key: cord-0858210-mb6peb16
authors: Carr, Tara F.; Kraft, Monica
title: Asthma and Atopy in COVID-19: 2021 Updates
date: 2021-12-21
journal: J Allergy Clin Immunol
DOI: 10.1016/j.jaci.2021.12.762
sha: c5487f7213e3005a7fdde38d03911c47e0581d27
doc_id: 858210
cord_uid: mb6peb16

nan

The SARS-CoV-2 pandemic has presented an unprecedented challenge for patients and their healthcare providers. Asthma is a disease in which patients are susceptible to viral-exacerbated morbidity. Asthmarelated complications seemed to decline during pandemic-inflicted isolation and distancing procedures, assumed to be a result of less circulation of and exposure to common viruses(1). However, the extent to which asthma or atopy is a risk factor for more severe COVID-19 disease-related outcomes such as respiratory failure, requirement for intensive care, and death, has been of significant interest. Additionally, the potential impact of therapy for asthma and atopic disease, such as corticosteroids and biologics, on those risks was not clearly understood. Research on this disease, spanning mechanistic to epidemiologic, has started to shed light on the major areas of concern to patients with asthma, their families, and their physicians.

Risk for severe COVID19 disease in asthma/severe asthma Early descriptive cohort studies of patients with COVID-19 disease reported low rates of asthma or atopic diseases. Bloom et al. presented data from all patients admitted to the hospital with COVID-19 disease across England, Scotland, and Wales between January and August of 2020, as captured by the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study (2) . The group identified patients with a diagnosis of asthma and/or chronic pulmonary disease, and measured mortality with adjustment for demographics, comorbidities and medications. Patients using an inhaled corticosteroid, long acting beta agonist, and third maintenance medication were designated as severe asthma. Patients with asthma were more likely than those without asthma to require critical care; mortality was increased for only those with severe asthma compared with no asthma (adjusted hazard ratio 1.96 [1.25-3.08] for 16-49 year olds and 1.24 [1.04-1.49] for 50+ year olds). In older patients with asthma, inhaled corticosteroid use within 2 weeks prior to hospital admission was associated with decreased mortality when compared with those not using medication for asthma. These data suggest that severe asthma, but not the use of inhaled corticosteroids, might be a risk factor for adverse outcomes with this infection.

In contrast, a retrospective analysis of inpatients and outpatients presenting to the Mount Sinai Health System in New York between March and June 2020 evaluated outcomes between those with and without asthma. Adjusting for COVID-19 disease severity, comorbidities and therapy, patients with asthma had a lower mortality and rate of hospitalization and ICU admission than those without asthma (3) . Additional cohorts continue to be published, with varied methods and outcomes, but asthma does not seem to be a consistent risk factor for COVID-19-related mortality.

Terry et al. (4) performed a meta-analysis of 150 studies worldwide that published the prevalence and severity of COVID-19 in patients with asthma, by region. While the proportion of patients with asthma in the cohorts varied by region, there was no clear relationship between asthma diagnosis and COVID-19 disease diagnosis or severity. In the authors' experience, however, many patients with asthma maintain relative hypervigilance against exposure to infectious disease, compared with those without a lung disease.

Taken together, the relationship between asthma and COVID-19 disease risk is complex, and is likely to be influenced by the presence of asthma, the severity of underlying lung disease, the therapies utilized, and possibly the presence of type 2 inflammation.

The ACE2 receptor is the target for SARS-CoV-2 spike protein binding, facilitated by TMPRSS2 for entry into cells. These molecules may be influenced by type 2 inflammation. Interestingly, our group showed that ACE2 expression in nasal and airway epithelial cells from patients with atopic rhinitis or asthma is negatively associated with type 2 cytokine expression, whereas TMPRSS2 expression was positively associated (5) . Ex vivo treatment of primary airway epithelial cells from patients with asthma with IL-13 can reduce ACE2 and increase TMPRSS2 expression. Jackson et al. (6) showed that in a pediatric cohort, allergic sensitization and type 2 biomarkers-including FeNO, IgE, and nasal IL-13 expression-were inversely related to ACE2 expression in the nasal epithelium regardless of asthma status; in an adult cohort, ACE2 expression decreased after exposure to relevant allergens. However, there was no reduction in ACE2 expression in those with nonatopic asthma, suggesting that the protection is limited to those with IL-13-mediated inflammation and allergy.

