Asthma and COVID-19 - A systematic review

Background. Severe coronavirus disease-19 (COVID-19) presents with progressive dyspnea, which results from acute lung in�ammatory edema leading to hypoxia. As with other infectious diseases that affect the respiratory tract, asthma has been cited as a potential risk factor for severe COVID-19. However, con�icting results have been published over the last few months and the putative association between these two diseases is still unproven. Methods. Here, we systematically reviewed all reports on COVID-19 published since its emergence in December 2019 to June 30, 2020, looking into the description of asthma as a premorbid condition, which could indicate its potential involvement in disease progression. Results. We found 372 articles describing the underlying diseases of 161,271 patients diagnosed with COVID-19. Asthma was reported as a premorbid condition in only 2,623 patients accounting for 1.6% of all patients. Conclusions. As the global prevalence of asthma is 4.4%, we conclude that either asthma is not a premorbid condition that contributes to the development of COVID-19 or clinicians and researchers are not accurately describing the premorbidities in COVID-19 patients.


Background
COVID-19 was rst reported in December, 2019 in Wuhan, China, and rapidly spread across the globe (1).It has affected more than 54 million people and has led to the death of over 1.3 million as of November 16, 2020 (www.who.org).Severely affected patients present fever, dry cough, dyspnea, and fatigue, which are commonly associated with the development of pneumonia and acute respiratory distress syndrome (ARDS) (2).Advanced age, ischemic and congestive heart disease, hypertension, diabetes, and chronic obstructive pulmonary disease (COPD) are the most important independent predictors of death (2,3).As with other infectious diseases affecting the lungs, asthma has been cited as a potential risk factor for severe COVID-19 (4)(5)(6)(7)(8).This association could be putatively explained on the basis of an abnormal immune response occurring in the context of the allergic condition and an abnormal respiratory function (9,10).However, no previous study has addressed this question looking into all studies that described the clinical features of COVID-19.
Here, we systematically reviewed all studies published on COVID-19 since its emergence in December 2019 to June 30, 2020, looking into the description of asthma as a premorbid condition and its putative association with severe progression of the disease.We show that out of 161,271 patients diagnosed with COVID-19 and having their premorbid conditions described, only 1,6% were reported as previously diagnosed with asthma.

Methods
This is a systematic review of the diagnosis of asthma as a premorbid condition in patients with COVID-19.The report was organized according to the Preferred Reporting Items for Systematic Reviews (11).
Two authors, NFM and CPJ, independently identi ed cross-sectional and longitudinal studies published before June 30, 2020, that reported on the prevalence of asthma as a premorbid condition of severe COVID-19 by systematically searching PubMed-NCBI, Google Scholar, Scopus and Web of Science databases.As previously reported, PubMed-NCBI alone covers more than 90% of MEDLINE providing a widely accessible biomedical resource (12).For database searches, language of the article was restricted to English.Search terms included the following: COVID-19 (COVID, COVID 19) or nCov or novel coronavirus or Sars-Cov-2 in the title and clinical characteristics or asthma anywhere in the text.Three authors, EM, EPA, and LAV, resolved eventual discrepancies by discussion and adjudication.
We found 1,069 articles that met the initial inclusion search criteria.All articles were assessed by authors and 598 were excluded (Supplementary Table 1) due to one or more of the following criteria: editorials; metanalyses; systematic reviews; commentaries; letters to the Editor; no description of patient's clinical characteristics or premorbid conditions; duplicated articles and main text in a language other than English.We found 99 studies duplicated, which were also excluded accordingly, allowing us to analyze only in one of the both versions.The remaining 372 articles were included in the study.Supplementary Table 2 depicts the details of all articles analyzed.Two authors, NFM and CPJ, independently extracted the following data from each article using a standardized form: study design; number of patients with COVID-19; mention of any respiratory disease; number of patients with any respiratory disease; mention of asthma; number of patients with the previous diagnosis of asthma.The entire body of the articles was presented descriptively.

