologic: Polycythemia or anemia (after ruling out other causes)

The diagnosis is made by fulfilling that major criterion, plus at least one objective assessment of pathologically increased release of MC mediators, including infiltrates, abnormal MC morphology, or MC genetic changes shown to increase MC activity. Other alternatives include evidence of above-normal levels of MC mediators, including tryptase, histamine or its metabolites, heparin, or chromatin A, in whole blood, serum, plasma, or urine. Symptomatic response to MC activation inhibitors can also be used but isn’t required as it is in the other definition. 
 

Underdiagnosis vs Overdiagnosis

Lawrence B. Afrin, MD, senior consultant in hematology/oncology at the AIM Center for Personalized Medicine, Westchester, New York, and lead author of the 2020 update of the broader “consensus-2” criteria, said in an interview, “we now know MCAS exists, and it’s prevalent, even though, for understandable and forgivable reasons, we’ve been missing it all along. ... If you see a patient who has this chronic, multisystem unwellness with general themes of inflammation plus or minus allergic issues and you can’t find some other rational explanation that better accounts for what’s going on ... then it’s reasonable to think to include MCAS in the differential diagnosis. If the patient happens not to fit the diagnostic criteria being advanced by one group, that doesn’t necessarily rule out the possibility that this is still going on.”

Afrin, along with his coauthors, faulted the narrower “consensus-1” definition for lacking data to support the “20% + 2” criteria for requiring the difficult determination of a patient’s “baseline” and for requiring evidence of response to treatment prior to making the diagnosis. Not all patients will respond to a given histamine blocker, he noted. 

But Lawrence B. Schwartz, MD, PhD, an author on both the Valent and AAAAI criteria, disagreed, noting that the narrower criteria “appear to have a high degree of specificity and sensitivity when the reaction is systemic and involves hypotension. Less severe clinical events, particularly involving the gastrointestinal or central nervous systems, do not have precise clinical or biomarker criteria for identifying mast cell involvement.” 

Added Schwartz, who is professor of medicine and chair of the Division of Rheumatology, Allergy, and Immunology and program director of Allergy and Immunology, Virginia Commonwealth University (VCU), Richmond, “when mast cell activation events occur only in the skin, we refer to it as chronic urticaria and in the airways or conjunctiva of allergic individuals as allergic asthma, rhinitis, and/or conjunctivitis. The absence of specific criteria for mast cell activation in the GI [gastrointestinal] tract or CNS [central nervous system] neither rules in mast cell involvement nor does it rule out mast cell involvement. Thus, more research is needed to find better diagnostic criteria.”

Schwartz also pointed to a recent paper reporting the use of artificial intelligence models to “quantify diagnostic precision and specificity” of “alternative” MCAS definitions. The conclusion was a “lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.”

During the meeting, Afrin acknowledged that the broader view risks overdiagnosis of MCAS. However, he also referenced Occam’s razor, the principle that the simplest explanation is probably the best one. “Which scenario is more likely? Multiple diagnoses and problems that are all independent of each other vs one diagnosis that’s biologically capable of causing most or all of the findings, ie, the simplest solution even if it’s not the most immediately obvious solution?”

He said in an interview: “Do we have any proof that MCAS is what’s underlying hypermobile Ehlers-Danlos or POTS or chronic fatigue? No, we don’t have any proof, not because anybody has done studies that have shown there to be no connection but simply because we’re so early in our awareness that the disease even exists that the necessary studies haven’t even been done yet.”

At the meeting, Afrin introduced proposals to turn the “Masterminds” group into a formal professional society and to launch a journal. He also gave an update on progress in developing a symptom assessment tool both for clinical use and to enable clinical trials of new drugs to target mast cells or their mediators. The plan is to field test the tool in 2025 and publish those results in 2026. 

Grach, Afrin, and Chang had no disclosures. Schwartz discovered tryptase and invented the Thermo Fisher tryptase assay, for which his institution (VCU) receives royalties that are shared with him. He also invented monoclonal antibodies used for detecting mast cells or basophils, for which VCU receives royalties from several companies, including Millipore, Santa Cruz, BioLegend, and Hycult Biotech, that are also shared with him. He is a paid consultant for Blueprint Medicines, Celldex Therapeutics, Invea, Third Harmonic Bio, HYCOR Biomedical, Jasper, TerSera Therapeutics, and GLG. He also serves on an AstraZeneca data safety monitoring board for a clinical trial involving benralizumab treatment of hypereosinophilic syndrome and receives royalties from UpToDate (biomarkers for anaphylaxis) and Goldman-Cecil Medicine (anaphylaxis).

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

SAN DIEGO — Chimeric antigen receptor (CAR) T-cell therapies offer the tantalizing prospect of dramatically altering the outcome of lung cancers, but there are many hurdles to treating patients with them, according to experts.

These hurdles include finding the right targets, minimizing the risks of the treatment, and reducing the enormous burdens getting these therapies places on patients.

“Precision immunotherapy,” or unleashing the immune system in a highly specific manner, “is obviously, in a way, a holy grail” in lung cancer, said Martin Forster, MD, PhD, who cochaired a session on the topic at the World Conference on Lung Cancer (WCLC) 2024.

He underlined, however, that “immunology is very complex, as is cancer biology,” and consequently, there are different avenues being explored, including CAR T-cell therapies, T-cell receptor therapies, and tumor-infiltrating lymphocytes, among others.

Antibody technology is also being harnessed to target chemotherapy, via antibody-drug conjugates, noted Forster, who is clinical lead of the early phase clinical trials programme at University College London in England.

Moreover, investigators are looking at combining various therapies, such as immune checkpoint inhibitors with T cell–engaging approaches.

He highlighted, however, that the ideal target for these approaches is something that is recognized by the immune system as being foreign, but is found within the cancer, “and you also want it ideally to be in all of the cancer cells.”

A good example is a clonal change, meaning an early evolutionary genetic alteration in the tumor that is present in all the cells, Forster said.
 

Identifying the Right Target

“One of the big challenges in all forms of targeted immunotherapy is around selecting the target and developing the right product for the right target,” Forster emphasized.

“This concept works really well in hematological malignancies” but is “proving to be more challenging to deliver within solid malignancies,” he added.

“The reason why so many lung tumors are resistant to immunotherapy is because they ‘re immunologically cold,” Roy Herbst, MD, PhD, Department of Medical Oncology, Yale Comprehensive Cancer Center, New Haven, Connecticut, said in an interview.

“There are no T cells in the tumor,” he explained, so it “doesn’t really matter how much you block checkpoint inhibitors, you still have to have a T cell in there in order to have effect.”

To overcome this problem CAR T-cell therapies are engineered to target a tumor, Herbst continued, but that “is a little hard in lung cancer because you need to have a unique antigen that’s on a lung tumor that’s not present on normal cells.”

Charu Aggarwal, MD, MPH, Leslye M. Heisler Associate Professor for Lung Cancer Excellence, Penn Medicine, Philadelphia, Pennsylvania, agreed, saying that there is “a lot of excitement with CAR T-cell therapies, and the promise of cure,” but “the biology is not as simple as we think.”

“For example, it’s not as simple as CD20 or CD19 targeting,” she said in an interview. “Most of the antigens that are being targeted in the solid tumor world, unfortunately, are also expressed on normal tissue. So there is always this potential for toxicity.”
 

A Question of Time

Another aspect of CAR T-cell therapy that is proving difficult is its delivery.

Forster outlined that the process involves first leukapheresis, in which T cells are obtained from a blood draw. These are then genetically modified to express chimeric antigen receptors before being multiplied in the laboratory and introduced to the patient.

This process can take several weeks, during which patients may require bridging treatment, such as chemotherapy or radiotherapy, to keep their cancer under control. “Sometimes, patients with solid tumors who are in later lines of therapy may not have the luxury of time to be able to wait for all of these steps,” Aggarwal said.

There is also the question of whether a bespoke treatment can be scaled up so that it can be delivered to more patients in a more timely manner.

“There are certainly lessons to be learned from use of off-the-shelf CAR T-cell products” in hematologic malignancies, she noted, “but we’re just not there yet in lung cancer.”
 

Life-Threatening Toxicities

To improve the chances of engraftment when the CAR T cells are introduced, patients will require prior lymphodepletion with chemotherapy.

This, Forster said, is a “relatively intensive part of treatment.” However, “if you just give immune cells to somebody, when the host body is already full of immune cells,” the CAR T cells are unlikely to engraft, and “so you need to create space for those cells to develop.”

“What you want is not an immediate effect” but rather an immune “memory” that will give an ongoing benefit, he underscored.

Many patients will need to stay in the hospital one or more nights “because when you bring T cells to a tumor, you get cytokine release syndrome [CRS],” Herbst said. This can cause hypotension, fever, and chills, similar to a viral response.

“So patients can get sick,” which in turn requires treatment and follow-up. That puts a “big burden on the health system” and is a major issue, Herbst said.

Patients are also at a risk for “significant neurotoxicity,” said session cochair Amy Moore, PhD, vice president of Global Engagement and Patient Partnerships, LUNGevity Foundation, Chicago. This, alongside CRS, “can be life threatening for our patients.”

Lengthy hospital stays also have a psychosocial impact on the patient and their quality of life, she emphasized, especially when they are treated in a center far away from family and loved ones.

“We’ve also heard anecdotally some reports recently of secondary malignancies” with CAR T cell and other therapies, and that’s something that needs to be monitored as more patients go on these treatments, she said.
 

‘At What Cost’ to Patients?

The difficulties faced by patients in receiving CAR T-cell therapy go far beyond the practicalities of generating the cells or the risks associated with lymphodepletion, however.

“These therapies are extraordinarily expensive,” although that has to be weighed against the cost of years of ongoing treatment with immunotherapy, Moore said.

Moreover, as CAR T-cell therapies are a “last resort” option, patients have to “exhaust all other treatments” before being eligible, she continued. There’s significant prior authorization challenges, which means patients “have to go through many hurdles before they can qualify for treatment with these therapies.”

This typically involves having numerous laboratory tests, which can add up to out-of-pocket expenses for patients often reaching tens of thousands of dollars, Moore said.

Another issue is that they must be administered in certified treatment centers, and there are a limited number of those in the United States, she added.

