'Not Where We Need to Be' for Treating Severe Asthma

Aaron B. Holley, MD


July 21, 2020

Patients with severe asthma continue to pose a challenge for providers. While they account for only 3%-10% of the overall asthma population, their care consumes 60% of all asthma-related medical expenditures. The American Thoracic Society and European Respiratory Society issued guidelines on the evaluation and treatment of severe asthma in 2014, and in the first quarter of 2020, several papers published in the journal CHEST have addressed severe asthma management.

A review published in January by authors from the National Heart, Lung, and Blood Institute (NHLBI) summarized recent data on the type 2-low (T2L) asthma endotype. T2L is sometimes referred to as "noneosinophilic" or "neutrophilic" asthma, and although these terms aren't precisely synonymous, they will be used interchangeably here.

The hallmark of T2L asthma is a poor response to corticosteroids. Corticosteroid therapies, whether inhaled or oral, are considered a staple of asthma treatment in all guidelines. Depending on which sample is studied, anywhere from 50% to 70% of all asthmatics are the T2L endotype. The conclusion is chilling ─ a large portion of asthmatics, maybe even a majority, won't respond to our most effective therapy. How often do we chase T2L asthma with higher and higher doses of inhaled and oral corticosteroids? Unfortunately, quite often.

So, what's new in T2L asthma? The NHLBI paper provides an outstanding review of where we're going and where we've been, but the clinical realities remain sobering.

The diagnosis is challenging for clinicians, because sputum cell counts are hard to get and sputum neutrophilia doesn't correlate well with serum neutrophil levels. It's difficult to study because the sputum neutrophil thresholds for labeling a patient's asthma T2L vary from 40% to 70% in the literature. Although there are multiple molecular targets within the T2L immune system pathway, it is challenging to treat. Creating functional neutropenia isn't something we normally do purposely, and targeting the T2L pathway has resulted in increased cancers and infections in some studies.

As of today, it's unclear how the practicing clinician should be managing T2L asthma. A recent study of patients with mild asthma found tiotropium wasn't effective. In a separate randomized controlled trial, azithromycin was shown to reduce exacerbations and improve quality of life even in patients with T2L disease. However, older asthma studies showed no benefit with azithromycin, and macrolides have yet to be added to asthma guidelines as a treatment option. Thus, T2L asthma probably accounts for a significant proportion of patients with severe asthma, and we still lack an effective diagnostic and treatment approach to managing these patients.

Australian authors recently reviewed registry data for patients receiving bronchial thermoplasty. Because randomized controlled trials of bronchial thermoplasty excluded patients with lower FEV1 (typically using 60% as a cutoff), the authors of this paper stratified their analysis by those with an FEV1 above and below 50%. They found equivalent results; bronchial thermoplasty was effective and safe for patients, regardless of FEV1.

While this paper provides reassurance for fans of bronchial thermoplasty and will inch the field forward, it's hardly a game changer. In an accompanying editorial, aptly titled, "Bronchial Thermoplasty: A Treatment in Search of a Phenotype," a well-established asthma clinician-researcher makes his pitch for acknowledging the efficacy of bronchial thermoplasty in international guidelines. His argument isn't unreasonable, and it includes cost-efficacy data. He also catalogues the existing barriers to widespread implementation and acknowledges the limitations to the current study. Perhaps someone should study bronchial thermoplasty in patients with severe, T2L asthma.

All in all, the review of severe asthma and phenotyping is disappointing. It's well-written and does a good job of outlining the different methods for pheno- and endotyping patients with asthma. However, it doesn't get us any closer to operationalizing what we know and how to use it within the confines of a busy clinic. Similar severe asthma reviews have been written and published before.

In summary, all these papers are worth reading. Before getting discouraged about T2L asthma or asthma phenotyping in clinical practice, I have to remind myself how far we've come. We're not where we need to be, but we have more treatment options than ever before, and our diagnostics are improving. Personalized asthma therapy gets closer to being reality every day.

Aaron B. Holley, MD, is an associate professor of medicine at Uniformed Services University and program director of pulmonary and critical care medicine at Walter Reed National Military Medical Center. He covers a wide range of topics in pulmonary, critical care, and sleep medicine.

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