American Thoracic Society 2024 International Conference

For immigrants, a new country and many health challenges

The journey to the United States is long and often dangerous for many immigrants, but the challenges do not stop after they arrive. A panel of experts moderated by Fernando Holguin, M.D., M.P.H., at the conference discussed specific health issues among immigrants and people lacking permanent legal status, situations that increase their vulnerability, logistical issues and barriers to care by state and what can be done to fix them.

Access to mental health services is one of the most overlooked health issues for immigrant population, according to Denisse Rojas Marquez, M.D., M.P.P., an emergency room resident at Boston Medical Center. She is also the co-founder of Pre-Health Dreamers, an organization that supports immigrants interested in working in healthcare. Marquez grew up in California as an undocumented immigrant.

“Having focus groups with immigrants, and honestly, from my own personal experiences, one thing that was so salient was the amount of trauma that they faced, from their home country to their journey to the United States to the stigma of being a new immigrant or undocumented or even a long-term immigrant and still having to face discrimination,” she said.

There are many reasons why immigrants are discriminated against, one being the misconception that they bring diseases from their home country, Marquez said.

“It’s easy to document the increased burden of occupational diseases and fatalities among immigrants,” according to Marc B. Schenker, M.D., M.P.H., professor emeritus of Public Health Sciences and Medicine at the UC Davis School of Medicine, another speaker. “If you look at the Bureau of Labor Statistics’ census of fatal occupational injuries, the rate for immigrant workers is 25%.”

“The idea of these infectious exposures is not that people are bringing this with them, but actually the conditions of migrations to which they’re exposed because of the structures and systems that we have, are actually worsening these risks,” Julie M. Linton, M.D., immediate past chair of the American Academy of Pediatrics Council on Immigrant Child and Family Health, said during the discussion.

Many undocumented people take unsafe jobs to make ends meet and may find it difficult to advocate for safer working conditions. The top three jobs held by immigrants are in the construction, transportation and agriculture industries, The top three jobs held by immigrants are jobs in construction, transportation and agriculture, all of which pose health risks.

“I think they consider it a part of the work,” Schenker said. “They’re not provided respirators; they’re not provided training safety; they’re not aware of the risk.”

People lacking permanent legal status are not currently able to purchase healthcare through the Affordable Care Act and are ineligible for Medicaid. If someone has certain forms of lawful status such as refugee status or asylum status, they may be eligible but may be subject to a five-year waiting period, depending on the state. Twelve states, including California, Utah and Illinois, provide coverage for children, regardless of immigration status through state funding. For these reasons, Linton said providers must be aware of state policies.

“What we need is immigration reform and more humane policies at the federal level, which could easily make [inequalities] go away,” Marquez said. “I think the solution to how to improve the health of immigrants is right here, literally right here in this room. That, for me, has been empowering.”

Most costs for advanced PAH are for medications

Medications to treat patients with pulmonary arterial hypertension (PAH) contribute significantly to payer costs, according to findings from a study of claim data presented at the conference.

PAH is a rare, progressive and life-threatening disease in which blood vessels in the lungs narrow, causing strain on the heart. About 40,000 people in the United States are living with PAH. The five-year mortality rate is about 43%.

The researchers who conducted the study, which was sponsored by Merck, wanted to assess the economic burden on patients who were treated with parenteral prostacyclin (pPCA) compared with other therapies. Prostacyclin — which is sold as a generic and under several brand names — dilates blood vessels and improves blood flow while also preventing blood clotting.

In this study, researchers used prostacyclin as a proxy or marker for advanced disease; pPCA is used in the most advanced cases, in addition to other PAH therapies, in alignment with guidelines, Anna Watzker, associate director, outcomes research at Merck, said in an email.

“The study relies on a claims data source, which limits our ability to assess disease severity,” said Watzker. “However, by using pPCA as a proxy, we can provide a recent real-world perspective on the cost burden of PAH patients, revealing an increasingly high burden for patients as their condition advances. We hope this study will aid in raising awareness of the burden faced by patients with the most-advanced PAH patients.”

The study assessed the costs of 11,670 adult patients covered by Medicare and 1,174 patients with commercial insurance who had been diagnosed with PAH between Jan. 1, 2019, and Nov. 30, 2020. Researchers assessed claims data from three large claims databases Per patient, per month costs were assessed separately for medical and pharmacy costs and summarized by the amounts paid by payer, excluding patient cost-sharing.