A commonly used biomarker of type 2 asthma, the eosinophil, is known to play a role in immunity against pathogens. Low eosinophil levels in COVID-19 may portend poorer outcomes or more severe illness, perhaps related to the cytokine storm and hyperinflammation of severe illness, characterized by IL-6, IL-1-beta, and tumor necrosis factor-alpha. In the aforementioned Mount Sinai study, patients with blood eosinophils ≥200 cells/µL had lower mortality, irrespective of asthma status.

Most, if not all, of our patients with asthma and atopy are being treated with some form of corticosteroid. As corticosteroids suppress inflammation, including the possibly protective type 2 inflammation, the concern about safety of these therapeutics in the face of the pandemic is not without merit. However, data suggest that topical and systemic corticosteroids may indeed show benefit as a treatment strategy for moderate to severe COVID-19 due to their anti-inflammatory effects. However, topical steroids administered intranasally or by inhalation may have other protective benefits against COVID-19 disease. For example, patients with asthma using inhaled corticosteroids were shown to have lower ACE2 levels expressed by sputum cells when compared with those asthma patients not using corticosteroids (7) , suggesting the possibility that steroid-mediated downregulation of the epithelial receptor for SARS-CoV-2 may be a strategy to reduce severity of infection. Providing clinical evidence in support of this hypothesis, Strauss and colleagues observed that in the Cleveland Clinic COVID-19 Research Registry, among adult patients with confirmed infection, use of intranasal steroid prior to hospitalization was associated with lower risk for hospitalization, ICU admission, and in-hospital mortality; these findings were replicated in sensitivity analyses excluding those with documented allergic rhinitis or use of inhaled steroids (8) . The aforementioned ISARIC CCP-UK study identified use of inhaled corticosteroids as possibly protective against mortality in patients hospitalized for COVID-19. Interventional studies for inhaled corticosteroids and systemic steroids are as yet inconclusive as to the optimal dose, timing, and duration of treatment, or expected benefit.

Further, ciclesonide and mometasone were shown to inhibit in vitro replication of SARS-CoV-2(9), providing an additional possible therapeutic benefit to use of corticosteroids as prevention or treatment for COVID-19 disease. Clinical trials are needed to quantify the benefit of these and other corticosteroid preparations.

J o u r n a l P r e -p r o o f Adir et al. published data from 80,602 patients at Clalit Health Services, the largest health care provider in Israel, to identify all adult patients with asthma (8,242) who underwent SARS-CoV-2 PCR testing between March and December 2020 (10) . In this cohort, neither use of asthma biologics, which target T2 pathways, nor systemic corticosteroids were associated with increased risk of infection. However, systemic corticosteroid use was associated with increased risk of moderate to severe COVID-19 disease or all-cause mortality.

Despite an as-yet undefined risk for our patients with asthma and atopy to have symptomatic disease, severe disease, or mortality from infection with SARS-CoV-2, current data support that usual therapy for asthma, including inhaled corticosteroids, may actually be protective against adverse outcomes ( Figure  1 ). The data presented herein cannot be considered definitive, however, due to various limitations related to study design. Despite this, the relationship between atopic inflammation, corticosteroids, and pathways related to COVID-19 disease point to complementary downregulation of viral receptors, inhibition of viral replication and reduction of hyperinflammation. Ongoing mechanistic work with live virus will further elucidate these relationships, including that of the impact of non-T2 inflammation such as interferon gamma. Further studies will be needed to carefully evaluate the risk among multiple ethnic groups, the efficacy of vaccination across patients with asthma on therapy, potential benefits or risks of asthma biologics, and risk mitigation strategies for those with severe asthma.

Changes in Influenza and Other Respiratory Virus Activity During the COVID-19 Pandemic -United States

Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19: a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK

The relationship between asthma, eosinophilia, and outcomes in coronavirus disease 2019 infection

Asthma in Adult Patients with COVID-19. Prevalence and Risk of Severe Disease

Type 2 inflammation modulates ACE2 and TMPRSS2 in airway epithelial cells

Association of respiratory allergy, asthma, and expression of the SARS-CoV-2 receptor ACE2

COVID-19-related Genes in Sputum Cells in Asthma. Relationship to Demographic Features and Corticosteroids

The Inhaled Steroid Ciclesonide Blocks SARS-CoV-2 RNA Replication by Targeting the Viral Replication-Transcription Complex in Cultured Cells

COVID-19 risk and outcomes in adult asthmatic patients treated with biologics or systemic corticosteroids: Nationwide real-world evidence

J o u r n a l P r e -p r o o f