key: cord-0942415-291oqafp
authors: Rogliani, Paola; Lauro, Davide; Di Daniele, Nicola; Chetta, Alfredo; Calzetta, Luigino
title: Reduced risk of COVID-19 hospitalization in asthmatic and COPD patients: a benefit of inhaled corticosteroids?
date: 2020-12-03
journal: Expert review of respiratory medicine
DOI: 10.1080/17476348.2021.1850275
sha: 949bb5d2ac6ace10e9abf304c2e1703ca016f238
doc_id: 942415
cord_uid: 291oqafp

Background: The comorbidities and clinical signs of coronavirus disease 2019 (COVID-19) patients have been reported mainly as descriptive statistics, rather than quantitative analysis even in very large investigations. The aim of this study was to identify specific patients’ characteristics that may modulate COVID-19 hospitalization risk. Research design and methods: A pooled analysis was performed on high-quality epidemiological studies to quantify the prevalence (%) of comorbidities and clinical signs in hospitalized COVID-19 patients. Pooled data were used to calculate the relative risk (RR) of specific comorbidities by matching the frequency of comorbidities in hospitalized COVID-19 patients with those of general population. Results: The most frequent comorbidities were hypertension, diabetes mellitus, and cardiovascular and/or cerebrovascular diseases. The RR of COVID-19 hospitalization was significantly (P < 0.05) reduced in patients with asthma (0.86, 0.77–0.97) or chronic obstructive pulmonary disease (COPD) (0.46, 0.40–0.52). The most frequent clinical signs were fever and cough. Conclusion: The clinical signs of hospitalized COVID-19 patients are similar to those of other infective diseases. Patients with asthma or COPD were at lower hospitalization risk. This paradoxical evidence could be related with the protective effect of inhaled corticosteroids that are administered worldwide to most asthmatic and COPD patients.

The outbreak of coronavirus disease 2019 (COVID-19) poses a very grave threat worldwide and it has been ranked as being the public enemy number one by the WHO Director-General [1] . Unexpectedly, in mid-February 2020 there was a sharp increase in cases and deaths due to COVID-19 in the Chinese province of Hubei, mainly related with the improvement of the diagnostic method due to the inclusion of clinically diagnosed cases via CT scan showing infected lung, rather than relying only on the genetic tests [2, 3] .

This scenario clearly suggests that the clinical profile of potentially infected subjects is crucial in the knowledge and prompt diagnosis of COVID-19. In this respect, comorbidities and clinical signs of COVID-19 patients have been included in epidemiological studies, although reported mainly as descriptive statistics [2, [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] even in very large investigations [14] .

Therefore, we performed a quantitative synthesis to assess whether there are specific patients' characteristics that may modulate the risk of COVID-19 hospitalization.

This study has been performed in agreement with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) [15] in order to identify potential-specific characteristics of patients infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may modulate the risk of hospitalization due to COVID-19. The PRISMA-P flow diagram of the study is reported in Figure 1 . This research satisfied all the recommended items reported by the PRISMA-P checklist [16] .

The MEDLINE search was performed on 25 May 2020 by using the following search string: (COVID-19 OR SARS-CoV-2 OR 2019-nCoV) AND epidemiology AND (comorbidity OR comorbidities OR comorbid). Two reviewers performed the comprehensive literature search without language restriction. As an example, Table 1 reports the literature search terms used for OVID MEDLINE.

least very common comorbidities and clinical signs (frequency ≥10%) in agreement with European Medicines Agency (EMA) recommendation [17] .

The co-primary endpoints were the frequencies (%) of comorbidities and clinical signs and the risk of hospitalization accordingly with comorbidities.

Data from included studies were extracted in agreement with Data Extraction for Complex Meta-anALysis (DECiMAL) recommendations [18] .

A pooled analysis was performed to quantify the frequency of comorbidities and clinical signs in COVID-19 patients. Pooled data were also used to calculate the relative risk (RR) of asthma, cardiovascular and/or cerebrovascular diseases, COPD, diabetes mellitus, and hypertension by matching the frequency of these comorbidities in COVID-19 hospitalized patients with those in the general population by using highquality large epidemiological reports [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] as gold standard for each comorbidity, as previously described [30] . Data on the general population included official National reports [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] that were selected to specifically cover the same geographical area in which patients were hospitalized to COVID-19, so that in turn the subjects hospitalized to COVID-19 were themselves included in the above reported high-quality large epidemiological reports. Raw data were extracted from each study and report included in the pooled analysis.