This study found that the majority of costs incurred are for medications, contributing to, on average, between 69% and 88% of monthly payer costs. Among Medicare beneficiaries at their end of life, medications still contributed to the majority (59%) of costs among patients receiving pPCA.

The cost for people with commercial insurance was $26,944 per patient per month compared with $13,992 for those who did not receive prostacyclin. For those covered by Medicare, the per-patient, per-month cost for those who received prostacyclin was $20,323 compared with $8,694 for those who did not receive it.

Among Medicare beneficiaries at their end of life, patients using pPCA had higher total costs — $144,857 compared with $84,335 — in the 180 days prior to death and a higher proportion of spending on medications (59% vs 34%) than patients without pPCA.

The largest proportion of spending was attributed to medication costs, including both pharmacy and nonpharmacy medications. Among patients being treated with prostacyclin, the proportion of total spending on nonpharmacy drugs was 54% for those covered by Medicare and 30% for those with commercial insurance.

Researchers said one of the limitations of the study was that it relied on administrative claims data that did not provide information on disease severity or other clinical factors. Comorbid conditions, into which the researchers did not have insight, could also have impacted the total costs.

Additionally, the researchers said that different sources, payer markets and time periods could produce different results.

After another negative phase 3 trial result,calls for rethinking treatment of idiopathic pulmonary fibrosis

An investigational monoclonal antibody to treat idiopathic pulmonary fibrosis failed in a phase 3 trial, according to results presented at the conference. The negative results for pamrevlumab come after two other treatments for idiopathic pulmonary fibrosis, ziritaxestat and zinpentraxin alfa, also flopped in phase 3 trials.

The presentation of the results at the conference prompted discussion during the question-and-answer period about overhauling the strategy for developing drugs for a serious disease with a median survival time of just three to five years. One framing of the problem points to the end points that have been used in the trials and suggests that a more comprehensive set of outcomes be used. The negative results for pamrevlumab hinged on the primary outcome of a change in forced vital capacity (FVC), a standard measurement of lung function. Another framing suggests that idiopathic pulmonary fibrosis currently lumps together conditions with important biological differences that should be teased apart and organized into subtypes for the purposes of drug development.

The negative trial results were published simultaneously in JAMA. An accompanying editorial that discussed the reasons for the failed phase 3 trials is titled, “When the Third Time Is Not the Charm — Trial Outcomes in Idiopathic Pulmonary Fibrosis.”

“We are using very traditional models still. But we are learning with research that is ongoing that all IPF [idiopathic pulmonary fibrosis] is not the same. The heterogeneity is something we have to embrace,” said Victor E. Ortega, M.D., Ph.D., one of the authors of the editorial, in a brief interview at the conference after the pamrevlumab results were presented. Ortega is a professor of medicine at the Mayo Clinic in Scottsdale, Arizona, and a genetic epidemiologist.

“If we had continued to treat all asthma the same, we would have never developed the current biologics [for asthma treatment] because they are the most effective in people with high blood eosinophils,” which is a biomarker of inflammation, Ortega noted.

Although every drug developer talks about unmet need, there is a strong case that one truly exists for idiopathic pulmonary fibrosis (IPF),a form of interstitial lung disease that involves the thickening and scarring of the walls of the lungs’ alveoli. The American Lung Association says approximately 58,000 new cases occur each year. Current treatment is limited to Ofev (nintedanib) and Esbriet (pirfenidone), drugs that interfere with the biologic process of lung tissue scarring; they are referred to as antifibrotic drugs. They are far from ideal drugs, though, with limited efficacy and serious side effects (e.g., nausea, fatigue and diarrhea). The poor tolerability and limited efficacy of these two drugs “leave patients with IPF with similarly poor prognosis as there is no definite disease-altering or curative treatment apart from a lung transplant,” Ortega and his co-authors wrote in the JAMA editorial.

