USF Health physician-scientist Dr. Juan Carlos Cardet was co-first author for the New England Journal of Medicine article reporting results of the long-awaited PREPARE trial

TAMPA, Fla (Feb. 26, 2022) — Black and Latinx patients suffer disproportionately from asthma, a chronic inflammatory disease with symptoms including shortness of breath, tightness in the chest, coughing, and wheezing. They experience more severe asthma, higher rates of asthma-related emergency department visits and hospitalizations, and approximately double the asthma death rates compared to white patients.

A new approach for managing moderate-to-severe asthma, known as single maintenance and reliever therapy, combines two medications in one inhaler for control of underlying inflammation and quick relief of acute symptoms. While this strategy has gained interest and led to updated guidelines for patients, no studies to date have focused on Black and Latinx populations.

To help address the lack of comparable data for these underrepresented populations, the PREPARE (PeRson EmPowered Asthma RElief) trial enrolled 1,201 Black and Latinx adults (ages 18 to 75)  with moderate-to-severe asthma. The study was conducted November 2017 to April 2021 at 19 sites in the U.S., including the USF Health Morsani College of Medicine, and Puerto Rico. Participants were randomized to one of two groups. In addition to continuing their usual asthma medications, half of the participants (intervention group) received one-time instruction on how to use inhaled corticosteroids whenever they dispensed airway-opening reliever medications via a nebulizer or rescue inhaler. The other half (control group) also continued their usual care (UC) but did not dispense inhaled corticosteroids as needed to treat asthma attacks along with quick-relief medications. All patients had one instructional visit followed by 15 monthly questionnaires.

The PREPARE study demonstrated that this new intervention, called Patient-Activated Reliever-Triggered Inhaled Corticosteroids (PARTICS), substantially reduced severe asthma attacks, improved asthma control and quality of life, and decreased lost days from work or school.

The study results were presented by USF Health physician-scientist Juan Carlos Cardet, MD, MPH, Feb. 26 at the 2022 Annual Meeting of the American Academy of Allergy, Asthma & Immunology (AAAAI) and simultaneously published in The New England Journal of Medicine.

“Despite decades spent trying to find effective solutions to address the health disparities in asthma care, we haven’t made a significant dent in the problem,” said Dr. Cardet, an assistant professor in the USF Health Division of Allergy and Immunology. “The patient-centered PARTICS intervention we investigated works in underrepresented populations with poorly controlled asthma. It’s feasible, low cost, and may be easy to implement and help reduce the burden of complications from asthma if we can bring it to the clinic.”

Dr. Juan Carlos Cardet of the USF Health Morsani College of Medicine’s Allergy and Immunology Division studies better ways to treat poorly controlled asthma, including in underserved populations.

Dr. Cardet was the PREPARE study’s co-first author along with Elliot Israel, MD, the Gloria M. and Anthony C. Simboli Distinguished Chair in Asthma Research and director of Clinical Research in the Pulmonary and Critical Care Division, Brigham and Women’s Hospital. Thomas Casale, MD, a professor of medicine and pediatrics in the USF Health Division of Allergy and Immunology, helped execute the study as the USF site principal investigator.

Among PREPARE’s key findings:

• The annualized rate of severe asthma exacerbations was 0.69 per patient for participants in the PARTICS+UC group; the rate was 0.82 for the control group.
• Participants in the PARTICS+UC group also showed improved scores for asthma control and quality of life compared to patients in the control group.
• Those in the PARTICS+UC group also missed fewer days of school, work or other usual activities compared to the control group (13.4 versus 16.8 days)

A distinctive aspect of the PREPARE trial was the degree of engagement by patients to help optimize the study. Researchers collaborated with Black and Latinx adults with asthma as well as asthma caregivers — called Patient Partners — who are among the NEJM paper’s coauthors.

Dr. Cardet, working with Dr. Israel worked with other collaborators, designed a symptom-driven treatment approach consistent with what patients wanted; that is, an intervention intended to help control the chronic inflammation of asthma (with an inhaled corticosteroid) at the same time an inhaled reliever medication is delivered to ease severe flare-ups of symptoms.

Many patients are prescribed complicated regimens of controller medications to be taken daily, even on days when they experience no need for a fast-acting medication to open their constricted airways,” Dr. Cardet said. “In real life, patients may or may not adhere to that regimen when they’re feeling OK, but they will use their medications when symptoms arise.”

This work was supported by a Patient-Centered Outcomes Research Institute (PCORI) Project Program Award (PCS-1504-30283), the Gloria M. and Anthony Simboli Distinguished Chair in Asthma Research Award, grant #K23AI125785 from the National Institute of Allergy and Infectious Diseases (NIAID) and grant #AI-835475 from the American Lung Association (ALA)/American Academy of Allergy, Asthma & Immunology (AAAAI).