This increases the risk of heightening disparities, as patients are “forced to travel, seek lodging, and have meal expenses,” and the costs “are not trivial,” Moore underlined. “It can rack up quickly and mount to $10,000 or more.”

For physicians, there are difficulties in terms of the logistics of following up with those patients who need to be treated at centers on the other side of the country, uncertainties around reimbursement, and restrictions in terms of staff time and resources, among others.

“I’m as excited as you are at the science,” but it is the implementation that is at issue, Moore said. In other words, there is the offer of a cure with CAR T-cell therapy, but “at what cost?”

“For patients, these considerations are real and they’re significant” and “we have to ensure that what we’re doing is in service of people with cancer,” she emphasized.

No funding was declared. Aggarwal declared relationships with Genentech, Celgene, AstraZeneca, Daiichi Sankyo, Turning Point, Janssen, Pfizer, Lilly, Merck, Regeneron/Sanofi, Eisai, BeiGene, Boehringer Ingelheim, Blueprint Genetics, and Shionogi. Forster declared relationships with AstraZeneca, Boehringer Ingelheim, Merck, MSD, Achilles, Amgen, Bayer, Bristol-Myers Squibb, Celgene, EQRx, GSK, Immutep, Janssen, Merck, Oxford Vacmedix, PharmaMar, Roche, Takeda, Syncorp, Transgene, and Ultrahuman. Moore declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

SAN DIEGO — Chimeric antigen receptor (CAR) T-cell therapies offer the tantalizing prospect of dramatically altering the outcome of lung cancers, but there are many hurdles to treating patients with them, according to experts.

These hurdles include finding the right targets, minimizing the risks of the treatment, and reducing the enormous burdens getting these therapies places on patients.

“Precision immunotherapy,” or unleashing the immune system in a highly specific manner, “is obviously, in a way, a holy grail” in lung cancer, said Martin Forster, MD, PhD, who cochaired a session on the topic at the World Conference on Lung Cancer (WCLC) 2024.

He underlined, however, that “immunology is very complex, as is cancer biology,” and consequently, there are different avenues being explored, including CAR T-cell therapies, T-cell receptor therapies, and tumor-infiltrating lymphocytes, among others.

Antibody technology is also being harnessed to target chemotherapy, via antibody-drug conjugates, noted Forster, who is clinical lead of the early phase clinical trials programme at University College London in England.

Moreover, investigators are looking at combining various therapies, such as immune checkpoint inhibitors with T cell–engaging approaches.

He highlighted, however, that the ideal target for these approaches is something that is recognized by the immune system as being foreign, but is found within the cancer, “and you also want it ideally to be in all of the cancer cells.”

A good example is a clonal change, meaning an early evolutionary genetic alteration in the tumor that is present in all the cells, Forster said.
 

Identifying the Right Target

“One of the big challenges in all forms of targeted immunotherapy is around selecting the target and developing the right product for the right target,” Forster emphasized.

“This concept works really well in hematological malignancies” but is “proving to be more challenging to deliver within solid malignancies,” he added.

“The reason why so many lung tumors are resistant to immunotherapy is because they ‘re immunologically cold,” Roy Herbst, MD, PhD, Department of Medical Oncology, Yale Comprehensive Cancer Center, New Haven, Connecticut, said in an interview.

“There are no T cells in the tumor,” he explained, so it “doesn’t really matter how much you block checkpoint inhibitors, you still have to have a T cell in there in order to have effect.”

To overcome this problem CAR T-cell therapies are engineered to target a tumor, Herbst continued, but that “is a little hard in lung cancer because you need to have a unique antigen that’s on a lung tumor that’s not present on normal cells.”

Charu Aggarwal, MD, MPH, Leslye M. Heisler Associate Professor for Lung Cancer Excellence, Penn Medicine, Philadelphia, Pennsylvania, agreed, saying that there is “a lot of excitement with CAR T-cell therapies, and the promise of cure,” but “the biology is not as simple as we think.”

“For example, it’s not as simple as CD20 or CD19 targeting,” she said in an interview. “Most of the antigens that are being targeted in the solid tumor world, unfortunately, are also expressed on normal tissue. So there is always this potential for toxicity.”
 

A Question of Time

Another aspect of CAR T-cell therapy that is proving difficult is its delivery.

Forster outlined that the process involves first leukapheresis, in which T cells are obtained from a blood draw. These are then genetically modified to express chimeric antigen receptors before being multiplied in the laboratory and introduced to the patient.

This process can take several weeks, during which patients may require bridging treatment, such as chemotherapy or radiotherapy, to keep their cancer under control. “Sometimes, patients with solid tumors who are in later lines of therapy may not have the luxury of time to be able to wait for all of these steps,” Aggarwal said.

There is also the question of whether a bespoke treatment can be scaled up so that it can be delivered to more patients in a more timely manner.

“There are certainly lessons to be learned from use of off-the-shelf CAR T-cell products” in hematologic malignancies, she noted, “but we’re just not there yet in lung cancer.”
 

Life-Threatening Toxicities

To improve the chances of engraftment when the CAR T cells are introduced, patients will require prior lymphodepletion with chemotherapy.

This, Forster said, is a “relatively intensive part of treatment.” However, “if you just give immune cells to somebody, when the host body is already full of immune cells,” the CAR T cells are unlikely to engraft, and “so you need to create space for those cells to develop.”

“What you want is not an immediate effect” but rather an immune “memory” that will give an ongoing benefit, he underscored.

Many patients will need to stay in the hospital one or more nights “because when you bring T cells to a tumor, you get cytokine release syndrome [CRS],” Herbst said. This can cause hypotension, fever, and chills, similar to a viral response.

“So patients can get sick,” which in turn requires treatment and follow-up. That puts a “big burden on the health system” and is a major issue, Herbst said.

Patients are also at a risk for “significant neurotoxicity,” said session cochair Amy Moore, PhD, vice president of Global Engagement and Patient Partnerships, LUNGevity Foundation, Chicago. This, alongside CRS, “can be life threatening for our patients.”

Lengthy hospital stays also have a psychosocial impact on the patient and their quality of life, she emphasized, especially when they are treated in a center far away from family and loved ones.

“We’ve also heard anecdotally some reports recently of secondary malignancies” with CAR T cell and other therapies, and that’s something that needs to be monitored as more patients go on these treatments, she said.
 

‘At What Cost’ to Patients?

The difficulties faced by patients in receiving CAR T-cell therapy go far beyond the practicalities of generating the cells or the risks associated with lymphodepletion, however.

“These therapies are extraordinarily expensive,” although that has to be weighed against the cost of years of ongoing treatment with immunotherapy, Moore said.

Moreover, as CAR T-cell therapies are a “last resort” option, patients have to “exhaust all other treatments” before being eligible, she continued. There’s significant prior authorization challenges, which means patients “have to go through many hurdles before they can qualify for treatment with these therapies.”

This typically involves having numerous laboratory tests, which can add up to out-of-pocket expenses for patients often reaching tens of thousands of dollars, Moore said.

Another issue is that they must be administered in certified treatment centers, and there are a limited number of those in the United States, she added.

This increases the risk of heightening disparities, as patients are “forced to travel, seek lodging, and have meal expenses,” and the costs “are not trivial,” Moore underlined. “It can rack up quickly and mount to $10,000 or more.”

For physicians, there are difficulties in terms of the logistics of following up with those patients who need to be treated at centers on the other side of the country, uncertainties around reimbursement, and restrictions in terms of staff time and resources, among others.

“I’m as excited as you are at the science,” but it is the implementation that is at issue, Moore said. In other words, there is the offer of a cure with CAR T-cell therapy, but “at what cost?”

“For patients, these considerations are real and they’re significant” and “we have to ensure that what we’re doing is in service of people with cancer,” she emphasized.

No funding was declared. Aggarwal declared relationships with Genentech, Celgene, AstraZeneca, Daiichi Sankyo, Turning Point, Janssen, Pfizer, Lilly, Merck, Regeneron/Sanofi, Eisai, BeiGene, Boehringer Ingelheim, Blueprint Genetics, and Shionogi. Forster declared relationships with AstraZeneca, Boehringer Ingelheim, Merck, MSD, Achilles, Amgen, Bayer, Bristol-Myers Squibb, Celgene, EQRx, GSK, Immutep, Janssen, Merck, Oxford Vacmedix, PharmaMar, Roche, Takeda, Syncorp, Transgene, and Ultrahuman. Moore declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

SAN DIEGO — Chimeric antigen receptor (CAR) T-cell therapies offer the tantalizing prospect of dramatically altering the outcome of lung cancers, but there are many hurdles to treating patients with them, according to experts.

These hurdles include finding the right targets, minimizing the risks of the treatment, and reducing the enormous burdens getting these therapies places on patients.

“Precision immunotherapy,” or unleashing the immune system in a highly specific manner, “is obviously, in a way, a holy grail” in lung cancer, said Martin Forster, MD, PhD, who cochaired a session on the topic at the World Conference on Lung Cancer (WCLC) 2024.

He underlined, however, that “immunology is very complex, as is cancer biology,” and consequently, there are different avenues being explored, including CAR T-cell therapies, T-cell receptor therapies, and tumor-infiltrating lymphocytes, among others.

Antibody technology is also being harnessed to target chemotherapy, via antibody-drug conjugates, noted Forster, who is clinical lead of the early phase clinical trials programme at University College London in England.

Moreover, investigators are looking at combining various therapies, such as immune checkpoint inhibitors with T cell–engaging approaches.

He highlighted, however, that the ideal target for these approaches is something that is recognized by the immune system as being foreign, but is found within the cancer, “and you also want it ideally to be in all of the cancer cells.”

A good example is a clonal change, meaning an early evolutionary genetic alteration in the tumor that is present in all the cells, Forster said.
 

Identifying the Right Target

“One of the big challenges in all forms of targeted immunotherapy is around selecting the target and developing the right product for the right target,” Forster emphasized.

“This concept works really well in hematological malignancies” but is “proving to be more challenging to deliver within solid malignancies,” he added.

“The reason why so many lung tumors are resistant to immunotherapy is because they ‘re immunologically cold,” Roy Herbst, MD, PhD, Department of Medical Oncology, Yale Comprehensive Cancer Center, New Haven, Connecticut, said in an interview.