The phase 3 trial of pamrevlumab, called Zephyrus I, enrolled 356 patients at 117 sites in 19 countries between July 2019 and July 2022. The average age of the participants was 70.2 and most (72.5%) were men. They were treated with pamrevlumab, which was administered intravenously, every three weeks for 48 weeks. Because of the COVID-19 epidemic, some of the treatments were delivered at home with the help of a home health service. Patients were excluded from the study if they were being treated with Ofev or Esbriet but once patients enrolled, those drugs could be added to their treatment, which wasn’t the case in the phase 2 trials of pamrevlumab. FibroGen Inc., the San Francisco biotech company that is developing pamrevlumab, paid for the study.

The patients in the pamrevlumab arm experienced a smaller decrease in FVC than those in the placebo group (260 milliliters [mL] vs. 330 mL), but the difference didn’t reach the statistical threshold for being a true difference. There was also no statistically significant difference in the five secondary outcomes and four exploratory outcomes that measured quality of life.

Corresponding and lead author Ganesh Raghu, M.D., a professor in the Division of Pulmonary, Critical Care and Sleep Medicine at University of Washington in Seattle, and his colleagues offered several possible explanations for pamrevlumab’s success in in phase 2 trials but not in this phase 3 trial. They noted that that patients in the phase 3 trial were sicker (i.e., they had greater lung function impairment and more symptoms), and the
phase 3 trial was much larger than the two phase 2 trials (356 patients vs. 90 and 103). They also pointed to the phase 3 trial design that allowed patients to be treated with Ofev and Esbriet. Approximately 20% of the patients in the pamrevlumab group and 15% of those in the placebo group were treated with the one of the two drugs.

More good news about Dupixent for COPD subgroup with type 2 inflammation

Dupixent (dupilumab) reduced moderate or severe exacerbations in people with chronic obstructive pulmonary disease (COPD) who have evidence of type 2 inflammation by 34%, according to results presented at the conference.

The results from this trial, called NOTUS, confirm positive findings from a previous phase 3 trial, called BOREAS, that were presented at the ATS conference last year. The FDA has set Sept. 27, 2024, as the date when it will announce the results of its review of the evidence for Dupixent and whether it will add COPD as a new indication.

Between 20% and 40% of people with COPD have evidence of type 2 inflammation, and its presence is associated with an increased risk of exacerbations, episodes of severe worsening of COPD that are characterized by shortness of breath, fatigue and a change in the color of sputum from clear to a deep yellow, green or brown.

Dupixent is a monoclonal antibody that blocks the interleukin-4 and interleukin-13 pathways that are instrumental in the cascade of events that constitute type 2 inflammation. The FDA has approved it as a treatment for five conditions in which wayward type 2 inflammation is a central contributing cause: atopic dermatitis, asthma with an eosinophilic phenotype, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis and prurigo nodularis.

In both trials, Dupixent was used as on add-on therapy to the trio of inhaled therapies commonly used to manage COPD: a glucocorticoid agent, a long-acting muscarinic antagonist (LAMA) and a long-acting beta-agonist (LABA).

The results of the NOTUS trial were published simultaneously with the ATS presentation in The New England Journal of Medicine.

Lead author and corresponding author Surya P. Bhatt, M.D., M.S.P.H., a professor of medicine in the Division of Pulmonary, Allergy and Critical Care Medicine at the University of Alabama at Birmingham, and his colleagues enrolled 935 patients in the NOTUS trial at 329 sites in 29 countries. All the participants had blood eosinophil counts of 300 cells per microliter or higher, a threshold that was used as a biomarker for the presence of type 2 inflammation (the average blood eosinophil count was 407 cells per microliter). Nearly all (98.8%) of the participants were on the inhaled glucocorticoid-LAMA-LABA combination.

The researchers randomly assigned the participants to receive a subcutaneous injection of Dupixent every two weeks or a placebo injection for a year. The primary outcome was an annualized rate of moderate or severe exacerbations. Moderate exacerbation was defined as an exacerbation that needed to be treated with antibiotics, a systemic glucocorticoid steroid or both. A severe one was defined as an exacerbation that led to a hospitalization or an emergency room visit.

Bhatt and his colleagues analyzed the trial data after a positive interim analysis, so the number of patients included in the analysis dropped from 935 to 721. On the primary end point of the annualized rate of moderate and severe exacerbations, they found a difference between the Dupixent group and the placebo group emerged early and grew larger. At 52 weeks, the rate in the Dupixent group was 34% lower than in the placebo group (0.86 vs. 1.30). The researchers noted that the difference in exacerbations was similar in prespecified subgroups of patients that were defined by age, sex, smoking status, lung function at the time of enrollment in the study and history of exacerbations.

