key: cord-0992609-9cg90zbo
authors: Panettieri, Reynold A.; Carson, Jeffrey; Horton, Daniel; Barrett, Emily; Roy, Jason; Radbel, Jared
title: Asthma and COVID: What are the Important Questions?
date: 2020-06-22
journal: J Allergy Clin Immunol Pract
DOI: 10.1016/j.jaip.2020.06.008
sha: f3c902a063615281c964940a0e14a4eeca1104b8
doc_id: 992609
cord_uid: 9cg90zbo

nan

Conflict of Interest Statement: The authors have no conflicts to disclose 27

The COVID-19 pandemic has created a global crisis that has led to substantial morbidity 28 and mortality and has devastated health systems and economies. In response, the global 29 scientific community has mobilized to seek insights to better understand, limit, and treat this 30 disease. In severe SARS-CoV-2 infection, a complex immunopathology exists that comprises 31 active viral replication and an armed, over-active immune and inflammatory response (1) . 32

Cytokines (such as IL-6 and IL-1) can evoke a cytokine storm syndrome (CSS) that features 33 elevated markers of inflammation (such as hsCRP, LDH, and ferritin) and an acquired 34 immunodeficiency (e.g., lymphopenia with reductions in T cells). Disruption of the coagulation 35 cascade (fibrinogen, factor VIII, and platelets) in CSS can lead to a coagulopathy with elevated 36 D-dimers and fibrin split products, reflecting a generalized severe endovascular process (2). 37

Tissue injury may then ensue from macro-and micro-thrombi in veins and arteries of major 38 organs including lungs, heart, kidneys and brain. Evidence of CSS is present in a high 39

proportion of severely ill patients (5). However, critical questions remain about the biologic and 40 clinical features that predispose to CSS and critical illness, including underlying comorbidities 41 such as asthma and the medications used to treat them. 42

Older age and comorbidities, especially heart disease, hypertension, chronic obstructive 43 pulmonary disease (COPD), diabetes and obesity, are reported risk factors for the development 44 and progression of COVID-19 (3). However, controversy exists as to whether patients with 45 asthma manifest high or elevated rates of COVID-19 incidence. Surprisingly, limited data exist 46 that severe asthma patients with markedly diminished lung function and receiving monoclonal antibodies are at greater risk than those with less severe disease. Are there pathophysiological 48 or pharmacological mechanisms that could explain why asthma, compared to non-asthma, asthma may become hyper-vigilant on personal hygiene and social distancing. Social 54 distancing could improve asthma control since individuals quarantined at home have diminished 55 exposure to seasonal triggers that include other respiratory viruses or allergens. Evidence also 56 suggests that the pandemic enhances asthma medication adherence (4). Thus, the pandemic 57 may have paradoxically improved some clinical outcomes of asthma management due to 58 improved trigger remediation and medication adherence. 59

Use of inhaled steroids: Inhaled corticosteroids, a mainstay in the management of asthma, 60 may directly modulate SARS-CoV-2 infectivity. In vitro models and drug library screening 61 approaches suggests that ciclesonide decreases SARS-CoV-2 replication. Inhaled steroids 62 have also been associated with decreased expression of angiotensin-converting enzyme 2 63 (ACE2), the co-receptor for SARS-CoV-2 raising the question of whether these drugs could Future studies should address whether inhaled steroids in patient with asthma and/or allergic 68 rhinitis increase or decrease risks of SARS-CoV-2 infection, and whether these effects different 69 across inhaled steroid types. Analyses of real-world data from health and pharmacy benefit 70 claims could address these critical questions. 71

Age: Susceptibility and severity to COVID-19 infection increases with age (3). Since asthma 72 sufferers tend to be younger than those with other co-morbidities, is age a factor in explaining 73 why asthma patients may not be at greater risk? To address this question, age-adjusted 74 models need to be formulated. Children and young adults with asthma manifest T2 high airway 75 inflammation that is driven predominantly by allergy, IL-4 and IL13. In comparison, older adults who can have T2 high airway inflammation also manifest an eosinophilic phenotype and other comorbidities of chronic rhinosinusitis with or without nasal polyps. Additionally, expression of 78 angiotensin-converting enzyme 2 (ACE2), the co-receptor for SARS-CoV-2, varies with age, 79 and ACE2 expression is increased by interferons, thought to be beneficial in clearing other 80 respiratory viruses especially in children (5). Whether these pathogenic mechanisms affect 81 SARS-CoV-2 infectivity in individuals with asthma remains unclear. 82

Asthma and comorbidities: Asthma tends to be associated with far fewer comorbidities than 83 COPD or cardiovascular disease (CVD). This observation could be a function of patients' age or 84 relate to the strongly associations between COPD, CVD, and adverse lifestyles/habits. If SARS-85

CoV-2 is a disease manifested by systemic consequences of endothelial cells dysfunction, then 86 diabetes, heart disease, obesity, and other diseases associated with endothelial dysfunction 87 may engender more susceptibility than asthma (1). By extension, older individuals with asthma 88 who also have hypertension, diabetes, or heart disease should manifest similar incidences of 89

In sum, whether asthma represents a co-morbidity associated with susceptibility to and 91 progression of COVID-19 remains unclear. The tropism for SARS-CoV-2 to the upper airway 92 epithelium and the use of inhaled steroids provide a real life laboratory to test whether these 93 attributes modulate infectivity and disease progression. More research is needed to address the 94 characteristics of those with asthma who develop COVID-19 and how asthma therapy, including 95 inhaled steroid or biologics, modulates such risks. 

Complex Immune Dysregulation in COVID-19 Patients with Severe 106

Ong 108 KH. Hematologic parameters in patients with COVID-19 infection

Clinical course and risk factors for mortality of 112 adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Changes in medication 115 adherence among patients with asthma and COPD during the COVID-19 pandemic