“There are no T cells in the tumor,” he explained, so it “doesn’t really matter how much you block checkpoint inhibitors, you still have to have a T cell in there in order to have effect.”

To overcome this problem CAR T-cell therapies are engineered to target a tumor, Herbst continued, but that “is a little hard in lung cancer because you need to have a unique antigen that’s on a lung tumor that’s not present on normal cells.”

Charu Aggarwal, MD, MPH, Leslye M. Heisler Associate Professor for Lung Cancer Excellence, Penn Medicine, Philadelphia, Pennsylvania, agreed, saying that there is “a lot of excitement with CAR T-cell therapies, and the promise of cure,” but “the biology is not as simple as we think.”

“For example, it’s not as simple as CD20 or CD19 targeting,” she said in an interview. “Most of the antigens that are being targeted in the solid tumor world, unfortunately, are also expressed on normal tissue. So there is always this potential for toxicity.”
 

A Question of Time

Another aspect of CAR T-cell therapy that is proving difficult is its delivery.

Forster outlined that the process involves first leukapheresis, in which T cells are obtained from a blood draw. These are then genetically modified to express chimeric antigen receptors before being multiplied in the laboratory and introduced to the patient.

This process can take several weeks, during which patients may require bridging treatment, such as chemotherapy or radiotherapy, to keep their cancer under control. “Sometimes, patients with solid tumors who are in later lines of therapy may not have the luxury of time to be able to wait for all of these steps,” Aggarwal said.

There is also the question of whether a bespoke treatment can be scaled up so that it can be delivered to more patients in a more timely manner.

“There are certainly lessons to be learned from use of off-the-shelf CAR T-cell products” in hematologic malignancies, she noted, “but we’re just not there yet in lung cancer.”
 

Life-Threatening Toxicities

To improve the chances of engraftment when the CAR T cells are introduced, patients will require prior lymphodepletion with chemotherapy.

This, Forster said, is a “relatively intensive part of treatment.” However, “if you just give immune cells to somebody, when the host body is already full of immune cells,” the CAR T cells are unlikely to engraft, and “so you need to create space for those cells to develop.”

“What you want is not an immediate effect” but rather an immune “memory” that will give an ongoing benefit, he underscored.

Many patients will need to stay in the hospital one or more nights “because when you bring T cells to a tumor, you get cytokine release syndrome [CRS],” Herbst said. This can cause hypotension, fever, and chills, similar to a viral response.

“So patients can get sick,” which in turn requires treatment and follow-up. That puts a “big burden on the health system” and is a major issue, Herbst said.

Patients are also at a risk for “significant neurotoxicity,” said session cochair Amy Moore, PhD, vice president of Global Engagement and Patient Partnerships, LUNGevity Foundation, Chicago. This, alongside CRS, “can be life threatening for our patients.”

Lengthy hospital stays also have a psychosocial impact on the patient and their quality of life, she emphasized, especially when they are treated in a center far away from family and loved ones.

“We’ve also heard anecdotally some reports recently of secondary malignancies” with CAR T cell and other therapies, and that’s something that needs to be monitored as more patients go on these treatments, she said.
 

‘At What Cost’ to Patients?

The difficulties faced by patients in receiving CAR T-cell therapy go far beyond the practicalities of generating the cells or the risks associated with lymphodepletion, however.

“These therapies are extraordinarily expensive,” although that has to be weighed against the cost of years of ongoing treatment with immunotherapy, Moore said.

Moreover, as CAR T-cell therapies are a “last resort” option, patients have to “exhaust all other treatments” before being eligible, she continued. There’s significant prior authorization challenges, which means patients “have to go through many hurdles before they can qualify for treatment with these therapies.”

This typically involves having numerous laboratory tests, which can add up to out-of-pocket expenses for patients often reaching tens of thousands of dollars, Moore said.

Another issue is that they must be administered in certified treatment centers, and there are a limited number of those in the United States, she added.

This increases the risk of heightening disparities, as patients are “forced to travel, seek lodging, and have meal expenses,” and the costs “are not trivial,” Moore underlined. “It can rack up quickly and mount to $10,000 or more.”

For physicians, there are difficulties in terms of the logistics of following up with those patients who need to be treated at centers on the other side of the country, uncertainties around reimbursement, and restrictions in terms of staff time and resources, among others.

“I’m as excited as you are at the science,” but it is the implementation that is at issue, Moore said. In other words, there is the offer of a cure with CAR T-cell therapy, but “at what cost?”

“For patients, these considerations are real and they’re significant” and “we have to ensure that what we’re doing is in service of people with cancer,” she emphasized.

No funding was declared. Aggarwal declared relationships with Genentech, Celgene, AstraZeneca, Daiichi Sankyo, Turning Point, Janssen, Pfizer, Lilly, Merck, Regeneron/Sanofi, Eisai, BeiGene, Boehringer Ingelheim, Blueprint Genetics, and Shionogi. Forster declared relationships with AstraZeneca, Boehringer Ingelheim, Merck, MSD, Achilles, Amgen, Bayer, Bristol-Myers Squibb, Celgene, EQRx, GSK, Immutep, Janssen, Merck, Oxford Vacmedix, PharmaMar, Roche, Takeda, Syncorp, Transgene, and Ultrahuman. Moore declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

VIENNA — Artificial Intelligence (AI) can assist doctors in assessing and diagnosing respiratory illnesses in infants and children, according to two new studies presented at the European Respiratory Society (ERS) 2024 Congress.

Researchers can train artificial neural networks (ANNs) to detect lung disease in premature babies by analyzing their breathing patterns while they sleep. “Our noninvasive test is less distressing for the baby and their parents, meaning they can access treatment more quickly, and may also be relevant for their long-term prognosis,” said Edgar Delgado-Eckert, PhD, adjunct professor in the Department of Biomedical Engineering at The University of Basel, Switzerland, and a research group leader at the University Children’s Hospital, Switzerland.

Manjith Narayanan, MD, a consultant in pediatric pulmonology at the Royal Hospital for Children and Young People, Edinburgh, and honorary senior clinical lecturer at The University of Edinburgh, United Kingdom, said chatbots such as ChatGPT, Bard, and Bing can perform as well as or better than trainee doctors when assessing children with respiratory issues. He said chatbots could triage patients more quickly and ease pressure on health services.
 

Chatbots Show Promise in Triage of Pediatric Respiratory Illnesses

Researchers at The University of Edinburgh provided 10 trainee doctors with less than 4 months of clinical experience in pediatrics with clinical scenarios that covered topics such as cystic fibrosis, asthma, sleep-disordered breathing, breathlessness, chest infections, or no obvious diagnosis. 

The trainee doctors had 1 hour to use the internet, although they were not allowed to use chatbots to solve each scenario with a descriptive answer. 

Each scenario was also presented to the three large language models (LLMs): OpenAI’s ChatGPT, Google’s Bard, and Microsoft’s Bing.

Six pediatric respiratory experts assessed all responses, scoring correctness, comprehensiveness, usefulness, plausibility, and coherence on a scale of 0-9. They were also asked to say whether they thought a human or a chatbot generated each response.

ChatGPT scored an average of 7 out of 9 overall and was believed to be more human-like than responses from the other chatbots. Bard scored an average of 6 out of 9 and was more “coherent” than trainee doctors, but in other respects, it was no better or worse than trainee doctors. Bing and trainee doctors scored an average of 4 out of 9. The six pediatricians reliably identified Bing and Bard’s responses as nonhuman.

“Our study is the first, to our knowledge, to test LLMs against trainee doctors in situations that reflect real-life clinical practice,” Narayanan said. “We did this by allowing the trainee doctors to have full access to resources available on the internet, as they would in real life. This moves the focus away from testing memory, where LLMs have a clear advantage.”

Narayanan said that these models could help nurses, trainee doctors, and primary care physicians triage patients quickly and assist medical professionals in their studies by summarizing their thought processes. “The key word, though, is “assist.” They cannot replace conventional medical training yet,” he told Medscape Medical News. 

The researchers found no obvious hallucinations — seemingly made-up information — with any of the three LLMs. Still, Narayanan said, “We need to be aware of this possibility and build mitigations.”

Hilary Pinnock, ERS education council chair and professor of primary care respiratory medicine at The University of Edinburgh who was not involved in the research, said seeing how widely available AI tools can provide solutions to complex cases of respiratory illness in children is exciting and worrying at the same time. “It certainly points the way to a brave new world of AI-supported care.” 

“However, before we start to use AI in routine clinical practice, we need to be confident that it will not create errors either through ‘hallucinating’ fake information or because it has been trained on data that does not equitably represent the population we serve,” she said.
 

AI Predicts Lung Disease in Premature Babies

Identifying bronchopulmonary dysplasia (BPD) in premature babies remains a challenge. Lung function tests usually require blowing out on request, which is a task babies cannot perform. Current techniques require sophisticated equipment to measure an infant’s lung ventilation characteristics, so doctors usually diagnose BPD by the presence of its leading causes, prematurity and the need for respiratory support.

Researchers at the University of Basel in Switzerland trained an ANN model to predict BPD in premature babies.

The team studied a group of 139 full-term and 190 premature infants who had been assessed for BPD, recording their breathing for 10 minutes while they slept. For each baby, 100 consecutive regular breaths, carefully inspected to exclude sighs or other artifacts, were used to train, validate, and test an ANN called a Long Short-Term Memory model (LSTM), which is particularly effective at classifying sequential data such as tidal breathing.

Researchers used 60% of the data to teach the network how to recognize BPD, 20% to validate the model, and then fed the remaining 20% of the data to the model to see if it could correctly identify those babies with BPD.

The LSTM model classified a series of flow values in the unseen test data set as belonging to a patient diagnosed with BPD or not with 96% accuracy.

“Until recently, this need for large amounts of data has hindered efforts to create accurate models for lung disease in infants because it is so difficult to assess their lung function,” Delgado-Eckert said. “Our research delivers, for the first time, a comprehensive way of analyzing infants’ breathing and allows us to detect which babies have BPD as early as 1 month of corrected age.”

The study presented by Delgado-Eckert received funding from the Swiss National Science Foundation. Narayanan and Pinnock reported no relevant financial relationships. 
 