The difference that favored the Dupixent group in forced expiratory volume in 1 second, a common test of lung function, emerged at 12 weeks and continued throughout the trial period. Results on secondary end points also favored Dupixent.

Bhatt and his colleagues wrote in the discussion section of The New England Journal of Medicine paper that their result “confirms the role of type 2 inflammation in the pathobiologic disease mechanisms in a subgroup of patients with COPD and the rule of dupilumab in treating this distinct COPD endotype.”

Laughs and gratitude
from Dr. Glaucomflecken, aka Will Flanary

Will Flanary, M.D., an ophthalmologist in Portland, Oregon, who goes by the name Dr. Glaucomflecken as a social media comedian, stitched together self-deprecating humor, jokes about residency, and funny observations about medicine and healthcare with serious commentary about his sudden cardiac arrest and the value of research in his talk at the opening ceremony of the conference.

Flanary, who has millions of followers on TikTok and YouTube, has won over many in healthcare with humor based on insider observations about medical training and send-ups of medical specialists. But he also ventures into biting satire that puts him into Jon Stewart territory as he takes on insurance companies, pharmaceutical benefit managers and pharmaceutical companies.

Will Flanary, M.D., left, on a receiving long after his presentation at the American Thoracic meeting in San Diego.

At the ATS conference, he stuck mainly with material from his personal life, telling stories and jokes about his two bouts with testicular cancer and an episode of sudden cardiac arrest in his sleep on May 11, 2020, that he survived partly because his wife, Kristin Flanary, administered cardiopulmonary resuscitation for 10 minutes until an ambulance arrived. Flanary made a plea for considering the impact that major medical events have “on people around the patient.”

“For an outside-of-hospital cardiac arrest, it is usually a loved one that responds. That has an effect on people. That is traumatic. We ask people to do chest compressions. We should also be giving support to people who do them,” Flanary said in a serious vein.

About his wife he said, “As grateful as I am for the people who took care of me in the ICU [intensive care unit], I am just as grateful for those who showed her some compassion along the way.”

Flanary had plenty of jokes and for-the-laughs commentary — about residency, discovering his testicular cancer, banking his sperm and his recovery and treatment from sudden cardiac arrest. Full-throated laughter rolled out easily and often from the audience of several thousand in one of the cavernous ballrooms of the San Diego Convention Center, and hundreds of Glaucomflecken fans lined up to have their picture taken with Flanary at a reception after his talk.

In his presentation, Flanary congratulated the audience: “You finally got an ophthalmologist to come in on a Saturday.”

He told a story about an attending physician who told him to him start an ECMO (extracorporeal membrane oxygenation) protocol when he was on an intensive care unit rotation as an intern at a community hospital. “I hung up the phone, I walked into the physician workroom, I took a deep breath, and I googled, ‘What is ECMO?’”

He said his first case of testicular cancer when he was a medical student was caught early and was treated with orchidectomy: “I was a little off balance, but I was fine.”

He said he learned two things when four years later he felt a lump in his other testicle when he was a senior resident at the University of Iowa.

“No. 1, I was part of the lucky less than 1% of people with testicular cancer who have a primary cancer in the other testicle. It is extraordinarily rare.The other thing I learned is that I am really good at finding my own testicular cancer. Could be a second career for me, which would be a weird thing to do as an ophthalmologist. Although it is all just balls.”

Flanary compared the wearable cardioverter defibrillator he wore after his sudden cardiac arrest to an “electric bra.” “But I was a good patient. I will wear this bra as long as you need me to, and now I know how amazing it feels to take a bra off at the end of a long day.”

Flanary said he did stand-up comedy when he was in high school in Houston. But rather than pursue a career in comedy, he said he took the easier route and became a doctor.

Flanary shared some observations about comedy and the appetite for it in healthcare and medical circumstances: “When we are faced with things in life that are beyond our control, humor allows us to take that thing and reassert control over it. You turn it into yours again. You present to others with humor. You share a laugh about it. That is why it is such a valuable coping mechanism, why so many people in healthcare over the past few years have been using a lot of humor, myself included, just to try to get through.”

Flanary touched only briefly on the business side of healthcare. Like many patients, he received multiple bills after the ospitalizations related to his cardiac arrest.