Dr. Cardet is a co-investigator for the Precision Interventions for Severe and/or Exacerbation-Prone Asthma Network (PrecISE) sponsored by the National Heart, Lung, and Blood Institute (NHLBI). This multisite clinical study, which aims to identify biomarkers to guide development of targeted treatments for severe asthma, is also seeking participants from underrepresented populations.

USF Health’s Dr. Juan Carlos Cardet was among the authors of a new multi-site clinical study reported in the New England Journal of Medicine

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Black children respond differently to step-up asthma therapy than black adolescents and adults, report authors of a major study published Sept. 26 in the New England Journal of Medicine. Among the NEJM authors of the multi-site Best African American Response to Asthma Drugs (BARD) clinical study was Juan Carlos Cardet, MD, MPH, assistant professor in the USF Health Morsani College of Medicine Division of Allergy and Immunology.

Nearly half of black children with poorly controlled asthma (46%) fare better by increasing their dose of inhaled steroid (glucocorticoids) alone, without adding a long-acting beta agonist (LABA), the researchers found. Just as many black children (46%) experience improved asthma control by adding a LABA to their lower-dose inhaled glucocorticoid regimen.

In contrast, black adolescents and adults are more likely to have a superior response by adding a LABA to their inhaled glucocorticoid treatment rather than only escalating (stepping up) the dose of inhaled glucocorticoids, the BARD researchers reported.

Dr. Cardet was an investigator for the BARD study when he was faculty member at Harvard Medical School. At USF Health, he is an investigator for several clinical research networks supported by the National Institutes of Health’s National Heart, Lung and Blood Institute (NHLBI), including its Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) network.

Inhaled glucocorticoids, which reduce airway inflammation, are a first-line therapy to control asthma. When asthma becomes severe and difficult to control, physicians often recommend adding a LABA (long-lasting bronchodilator that relaxes constricted airways) to the inhaled steroid treatment as the gold standard step-up therapy. However, this standard was based on other studies that historically included by too few black people, who suffer higher rates of serious asthma attacks, hospitalizations and asthma-related deaths than white people, Dr. Cardet said.

To address this disparity, two parallel randomized double-blind sequential cross-over BARD trials compared the effectiveness of different doses of inhaled glucocorticoids, with or without the addition of the LABA (salmeterol) in two groups: children ages 5 to 11, and adolescents and adults (ages 12 and older). All 574 participants had at least one grandparent who identified as black and asthma inadequately controlled while on a low dose of inhaled glucocorticoids. A composite measure incorporating frequency of asthma attacks and asthma control days as well as changes in lung function was used to calculate treatment response during each 14-week regimen.

Juan Carlos Cardet, MD, MPH

While several previous retrospective studies suggested otherwise, most of the black adolescents and adults with poorly controlled asthma responded better to adding a LABA to step-up treatment compared to those only receiving increased inhaled steroid doses. This BARD trial finding was similar to that in previous mixed (largely white) population studies – although 20-25% of the black adolescents and adults showed no difference in their responses to these approaches.

“But the black children responded differently. They had an equal chance of responding best to increasing their dose of inhaled steroid as they did to the addition of a long-acting beta agonist,” Dr. Cardet said.

The researchers also found that neither the percentage of African ancestry (evaluated by genotyping) nor baseline biomarkers could predict the response to step-up therapy.

A larger, more simplified trial is needed to determine which step-up therapy option works best for which black children, the researchers wrote, adding that their study demonstrates a need for trials of specific subgroups: “These findings suggest that data cannot be extrapolated from mixed populations to specific subgroups, including those of different ages and races.”

An NIH-funded physician scientist, Dr. Cardet says he is driven to improve asthma therapy through translational research by a family history of the chronic disease and by racial and ethnic disparities in asthma illness and deaths, including in his native Puerto Rican community. He is a co-investigator for the PREPARE Study for PeRson EmPowered Asthma Relief, a multisite trial sponsored by the Patient-Centered Outcomes Research Institute (PCORI), which focuses on African-American, Hispanic and Latino adults. Dr. Cardet is also the local principal investigator for a NHLBI PrecISE grant aiming to identify biomarkers to guide development of targeted treatments for severe asthma.

As the principal investigator for a five-year K23 National Institute of Allergy and Infectious Diseases (NIAID) grant, he has been examining whether higher levels of the gut microbe metabolite enterolactone may benefit asthma control. Dr. Cardet is testing the effects of enterolactone, a plant estrogen with antioxidant and anti-inflammatory properties, in preclinical models of allergic airway inflammation.