A version of this article appeared on Medscape.com.

VIENNA — Artificial Intelligence (AI) can assist doctors in assessing and diagnosing respiratory illnesses in infants and children, according to two new studies presented at the European Respiratory Society (ERS) 2024 Congress.

Researchers can train artificial neural networks (ANNs) to detect lung disease in premature babies by analyzing their breathing patterns while they sleep. “Our noninvasive test is less distressing for the baby and their parents, meaning they can access treatment more quickly, and may also be relevant for their long-term prognosis,” said Edgar Delgado-Eckert, PhD, adjunct professor in the Department of Biomedical Engineering at The University of Basel, Switzerland, and a research group leader at the University Children’s Hospital, Switzerland.

Manjith Narayanan, MD, a consultant in pediatric pulmonology at the Royal Hospital for Children and Young People, Edinburgh, and honorary senior clinical lecturer at The University of Edinburgh, United Kingdom, said chatbots such as ChatGPT, Bard, and Bing can perform as well as or better than trainee doctors when assessing children with respiratory issues. He said chatbots could triage patients more quickly and ease pressure on health services.
 

Chatbots Show Promise in Triage of Pediatric Respiratory Illnesses

Researchers at The University of Edinburgh provided 10 trainee doctors with less than 4 months of clinical experience in pediatrics with clinical scenarios that covered topics such as cystic fibrosis, asthma, sleep-disordered breathing, breathlessness, chest infections, or no obvious diagnosis. 

The trainee doctors had 1 hour to use the internet, although they were not allowed to use chatbots to solve each scenario with a descriptive answer. 

Each scenario was also presented to the three large language models (LLMs): OpenAI’s ChatGPT, Google’s Bard, and Microsoft’s Bing.

Six pediatric respiratory experts assessed all responses, scoring correctness, comprehensiveness, usefulness, plausibility, and coherence on a scale of 0-9. They were also asked to say whether they thought a human or a chatbot generated each response.

ChatGPT scored an average of 7 out of 9 overall and was believed to be more human-like than responses from the other chatbots. Bard scored an average of 6 out of 9 and was more “coherent” than trainee doctors, but in other respects, it was no better or worse than trainee doctors. Bing and trainee doctors scored an average of 4 out of 9. The six pediatricians reliably identified Bing and Bard’s responses as nonhuman.

“Our study is the first, to our knowledge, to test LLMs against trainee doctors in situations that reflect real-life clinical practice,” Narayanan said. “We did this by allowing the trainee doctors to have full access to resources available on the internet, as they would in real life. This moves the focus away from testing memory, where LLMs have a clear advantage.”

Narayanan said that these models could help nurses, trainee doctors, and primary care physicians triage patients quickly and assist medical professionals in their studies by summarizing their thought processes. “The key word, though, is “assist.” They cannot replace conventional medical training yet,” he told Medscape Medical News. 

The researchers found no obvious hallucinations — seemingly made-up information — with any of the three LLMs. Still, Narayanan said, “We need to be aware of this possibility and build mitigations.”

Hilary Pinnock, ERS education council chair and professor of primary care respiratory medicine at The University of Edinburgh who was not involved in the research, said seeing how widely available AI tools can provide solutions to complex cases of respiratory illness in children is exciting and worrying at the same time. “It certainly points the way to a brave new world of AI-supported care.” 

“However, before we start to use AI in routine clinical practice, we need to be confident that it will not create errors either through ‘hallucinating’ fake information or because it has been trained on data that does not equitably represent the population we serve,” she said.
 

AI Predicts Lung Disease in Premature Babies

Identifying bronchopulmonary dysplasia (BPD) in premature babies remains a challenge. Lung function tests usually require blowing out on request, which is a task babies cannot perform. Current techniques require sophisticated equipment to measure an infant’s lung ventilation characteristics, so doctors usually diagnose BPD by the presence of its leading causes, prematurity and the need for respiratory support.

Researchers at the University of Basel in Switzerland trained an ANN model to predict BPD in premature babies.

The team studied a group of 139 full-term and 190 premature infants who had been assessed for BPD, recording their breathing for 10 minutes while they slept. For each baby, 100 consecutive regular breaths, carefully inspected to exclude sighs or other artifacts, were used to train, validate, and test an ANN called a Long Short-Term Memory model (LSTM), which is particularly effective at classifying sequential data such as tidal breathing.

Researchers used 60% of the data to teach the network how to recognize BPD, 20% to validate the model, and then fed the remaining 20% of the data to the model to see if it could correctly identify those babies with BPD.

The LSTM model classified a series of flow values in the unseen test data set as belonging to a patient diagnosed with BPD or not with 96% accuracy.

“Until recently, this need for large amounts of data has hindered efforts to create accurate models for lung disease in infants because it is so difficult to assess their lung function,” Delgado-Eckert said. “Our research delivers, for the first time, a comprehensive way of analyzing infants’ breathing and allows us to detect which babies have BPD as early as 1 month of corrected age.”

The study presented by Delgado-Eckert received funding from the Swiss National Science Foundation. Narayanan and Pinnock reported no relevant financial relationships. 
 

A version of this article appeared on Medscape.com.

VIENNA — Artificial Intelligence (AI) can assist doctors in assessing and diagnosing respiratory illnesses in infants and children, according to two new studies presented at the European Respiratory Society (ERS) 2024 Congress.

Researchers can train artificial neural networks (ANNs) to detect lung disease in premature babies by analyzing their breathing patterns while they sleep. “Our noninvasive test is less distressing for the baby and their parents, meaning they can access treatment more quickly, and may also be relevant for their long-term prognosis,” said Edgar Delgado-Eckert, PhD, adjunct professor in the Department of Biomedical Engineering at The University of Basel, Switzerland, and a research group leader at the University Children’s Hospital, Switzerland.

Manjith Narayanan, MD, a consultant in pediatric pulmonology at the Royal Hospital for Children and Young People, Edinburgh, and honorary senior clinical lecturer at The University of Edinburgh, United Kingdom, said chatbots such as ChatGPT, Bard, and Bing can perform as well as or better than trainee doctors when assessing children with respiratory issues. He said chatbots could triage patients more quickly and ease pressure on health services.
 

Chatbots Show Promise in Triage of Pediatric Respiratory Illnesses

Researchers at The University of Edinburgh provided 10 trainee doctors with less than 4 months of clinical experience in pediatrics with clinical scenarios that covered topics such as cystic fibrosis, asthma, sleep-disordered breathing, breathlessness, chest infections, or no obvious diagnosis. 

The trainee doctors had 1 hour to use the internet, although they were not allowed to use chatbots to solve each scenario with a descriptive answer. 

Each scenario was also presented to the three large language models (LLMs): OpenAI’s ChatGPT, Google’s Bard, and Microsoft’s Bing.

Six pediatric respiratory experts assessed all responses, scoring correctness, comprehensiveness, usefulness, plausibility, and coherence on a scale of 0-9. They were also asked to say whether they thought a human or a chatbot generated each response.

ChatGPT scored an average of 7 out of 9 overall and was believed to be more human-like than responses from the other chatbots. Bard scored an average of 6 out of 9 and was more “coherent” than trainee doctors, but in other respects, it was no better or worse than trainee doctors. Bing and trainee doctors scored an average of 4 out of 9. The six pediatricians reliably identified Bing and Bard’s responses as nonhuman.

“Our study is the first, to our knowledge, to test LLMs against trainee doctors in situations that reflect real-life clinical practice,” Narayanan said. “We did this by allowing the trainee doctors to have full access to resources available on the internet, as they would in real life. This moves the focus away from testing memory, where LLMs have a clear advantage.”

Narayanan said that these models could help nurses, trainee doctors, and primary care physicians triage patients quickly and assist medical professionals in their studies by summarizing their thought processes. “The key word, though, is “assist.” They cannot replace conventional medical training yet,” he told Medscape Medical News. 

The researchers found no obvious hallucinations — seemingly made-up information — with any of the three LLMs. Still, Narayanan said, “We need to be aware of this possibility and build mitigations.”

Hilary Pinnock, ERS education council chair and professor of primary care respiratory medicine at The University of Edinburgh who was not involved in the research, said seeing how widely available AI tools can provide solutions to complex cases of respiratory illness in children is exciting and worrying at the same time. “It certainly points the way to a brave new world of AI-supported care.” 

“However, before we start to use AI in routine clinical practice, we need to be confident that it will not create errors either through ‘hallucinating’ fake information or because it has been trained on data that does not equitably represent the population we serve,” she said.
 

AI Predicts Lung Disease in Premature Babies

Identifying bronchopulmonary dysplasia (BPD) in premature babies remains a challenge. Lung function tests usually require blowing out on request, which is a task babies cannot perform. Current techniques require sophisticated equipment to measure an infant’s lung ventilation characteristics, so doctors usually diagnose BPD by the presence of its leading causes, prematurity and the need for respiratory support.

Researchers at the University of Basel in Switzerland trained an ANN model to predict BPD in premature babies.

The team studied a group of 139 full-term and 190 premature infants who had been assessed for BPD, recording their breathing for 10 minutes while they slept. For each baby, 100 consecutive regular breaths, carefully inspected to exclude sighs or other artifacts, were used to train, validate, and test an ANN called a Long Short-Term Memory model (LSTM), which is particularly effective at classifying sequential data such as tidal breathing.

Researchers used 60% of the data to teach the network how to recognize BPD, 20% to validate the model, and then fed the remaining 20% of the data to the model to see if it could correctly identify those babies with BPD.

The LSTM model classified a series of flow values in the unseen test data set as belonging to a patient diagnosed with BPD or not with 96% accuracy.

“Until recently, this need for large amounts of data has hindered efforts to create accurate models for lung disease in infants because it is so difficult to assess their lung function,” Delgado-Eckert said. “Our research delivers, for the first time, a comprehensive way of analyzing infants’ breathing and allows us to detect which babies have BPD as early as 1 month of corrected age.”

The study presented by Delgado-Eckert received funding from the Swiss National Science Foundation. Narayanan and Pinnock reported no relevant financial relationships. 
 

A version of this article appeared on Medscape.com.

