Nasal samples identify asthma endotypes among minoritized youth

Key takeaways:

• Nasal sampling is considered safe and feasible among children.
• T2^LOW profiles were more predominant than T2^HIGH profiles.
• The study found 3,516 differentially expressed genes for T2^HIGH profiles.

Most youths with asthma had T17^HIGH and T2^LOW/T17^LOW endotypes of the disease based on transcriptomic profiles of nasal epithelium, according to a study published in JAMA.

Generally, T2^HIGH has been considered the most common endotype among youths with asthma, Juan Celedón, MD, DrPH, chief of pulmonary medicine at UPMC Children’s Hospital of Pittsburgh, and colleagues wrote.

“At present, we lack noninvasive tests to identify asthma subtypes or endotypes based on these cell types in school-aged children and adolescents,” Celedón, who also is professor of pediatrics at the University of Pittsburgh School of Medicine, told Healio.

Juan Celedón

“Identification of these endotypes is key to better understand causal pathways and develop effective treatments for asthma in youths, particularly those in minoritized groups with high asthma burden,” he continued.

Noting that asthma is the most common chronic respiratory illness among children around the world, the researchers said, racially and ethnically minoritized groups in the United States are disproportionately affected by childhood asthma.

Yet there have been few studies of proportions of asthma endotypes among youth, the researchers continued, including underserved groups, because bronchoscopies are difficult to conduct in children.

“We aimed to identify asthma endotypes in school-aged youth aged 6 to 20 years by studying the distribution and characteristics of transcriptomic (or gene expression) profiles in nasal epithelial samples,” Celedón said.

Nasal sampling is promising for characterizing transcriptomic profiles of asthma endotypes among these patients, the researchers said, because it is safe and feasible and because nasal and bronchial epithelial expression in children have high correlation.

Transcriptomic profiles

The researchers used data from three studies of youth with asthma:

• the Stress and Treatment Response in Puerto Rican and African American Children with Asthma, or STAR, study (n = 156; mean age, 14.2 years; 53.2% female; 71.8% Black or African American);
• the Epigenetic Variation and Childhood Asthma in Puerto Ricans, or EVA-PR, study (n = 237; mean age 15.4 years; 43% female; 100% Puerto Rican);
• the Vitamin D Kids Asthma, or VDKA, study (n = 66; mean age, 10.3 years; 41% female; 57.6% Black or African American); and

Nasal samples were collected and analyzed for gene expression from patients in each study.

Using k-means clustering based on eight signature genes, the researchers identified three distinct nasal epithelial transcriptomic profiles in each study:

• high expression of T2 pathway genes, which corresponds with the T2^HIGH asthma endotype;
• high expression of T17 pathway genes, which corresponds with the T17^HIGH asthma endotype; and
• low expression of T2 and T17 pathway genes, which corresponds with the T2^LOW/T17^LOW asthma endotype.

“The three nasal epithelial transcriptomic profiles occurred in similar proportions across the three study cohorts, despite differences in racial or ethnic composition and geographic location,” Celedón said.

In all three studies, he continued, the T2^HIGH profile was least common.

Proportions of patients with upregulated T2 signature genes included 25.6% (n = 40) in STAR, 29.1% (n = 69) in EVA-PR and 22.7% (n = 15) in VDKA.

Proportions of patients with upregulated expression of T17 signature genes or T17^HIGH profile included 36.5% (n = 57) in STAR, 35% (n = 83) in EVA-PR and 47% (n = 31) in VDKA.

Proportions of patients with no upregulated expression of T2 or T17 signature genes or T2^LOW/T17^LOW profile included 37.8% (n = 59) in STAR, 35.9% (n = 85) in EVA-PR and 30.3% (n = 20) in VDKA.

Patients with a T2^HIGH profile in STAR were more likely to be Puerto Rican and have allergic rhinitis as diagnosed by a physician, higher annual household incomes, and one or more asthma-related visit to urgent care or the ED during the prior year compared with those patients with a T2^LOW profile.

