Nasal Swab Test Characterizes Asthma Endotype from Transcriptomic Profiles

Researchers at the University of Pittsburgh have developed a nasal swab test for children and youth that helps clinicians diagnose specific asthma subtypes, or endotypes, using nasal epithelial gene expression data. The developers say the noninvasive approach could help clinicians prescribe medications more precisely for individual patients, and pave the way for research toward better treatments for lesser-studied asthma types, which have previously been difficult to diagnose.

The investigators report on data from three independent U.S.-based studies with the test, which focused on Puerto Rican and African American youths, who have higher rates of asthma and are more likely to die from the disease than their non-Hispanic white counterparts.

“Asthma is the most common chronic disease of childhood, and it disproportionately affects Black and Puerto Rican children, so it’s essential that we develop new therapies to better treat these young patients,” said Juan Celedón, MD, DrPH, professor of pediatrics at Pitt and chief of pulmonary medicine at UPMC Children’s Hospital of Pittsburgh. “Because asthma is a highly variable disease with different endotypes, which are driven by different immune cells and respond differently to treatments, the first step toward better therapies is accurate diagnosis of endotype.”

Celedón is senior author of the researcher’s published paper in JAMA, titled, “Transcriptomic Profiles in Nasal Epithelium and Asthma Endotypes in Youth.”

Asthma is the most common chronic respiratory illness among children worldwide, the authors wrote. In the United States, there are higher rates of emergency department and urgent care visits for asthma in Puerto Rican and non-Hispanic black children, than for non-Hispanic white youths, aged 6 to 20 years.

Traditionally, asthma has been classified into endotypes known as T2-high or T2-low based on the amount of T helper 2 (T2) inflammation present. “T helper 2 (T2)–high asthma is characterized by enhanced T2 immune responses with high serum levels of T2 cytokines (interleukin [IL]-4, IL-5, and IL-13) and elevated total immunoglobulin E (IgE) and airway eosinophils,” the authors wrote. “Several monoclonal antibodies are currently used to treat T2-high asthma, with medications selected according to T2 biomarkers, such as blood eosinophils and total IgE.” In contrast, far less is known about identifying and treating T2-low asthma. More recently, T2-low has been split into two endotypes, T17-high, which has less T helper 2 inflammation and more T helper 17 inflammation, and T2-low/T17-low (low-low), which has low levels of both types of inflammation.

Precise diagnosis of endotype usually involves genetic analysis of a lung tissue sample taken by a procedure called a bronchoscopy, which is done under general anesthesia. For children, especially those with milder disease, it’s not feasible or ethical to perform this invasive procedure. “Few studies have been published about the frequency of asthma endotypes in youth, including underserved groups, due to the difficulty of conducting bronchoscopies in children,” the team wrote. Clinicians have instead had to rely on imperfect tools, including immune markers in the blood, lung function, and whether or not they have allergies.

“These tests allow us to presume whether a child has T2-high disease or not,” said Celedón. “But they are not 100% accurate, and they cannot tell us whether a child has T17-high or low-low disease. There is no clinical marker for these two subtypes. This gap motivated us to develop better approaches to improve the accuracy of asthma endotype diagnosis.” The authors further stated, “A promising approach to characterizing transcriptomic profiles of asthma endotypes in youth is nasal sampling, given its safety, feasibility, and evidence of high correlation between nasal and bronchial epithelial expression in children.”

For their reported study, Celedón and team, including first authors Molin Yue, a Pitt graduate student, and Kristina Gaietto, MD, MPH, instructor of pediatrics at Pitt, collected nasal swab samples from 459 youth across three different studies. They then analyzed the expression of eight T2 and T17 signature genes.

The results confirmed that analysis of nasal swab samples revealed a patient’s endotype. Across the three studies, 23–29% of participants had T2 high, 35–47% had T17-high, and 30–38% had low-low endotype. “Cluster analysis of 8 signature genes in nasal epithelium from 3 studies of predominantly racially and ethnically minoritized youths with asthma revealed 3 mutually exclusive profiles corresponding to T helper 2 (T2)–high, T helper 17 (T17)–high, and T2-low/T17-low asthma endotypes, which were identified in similar proportions across the 3 studies, despite differences in racial and ethnic composition and geographic location,” the team reported.

T2-high had been considered the most common asthma endotype in school-aged youths aged 6–20 years, but the study showed that T2-low endotypes, including T17-high and T2-low/T17-low transcriptomic profiles, were more prevalent in all three studies.

Biologic drugs that target the immune cells driving disease are available for treating severe T2-high asthma, but there are no available asthma biologics that directly target T17-high and low-low endotypes. And in the absence of T17-high biomarkers, trials of T17 pathway-blocking agents have been conducted in patients with any asthma endotype, and have yielded disappointing results, the authors noted.

“We have better treatments for T2-high disease, in part, because better markers have propelled research on this endotype,” said Celedón. “But now that we have a simple nasal swab test to detect other endotypes, we can start to move the needle on developing biologics for T17-high and low-low disease.” The authors added, “Nasal transcriptomic profiling may enable endotype-targeted trials of much-needed therapies for T17-high asthma, particularly in racially and ethnically minoritized youths.”

The team’s rapid test for asthma endotype could also help push forward other areas of asthma research. “This study developed expanded T2 and T17 transcriptomic signatures … as a resource for the identification of additional pathway-related genes to inform the development of precision biomarker profiles and therapeutics,” the investigators stated.

“One of the million-dollar questions in asthma is why some kids get worse as they enter puberty, some stay the same, and others get better. Before puberty, asthma is more common in boys, but the incidence of asthma goes up in females in adulthood,” said Celedón. “Is this related to endotype? Does endotype change over time or in response to treatments? We don’t know. But now that we can easily measure endotype, we can start to answer these questions.”

Commenting on the research, Gustavo Matute-Bello, MD, acting director of the Division of Lung Diseases at the National Heart, Lung, and Blood Institute, part of the National Institutes of Health (NIH) added, “Having tools to test which biological pathways have a major role in asthma in children, especially those who have a disproportionate burden of disease, may help achieve our goal of improving asthma outcomes. This research has the potential to pave the way for more personalized treatments, particularly in minority communities. More studies are needed.”

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