Treatment options in type-2 low asthma

Abstract

Monoclonal antibodies targeting IgE or the type-2 cytokines IL-4, IL-5 and IL-13 are proving highly effective in reducing exacerbations and symptoms in people with severe allergic and eosinophilic asthma respectively. However, these therapies are not appropriate for 30–50% of patients in severe asthma clinics who present with non-allergic, non-eosinophilic, “type-2 low” asthma. These patients constitute an important and common clinical asthma phenotype, driven by distinct, though poorly understood pathobiological mechanisms. In this review we describe the heterogeneity and clinical characteristics of type-2 low asthma and summarise current knowledge on the underlying pathobiological mechanisms, which includes neutrophilic airway inflammation often associated with smoking, obesity, occupational exposures and may be driven by persistent bacterial infections and by activation of a recently-described IL-6 pathway. We review the evidence base underlying existing treatment options for specific treatable traits which can be identified and addressed. We particularly focus on severe asthma as opposed to difficult-to-treat asthma, on emerging data on the identification of airway bacterial infection, on the increasing evidence base for the use of long-term low-dose macrolides, a critical appraisal of bronchial thermoplasty, and evidence for the use of biologics in type-2 low disease. Finally we review ongoing research into other pathways including TNF, IL-17, resolvins, apolipoproteins, type I interferons, IL-6 and mast cells. We suggest that type-2 low disease frequently presents opportunities for identification and treatment of tractable clinical problems and is currently a rapidly evolving field with potential for the development of novel targeted therapeutics.

Uncontrolled Asthma: Unmet Needs in the Management of Patients

“…41 The most frequent extra-respiratory comorbidities are atopy, chronic rhino-sinusitis, sleep apnoea, gastroesophageal reflux and obesity, whereas smoking habits, psychological disorders such as depression or anxiety are the most common psychosocial traits. 44 Vocal cord dysfunction affects one out of four patients with asthma 45 and its prevalence is even higher in severe asthma; 46 if not properly treated with speech and language therapy it may be responsible for pharmacological over-treatment. The same problem may be due to dysfunctional breathing, which can be successfully cured with physiotherapy.…”

“…Other treatable traits, such as rhinitis and gastroesophageal reflux, have a slight role in the control of the disease. 41,44 The identification of different inflammatory phenotypes of severe asthma as T2 high eosinophilic or T2 low, neutrophilic or paucigranulocytic has led to a more personalized therapy, based on the use of different monoclonal antibodies.…”

“…50 Moreover, the currently available biologics are only effective in eosinophilic or allergic asthma, whereas no options exist in non-eosinophilic asthma. 44 Furthermore, the different biology of neutrophils, which https://doi.org/10.2147/JAA.S260604…”

“…Journal of Asthma and Allergy 2021:14 are widely involved in the immune response and other biologic processes, suggests that a treatment strategy based on anti-IL-5 or anti-IgE mechanisms, leading to a strong reduction or elimination of eosinophils or IgE, may be not optimal in every patient. 44,48 Currently, although several pathways may be potentially targeted in T2 low asthma, no specific treatments are available. Moreover, concomitant treatable traits in the same patient with eosinophilic asthma may enhance the inflammation with a specific different inflammatory pattern.…”

Targeting neutrophils in asthma: A therapeutic opportunity?

“…The neutrophilic component in asthma is considered to mainly originate from innate immune responses towards air pollutants (vehicle exhaust or cigarette smoke) or infectious agents, but also obesity and gastroesophageal reflux could promote airway neutrophilia [4]. The mechanisms underlying neutrophilic asthma are less understood, but include the induction of Th1 or Th17 responses, leading to interferon γ (IFN γ) and IL-17 release, which are critical for antimicrobial responses and promote neutrophil and monocyte recruitment to sites of inflammation.…”