Higher concentrations of specific volatile organic compounds (VOCs) in daycare centers were significantly associated with an increased risk for wheezing in children who attended these centers, based on data from more than 500 children.

“There is an increasing concern about of the role of Indoor Air Quality (IAQ) in development of respiratory disorders like asthma, especially in children whose immune system is under development, and they are more vulnerable to the effects of poor air quality,” lead author Ioannis Sakellaris, PhD, of Université Paris-Saclay, Villejuif, France, said in an interview. However, the effects of specific pollutants on the health of young children in daycare settings has not been examined, he said. 

In a presentation at the European Respiratory Society Congress, Sakellaris reviewed data from the French CRESPI cohort study, an epidemiological study of the impact of exposures to disinfectants and cleaning products on workers and children in daycare centers in France.

The study population included 532 children (47.4% girls) with a mean age of 22.3 months (aged 3 months to 4 years) in 106 daycare centers. A total of 171 children reportedly experienced at least one episode of wheezing since birth. 

A total of 67 VOCs were measured during one day, and concentrations were studied in four categories based on quartiles. The researchers evaluated three child wheezing outcomes based on parental questionnaires: Ever wheeze since birth, recurrent wheeze (≥ 3 times since birth), and ever wheeze with inhaled corticosteroid use. The researchers adjusted for factors including child age and parental smoking status and education level.

Overall, ever wheezing was significantly associated with higher concentrations of 1,2,4-trimethylbenzene (odds ratio [OR] for Q4 vs Q1, 1.56; P = .08 for trend), 1-methoxy-2-propylacetate (OR, 1.62; P = .01), decamethylcyclopentasiloxane (OR, 2.12; P = .004), and methylisobutylcetone (OR, 1.85; P < .001).

The results emphasize the significant role of IAQ in respiratory health, said Sakellaris. “Further efforts to reduce pollutant concentrations and limit sources are needed,” he said. In addition, more studies on the combined effect of multiple VOCs are necessary for a deeper understanding of the complex relations between IAQ and children’s respiratory health, he said.
 

Pay Attention to Indoor Pollutants

“Since the COVID-19 pandemic, the use of cleaning products and disinfectants has exploded,” Alexander S. Rabin, MD, of the University of Michigan, Ann Arbor, Michigan, said in an interview. Although many of these cleaning agents contain chemicals, including VOCs, that are known respiratory irritants, little is known about the relationship between VOCs and children’s respiratory outcomes in daycare settings, said Rabin, who was not involved in the study.

“I was struck by the wide array of VOCs detected in daycare settings,” Rabin said. However, the relationship to childhood wheeze was not entirely surprising as the VOCs included the known irritants benzene and toluene, he added.

The results suggest that exposure to VOCs, not only in cleaning agents but also building materials and other consumer products in daycare settings, may be associated with an increased risk for wheeze in children, said Rabin. 

However, “it is important to know more about confounding variables, including concurrent rates of respiratory infection that are common among children,” said Rabin. “As the authors highlight, further work on the compound effects of multiple pollutants would be of interest. Lastly, it would be helpful to clearly identify the most common sources of VOCs that place children at greatest risk for wheeze, so that appropriate steps can be taken to mitigate risk,” he said.

The original CRESPI cohort study was supported by ANSES, ADEME, Fondation de France, and ARS Ile-de-France. Sakellaris and Rabin had no financial conflicts to disclose.
 

A version of this article appeared on Medscape.com.

Higher concentrations of specific volatile organic compounds (VOCs) in daycare centers were significantly associated with an increased risk for wheezing in children who attended these centers, based on data from more than 500 children.

“There is an increasing concern about of the role of Indoor Air Quality (IAQ) in development of respiratory disorders like asthma, especially in children whose immune system is under development, and they are more vulnerable to the effects of poor air quality,” lead author Ioannis Sakellaris, PhD, of Université Paris-Saclay, Villejuif, France, said in an interview. However, the effects of specific pollutants on the health of young children in daycare settings has not been examined, he said. 

In a presentation at the European Respiratory Society Congress, Sakellaris reviewed data from the French CRESPI cohort study, an epidemiological study of the impact of exposures to disinfectants and cleaning products on workers and children in daycare centers in France.

The study population included 532 children (47.4% girls) with a mean age of 22.3 months (aged 3 months to 4 years) in 106 daycare centers. A total of 171 children reportedly experienced at least one episode of wheezing since birth. 

A total of 67 VOCs were measured during one day, and concentrations were studied in four categories based on quartiles. The researchers evaluated three child wheezing outcomes based on parental questionnaires: Ever wheeze since birth, recurrent wheeze (≥ 3 times since birth), and ever wheeze with inhaled corticosteroid use. The researchers adjusted for factors including child age and parental smoking status and education level.

Overall, ever wheezing was significantly associated with higher concentrations of 1,2,4-trimethylbenzene (odds ratio [OR] for Q4 vs Q1, 1.56; P = .08 for trend), 1-methoxy-2-propylacetate (OR, 1.62; P = .01), decamethylcyclopentasiloxane (OR, 2.12; P = .004), and methylisobutylcetone (OR, 1.85; P < .001).

The results emphasize the significant role of IAQ in respiratory health, said Sakellaris. “Further efforts to reduce pollutant concentrations and limit sources are needed,” he said. In addition, more studies on the combined effect of multiple VOCs are necessary for a deeper understanding of the complex relations between IAQ and children’s respiratory health, he said.
 

Pay Attention to Indoor Pollutants

“Since the COVID-19 pandemic, the use of cleaning products and disinfectants has exploded,” Alexander S. Rabin, MD, of the University of Michigan, Ann Arbor, Michigan, said in an interview. Although many of these cleaning agents contain chemicals, including VOCs, that are known respiratory irritants, little is known about the relationship between VOCs and children’s respiratory outcomes in daycare settings, said Rabin, who was not involved in the study.

“I was struck by the wide array of VOCs detected in daycare settings,” Rabin said. However, the relationship to childhood wheeze was not entirely surprising as the VOCs included the known irritants benzene and toluene, he added.

The results suggest that exposure to VOCs, not only in cleaning agents but also building materials and other consumer products in daycare settings, may be associated with an increased risk for wheeze in children, said Rabin. 

However, “it is important to know more about confounding variables, including concurrent rates of respiratory infection that are common among children,” said Rabin. “As the authors highlight, further work on the compound effects of multiple pollutants would be of interest. Lastly, it would be helpful to clearly identify the most common sources of VOCs that place children at greatest risk for wheeze, so that appropriate steps can be taken to mitigate risk,” he said.

The original CRESPI cohort study was supported by ANSES, ADEME, Fondation de France, and ARS Ile-de-France. Sakellaris and Rabin had no financial conflicts to disclose.
 

A version of this article appeared on Medscape.com.

Higher concentrations of specific volatile organic compounds (VOCs) in daycare centers were significantly associated with an increased risk for wheezing in children who attended these centers, based on data from more than 500 children.

“There is an increasing concern about of the role of Indoor Air Quality (IAQ) in development of respiratory disorders like asthma, especially in children whose immune system is under development, and they are more vulnerable to the effects of poor air quality,” lead author Ioannis Sakellaris, PhD, of Université Paris-Saclay, Villejuif, France, said in an interview. However, the effects of specific pollutants on the health of young children in daycare settings has not been examined, he said. 

In a presentation at the European Respiratory Society Congress, Sakellaris reviewed data from the French CRESPI cohort study, an epidemiological study of the impact of exposures to disinfectants and cleaning products on workers and children in daycare centers in France.

The study population included 532 children (47.4% girls) with a mean age of 22.3 months (aged 3 months to 4 years) in 106 daycare centers. A total of 171 children reportedly experienced at least one episode of wheezing since birth. 

A total of 67 VOCs were measured during one day, and concentrations were studied in four categories based on quartiles. The researchers evaluated three child wheezing outcomes based on parental questionnaires: Ever wheeze since birth, recurrent wheeze (≥ 3 times since birth), and ever wheeze with inhaled corticosteroid use. The researchers adjusted for factors including child age and parental smoking status and education level.

Overall, ever wheezing was significantly associated with higher concentrations of 1,2,4-trimethylbenzene (odds ratio [OR] for Q4 vs Q1, 1.56; P = .08 for trend), 1-methoxy-2-propylacetate (OR, 1.62; P = .01), decamethylcyclopentasiloxane (OR, 2.12; P = .004), and methylisobutylcetone (OR, 1.85; P < .001).

The results emphasize the significant role of IAQ in respiratory health, said Sakellaris. “Further efforts to reduce pollutant concentrations and limit sources are needed,” he said. In addition, more studies on the combined effect of multiple VOCs are necessary for a deeper understanding of the complex relations between IAQ and children’s respiratory health, he said.
 

Pay Attention to Indoor Pollutants

“Since the COVID-19 pandemic, the use of cleaning products and disinfectants has exploded,” Alexander S. Rabin, MD, of the University of Michigan, Ann Arbor, Michigan, said in an interview. Although many of these cleaning agents contain chemicals, including VOCs, that are known respiratory irritants, little is known about the relationship between VOCs and children’s respiratory outcomes in daycare settings, said Rabin, who was not involved in the study.

“I was struck by the wide array of VOCs detected in daycare settings,” Rabin said. However, the relationship to childhood wheeze was not entirely surprising as the VOCs included the known irritants benzene and toluene, he added.

The results suggest that exposure to VOCs, not only in cleaning agents but also building materials and other consumer products in daycare settings, may be associated with an increased risk for wheeze in children, said Rabin. 

However, “it is important to know more about confounding variables, including concurrent rates of respiratory infection that are common among children,” said Rabin. “As the authors highlight, further work on the compound effects of multiple pollutants would be of interest. Lastly, it would be helpful to clearly identify the most common sources of VOCs that place children at greatest risk for wheeze, so that appropriate steps can be taken to mitigate risk,” he said.

The original CRESPI cohort study was supported by ANSES, ADEME, Fondation de France, and ARS Ile-de-France. Sakellaris and Rabin had no financial conflicts to disclose.
 

A version of this article appeared on Medscape.com.

