key: cord-0930178-xz4gx1im
authors: Padayachee, Yorissa; Faiez, Tasnim Shahridan; Singanayagam, Aran; Mallia, Patrick; Johnston, Sebastian Lennox
title: Asthma and viruses (a focus on rhinoviruses and SARS-CoV-2)
date: 2021-03-13
journal: J Allergy Clin Immunol
DOI: 10.1016/j.jaci.2021.03.011
sha: abf0800f7204a031800c740b10d2f862f2e38eb5
doc_id: 930178
cord_uid: xz4gx1im

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Acute asthma exacerbations (AEs) are common, events that result in high morbidity, 26 mortality and place a major burden on healthcare services. The most prominent trigger for 27

AEs are viral respiratory infections, particularly rhinoviruses (RVs) which have been strongly 28 linked as causative agents by studies of naturally occurring and experimentally induced 29 exacerbations 1,2 . RVs induce enhanced airway inflammation and clinical symptom severity in 30 asthma compared to healthy individuals 1 . Impaired innate anti-viral immunity and 31

augmented T-helper cell type-2 (Th2) inflammation in people with asthma are two potential 32 mechanisms linked to increased severity of virus-induced AEs pathogenesis. Here, we review The importance of IFN impairment in AE pathogenesis is strongly supported by a study 48

showing that IFN impairment at baseline is strongly related to symptom severity, airway 49 inflammation and viral load in subsequent experimental virus induced AEs 3 . 50

An elegant study applying transcriptome network analysis, in children with asthma, also 51 demonstrated that a low type-I IFN response at baseline was a robust predictor of short-52 term AE risk 1 . The same study reported a 'type-I IFN response' module, which contained 53 numerous antiviral effector molecules, was upregulated in nasal and blood samples during The study applying transcriptome network analysis in children with asthma demonstrated 85 that high type-2 inflammation and low type-I IFN responses at baseline were robust 86 predictors of short-term AE risk 1 , suggesting the two pathways interact. This hypothesis is 87 supported by type-2 inflammation being associated with increased severity of AE. Figure 1A ). This mechanism is strongly supported by studies showing 95 that anti-IgE therapy restores impaired IFN responses in people with asthma 6 . 96

expression and IRF3 activation, thus increasing virus replication ( Figure 1B) . Both cytokines 98 also induce suppressor of cytokine signaling 1 (SOCS1) expression in HBECs, and SOCS1 99 suppresses virus induced IFNs in HBECs ( Figure 1B) . Surprisingly though, many studies reported that asthma was no more prevalent among 119 people with COVID-19 of varying degrees of severity than among the general population. 120

These estimates of the risk posed by having asthma may be underestimates as people with 121 asthma are likely taking extra precautions by shielding, wearing masks and taking their 122

prophylactic asthma medications to protect themselves from COVID-19. OpenSAFELY, a 123 databank with >17 million UK primary healthcare records reported severe asthma (defined 124 by recent oral corticosteroid use) was a risk factor for COVID-19 mortality(PMID:32640463). 125

Additionally, asthma patients on high-dose ICS had increased COVID-19 mortality risk 126 compared to those on short-acting beta-agonists only 8 . However, OpenSAFELY is a 127 retrospective observational study using GP records to define asthma which may reveal 128 potential associations but cannot define causal relationships 8 . Furthermore, the study could 129 not expand on other underlying disease characteristics that may not be captured in primary 130 healthcare records, which may reveal individuals with an increased susceptibility to viral 131 infections as well as more severe asthma 8 . 132

The International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) 133 analysed >75,000 UK COVID-19 hospital admissions and reported patients aged 16 and over, 134 asthma are T2-high (Table A) , and recent studies suggest the possibility of type-2 immunity 143 being protective against COVID-19. UK Biobank data reported that non-allergic asthma (but 144 not allergic/atopic asthma) was a risk factor for severe COVID-19 9 . This may be because non-145 type-2 asthma patients may have higher baseline inflammation due to pre-existing 146 comorbidities, such as obesity and age. These comorbidities may play a more important role 147 in driving COVID-19 severity than the underlying asthma itself (Table A) . Additionally, atopic 148 patients, had significantly lower odds of hospitalisation for COVID-19, and atopy was 149 associated with a decreased duration of COVID-19 hospitalisation 9 . This may be related to 150 reduced ACE2 expression levels in atopy that correlated with allergic sensitisation, total IgE 151 levels and type-2 cytokines 9 . 152

Another major endotype that may be susceptible are individuals with asthma, who also 153 have pre-existing IFN impairment. IFN impairment has been postulated to be the major J o u r n a l P r e -p r o o f

Transcriptome 168 networks identify mechanisms of viral and nonviral asthma exacerbations in 169 children

Jerico 172 et al. IL-33-dependent type 2 inflammation during rhinovirus-induced asthma 173 exacerbations in vivo

Role of deficient type III interferon-lambda production in asthma exacerbations

A Comprehensive Evaluation of Nasal and Bronchial Cytokines and Chemokines 181

Following Experimental Rhinovirus Infection in Allergic Asthma

IFN-γ and IFN-λ) and Type 2 Inflammation (IL-5 and IL-13). EBioMedicine

Enhanced 190 plasmacytoid dendritic cell antiviral responses after omalizumab

TMPRSS2, and furin gene expression in the airways of people with asthma-195 implications for COVID-19

Risk of 199 COVID-19-related death among patients with chronic obstructive pulmonary disease 200 or asthma prescribed inhaled corticosteroids: an observational cohort study using 201 the OpenSAFELY platform

Asthma-associated risk for

COVID-19 development

Risk of Adverse Outcomes in Patients with Underlying Respiratory Conditions 209

Admitted to Hospital with COVID-19: A National