Results
Figure 1 is a schematic representation of search, inclusion and exclusion of articles.Our search criteria resulted in the identi cation of 1069 articles that were pre-selected for detailed analysis resulting in the exclusion of 598 articles (Suppl.Table 1) due to one or more of the following reasons: editorials; metanalyses; systematic reviews; commentaries; letters to the Editor; no description of patient's clinical characteristics or premorbid conditions; and main text in a language other than English.The remaining 372 articles (Suppl.Table 2) described the clinical aspects of 161,271 COVID-19 patients.Two hundred and one studies mentioned the existence of other respiratory premorbidities except for asthma.Althought asthma was mentioned as a underlying disease in 67 studies, only 52 articles have described the exact number of the COVID-19 patients with asthma (Table 1).The other 15 studies presented asthma together with other respiratory diseases, making it impossible to identify the number of COVID-19 asthmatic patients.There was a total of 40,948 COVID-19 patients included in the studies mentioning asthma, of which 8,439 were previously diagnosed with asthma.In most of the studies describing other respiratory illnesses, COPD was the leading diagnosis.The United States was the country with the largest number of studies describing asthma, followed by China, France, Spain and the United Kingdom (Figure 2A).Thus, according to current COVID-19 clinical records, 6.4% of patients included in articles describing the clinical characteristics of COVID-19 patients and citing asthma were previously diagnosed with asthma (Fig. 2B).If all studies providing any clinical description of COVID-19 comorbidities are taken into consideration, asthma was present in only 1.6% of patients (Fig. 2C).
Respiratory viruses can trigger asthma exacerbations, which can increase the severity of the infectious condition (14).In the past, coronaviruses have been implicated as triggers of asthma exacerbations (15,16); this is also true for in uenza virus (17).However, as for the new coronavirus, SARS-CoV-2, there is still controversy regarding the putative role of asthma as a premorbid that could worsen disease progression (7,8,18).
Here, we evaluated all studies on COVID-19 published since its emergence up to June 30, 2020.We showed that asthma was described as a premorbid condition in only 1.6% of all patients.These numbers are far less than expected considering the prevalence of asthma in the world (http://www.globalasthmareport.org; https://www.who.int/news-room/q-a-detail/asthma) and could suggest that having asthma as a premorbid condition either represents no risk for COVID-19 or could be a protective factor against the development of the disease.However, there are some aspects that should be considered as potentially impactful for the ndings herein reported.First, the prevalence of asthma varies across the globe, ranging from 21% in Australia to less than 2% in China, Kazakhstan and Vietnam (19).
Likewise, the most common risk factors for COVID-19, obesity, diabetes and hypertension, have distinct prevalences in different countries (www.who.org).Thus, the geographical origin of the studies could have in uenced the results.However, as the studies included in this systematic review were mostly originated from countries presenting a wide range of prevalences for both asthma and the main comorbidities for COVID-19, we believe this factor plays a minor role in the reported ndings.
Another aspect that could explain our results is that asthma treatment with inhaled corticosteroids allied to improved therapeutic and prophylactic adhesion has increased over the years, resulting in the reduction of respiratory distress episodes and allergy associated immunological imbalance (20)(21)(22)(23).Moreover, allergy and asthma international associations were e cient to rapidly produce and release COVID-19 guidelines that provided advice for health professionals involved in the care of asthma patients, as well as for reaching the general public (24)(25)(26)(27).These actions could have bene cially impacted on the control of asthma and also in uenced patients to follow social isolation procedures; thus, mitigating the risk of contracting COVID-19.
It has been suggested that the particular in ammatory environment in the bronchioalveolar system of asthma patients could lead to a reduced expression of SARS-CoV-2 receptor, angiotensin converting enzyme 2 (ACE2), rendering asthma patients protected from the infection (28-30).This could be due to the fact that interleukin-13 (IL-13), a cytokine involved in eosinophil recruitment to the bronchial epithelia (31), is capable of reducing ACE2 expression in bronchial ex-vivo human samples (28).In line with these ndings, it has been reported that progressive increase in blood eosinophil counts is related to COVID-19 recovery.Thus, if proven correct, these data could suggest that only patients with allergic asthma are protected from COVID-19, as recently suggested (32, 33).However, currently available data provides no su cient detail regarding asthma etiological classi cation and further studies would be required in order to provide advance in this issue.
The main weaknesses of this systematic review rely on the facts that we included publications covering the initial 6 months of pandemics and as new data is published on a daily basis, some changes in the frequency of asthma could appear; moreover, readers should keep in mind that some reports show that in certain pocket populations, asthma could be an important comorbidity for COVID-19 (34).The reasons for these apparent discrepancies should be a focus of further studies.
Thus, as for the data analyzed in this systematic review, asthma does not seem to be an important premorbid condition in COVID-19 patients; or, conversely, it could be a protective factor, as previously proposed (18).The ndings herein reported could be an epidemiological truth that should be further explored in mechanistic studies or could be due to the fact that researchers are not properly investigating and describing the premorbidities in COVID-19 patients.Whatever the reasons, the medical community should be aware of the implications of missing the diagnosis of a potentially severe respiratory disease such as asthma that could worsen the prognosis of COVID-19 patients.

Declarations
Ethics approval and consent to participate.The study does not require ethical approval because the systematic review is based on published research and the original data are anonymous.Consent for publication.Authors are the sole responsible for the publication of this study.

Table 1 .
Availability of data and materials.Data are available upon request.Competing interests.Authors have no competing interests to declare.Funding.NFM was supported by The São Paulo Research Foundation (grant: 2016/17810-3), and CPJ was supported by Coordination for the Improvement of Higher Education Personnel (CAPES) grant: 1744875 and 88882.434715/2019-01.EM, LAV and EPA are supported by grants from São Paulo Research Foundation (grants: 2013/07607-8 and 2020/) and Brazilian National Council of Scienti c and Technological Development (CNPq).Authors' contributions.NFM and CPJ performed article search and rst round of inclusions.EM, EPA and LAV performed second round of inclusion.LAV and NFM performed statistics analysis.LAV and NFM wrote the manuscript.All authors read manuscript and provided approval.31.Kumar RK, Herbert C, Yang M, Koskinen AM, McKenzie AN, and Foster PS.Role of interleukin-13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma.Clin Exp Allergy.2002;32(7):1104-11.32.Yang JM, Koh HY, Moon SY, Yoo IK, Ha EK, You S, et al.Allergic disorders and susceptibility to and severity of COVID-19: A nationwide cohort study.J Allergy Clin Immunol.2020;146(4):790-8.Details the articles that mention asthma.
Table The Epidemiological and Clinical Characteristics of 81 Children with COVID-19 in a Pandemic Hospital in Turkey: an Observational Cohort Clinical and epidemiological characteristics of pediatric SARS-CoV-2 infections in China: A multicenter case series 10.1371/journal.pmed.