BOSTON — With the remarkable advances made in therapy over the past decade, many patients with cystic fibrosis (CF) can expect to survive into their 50s and even well beyond. But as patients with CF live longer, they are increasingly likely to develop complications such as cardiovascular diseases (CVDs) that beset many older adults. And as evidence from a new study suggests, there is an increasing need for cardiovascular screening and specialized cardiac care for these patients.

Among more than 83,000 patients with CF hospitalized for any reason from 2016 through 2021, less than 1% of patients had a cardiac cause listed, but in unadjusted analyses, these patients had a more than twofold risk for in-hospital death than those with CF hospitalized for other causes, reported Adnan Bhat, MD, assistant professor of hospital medicine at the University of Florida, Gainesville.

Although the excess mortality was no longer statistically significant in analyses adjusted for potential confounding factors, the data highlight a trend that requires further exploration, he said during an oral abstract session at the annual meeting of the American College of Chest Physicians (CHEST).

“There’s a trend for people with cystic fibrosis admitted for cardiac causes to have a higher in-hospital mortality and increased rate of discharge to nursing facilities, especially for patients admitted for heart failure. The clinical implication is that there is an increased need to start screening for cardiovascular risk factors,” he said.
 

National Database Sample

Bhat and colleagues conducted a retrospective study using the National Inpatient Sample database to identify all hospitalizations among patients with CF in the United States from 2016 through 2021.

They included all hospitalizations with a principal diagnosis code for atrial fibrillation, heart failure, or myocardial infarction.

Of 83,250 total hospitalizations during the study period, 415 (0.5%) were for primary cardiac causes. These included 170 hospitalizations for atrial fibrillation, 95 for heart failure, and 150 for myocardial infarction.

Patients hospitalized for cardiac causes had a higher mean age (59.5 vs 34.5 years) and more comorbidities than patients hospitalized for other causes. These comorbidities included hyperlipidemia, chronic kidney disease, obesity, and a family history of coronary artery disease.

In all, 5% of patients hospitalized for cardiac cause died in hospital, compared with 2% of patients hospitalized for other reasons (P = .044).

However, in logistic regression analyses adjusting for age, sex, and race, this difference was no longer significant.

Similarly, an unadjusted analysis showed that patients with cardiac disease were twice as likely to be discharged to a nursing facility (8% vs 4%, respectively), but this difference too disappeared in adjusted analyses.

The risk for in-hospital mortality appeared to be highest among those patients with a primary diagnosis of heart failure, who had an 11% rate of in-hospital death, compared with 2% among patients with CF hospitalized for other causes.

The total number of deaths was too small, however, to allow for regression analysis, Bhat said.

Nonetheless, taken together, the data indicate a trend toward increased mortality from cardiovascular causes among older patients with CF, as well as the need for further research into the cardiovascular health of these patients, Bhat concluded.
 

Better Nutrition, Higher Risk

In an interview, Yuqing A. Gao, MD, from the Santa Monica Pulmonary Sleep Clinic in California, who was not involved in the study, commented that with the advent of elexacaftor/tezacaftor/ivacaftor modulator therapy, patients with CF tend to have increases in body mass index and improved nutritional intake and absorption, which in turn could increase hyperlipidemia and other factors that might in turn contribute to increased CVD risk.

“It’s really an interesting area of research, and there’s hope that this will bring more focus on how to better screen [for CVD risk] because that’s something that’s very much not known at this time,” she said.

Gao was co-moderator for the session where Bhat presented the data. Bhat did not report a study funding source. Bhat and Gao reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

BOSTON — With the remarkable advances made in therapy over the past decade, many patients with cystic fibrosis (CF) can expect to survive into their 50s and even well beyond. But as patients with CF live longer, they are increasingly likely to develop complications such as cardiovascular diseases (CVDs) that beset many older adults. And as evidence from a new study suggests, there is an increasing need for cardiovascular screening and specialized cardiac care for these patients.

Among more than 83,000 patients with CF hospitalized for any reason from 2016 through 2021, less than 1% of patients had a cardiac cause listed, but in unadjusted analyses, these patients had a more than twofold risk for in-hospital death than those with CF hospitalized for other causes, reported Adnan Bhat, MD, assistant professor of hospital medicine at the University of Florida, Gainesville.

Although the excess mortality was no longer statistically significant in analyses adjusted for potential confounding factors, the data highlight a trend that requires further exploration, he said during an oral abstract session at the annual meeting of the American College of Chest Physicians (CHEST).

“There’s a trend for people with cystic fibrosis admitted for cardiac causes to have a higher in-hospital mortality and increased rate of discharge to nursing facilities, especially for patients admitted for heart failure. The clinical implication is that there is an increased need to start screening for cardiovascular risk factors,” he said.
 

National Database Sample

Bhat and colleagues conducted a retrospective study using the National Inpatient Sample database to identify all hospitalizations among patients with CF in the United States from 2016 through 2021.

They included all hospitalizations with a principal diagnosis code for atrial fibrillation, heart failure, or myocardial infarction.

Of 83,250 total hospitalizations during the study period, 415 (0.5%) were for primary cardiac causes. These included 170 hospitalizations for atrial fibrillation, 95 for heart failure, and 150 for myocardial infarction.

Patients hospitalized for cardiac causes had a higher mean age (59.5 vs 34.5 years) and more comorbidities than patients hospitalized for other causes. These comorbidities included hyperlipidemia, chronic kidney disease, obesity, and a family history of coronary artery disease.

In all, 5% of patients hospitalized for cardiac cause died in hospital, compared with 2% of patients hospitalized for other reasons (P = .044).

However, in logistic regression analyses adjusting for age, sex, and race, this difference was no longer significant.

Similarly, an unadjusted analysis showed that patients with cardiac disease were twice as likely to be discharged to a nursing facility (8% vs 4%, respectively), but this difference too disappeared in adjusted analyses.

The risk for in-hospital mortality appeared to be highest among those patients with a primary diagnosis of heart failure, who had an 11% rate of in-hospital death, compared with 2% among patients with CF hospitalized for other causes.

The total number of deaths was too small, however, to allow for regression analysis, Bhat said.

Nonetheless, taken together, the data indicate a trend toward increased mortality from cardiovascular causes among older patients with CF, as well as the need for further research into the cardiovascular health of these patients, Bhat concluded.
 

Better Nutrition, Higher Risk

In an interview, Yuqing A. Gao, MD, from the Santa Monica Pulmonary Sleep Clinic in California, who was not involved in the study, commented that with the advent of elexacaftor/tezacaftor/ivacaftor modulator therapy, patients with CF tend to have increases in body mass index and improved nutritional intake and absorption, which in turn could increase hyperlipidemia and other factors that might in turn contribute to increased CVD risk.

“It’s really an interesting area of research, and there’s hope that this will bring more focus on how to better screen [for CVD risk] because that’s something that’s very much not known at this time,” she said.

Gao was co-moderator for the session where Bhat presented the data. Bhat did not report a study funding source. Bhat and Gao reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

BOSTON — With the remarkable advances made in therapy over the past decade, many patients with cystic fibrosis (CF) can expect to survive into their 50s and even well beyond. But as patients with CF live longer, they are increasingly likely to develop complications such as cardiovascular diseases (CVDs) that beset many older adults. And as evidence from a new study suggests, there is an increasing need for cardiovascular screening and specialized cardiac care for these patients.

Among more than 83,000 patients with CF hospitalized for any reason from 2016 through 2021, less than 1% of patients had a cardiac cause listed, but in unadjusted analyses, these patients had a more than twofold risk for in-hospital death than those with CF hospitalized for other causes, reported Adnan Bhat, MD, assistant professor of hospital medicine at the University of Florida, Gainesville.

Although the excess mortality was no longer statistically significant in analyses adjusted for potential confounding factors, the data highlight a trend that requires further exploration, he said during an oral abstract session at the annual meeting of the American College of Chest Physicians (CHEST).

“There’s a trend for people with cystic fibrosis admitted for cardiac causes to have a higher in-hospital mortality and increased rate of discharge to nursing facilities, especially for patients admitted for heart failure. The clinical implication is that there is an increased need to start screening for cardiovascular risk factors,” he said.
 

National Database Sample

Bhat and colleagues conducted a retrospective study using the National Inpatient Sample database to identify all hospitalizations among patients with CF in the United States from 2016 through 2021.

They included all hospitalizations with a principal diagnosis code for atrial fibrillation, heart failure, or myocardial infarction.

Of 83,250 total hospitalizations during the study period, 415 (0.5%) were for primary cardiac causes. These included 170 hospitalizations for atrial fibrillation, 95 for heart failure, and 150 for myocardial infarction.

Patients hospitalized for cardiac causes had a higher mean age (59.5 vs 34.5 years) and more comorbidities than patients hospitalized for other causes. These comorbidities included hyperlipidemia, chronic kidney disease, obesity, and a family history of coronary artery disease.

In all, 5% of patients hospitalized for cardiac cause died in hospital, compared with 2% of patients hospitalized for other reasons (P = .044).

However, in logistic regression analyses adjusting for age, sex, and race, this difference was no longer significant.

Similarly, an unadjusted analysis showed that patients with cardiac disease were twice as likely to be discharged to a nursing facility (8% vs 4%, respectively), but this difference too disappeared in adjusted analyses.

The risk for in-hospital mortality appeared to be highest among those patients with a primary diagnosis of heart failure, who had an 11% rate of in-hospital death, compared with 2% among patients with CF hospitalized for other causes.

The total number of deaths was too small, however, to allow for regression analysis, Bhat said.

Nonetheless, taken together, the data indicate a trend toward increased mortality from cardiovascular causes among older patients with CF, as well as the need for further research into the cardiovascular health of these patients, Bhat concluded.
 

Better Nutrition, Higher Risk

In an interview, Yuqing A. Gao, MD, from the Santa Monica Pulmonary Sleep Clinic in California, who was not involved in the study, commented that with the advent of elexacaftor/tezacaftor/ivacaftor modulator therapy, patients with CF tend to have increases in body mass index and improved nutritional intake and absorption, which in turn could increase hyperlipidemia and other factors that might in turn contribute to increased CVD risk.

“It’s really an interesting area of research, and there’s hope that this will bring more focus on how to better screen [for CVD risk] because that’s something that’s very much not known at this time,” she said.