“It is extremely confusing. It was confusing for me, and I am a whole-
assed physician. You can imagine what it is like for our patients. That is what we are putting people through in this country when they are trying to recover from whatever they were in the hospital with. We are making them do this, [which] in my opinion, is often worse than the actual recovery from whatever illness they have.”

He ended with an expression of gratitude to the researchers in the audience. “I don’t know why you do what you do. I barely understand what a p value is. But I know it [research] is important.” Flanary continued, “As someone who has along the way benefited from the research that has brought the medical field to where it is today, I personally want to say thank you for the work that you do.”

Orangutans and humans are not that far apart when it comes to respiratory disease

Ecosystem health, animal health and human health are closely intertwined. Interdisciplinary collaboration between veterinarians and physicians can help each understand the larger picture of disease, said speakers at a plenary session at the conference.

Joining forces has been especially helpful when it comes to diagnosing and treating the respiratory illnesses of orangutans, many of which mirror the lung-related illnesses that affect people, said the experts who spoke at the plenary session.

Human and orangutans share about 97% of their genome with humans and have similar medical physiology and disease processes. Orangutans can contract human respiratory pathogens, resulting in acute and chronic airway disease, said Nancy Lung, V.M.D., M.S., editor in chief of the Journal of Zoo and Wildlife Medicine.

The orange-colored great apes are native to the Southeast Asian islands of Sumatra and Borneo. Their population has declined significantly over the past 50 years, and they are listed as endangered, Lung said. Much of their rainforest habitat has been lost to plantations of palm oil trees that yield palm oil, a versatile vegetable oil. “What’s happening in Indonesia and, more recently, in Africa and in South America is a well-
organized, multibillion-dollar corporate takeover of the rainforest to replace those forests with monocultures of oil palm,” Lung told
the ATS audience.

She said that the orangutan population in zoos and rescue centers worldwide is about 2,000. But about 20% of the orangutans in that population experience a respiratory disease similar to human cystic fibrosis. The disease, which is called orangutan respiratory disease syndrome (ORDS), is a chronic condition that affects the sinuses and air sacs in the lungs and is the leading cause of death among adolescent and adult orangutans.

“Orangutan respiratory disease syndrome is a constellation of recurrent infections in the sinuses in the airways of these animals. Over time, these recurrent infections lead to progressive airway destruction and early death,” said Jennifer Taylor-Cousar, M.D., M.S.C.S., A.T.S.F., a pediatric and adult pulmonologist at National Jewish Health, a leading respiratory hospital in Denver.

She said animal health researchers have had theories about the causes of ORDS, ranging from exposure to toxins or people to disease spread through fecal matter that is the result of overcrowding in zoos and rescue centers to the stress of captivity causing immunosuppression and greater chances of respiratory infection.

Now investigators are looking at whether ORDS results from variants of the cystic fibrosis transmembrane conductance regulator (CFTR). In people, patients with cystic fibrosis inherit two copies of a mutated CFTR gene. These mutated genes disrupt the function of the CFTR protein found in lung cells, which leads to a buildup of mucus and lung infections, as well as destruction of the pancreas.

Taylor-Cousar, along with Garry R. Cutting, M.D., in the McKusick-
Nathans Institute of Genetic Medicine of the Johns Hopkins University School of Medicine, published a study in January 2020 of 50 orangutans, 10 of which had chronic respiratory signs and symptoms. They found one potentially lethal variation of a CFTR allele in a healthy orangutan that is not found in humans. This altered gene was also found in the orangutan’s offspring that had died before birth.

But Taylor-Cousar and her colleagues did not find any other cystic fibrosis disease-causing CFTR mutations in the remaining population studied. “The fact that we did not find CFTR mutations in the 10 animals with the respiratory disease does not diminish the possibility of having mutations elsewhere in the genome,” they wrote.

During the ATS meeting, Taylor-Cousar said they plan to do a genomewide association study on these animals to identify what exactly is causing this respiratory disease.

Diseases in animals can provide insight about human health and vice versa, both Taylor-Cousar and Lung said during the session. “This is something we are beginning to understand, even more so because of climate change and its impact on environment and human health,” Taylor-Cousar said. “Interdisciplinary collaborations are necessary in the long run.”