How We Treat Type 2 Low Asthma

Figure 1 reflects our multidisciplinary approach to the patient with poorly controlled, severe asthma who has run the gamut of guideline-based therapies. Our approach starts with ensuring the patient has objective physiologic and radiographic data that support a diagnosis of asthma. If not already recently completed, we begin our evaluation with complete pulmonary function tests (PFTs; including spirometry with bronchodilator, lung volumes, and diffusing capacity) and obtain a high-resolution chest CT scan (HRCT). Normal PFTs would not be expected in a patient with severe persistent asthma, especially if symptomatic at the time of testing (as would be expected with this diagnosis). In addition, a patient with severe asthma should have CT-evidence of airway wall thickening and air trapping. In patients who have a confirmed asthma diagnosis with typical PFT and HRCT findings, poor disease control should prompt consideration of challenges with inhaler adherence, affordability, or improper technique. Unaddressed social and environmental drivers of asthma control are additionally paramount to address and often require a multidisciplinary approach with social work, legal aid, and/or asthma educators.¹

Figure 1.

In the absence of PFT or HRCT changes typical of asthma, we consider alternative diagnoses. In those with normal PFT and HRCT, we explore vocal cord dysfunction/irritable laryngeal syndrome, gastroesophageal reflux/microaspiration, and posterior pharyngeal drainage. Abnormal findings on HRCT such as bronchiectasis, ground glass opacifications, consolidations, or tree-in-bud opacity warrant referral to pulmonary for additional diagnostic testing, including consideration of bronchoscopy.

When HRCT and PFT are consistent with asthma and no additional diagnoses are considered in a patient who has failed multiple biologics, additional treatment should be individualized. Although asthma phenotyping usually hinges on non-invasive testing (including exhaled nitric oxide (eNO)), there can be remarkable discordance between biomarkers of inflammation (e.g. blood eosinophil levels) and actual airway inflammation. Bronchoscopy can be used to clarify the subtype of airway inflammation present. BAL inflammatory signatures can be defined as eosinophilic (≥1%), neutrophilic (≥6%), mixed granulocytic (both), or paucigranulocytic (neither).²

Paucigranulocytic disease may reflect severe airway remodeling, smooth muscle hypertrophy, neurogenic inflammation, or a primary mast cell process. This endotype might respond to long-acting muscarinic antagonists (LAMAs) or theophylline. Neutrophilic asthma invites several approaches. Corticosteroids (CCS) are ineffective and may actually worsen neutrophilic asthma through their inhibitory effects on neutrophil apoptosis, thereby paradoxically promoting PMN accumulation.³ Furthermore, CCS can promote infectious complications. LAMAs should be utilized especially for their potential in preventing exacerbations.⁴ Azithromycin can be remarkably beneficial in neutrophilic inflammatory airway diseases, acting more through its anti-inflammatory than its antimicrobial effects.^5,6 The disappearance of theophylline from our armamentarium may have denied patients with non-T2 disease access to an agent that could be beneficial. Both theophylline and phosphodiesterase 4 antagonists have anti-inflammatory signatures that suggest efficacy in neutrophilic disease.^7,8 Currently only anecdotal reports suggest plausible interventions when these approaches fail, such as utilization of hydroxychloroquine, methotrexate, and anti-inflammatory agents. These studies all suffer from a failure of assiduously defining inflammatory phenotype before enrolling subjects. For example, methotrexate was widely explored for its efficacy in steroid-dependent asthma with controlled studies arguing for and against its use.^9,10 Methotrexate displays effective anti-inflammatory efficacy in other neutrophilic disorders and it is intriguing whether inclusion of exclusively neutrophilic asthmatics in those earlier studies would have demonstrated less ambiguous support for its use.

In summary, a multidisciplinary approach is critical to improve the health of the patient with severe asthma. Our practice revolves around 1) Confirming asthma with PFT and often HRCT; 2) considering alternative or concomitant diagnoses; 3) eliminating social or environmental determinants of poor asthma control; and 4) illuminating airway inflammatory subtypes to help determine which patient-targeted therapies to utilize.