Childhood asthma heterogeneity at the era of precision medicine: Modulating the immune response or the microbiota for the management of asthma attack

Abstract

Exacerbations are a main characteristic of asthma. In childhood, the risk is increasing with severity. Exacerbations are a strong phenotypic marker, particularly of severe and therapy-resistant asthma. These early-life events may influence the evolution and be involved in lung function decline. In children, asthma attacks are facilitated by exposure to allergens and pollutants, but are mainly triggered by microbial agents. Multiple studies have assessed immune responses to viruses, and to a lesser extend bacteria, during asthma exacerbation. Research has identified impairment of innate immune responses in children, related to altered pathogen recognition, interferon release, or anti-viral response. Influence of this host-microbiota dialog on the adaptive immune response may be crucial, leading to the development of biased T helper (Th)2 inflammation. These dynamic interactions may impact the presentations of asthma attacks, and have long-term consequences. The aim of this review is to synthesize studies exploring immune mechanisms impairment against viruses and bacteria promoting asthma attacks in children. The potential influence of the nature of infectious agents and/or preexisting microbiota on the development of exacerbation is also addressed. We then discuss our understanding of how these diverse host-microbiota interactions in children may account for the heterogeneity of endotypes and clinical presentations. Finally, improving the knowledge of the pathophysiological processes induced by infections has led to offer new opportunities for the development of preventive or curative therapeutics for acute asthma. A better definition of asthma endotypes associated with precision medicine might lead to substantial progress in the management of severe childhood asthma.

Keywords: Acute asthma; Asthma exacerbation; Childhood; Microbiota; Therapeutics; Virus.

Graphical abstract

Fig. 1

Summary of the main mechanisms favoring asthma development and involved in asthma attack. These mechanisms (in red) involve: (1) Impairment of innate immune responses; (2) Influence of the host-microbiota dialog on Th2 inflammation; (3) Pathogen characteristics; (4) Airway leukocyte inflammation. These dynamic interactions may impact the presentations of asthma attacks, and have long-term consequences. AM: Alveolar macrophages; AEC: airway epithelial cells; DC: dendritic cells; IFN: Interferon; IL: Interleukin; ILC2: type 2 innate lymphoid cells; IRF: interferon regulatory factor; PAMP: Pathogen-associated molecular pattern; PRR: pattern recognition receptor; RV: Rhinovirus; TSLP: Thymic stromal lymphopoietin.

Fig. 2

Possible therapeutics strategies to limit asthma development/progression and attacks. These strategies (in green) target: (1) Enhancement of the innate immune responses; (2) Anti-infectious therapeutics and strategies to modulate the microbiota; (3) Alarmins and anti-Th2 biologics. AM: Alveolar macrophages; AEC: airway epithelial cells; DC: dendritic cells; IFN: Interferon; IL: Interleukin; ILC2: type 2 innate lymphoid cells; IRF: interferon regulatory factor; PAMP: Pathogen-associated molecular pattern; PRR: pattern recognition receptor; RV: Rhinovirus; SCFA: Short Chain Fatty Acid, TSLP: Thymic stromal lymphopoietin.