‘Popcorn Lung': Making a Historically Difficult Diagnosis

Medscape

18-06-2025

Among the many things that the Industrial Revolution gave rise to was the potential for more rapid spread of public health crises. Communicable diseases such as cholera, typhus, and tuberculosis all spiked during this era due to urbanized living, increased mass communication, and still-evolving sanitation safety measures. The early 20th century also marked increased prevalence of occupational respiratory illnesses, such as silicosis, chronic obstructive pulmonary disease (COPD), and a newly-identified condition — bronchiolitis obliterans — that in many ways has puzzled healthcare professionals ever since.
First diagnosed in 1901 among healthy factory workers who were exposed to nitrogen dioxide, this fibrosing obstructive lung disease has earned the moniker 'popcorn lung' because of its connection to an outbreak at a factory 25 years ago. That outbreak in Jasper, Missouri, was among workers who inhaled diacetyl, a synthetic flavoring agent for microwavable popcorn. Although the disease can also be caused by other harmful food production exposures.
Characterized by a dry cough, shortness of breath, wheezing, and inflammation that results in partial or complete obliteration of the lung's smallest airways and irreversible scaring, the disease continues to be difficult to diagnose. The disease also is more challenging to care for the longer it goes undetected.
While it frequently develops in patients who undergo lung transplant and is associated with rheumatic conditions and various respiratory infections, bronchiolitis obliterans is rare and can masquerade as other common pulmonary diseases when symptoms aren't properly recognized.
Difficult Diagnosis
In August 2000, employees at Gilster-Mary Lee Corporation, a food manufacturing and distribution company, experienced a similar set of respiratory issues, including cold-like symptoms that didn't improve with medication. The National Institute for Occupational Safety and Health (NIOSH) and the Missouri Department of Health and Senior Services launched an investigation.
'There was this clustering of workers who had developed severe obstructive airway disease and were initially being variously diagnosed with conditions such as emphysema, but, for the most part, they were never smokers,' explained Cecile S. Rose, MD, MPH, a board-certified pulmonology and occupational medicine physician at National Jewish Health, Denver. 'The NIOSH began looking at the workers' epidemiologically and sampling the air. They found that this exposure to diacetyl-containing butter flavoring was the cause. And that's when we began to realize that these types of chemicals, even though they had been stored in very large vats that had lids and were recognized as safe for ingestion, were never safe to be inhaled in large quantities.'
The most likely symptoms of 'popcorn lung' are a persistent cough, plus or minus wheezing, and shortness of breath that worsens with physical exertion — none of which are particularly distinctive. 'The typical symptoms are very nonspecific and are not temporally linked to exposure,' said Rose. 'They are insidious. They creep up. And the symptoms don't help you very much in terms of linking the exposure to the risk of lung disease or its symptoms. But sometimes patients will describe upper airway irritation symptoms, such as sore throat, or eye burning.'
But there are additional symptoms that can complicate diagnosis.
According to Jim Mendez, PhD, CRNP, ANP-BC, clinical associate professor and adult primary care nurse practitioner in the M. Louise Fitzpatrick College of Nursing at Villanova University, Villanova, Pennsylvania, the full spectrum of signs can also include fatigue and chest discomfort. Another troubling indication can be when wheezing is present and does not respond to standard asthma medications, Mendez said.
Eric Costanzo, DO, director of Medical Intensive Care and director of the Pulmonary and Critical Care Fellowship Program at Jersey Shore University Medical Center, Hackensack Meridian Health, Neptune City, New Jersey, said that patients will also often experience nonspecific symptoms that can resemble conditions such as asthma or COPD, including exertional dyspnea and low-grade fever. Weight loss may also be seen, he said.
'But the pathology itself can happen for a number of different reasons, just by virtue of the fact that the lungs have only a few ways to respond to injury — and this injury pattern of bronchiolitis obliterans is one of those ways,' said Amy Hajari Case, MD, chief medical officer of the Pulmonary Fibrosis Foundation and director of the Pulmonary Fibrosis Care Center at Piedmont Healthcare in Atlanta. 'There is inflammation and obliteration of the bronchioles, and it's a situation where the inflammation creates airflow obstruction on the smallest level that sets up a clinical picture that we can now recognize.'
Functional Testing Can Speed Diagnosis
Before a diagnosis can be confirmed, pulmonary function tests are essential to help detect the restricted airflow typical of the condition, suggests Shawn George, DO, an internal medicine physician at Yorktown Health, Vernon Hills, Illinois. 'A computed tomography scan can show damage to the airways, but a biopsy might be needed to confirm the diagnosis.'
The disease is more common among patients who undergo bone marrow or lung transplants, a form of chronic allograft rejection, referred to as defined as 'bronchiolitis obliterans syndrome.'
According to research conducted by the Cleveland Clinic, approximately 50% of patients who undergo lung transplants will develop bronchiolitis obliterans syndrome within 5 years of surgery while approximately 10% of marrow recipients will develop bronchiolitis obliterans syndrome within 5 years.
'Patients can have this type of lung injury related to some of the transplant immunology that occurs,' said Case. 'It can also happen because of certain types of viral or bacterial infections that set up a more acute situation.' These include respiratory syncytial virus and measles, particularly in children.
