key: cord-1001141-qkkymj2d
authors: Johnston, Sebastian L.
title: Asthma and COVID‐19: is asthma a risk factor for severe outcomes?
date: 2020-05-02
journal: Allergy
DOI: 10.1111/all.14348
sha: ef37e8889922a0dde5f567eae7895923eb901f6c
doc_id: 1001141
cord_uid: qkkymj2d

When I first read the manuscript that accompanies this editorial, upon its online publication on February 19(th) 2020(1), COVID‐19 had already killed 2118 people in China, but only one person in Europe – an 80‐year‐old tourist from China, who died in France on the 15(th) February. I read the manuscript with grim fascination, as it was clear that SARS‐CoV‐2 had spread very rapidly in China which already had 74,576 cases and in South Korea which already had 58 cases, and that it was then invading Europe also, as France already had 12 cases, Germany 16, the UK 9, Italy 3, Spain 2 and other countries too.

doing to limit spread of SARS-CoV-2, we would be subject to a catastrophe as terrible as the one Wuhan was then experiencing. I did not then think that by the time of writing (4 th April, only 6 weeks later) COVID-19 mortality in four major European countries would already have exceeded that in China (2) . Such shocking statistics bring into sharp focus the need to identify risk factors for severe outcomes with COVID-19, and if possible, to favourably modify any risk factors that are amenable to modification.

We have known for 18 years that people with asthma are at risk of more severe outcomes with common cold virus infections than are people without asthma(3), and we also know that if asthma is not well controlled, virus-induced exacerbation severity is dramatically worsened in relation to the degree of lack of control (4) . We also know that many people with asthma have deficient and delayed innate anti-viral immune responses, with deficiency and delay in lung cell interferon (IFN)-α(5), IFNβ(6) and IFN-λ(7) responses reported in many studies, and deficiency of the latter IFN clearly related to increased asthma exacerbation severity (7) . Based on this evidence it would seem inevitable that asthma should be identified as a risk factor for severe outcomes in COVID-19. 

This article is protected by copyright. All rights reserved severe outcomes in COVID-19 in any of the larger case series reported to date either (9) . This is a surprise, but chronic respiratory disease had the third highest case fatality ratio, after cardiovascular disease and diabetes, in the largest case series (44,672 confirmed COVID-19 cases) reported to date(10). It is probable that cases of asthma were among those 511 chronic respiratory disease cases, but this information was not provided. I believe that as more case series with larger numbers of people with asthma included are reported, that asthma (particularly asthma in older people, as age has already been identified as the most important risk factor) will likely emerge as a significant risk factor for severity in COVID-19.

If that is the case, what can we do about mitigating this risk? Of course, even more than in "normal" times patients with asthma should refrain from smoking, as smoking has been clearly associated with worse outcomes in COVID-19 (11) . Since poor asthma control is a risk factor for greater virus-induced exacerbation severity(4), maintaining optimal asthma control will inevitably reduce risk of severe outcomes in COVID-19. Since all methods of optimising asthma control, whether they be inhaled steroids, combination inhaled steroid plus long acting bronchodilator therapies, or monoclonal antibody therapies, have been shown to substantially reduce exacerbation risk (the great majority of which are virus-induced), all standard asthma therapies should continue to be used to optimise asthma control, with certainty that this will reduce risk of adverse outcomes with COVID-19. Specific concerns have been raised in relation to steroid therapy and possible risk of adverse outcomes in COVID-19(12), however, since allergic airway inflammation in the lung, as occurs in asthma, will suppress anti-viral immunity in the lung(13), suppressing allergic airway inflammation with a topical steroid will restore antiviral immunity, so inhaled steroid treatment should be initiated/continued/increased as clinically indicated. These recommendations are supported by a recently published statement from the EAACI Section on Pediatrics (14) which concludes that "optimal disease control of allergic, asthmatic and immunodeficient children should be sought according to usual treatment guidelines".

One further specific method of modifying risk of severe outcomes with COVID-19 for people with asthma deserves special focus. Azithromycin 500mg three times per week has been shown to reduce asthma exacerbation frequency by ~40% and to improve quality of life in people with asthma that was

This article is protected by copyright. All rights reserved not adequately controlled on standard inhaler therapy (15) . The mechanisms of action of azithromycin in this study were not elucidated, but since we know that the great majority of asthma exacerbations are virus-induced, it seems likely that effects on antiviral immunity may have been involved.

We previously reported that azithromycin (but not erythromycin or telithromycin) substantially augments IFN-β and IFN-λ production from rhinovirus-infected human bronchial epithelial cells in vitro (16) . IFN-β and IFN-λ-induction by azithromycin in virus-infected bronchial epithelial cells in vitro was subsequently confirmed in a separate study, which also confirmed this property was variable among the 225 novel macrolides studied (potent in some, absent in others). One related macrolide induced IFNs ~5-fold, and was shown to significantly (P=0.023) suppress virus replication in bronchial epithelial cells from people with asthma (17) .

Anti-viral IFN production by virus-infected respiratory cells will be critical to host defense mediated by innate anti-viral immunity against SARS-CoV-2, a virus that we have no acquired immune response to.

Thus, treating/preventing COVID-19 severity with azithromycin in people with asthma in order to substantially boost IFN production by respiratory cells when infected with SARS-CoV-2, is clearly likely to be highly effective at reducing risk of severe outcomes. This conclusion is strongly supported by high quality clinical trial evidence that azithromycin prevents asthma exacerbations (which are mostly virusinduced) (15) and is effective in prevention of severe lower respiratory tract illnesses (respiratory viral infections) in preschool children (18) .

This conclusion is also supported by a study in COVID-19 patients without asthma (at least asthma was not mentioned in the entire manuscript), which found substantially greater benefit in SARS-CoV-2 virus load clearance in 6 patients treated with both azithromycin and hydroxychloroquine, compared to those treated with hydroxychloroquine alone (though the authors' rationale for giving azithromycin was "to prevent bacterial super-infection", not because of its virus-specific IFN-inducing properties, which they did not mention) (19) .

I would not normally make treatment recommendations in the absence of controlled clinical trials. However, these are not normal times. My recommendations to people with asthma and those treating them are most importantly to optimize asthma control with standard therapies, but if asthma control is not optimal despite appropriate use of standard therapies, to have a low threshold for starting azithromycin prophylaxis (because of its innate antiviral (IFN-boosting) property, at this time of enormous threat from COVID-19.

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