Trends in Molecular Medicine
Volume 26, Issue 11, November 2020, Pages 1047-1058
Journal home page for Trends in Molecular Medicine

Review
Novel Therapies for Pneumonia-Associated Severe Asthma Phenotypes

https://doi.org/10.1016/j.molmed.2020.07.006Get rights and content

Highlights

  • Streptococcus pneumoniae is a leading global cause of pneumonia. While asthma is now recognised as a heterogeneous disease, people with severe asthma are fourfold more likely to develop pneumonia.

  • Pneumococcal nasopharyngeal carriage and viral infections frequently coexist in asthmatics. Respiratory viruses will cause bacterial dispersion deeper into the lower airways to cause pneumonia.

  • Type-2 inflammation results in the emergence of alternatively activated macrophages in asthma that are defective at phagocytosing bacteria, which can permit the establishment of lower respiratory tract infections.

  • Excessive neutrophilic inflammation is an inflammatory feature of both pneumonia and severe asthma. Novel therapies that target both neutrophils and type-2 inflammation have the potential to improve the pathological features of severe asthma.

Distinct asthma phenotypes are emerging from well-defined cohort studies and appear to be associated with a history of pneumonia. Asthmatics are more susceptible to infections caused by Streptococcus pneumoniae; however, the mechanisms that underlie defective immunity to this pathogen are still being elucidated. Here, we discuss how alternatively activated macrophages (AAMs) in asthmatics are defective in bacterial phagocytosis and how respiratory viruses disrupt essential host immunity to cause bacterial dispersion deeper into the lungs. We also describe how respiratory pathogens instigate neutrophilic inflammation and amplify type-2 inflammation in asthmatics. Finally, we propose novel dual-acting strategies including granulocyte-colony-stimulating factor receptor (G-CSFR) antagonism and specialised pro-resolving mediators (SPMs) to suppress type-2 and neutrophilic inflammation without compromising pathogen clearance.

Section snippets

The Link between Pneumococcal Pneumonia and Asthma

Asthma is a chronic airway inflammatory disease that affects over 300 million people worldwide [1]. Typically, the airways in asthmatic patients have pathological levels of airway remodelling that leads to variable and reversible airflow obstruction manifesting as bronchial hyperresponsiveness [2]. These pathologies are classically driven by a dominant CD4+ T-helper type-2 (Th2) inflammatory response commonly caused by exposures to aeroallergens such as house dust mites (HDMs) [3]. The release

Increased Pneumonia Risk in Distinct Severe Asthma Phenotypes

Asthma is now recognised as a heterogenous disease (Box 1) which can vary in both phenotype and severity. Of the total asthmatic population, it is estimated around 3%–10% suffer from severe asthma [15,16] which can account for up to 60% of asthma-associated healthcare costs [17]. Severe asthmatics are those that require maximal inhaler therapy, namely, the use of high-dose inhaled corticosteroids with or without a systemic corticosteroid [16]. Despite proper inhaler use, an estimated 3.6% of

Immune Response to Combat Streptococcus pneumoniae

Once colonisation of the nasopharynx has been established, varying circumstances afford Spn access to tissues beyond the nasal epithelium. The development of pneumonia is reliant on Spn accessing the lower airways where a bombardment of innate immune responses perpetuates lung injury. During the initial stages of infection, pneumococci encounter the respiratory epithelium which serves as a physical barrier against infection while also promoting leukocyte trafficking and secretion of

Mechanisms Involved in Reduced Bacterial Control in Asthmatics

The relationship between bacteria and asthma is complex and interrelated. For example, the ‘hygiene hypothesis’ is supported by epidemiological studies showing that asthma rates are lower in environments where early life endotoxin levels are elevated, as bacterial molecules can educate the immune system to mount an appropriate and proportionate response to airborne allergens. Consistent with the hygiene hypothesis, Spn antigens attenuate type-2 inflammation in allergic airways disease models.

Exuberant Immune Response to Respiratory Pathogens in Asthmatics

The consequence of repeated aeroallergen sensitisation and increased susceptibility to respiratory pathogens is the persistent recruitment and activation of neutrophils in the background of type-2 allergic inflammation (Figure 1). Neutrophils isolated from individuals with poorly controlled asthma also appear functionally altered compared with well-controlled asthmatics and healthy individuals. For instance, CXCL8 and neutrophil elastase release following fMLF

Novel Approaches in Targeting Neutrophils in Infection-Dependent Severe Asthma

Dual therapy strategies that block type-2 and neutrophilic inflammation without compromising bacterial or viral clearance mechanisms are needed to reduce the burden of severe asthma (Figure 2 and Clinician’s Corner). Currently available anti-inflammatory therapies, such as corticosteroids, treat type-2 inflammation, but they do not specifically target neutrophilic inflammation in asthmatics. The use of corticosteroids has also been shown to increase lung neutrophil survival [78] and is

Concluding Remarks

Independently, asthma and pneumonia constitute a significant global health problem. While there is a complex interplay between the two, it has become increasingly clear that asthmatics are more susceptible to developing pneumonia associated with increased viral–bacterial co-infections and the polarisation towards AAMs (see Outstanding Questions). It is conceivable that repeated incidents of lower respiratory tract infections could mediate the transition to severe asthma. Currently, severe

Acknowledgements

All figures were created with BioRender.com.

Disclaimer Statement

S.B. and N.W. have a patent that is relevant to this review.

Glossary

Alternatively activated macrophages (AAMs)
in contrast to classically activated macrophages polarised by interferon-γ, AAMs are induced by Th2-associated cytokines IL-4 and IL-13. While their role in asthma is debated, AAMs release anti-inflammatory cytokines such as IL-10 and upregulate markers such as arginase, chitinase and found in inflammatory zone 1 (FIZZ1).
Alveolar macrophages (AMs)
important phagocytic cells that provide the initial defence against pathogens that enter the airspaces. AMs

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