Gao was co-moderator for the session where Bhat presented the data. Bhat did not report a study funding source. Bhat and Gao reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

BOSTON — Patients with pulmonary embolism (PE) who also present with interstitial lung disease (ILD) have worse outcomes with respect to in-hospital mortality, length of hospital stay, hospital cost, and all-cause readmission, according to results from a new retrospective analysis.

“There’s a lot of evidence now that demonstrates that ILD, in general, leads to worse mortality, morbidity in hospital complications, and overall [outcomes]. It’s not hard to extrapolate this to pulmonary embolism outcomes, too. Unfortunately, there’s not a whole lot of evidence out there to really demonstrate it,” Leah Yuan, MD, said during a presentation of the results at the American College of Chest Physicians (CHEST) 2024 Annual Meeting.

The question is complicated by the nebulous nature of ILD, which includes a diverse set of diseases and etiologies, and different levels of inflammation and fibrosis. It has been employed in the Pulmonary Embolism Severity Index but counts for only 10 points out of 210. “If you look at ILD and PE outcomes, there’s nothing really out there [in the literature],” Yuan said in an interview. She is a resident physician at Cook County Health and Hospitals System.

The new study suggested that ILD could have an important influence and perhaps should have greater weight in risk stratification of patients with PE, she said. “We looked at all-cause readmissions and we looked at in-hospital mortality, [both] of which are significant for increased odds ratio. One thing that I’m very curious to see is whether there is increased PE readmissions [associated with ILD], which is something that we couldn’t find to be significant in our study,” said Yuan.

The researchers used data from hospitalizations for PE drawn from the Nationwide Readmissions Database in 2019, using International Classification of Diseases, Tenth Revision, codes to identify admissions. Among a total of 105,133 patients admitted for PE, 158 patients also had ILD. The mean age was 63.6 years for those without ILD (SD, 0.1) and 66.5 years for those with ILD (SD, 1.3).

Admission with ILD was associated with all-cause readmission (odds ratio [OR], 4.12; P < .01), in-hospital mortality (OR, 2.17; P = .01), a longer length of stay (+2.07 days; P < .01), and higher hospitalization charges (+$22,627; P < .01).

In the Q&A period after the presentation, Parth Rali, MD, professor of thoracic medicine and surgery at Temple University, Philadelphia, suggested phenotyping patients to better understand the location of the PE in relation to the ILD. “It may not fall into your classic PE classification. It may just depend on where the clot is in relationship to the interstitial lung disease. I think that’s where the field is going to evolve,” he later said in an interview.

“What is interesting is that patients with interstitial lung disease have a lot of fibrotic disease, and they do not need to have a large clot burden to make them sick. An example [is someone] who has undergone a lung transplant evaluation, and if their right lung is completely diseased from interstitial lung disease and if they get a big blood clot on the right side, it doesn’t affect them because the lung is already fibrotic, so the clot doesn’t matter. If they get a small clot [in the left lung], even though if you look at the standard PE classification they may qualify as a low-risk PE or even as an intermediate-low-risk PE, they are much sicker because that’s the functioning part of the lung,” said Rali.

He advised physicians to pay close attention to the location of PEs in relation to fibrotic tissue in patients with ILD. A PE in healthy lung tissue could have an outsized effect on hemodynamics, whereas a PE in fibrotic tissue may be clinically insignificant and not require treatment. “So it goes both ways: You don’t overtreat and you don’t undertreat,” Rali said.

Yuan and Rali disclosed no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

BOSTON — Patients with pulmonary embolism (PE) who also present with interstitial lung disease (ILD) have worse outcomes with respect to in-hospital mortality, length of hospital stay, hospital cost, and all-cause readmission, according to results from a new retrospective analysis.

“There’s a lot of evidence now that demonstrates that ILD, in general, leads to worse mortality, morbidity in hospital complications, and overall [outcomes]. It’s not hard to extrapolate this to pulmonary embolism outcomes, too. Unfortunately, there’s not a whole lot of evidence out there to really demonstrate it,” Leah Yuan, MD, said during a presentation of the results at the American College of Chest Physicians (CHEST) 2024 Annual Meeting.

The question is complicated by the nebulous nature of ILD, which includes a diverse set of diseases and etiologies, and different levels of inflammation and fibrosis. It has been employed in the Pulmonary Embolism Severity Index but counts for only 10 points out of 210. “If you look at ILD and PE outcomes, there’s nothing really out there [in the literature],” Yuan said in an interview. She is a resident physician at Cook County Health and Hospitals System.

The new study suggested that ILD could have an important influence and perhaps should have greater weight in risk stratification of patients with PE, she said. “We looked at all-cause readmissions and we looked at in-hospital mortality, [both] of which are significant for increased odds ratio. One thing that I’m very curious to see is whether there is increased PE readmissions [associated with ILD], which is something that we couldn’t find to be significant in our study,” said Yuan.

The researchers used data from hospitalizations for PE drawn from the Nationwide Readmissions Database in 2019, using International Classification of Diseases, Tenth Revision, codes to identify admissions. Among a total of 105,133 patients admitted for PE, 158 patients also had ILD. The mean age was 63.6 years for those without ILD (SD, 0.1) and 66.5 years for those with ILD (SD, 1.3).

Admission with ILD was associated with all-cause readmission (odds ratio [OR], 4.12; P < .01), in-hospital mortality (OR, 2.17; P = .01), a longer length of stay (+2.07 days; P < .01), and higher hospitalization charges (+$22,627; P < .01).

In the Q&A period after the presentation, Parth Rali, MD, professor of thoracic medicine and surgery at Temple University, Philadelphia, suggested phenotyping patients to better understand the location of the PE in relation to the ILD. “It may not fall into your classic PE classification. It may just depend on where the clot is in relationship to the interstitial lung disease. I think that’s where the field is going to evolve,” he later said in an interview.

“What is interesting is that patients with interstitial lung disease have a lot of fibrotic disease, and they do not need to have a large clot burden to make them sick. An example [is someone] who has undergone a lung transplant evaluation, and if their right lung is completely diseased from interstitial lung disease and if they get a big blood clot on the right side, it doesn’t affect them because the lung is already fibrotic, so the clot doesn’t matter. If they get a small clot [in the left lung], even though if you look at the standard PE classification they may qualify as a low-risk PE or even as an intermediate-low-risk PE, they are much sicker because that’s the functioning part of the lung,” said Rali.

He advised physicians to pay close attention to the location of PEs in relation to fibrotic tissue in patients with ILD. A PE in healthy lung tissue could have an outsized effect on hemodynamics, whereas a PE in fibrotic tissue may be clinically insignificant and not require treatment. “So it goes both ways: You don’t overtreat and you don’t undertreat,” Rali said.

Yuan and Rali disclosed no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

BOSTON — Patients with pulmonary embolism (PE) who also present with interstitial lung disease (ILD) have worse outcomes with respect to in-hospital mortality, length of hospital stay, hospital cost, and all-cause readmission, according to results from a new retrospective analysis.

“There’s a lot of evidence now that demonstrates that ILD, in general, leads to worse mortality, morbidity in hospital complications, and overall [outcomes]. It’s not hard to extrapolate this to pulmonary embolism outcomes, too. Unfortunately, there’s not a whole lot of evidence out there to really demonstrate it,” Leah Yuan, MD, said during a presentation of the results at the American College of Chest Physicians (CHEST) 2024 Annual Meeting.

The question is complicated by the nebulous nature of ILD, which includes a diverse set of diseases and etiologies, and different levels of inflammation and fibrosis. It has been employed in the Pulmonary Embolism Severity Index but counts for only 10 points out of 210. “If you look at ILD and PE outcomes, there’s nothing really out there [in the literature],” Yuan said in an interview. She is a resident physician at Cook County Health and Hospitals System.

The new study suggested that ILD could have an important influence and perhaps should have greater weight in risk stratification of patients with PE, she said. “We looked at all-cause readmissions and we looked at in-hospital mortality, [both] of which are significant for increased odds ratio. One thing that I’m very curious to see is whether there is increased PE readmissions [associated with ILD], which is something that we couldn’t find to be significant in our study,” said Yuan.

The researchers used data from hospitalizations for PE drawn from the Nationwide Readmissions Database in 2019, using International Classification of Diseases, Tenth Revision, codes to identify admissions. Among a total of 105,133 patients admitted for PE, 158 patients also had ILD. The mean age was 63.6 years for those without ILD (SD, 0.1) and 66.5 years for those with ILD (SD, 1.3).

Admission with ILD was associated with all-cause readmission (odds ratio [OR], 4.12; P < .01), in-hospital mortality (OR, 2.17; P = .01), a longer length of stay (+2.07 days; P < .01), and higher hospitalization charges (+$22,627; P < .01).

In the Q&A period after the presentation, Parth Rali, MD, professor of thoracic medicine and surgery at Temple University, Philadelphia, suggested phenotyping patients to better understand the location of the PE in relation to the ILD. “It may not fall into your classic PE classification. It may just depend on where the clot is in relationship to the interstitial lung disease. I think that’s where the field is going to evolve,” he later said in an interview.

“What is interesting is that patients with interstitial lung disease have a lot of fibrotic disease, and they do not need to have a large clot burden to make them sick. An example [is someone] who has undergone a lung transplant evaluation, and if their right lung is completely diseased from interstitial lung disease and if they get a big blood clot on the right side, it doesn’t affect them because the lung is already fibrotic, so the clot doesn’t matter. If they get a small clot [in the left lung], even though if you look at the standard PE classification they may qualify as a low-risk PE or even as an intermediate-low-risk PE, they are much sicker because that’s the functioning part of the lung,” said Rali.

He advised physicians to pay close attention to the location of PEs in relation to fibrotic tissue in patients with ILD. A PE in healthy lung tissue could have an outsized effect on hemodynamics, whereas a PE in fibrotic tissue may be clinically insignificant and not require treatment. “So it goes both ways: You don’t overtreat and you don’t undertreat,” Rali said.

Yuan and Rali disclosed no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

BOSTON — The use of sodium-glucose cotransporter-2 (SGLT2) inhibitors is associated with reduced short- and long-term mortality among patients with pulmonary arterial hypertension (PAH), according to results from a new propensity score–matched analysis.