Also, the researchers said, 81.9% of the patients with T2^LOW profiles in STAR were African American.

The patients with T2^LOW/T17^LOW profiles were older than the patients with T17^HIGH profiles in both STAR and VDKA.

In STAR and EVA-PR, overweight and obesity were more common among patients with a T2^LOW profile. In VDKA, overweight and obesity were more common among patients with a T2^HIGH profile.

Patients with T2^HIGH profiles had higher total IgE and eosinophils than those with T2^LOW profiles across all three studies, with a P value of less than .001 in STAR.

Proportions of patients with the T2^HIGH profile and one or more positive allergen-specific IgE totals, defined as 0.35 IU/mL or higher, included 91.9% in STAR, 95.5% in EVA-PR and 66.7% in VDKA. These proportions ranged from 50% to 73.3% for those with T2^LOW profiles in all three studies.

Patients with T2^HIGH profiles had higher fractional exhaled nitric oxide than those with T2^LOW profiles in STAR (P < .001), the researchers added, but there were no significant differences between the profiles in lung function measures in any of the studies.

Further, the researchers aimed to identify the T2^HIGH profile via common biomarkers, including 417.5 IU/mL for total IgE, 210.4 cells/µL for eosinophils and 32.5 parts per billion for FeNO as cutoffs.

Proportions of patients in STAR who met these cutoffs included 84% for total IgE, 69% for eosinophils and 75% for FeNO. These proportions also included 70% for total IgE, 61% for eosinophils and 77% for predicted FeNO in EVA-PR and 58% for total IgE, 48% for eosinophils and 79% for predicted FeNO in VDKA.

A differential expression meta-analysis of 358 patients with consensus profiles, including 129 from STAR, 177 from EVA-PR and 52 from VDKA, identified 3,516 differentially expressed genes for T2^HIGH and 2,494 differentially expressed genes for T17^HIGH.

Also, a canonical pathway enrichment analysis of upregulated genes found that the highest enriched pathways for T2^HIGH were related to cellular signaling and that those for T17^HIGH were related to neutrophils or T17 signaling.

In gene ontology analyses of select T2 and T17 gene modules, glycoprotein-related pathways and IL-13 signaling were upregulated in the T2^HIGH profile, and pathways that were related to virus, cytokine and interferon-gamma responses were upregulated in the T17^HIGH profile.

Conclusions, next steps

Based on these findings, the researchers concluded that T2^LOW asthma endotypes were more common than T2^HIGH endotypes among racially and ethnically minoritized youths with asthma.

“We also show that atopy (sensitization to at least one allergen) alone or any single biomarker (eg, total immunoglobulin E or blood eosinophils) has poor accuracy to define T2^HIGH asthma, which may explain why some persons considered to have T2^HIGH asthma based on single biomarkers do not respond well to monoclonal antibodies for severe asthma,” Celedón said.

The researchers also said that their cutoffs of 418 IU/mL for total IgE and 28 ppb for FeNO, which are higher than those typically used in clinical practice, could be used to identify T2^HIGH asthma and predict a T2^HIGH profile with high accuracy.

“These study results should enable endotype-targeted clinical trials of new and much-needed therapies for T17^HIGH asthma in diverse youth,” Celedón said.

Precision biomarkers and therapeutics may result from the expanded T2 and T17 transcriptomic signatures developed in this study, the researchers added, which may be resources in identifying additional pathway-related genes.

“We are planning longitudinal studies to assess whether and how asthma endotypes change over time (eg, after puberty) or as a result of treatment,” Celedón said. “Moreover, we will be studying potential risk factors for the different asthma endotypes.”

Reference:

• The nose knows: Nasal swab detects asthma type in kids. https://www.chp.edu/media/news/010225-asthma-test. Published Jan. 2, 2025 Accessed Jan. 2, 2025.