According to Costanzo, rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease-related lung disease can also be triggers. 'Histologically they differ from other lung diseases characterized by concentric fibrosis of the bronchioles and eventual obliteration of the airway lumen,' said Costanzo.
Treatment Approaches and Suggestions
Quality of life and disease management can be difficult for patients, said Case. 'There isn't a well-defined standard of care practice for how to help people improve their lung function and there isn't extensive data to guide management in this condition. The first thing to do is to halt any culprit exposure to immediately keep the patient from having continued lung damage.'
Assuming that can be accomplished, there are a range of over-the-counter and prescription options that Case and other physicians are willing to try for their patients. 'Cough suppressants and inhaled bronchodilators are used for symptom management, as well as oxygen therapy if the patient is hypoxemic,' said Case.
'Pulmonary rehabilitation is also utilized for its various benefits, and other treatments such as macrolide antibiotics, systemic steroids, and immunosuppression are tried on an individual basis. But this is a condition that in many cases doesn't respond well to the things that we do. And so patients do not get that same relief as other patients for which we do have a lot of tools and a lot of evidence for using them, even if that condition is not going to go away, such as COPD.'
When it comes to syndrome patients, treatments might also include extracorporeal photopheresis and total lung irradiation. In the worst of all types of cases, patients will require lung transplant. 'One percent of transplants are listed as being for bronchiolitis obliterans for all different etiologies,' said Case.
Vagaries of Vaping
Another potential cause of bronchiolitis obliterans, but for which more substantial evidence is needed, is use of a vape to inhale nicotine-based chemicals, including those that contain diacetyl. Prior to the COVID-19 pandemic, a rash of e-cigarette or vaping-associated lung injury (EVALI) cases had been seen in hospitals across the country.
According to CDC data, more than 2800 hospitalizations and nearly 70 US deaths reported as of February 2020 among people of all ages were attributed to the use of e-cigarettes and vaping products, particularly those containing vitamin E acetate (VEA).
'While the association between vaping and popcorn lung is a concern that has received widespread media attention, it remains less common in clinical practice,' said Dr. Mendez.
'Some flavored e-cigarettes have been found to contain diacetyl; however, there have been very few confirmed cases of bronchiolitis obliterans directly attributable to vaping. What we are seeing more frequently are other vaping-related lung injuries, such as EVALI, which can mimic some of the same respiratory symptoms but represents a different disease process. There is some indication that one of the primary causative agents in EVALI is VEA, although there may be other causes. Continued research and regulation are needed to fully understand the long-term pulmonary risks associated with vaping.'
Costanzo said he believes there's a correlation to be concerned about between an increasing prevalence of bronchiolitis obliterans in recent years driven by the popularity of vaping products. Rose is convinced that time will prove a direct causation.
'It might not be as obvious as it was for workers who were exposed to large quantities, but chronic vaping of these chemicals could lead to substantial adverse lung health outcomes in the longer term,' she said. 'The [people] who are vaping regularly might seem fine, but if they're doing that every day for the next 10 years, we might start to see affects. Or they might have more accelerated decline in lung function without having many other symptoms.'
Case said she has already seen enough incidences to determine a link. 'For me, the evidence is there,' she said. 'When we talk about vaping-associated lung diseases, bronchiolitis obliterans is one of them.'
'But the problem of lack of clarity is that you can put anything into a vape. Because there is so much variability, it's become more difficult to pin down what can cause this by vaping. There are so many additives to the flavors,' continued Case. 'We need to talk about this as being generally harmful because you lose the weight of evidence when we try to get more specific on something that we just don't have enough information on. And as vaping has become more prevalent, it stands to reason that the people who are more susceptible to lung injury from it will experience it at a higher rate.'
Protocols for Better Awareness
Greater awareness and suspicion of 'popcorn lung' is needed in the presence of certain symptoms and occupational hazards, experts suggest.
'When a clinician sees signs of emphysema or small airways disease in never smokers, their alarms for work-related or exposure-related lung disease should go up,' said Rose.
'The most important thing is to take a careful occupational history — take the time to ask patients about what they spend their time doing. If they're working in food production or fragrance, that should trigger an understanding that there could be a risk to artificial chemicals or flavorings that can confer risk for lung disease. We're very well-conditioned to taking a careful history for those patients who smoke, but we need the same to be true for vaping now too. We also need to take into account things like hookah or other types of inhalants that may confer risk for small airway diseases.'
There's also a significant need to improve awareness of the disease among the general public, especially for those who work in high-risk settings and/or use a vape or similar device.
'The person experiencing it probably doesn't know anyone else who has been diagnosed,' said Case. 'There's not a drug being promoted to treat it. We need to promote self-advocacy and advocacy for loved ones. When our patients are experiencing these symptoms, it's an important message that they need to know. The old medical adage says, 'when you hear hoofbeats think horses, not zebras,' but this is truly one of the zebras. It's being missed.'
Case, Costanzo, and Mendez reported no relevant financial disclosures.