“There are a lot of new studies that show benefits [of SGLT2 inhibitors] in heart failure, in [chronic kidney disease], and of course, in diabetes. Group one pulmonary hypertension includes not only the inflammatory cascades but also fibrotic and neurovascularization, and all these different parts of the pathophysiology are linked to each other. There are studies that show that SGLT2 inhibitors can have an impact on inflammatory cascades, fibrosis, and vascular remodeling in general. Together, all this data triggered this idea for me, and that’s when I decided to conduct further studies,” said Irakli Lemonjava, MD, who presented the study at the American College of Chest Physicians (CHEST) 2024 Annual Meeting.

The researchers drew data on 125,634 adult patients from the TriNetX database who were diagnosed with PAH after January 1, 2013. They used propensity score matching to account for demographic characteristics and 10 organ system disorders to compare patients with exposure to SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin; n = 6238) with those without such exposure (n = 6243).

At 1 year, 8.1% of patients taking SGLT2 inhibitors had died, compared with 15.5% of patients not taking SGLT2 inhibitors (risk reduction [RR], 0.52; P < .0001). The values were 13% and 22.5% (RR, 0.579; P < .0001) at 3 years and 14.6% and 25% at 5 years (RR, 0.583; P < .0001).

The study generated discussion during the Q&A period following the talk. One audience member asked if the group was able to access patients both inside and outside the United States. “Because I wonder if access to GLP2 inhibitors is actually a surrogate marker for access to other medications,” the questioner said.

Although the finding is intriguing, it shouldn’t change clinical practice, according to Lemonjava. “I don’t think we can make any changes based on what I shared today. Our purpose was to trigger the question. I think the numbers are so impressive that it will trigger more studies. I think if in the future it’s demonstrated by clinical trials that [SGLT2 inhibitors are beneficial], it will not be a problem to prescribe for someone with pulmonary arterial hypertension because they do not have many side effects,” he said. Lemonjava is a resident physician at Jefferson Einstein Philadelphia Hospital, Philadelphia.

Session co-moderator said Syed Rehan Quadery, MD, praised the study but emphasized the remaining uncertainty. “It’s an excellent proof of concept study. More trials need to [be done] on it, and we don’t understand the mechanism of action in which it improves survival in patients with pulmonary artery hypertension. The majority of the patients with pulmonary hypertension are much older and they have comorbidities, including cardiovascular risk factors, and maybe that is one of the ways in which this drug helps. Plus, there are multiple mechanisms in which it may be working, including anti-inflammatory as well as antiproliferative mechanisms through inhibiting the Notch-3 signaling pathway,” said Quadery, who is a consultant respiratory physician at National Pulmonary Hypertension Unit, Dublin, Ireland.

Quadery and his co-moderator Zeenat Safdar, MD, both noted that SGLT2 inhibitors have already been demonstrated to improve outcomes in heart failure. “[SGLT2 inhibition] improves survival, it decreases hospitalization, it improves morbidity and mortality. There are a lot of things that can be shown in different [animal or in vitro] models. In humans, we actually don’t know exactly how it works, but we know that it does. If it works in left heart failure, it also [could] work in right heart failure,” said Safdar, who is the director of the Houston Methodist Lung Center, Houston Methodist Hospital, Houston.

The study was independently supported. Lemonjava, Quadery, and Safdar reported no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

BOSTON — The use of sodium-glucose cotransporter-2 (SGLT2) inhibitors is associated with reduced short- and long-term mortality among patients with pulmonary arterial hypertension (PAH), according to results from a new propensity score–matched analysis.

“There are a lot of new studies that show benefits [of SGLT2 inhibitors] in heart failure, in [chronic kidney disease], and of course, in diabetes. Group one pulmonary hypertension includes not only the inflammatory cascades but also fibrotic and neurovascularization, and all these different parts of the pathophysiology are linked to each other. There are studies that show that SGLT2 inhibitors can have an impact on inflammatory cascades, fibrosis, and vascular remodeling in general. Together, all this data triggered this idea for me, and that’s when I decided to conduct further studies,” said Irakli Lemonjava, MD, who presented the study at the American College of Chest Physicians (CHEST) 2024 Annual Meeting.

The researchers drew data on 125,634 adult patients from the TriNetX database who were diagnosed with PAH after January 1, 2013. They used propensity score matching to account for demographic characteristics and 10 organ system disorders to compare patients with exposure to SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin; n = 6238) with those without such exposure (n = 6243).

At 1 year, 8.1% of patients taking SGLT2 inhibitors had died, compared with 15.5% of patients not taking SGLT2 inhibitors (risk reduction [RR], 0.52; P < .0001). The values were 13% and 22.5% (RR, 0.579; P < .0001) at 3 years and 14.6% and 25% at 5 years (RR, 0.583; P < .0001).

The study generated discussion during the Q&A period following the talk. One audience member asked if the group was able to access patients both inside and outside the United States. “Because I wonder if access to GLP2 inhibitors is actually a surrogate marker for access to other medications,” the questioner said.

Although the finding is intriguing, it shouldn’t change clinical practice, according to Lemonjava. “I don’t think we can make any changes based on what I shared today. Our purpose was to trigger the question. I think the numbers are so impressive that it will trigger more studies. I think if in the future it’s demonstrated by clinical trials that [SGLT2 inhibitors are beneficial], it will not be a problem to prescribe for someone with pulmonary arterial hypertension because they do not have many side effects,” he said. Lemonjava is a resident physician at Jefferson Einstein Philadelphia Hospital, Philadelphia.

Session co-moderator said Syed Rehan Quadery, MD, praised the study but emphasized the remaining uncertainty. “It’s an excellent proof of concept study. More trials need to [be done] on it, and we don’t understand the mechanism of action in which it improves survival in patients with pulmonary artery hypertension. The majority of the patients with pulmonary hypertension are much older and they have comorbidities, including cardiovascular risk factors, and maybe that is one of the ways in which this drug helps. Plus, there are multiple mechanisms in which it may be working, including anti-inflammatory as well as antiproliferative mechanisms through inhibiting the Notch-3 signaling pathway,” said Quadery, who is a consultant respiratory physician at National Pulmonary Hypertension Unit, Dublin, Ireland.

Quadery and his co-moderator Zeenat Safdar, MD, both noted that SGLT2 inhibitors have already been demonstrated to improve outcomes in heart failure. “[SGLT2 inhibition] improves survival, it decreases hospitalization, it improves morbidity and mortality. There are a lot of things that can be shown in different [animal or in vitro] models. In humans, we actually don’t know exactly how it works, but we know that it does. If it works in left heart failure, it also [could] work in right heart failure,” said Safdar, who is the director of the Houston Methodist Lung Center, Houston Methodist Hospital, Houston.

The study was independently supported. Lemonjava, Quadery, and Safdar reported no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

BOSTON — The use of sodium-glucose cotransporter-2 (SGLT2) inhibitors is associated with reduced short- and long-term mortality among patients with pulmonary arterial hypertension (PAH), according to results from a new propensity score–matched analysis.

“There are a lot of new studies that show benefits [of SGLT2 inhibitors] in heart failure, in [chronic kidney disease], and of course, in diabetes. Group one pulmonary hypertension includes not only the inflammatory cascades but also fibrotic and neurovascularization, and all these different parts of the pathophysiology are linked to each other. There are studies that show that SGLT2 inhibitors can have an impact on inflammatory cascades, fibrosis, and vascular remodeling in general. Together, all this data triggered this idea for me, and that’s when I decided to conduct further studies,” said Irakli Lemonjava, MD, who presented the study at the American College of Chest Physicians (CHEST) 2024 Annual Meeting.

The researchers drew data on 125,634 adult patients from the TriNetX database who were diagnosed with PAH after January 1, 2013. They used propensity score matching to account for demographic characteristics and 10 organ system disorders to compare patients with exposure to SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin; n = 6238) with those without such exposure (n = 6243).

At 1 year, 8.1% of patients taking SGLT2 inhibitors had died, compared with 15.5% of patients not taking SGLT2 inhibitors (risk reduction [RR], 0.52; P < .0001). The values were 13% and 22.5% (RR, 0.579; P < .0001) at 3 years and 14.6% and 25% at 5 years (RR, 0.583; P < .0001).

The study generated discussion during the Q&A period following the talk. One audience member asked if the group was able to access patients both inside and outside the United States. “Because I wonder if access to GLP2 inhibitors is actually a surrogate marker for access to other medications,” the questioner said.

Although the finding is intriguing, it shouldn’t change clinical practice, according to Lemonjava. “I don’t think we can make any changes based on what I shared today. Our purpose was to trigger the question. I think the numbers are so impressive that it will trigger more studies. I think if in the future it’s demonstrated by clinical trials that [SGLT2 inhibitors are beneficial], it will not be a problem to prescribe for someone with pulmonary arterial hypertension because they do not have many side effects,” he said. Lemonjava is a resident physician at Jefferson Einstein Philadelphia Hospital, Philadelphia.

Session co-moderator said Syed Rehan Quadery, MD, praised the study but emphasized the remaining uncertainty. “It’s an excellent proof of concept study. More trials need to [be done] on it, and we don’t understand the mechanism of action in which it improves survival in patients with pulmonary artery hypertension. The majority of the patients with pulmonary hypertension are much older and they have comorbidities, including cardiovascular risk factors, and maybe that is one of the ways in which this drug helps. Plus, there are multiple mechanisms in which it may be working, including anti-inflammatory as well as antiproliferative mechanisms through inhibiting the Notch-3 signaling pathway,” said Quadery, who is a consultant respiratory physician at National Pulmonary Hypertension Unit, Dublin, Ireland.

Quadery and his co-moderator Zeenat Safdar, MD, both noted that SGLT2 inhibitors have already been demonstrated to improve outcomes in heart failure. “[SGLT2 inhibition] improves survival, it decreases hospitalization, it improves morbidity and mortality. There are a lot of things that can be shown in different [animal or in vitro] models. In humans, we actually don’t know exactly how it works, but we know that it does. If it works in left heart failure, it also [could] work in right heart failure,” said Safdar, who is the director of the Houston Methodist Lung Center, Houston Methodist Hospital, Houston.

The study was independently supported. Lemonjava, Quadery, and Safdar reported no relevant financial relationships.
 

A version of this article appeared on Medscape.com.