Discussion
Based on the available literature, there was no clear evidence that patients with asthma were at a higher risk of being infected or becoming severely ill with SARS-CoV-2, although recent reports from the USA and the UK suggest that asthma is much more common in children and adults with COVID-19 than it was previously reported in Asia and in the first surveys in continental Europe.
Nevertheless, the prevalence of several underlying conditions identified in USA hospitalized patients with COVID-19 were similar to those for hospitalized influenza patients during influenza seasons 2014–15 through 2018–19, namely regarding chronic respiratory diseases (29% to 31%).41
Of particular note in the UK results of the association of asthma with higher risk of COVID-19 hospital death, with the HR increasing further for those that received oral corticosteroid (OCS), probably indicating greater severity of disease. This contrasts with previous findings, in several countries, where asthma and other chronic respiratory diseases were underrepresented in hospitalized patients.36 Also in the UK it was reported asthma in 14,0% and 17,9% of hospitalized patients but with no increased risk of death.35,37
Among school-age children, viral infection reportedly accounts for up to 85% of asthma exacerbations, and viruses are more frequently isolated from symptomatic patients than from asymptomatic patients.42,43 Even though respiratory viruses are one of the most common triggers for asthma exacerbations in all age groups, not all of these viruses affect patients equally. In particular, the human rhinovirus was identified as the main individual contributor for asthma exacerbations, being coronavirus one of the less identified trigger of asthma exacerbations in children as in adults.44 A recent literature review concerning virus detection during asthma exacerbations, confirmed that exacerbations were mainly associated with rhinovirus infection in all continents.45
In previous SARS outbreaks, patients with asthma, in particular children, appeared to be less susceptible to the coronavirus, with reported low rate of asthma exacerbations and good prognosis on follow-up.10,46 In contrast, during influenza epidemics, asthma was associated with more severe disease, including the need of mechanical ventilation, not only in adults but also in children.47 The exact reasons for this remain unknown, but it was confirmed during the current coronavirus pandemic.48
From the recent COVID-19 literature, no definite conclusions can be drawn regarding asthma control or severity. Similarly, no information can be extrapolated about asthma phenotypes, namely regarding whether asthma was allergic or not.
COVID-19 outcomes vary from asymptomatic infection to death and it is possible that this clinical range may reflect different airway levels of the SARS-CoV-2 receptor, ACE2, and the spike protein activator transmembrane protease serine 2 (TMPRSS2), considering that the virus cell entry also depends on S-protein priming by host cell proteases.
Blood eosinophil levels are a well-known predictor of airway T2 inflammation,49 and the measurement of blood eosinophil levels can be used as an accessible (not strong), proxy for investigating the association between airway T2 inflammation and COVID-19 outcomes.
In early reports from China, a detailed clinical investigation of hospitalized COVID‐19 cases suggested severe eosinopenia together with lymphopenia as a potential indicator for diagnosis and to a worse prognosis, including death.15 It was believed that low eosinophil counts in peripheral blood would be related with the SARS-CoV-2 infection itself. However, more recent studies from China and from Italy did not report eosinopenia in patients with severe COVID-19.26,31,50
Although the relationship between eosinophil counts and COVID-19 is uncertain, attention is warranted to monitor eosinophil counts among patients with asthma who are using biological therapies that lead to decreased eosinophil counts, and the clinical course of COVID-19 if they get infected with the SARS-CoV-2.51
Sajuthi et al52 studied in children the role for both T2 inflammation and viral infection in regulating the gene expression of ACE2 and TMPRSS2 and found a strong influence of T2 cytokine-driven inflammation on both ACE2 (downregulation) and TMPRSS2 (upregulation) expression levels, which can have clinical implications on COVID-19 outcomes. In contrast, the authors found an equally strong positive influence of respiratory virus infections on ACE2 expression.52 So, at least theoretically, in patients with asthma and high T2 inflammation, the consequence of an interferon dependent inflammation requires a close monitoring given the enhanced risk of complications due to SARS-CoV-2 infection.
A recent study that included asthma patients from three different cohorts of children and adults, found that ACE2 receptors expression was lower in those patients with high allergic sensitization, but non-atopic asthma was not associated with this reduced expression.53 These data suggest that this reduced ACE2 expression may be a potential contributor, among several other factors, of reduced COVID-19 severity in patients with respiratory allergies, namely allergic asthma.53
Additionally, there is some early evidence coming from the Severe Asthma Research Program-3 (SARP), that inhaled corticosteroid therapy is also associated with reduction on ACE2 and TMPRSS2 gene expression from sputum.54 These data stress the importance of maintain asthma controlled using the treatment according to the best practices, including with inhaled steroids.
There is also evidence to support that taking ICS may be beneficial in dealing with coronavirus infections. In vitro studies showed inhibitory actions of budesonide on coronavirus HCoV-229E replication and cytokine production55 and, preliminary not yet peer-reviewed data, suggest that ciclesonide blocks SARS-CoV-2 ribonucleic acid replication56 and inhibits its cytopathic activity57 which may have clinical implications.
Although gene expression for ACE2 and TMPRSS2 did not differ in healthy and asthmatic patients, it was also found that males, African Americans and patients with diabetes have increased expression of ACE2 and TMPRSS2 in their sputum cells, which may be associated with the poor prognosis of these patients when infected with the SARS-CoV-2.54
Dong et al.58 very elegantly described selected cases of patients with COVID-19, children and adults, demonstrating the profile complexity and different clinical presentations from mild to severe cases. Patients with common allergic diseases, such as rhinitis or atopic dermatitis, did not develop distinct symptoms or had severe courses, which may suggest a positive balance of type 2 immune regulation in COVID-19 pathogenesis.
New data are emerging daily, rapidly updating our understanding of this novel coronavirus, but it’s crucial that patients with asthma and other allergic diseases such as allergic rhinitis, maintain their controller medication, from inhaled corticosteroids to biologics,51,59,60 including allergen immunotherapy,61 without self-making any dose adjustments or stopping medication that may lead to higher risk of asthma exacerbations, increased OCS use and higher probability to emergency room access and hospitalization that represent themselves risk factors for coronavirus exposure and spread. Likewise, it is important to maintain well-controlled rhinitis and rhinosinusitis, together with other known risk factors for asthma exacerbations.62
The available data about OCS use in asthma exacerbations, although limited to 3 reported cases in mild asthmatics,26 are in accordance with data from previous coronavirus outbreaks, showing that systemic corticosteroids can be associated with a higher viral load.63,64 The UK data suggesting an increased death risk in patients with asthma specially in those that recently received systemic steroids,36 stress that clinicians must be cautious and recognize the differences between hypoxic respiratory failure and bronchospasm to carefully balance the need for OCS prescription,51 and bronchodilators must be delivered by metered dose inhalers with spacers in order to prevent the viral spread related with nebulizers use.65
As it was shown by Kaye et al,66 there is evidence on increased adherence to asthma (and COPD) pharmacologic treatment during the first months of the COVID-19 which is encouraging, and hopefully will have a positive effect on improving control of asthma and minimize the need for acute care for this inflammatory chronic respiratory disease.
In conclusion, it is unclear whether patients with asthma are at higher of developing COVID-19 and/or become severely ill. Future studies in all age groups are needed to provide greater understanding of the impact of underlying asthma, other allergic diseases and T2 inflammation on COVID-19 susceptibility and disease outcomes. The best we will understand these interactions, the best we will protect the most vulnerable people included in high risk groups.
Table: Asthma prevalence in COVID-19 studies