Abstract

As coronavirus disease 2019 (COVID-19) continues to spread across the world, there are concerns that patients with asthma will be at higher risk for the disease or poorer outcomes. There is also concern about whether asthma treatments themselves could worsen the risk of disease or severity. Current evidence indicates that asthma is not in the top 10 comorbidities associated with COVID-19 fatalities, with obesity, diabetes, and chronic heart disease more commonly reported.1Hakim D. Asthma is absent among top Covid-19 risk factors, early data shows. New York Times. April 16, 2020.https://www.nytimes.com/2020/04/16/health/coronavirus-asthma-risk.htmlGoogle Scholar This finding is consistent with trends during the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV) epidemic, caused by a virus with close sequence homology to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), during which diabetes and heart disease and not asthma were the leading comorbidities.2Yin Y. Wunderink R.G. MERS, SARS and other coronaviruses as causes of pneumonia.Respirology. 2018; 23: 130-137Crossref PubMed Scopus (653) Google Scholar However, comorbidities found with COVID-19 fatalities may reflect confounding by age, and the Centers for Disease Control and Prevention has reported that among younger patients hospitalized for COVID-19 the most common comorbidities were obesity, asthma, and diabetes.3Garg S. Kim L. Whitaker M. et al.Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019: COVID-NET, 14 states, March 1-30, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 458-464Crossref PubMed Scopus (3) Google Scholar Although the role of asthma in increasing the severity of COVID-19 infections remains unclear, anxiety continues to be high among patients and their caregivers. These concerns are not baseless. Asthma may increase the risk of developing viral respiratory illnesses, and even human rhinovirus, the most common cause of the common cold, is a potent trigger of asthma exacerbations.4Busse W.W. Lemanske Jr., R.F. Gern J.E. Role of viral respiratory infections in asthma and asthma exacerbations.Lancet. 2010; 376: 826-834Abstract Full Text Full Text PDF PubMed Scopus (536) Google Scholar Synergism between allergen sensitization and viral infections in patients with allergic asthma, weaker antiviral defenses, and lower interferon production, all seem to contribute to the higher risk of viral infections in patients with asthma.4Busse W.W. Lemanske Jr., R.F. Gern J.E. Role of viral respiratory infections in asthma and asthma exacerbations.Lancet. 2010; 376: 826-834Abstract Full Text Full Text PDF PubMed Scopus (536) Google Scholar Allergic sensitization and eosinophilic inflammation can breach the integrity of the airway epithelium, contributing to a milieu that may foster viral infections that involve the lower airways and limit the ability of the respiratory tract to appropriately clear viruses. Although the usual coronavirus infections are more likely confined to the upper airway, the predilection for COVID-19 to infect the lower airway, even in healthy individuals, creates even greater concern in patients with asthma. Additional questions of concern relate to the effects that asthma medications may have on COVID-19 infections. Inhaled corticosteroids are the mainstay of treatment of persistent asthma, and oral corticosteroids are frequently used during acute exacerbations.5Oliver B.G. Robinson P. Peters M. Black J. Viral infections and asthma: an inflammatory interface?.Eur Respir J. 2014; 44: 1666-1681Crossref PubMed Scopus (48) Google Scholar Multiple in vitro studies have found that corticosteroids inhibit viral-induced cytokines but do not inhibit interferons, which are an important antiviral defense mechanism.5Oliver B.G. Robinson P. Peters M. Black J. Viral infections and asthma: an inflammatory interface?.Eur Respir J. 2014; 44: 1666-1681Crossref PubMed Scopus (48) Google Scholar Despite these inhibitory effects and the overall efficacy of corticosteroids, patients with asthma well-controlled with inhaled corticosteroids can still have virally induced exacerbations. As an added concern, corticosteroids produce a dose-response increase in the risk of pneumonia in patients with asthma, and asthma itself is an independent risk factor for severe pneumococcal disease.6Talbot T.R. Hartert T.V. Mitchel E. et al.Asthma as a risk factor for invasive pneumococcal disease.N Engl J Med. 2005; 352: 2082-2090Crossref PubMed Scopus (329) Google Scholar Pneumonia is not an uncommon feature of COVID-19, but whether asthma and corticosteroid use would increase the risk of secondary bacterial infection with COVID-19 remains to be determined. Given the current state of information, it is impossible to make conclusive statements about the effect corticosteroids might have on the disease course of any patient with asthma. For instance, the timing of steroid administration during the course of human rhinovirus–induced illness considerably affects suppression of cytokine production and inflammation.5Oliver B.G. Robinson P. Peters M. Black J. Viral infections and asthma: an inflammatory interface?.Eur Respir J. 2014; 44: 1666-1681Crossref PubMed Scopus (48) Google Scholar Indeed, current expert guidelines discourage the use of corticosteroids in the treatment of COVID-19 in patients in general.7Russell C.D. Millar J.E. Baillie J.K. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.Lancet. 2020; 395: 473-475Abstract Full Text Full Text PDF PubMed Scopus (1383) Google Scholar For patients with asthma treated with inhaled corticosteroids, both the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology recommend that patients continue to use their maintenance medications even during the pandemic.8Shaker MS, Oppenheimer J, Grayson M, et al. COVID-19: pandemic contingency planning for the allergy and immunology clinic [e-pub ahead of print]. J Allergy Clin Immunol Pract. https://doi.org/10.1016/j.jaip.2020.03.012, accessed April 26, 2020.Google Scholar Continuation of therapy even with potential exposure to COVID-19 is extremely important because poorly controlled asthma is always the greatest risk factor for exacerbations with any viral infection. With regard to biologics approved for asthma treatment, effects on the risk of COVID-19 may differ. Omalizumab (an anti–immunoglobulin E [IgE] antibody), mepolizumab and reslizumab (which block interleukin [IL] 5), benralizumab (which blocks the IL-5 receptor), and dupilumab (which blocks IL-4 receptor α, a receptor shared by IL-4 and IL-13) reduce asthma-related exacerbations and have all been approved for the treatment of severe asthma. Approximately 80% of asthma exacerbations are related to viral infections.4Busse W.W. Lemanske Jr., R.F. Gern J.E. Role of viral respiratory infections in asthma and asthma exacerbations.Lancet. 2010; 376: 826-834Abstract Full Text Full Text PDF PubMed Scopus (536) Google Scholar,5Oliver B.G. Robinson P. Peters M. Black J. Viral infections and asthma: an inflammatory interface?.Eur Respir J. 2014; 44: 1666-1681Crossref PubMed Scopus (48) Google Scholar Thus, these effects on overall exacerbations suggest that these biologics may affect virally exacerbated disease. This effect has been best established for omalizumab, which prevents IgE from binding to its receptor on plasmacytoid dendritic cells. Cross-linking of IgE leads to lower type 1 interferon production, and in clinical studies, omalizumab has been found to decrease the risk of, duration, and viral shedding of human rhinovirus in children with allergy.9Durrani S.R. Montville D.J. Pratt A.S. et al.Innate immune responses to rhinovirus are reduced by the high-affinity IgE receptor in allergic asthmatic children.J Allergy Clin Immunol. 2012; 130: 489-495Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar Mepolizumab, reslizumab, and benralizumab also potentially play a role in enhancing immune responses to viral infections given that a higher ratio of interferon gamma to IL-5 messenger RNA is associated with lower viral shedding and faster disease clearance.10Gern J.E. Vrtis R. Grindle K.A. Swenson C. Busse W.W. Relationship of upper and lower airway cytokines to outcome of experimental rhinovirus infection.Am J Respir Crit Care Med. 2000; 162: 2226-2231Crossref PubMed Scopus (240) Google Scholar In addition, recognizing that IL-5 plays an essential role in airway eosinophilic inflammation, its inhibition may make the airway less susceptible to additional lung injury from diseases such as COVID-19.10Gern J.E. Vrtis R. Grindle K.A. Swenson C. Busse W.W. Relationship of upper and lower airway cytokines to outcome of experimental rhinovirus infection.Am J Respir Crit Care Med. 2000; 162: 2226-2231Crossref PubMed Scopus (240) Google Scholar Dupilumab decreases airway inflammation, allergic airway response, and asthma exacerbations. Interleukin 4 is vital for antibody switching to IgE, and IL-13 is a TH2 cytokine involved in airway hyperresponsiveness and in airway remodeling, all of which are involved in susceptibility to and clearance of lower airway viral infections.4Busse W.W. Lemanske Jr., R.F. Gern J.E. Role of viral respiratory infections in asthma and asthma exacerbations.Lancet. 2010; 376: 826-834Abstract Full Text Full Text PDF PubMed Scopus (536) Google Scholar Thus, it is likely that these biologics will lessen the risk of severe asthma exacerbations with COVID-19, at least by reducing baseline airway inflammation and possibly through specific antiviral properties. SARS-CoV-2 is an enveloped virus of the extremely diverse family of coronaviruses. Mapping of the mechanism of COVID-19 clearance by the immune system of a patient who recovered from COVID-19 found that immunoglobulin M and immunoglobulin G antibodies to SARS-CoV-2, follicular T-helper cells, and antibody-secreting cells were all detected in the patient's blood before recovery.11Thevarajan I. Nguyen T.H.O. Koutsakos M. et al.Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19.Nat Med. 2020; 26: 453-455Crossref PubMed Scopus (668) Google Scholar With our knowledge of how the currently approved biologics work, we do not believe that these medications would interfere adversely with any of these pathways or worsen an individual's immune response to COVID-19. It is actually plausible that these biologics, by limiting TH2 skewing, may make the immune system better poised to clear SARS-CoV-2. Although the immune mechanisms for COVID-19 are yet to be fully defined, it is less likely that these biologics will interfere with the pattern-recognition receptor system by which the innate immune system recognizes pathogen-associated molecular patterns. We admit that current data on the risk of acquiring COVID-19 or disease severity in patients with asthma are limited. Key areas for future research are highlighted in Table 1. From previous knowledge and mechanistic studies, the effect of steroids on the risk of acquiring COVID-19 and the outcomes of COVID-19 infections would likely depend on multiple individual-level factors, most importantly baseline asthma control and possibly the dose of steroid used. We do not believe any of the currently approved biologics for asthma treatment would increase the risk of disease or worse outcomes. On the contrary, we postulate that the reversal of the TH2 skew and the improvement in airway allergic and eosinophilic inflammation and bronchial responsiveness induced by these biologics could be advantageous in patients with asthma who are already taking these medications before contracting COVID-19. Nonetheless, patients with asthma need to continue to exercise extreme caution while we make efforts to learn more and quell this pandemic.Table 1Current Gaps and Future Direction in COVID-19 TreatmentCurrent gap or issueFuture directionTo date, COVID-19–related studies have combined patients with asthma and chronic obstructive lung disease, making the effect of asthma on COVID-19 outcomes unclearPursue studies that isolate the effect of asthma from chronic obstructive lung disease in COVID-19 severity and outcomesEmerging evidence suggests that asthma is underrepresented as a comorbidity in COVID-19 fatalitiesEvaluate age-stratified incidence rates and fatality rates of COVID-19 among patients with and without asthmaUnclear how maintenance medications, including inhaled or oral corticosteroids and biologics affect risk, severity, and outcomes of COVID-19Conduct epidemiologic studies describing disease course in patients on these medicationsPerform mechanistic studies that might help answer these questionsPost–COVID-19 respiratory sequelae are unclearProspectively follow patients to determine pulmonary outcomes and sequelae after COVID-19 infectionRacial and ethnic minorities are more likely to die of COVID-19Explore racial and ethnic disparities in outcomes from COVID-19 infection in patients with asthmaAbbreviation: COVID-19, coronavirus disease 2019. Open table in a new tab Abbreviation: COVID-19, coronavirus disease 2019. Children and adolescents with allergy and/or asthma seem to be protected from coronavirus disease 2019Annals of Allergy, Asthma & ImmunologyVol. 125Issue 3PreviewAkenroye et al1 discussed the use of corticosteroids and biologics in asthma during coronavirus disease 2019 (COVID-19) pandemic. COVID-19 began in the People's Republic of China and rapidly spread worldwide.2 Italy was the first European country involved in the pandemic and the first cluster occurring in South Lombardy. The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), penetrates the host cells binding to the angiotensin-converting enzyme 2 (ACE2) receptors. Full-Text PDF Authors' responseAnnals of Allergy, Asthma & ImmunologyVol. 125Issue 3PreviewWe thank Ciprandi et al1 for their salient points related to our recent article and description of their experiences with Italian patients.2 As they pointed out, children and those with allergy and asthma seem to be at a lower risk of coronavirus disease 2019 (COVID-19) and have milder disease.3,4 Recently, however, a severe complication called multisystem inflammatory syndrome in children, which appears to be associated with COVID-19, has been described in pediatric patients.5 The incidence of this Kawasaki disease–like condition, its causes, and optimal management are still under investigation. Full-Text PDF

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