The pooled analysis was performed in agreement with standardized procedures [31] . Heterogeneity (I 2 ) was not calculated as this is a pooled analysis and not a meta-analysis. The effect estimate was expressed as the prevalence (%) or RR with 95% confidence interval (95%CI), with statistical significance for P < 0.05. Raw data concerning positive and negative outcomes of experimental and control groups (COVID-19 hospitalized patients and general population, respectively) were extracted from the original studies and reports, and then included in the 2 × 2 table to calculate the RR and 95%CI via the Mantel-Haenszel approach by using the OpenEpi software [31] [32] [33] .

A modified version of the Newcastle-Ottawa Scale (NOS) was used to assess the quality of the studies and it was adapted to fit the intrinsic characteristics of the included epidemiological studies [34] . According to NOS, a study can be awarded with a maximum of one star for each item within the 'Selection' and 'Outcome' categories, and a maximum of two stars can be given for 'Comparability' [34] . In the present pooled analysis, the NOS quality assessment score was established to be in the range between zero and a maximum of six stars. The detailed modifications to make the NOS suitable for the specific studies included in this pooled analysis are described in the legend of Tables 2 and 3 . Two reviewers independently assessed the quality score of individual studies, and any difference in opinion was resolved by consensus.

Data of 8476 COVID-19 hospitalized patients (age 53.29, 95%CI 48.19-58.40) were extracted from 11 epidemiological studies [2, [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] including cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from 11 December 2019 to 4 April 2020. Table 2 reports the characteristics of the studies included in the pooled analysis, whereas Table 3 describes the characteristics of the large epidemiological reports on the general population, used as gold-standards for each comorbidity.

The most frequent comorbidities were hypertension (23.24%), diabetes mellitus (13.89%), and cardiovascular and/or cerebrovascular diseases (11.84%). Chronic obstructive pulmonary disease (COPD) and asthma were reported in only 1.76% and 1.20% of COVID-19 hospitalized patients. Details on the prevalence of comorbidities are reported in Table 4 . A significant (P < 0.05) increased risk of hospitalization due to COVID-19 was detected in patients affected by diabetes mellitus (RR 2.02, 95%CI 1.89-2.16), cardiovascular and/or cerebrovascular diseases (RR 1.13, 95%CI 1.05-1.22), and hypertension (RR 1.10, 95%CI 1.07-1.15). The risk of hospitalization was significantly (P < 0.05) reduced in patients affected by asthma (RR 0.86, 95%CI 0.77-0.97) or COPD (RR 0.46, 95%CI 0.40-0.52) Figure 2 reports the risk of hospitalization for COVID-19 patients concerning different comorbidities.

The most frequent clinical signs were fever (90.88%), cough (71.27%), fatigue (40.34%), dyspnea (34.98%), and myalgia (21.52%). Less frequent (≤20.00%) although statistically significant clinical signs were expectoration, diarrhea, headache, nausea, and/or vomiting, anorexia, chest pain, sore throat, chill, abdominal pain, dizziness, rhinorrea, hemoptysis, and conjunctival congestion. Details on the prevalence of clinical signs are reported in Table 5 .

The clinical profile of patients hospitalized due to COVID-19 is mainly characterized by subjects with fever and cough affected by hypertension in ≈23.00% of cases, diabetes mellitus in ≈14.00% of cases, and cardiovascular and/or cerebrovascular diseases in ≈12.00% of cases.

Such a clinical profile is not specific of COVID-19, leading to partially incorrect informing practice that SARS-CoV-2 infection is most likely to occur in older people with comorbid conditions, as is the case of influenza (available at https:// www.jwatch.org/na50821/2020/01/31/clinical-characteristics -2019-novel-coronavirus-infection). Certainly, fever and cough are typical of several infective respiratory disorders; however, we have to highlight that first, an average age of ≈53 years does not include elderly patients [35] ; second, clinical signs are related with the disease, not with the infection [36] ; third, comorbidities do not necessarily have to be positively associated with an infectious disease.

The last point is of specific interest by considering the risk of hospitalization for COVID-19. While there was a significantly increased risk of hospitalization in COVID-19 patients affected by diabetes mellitus, cardiovascular and/or cerebrovascular diseases, and hypertension, paradoxically we have found that asthmatic and COPD patients were at reduced risk of hospitalization. This finding is consistent with recent observation that despite a high burden of asthma and COPD, these chronic respiratory disorders have not been consistently identified as a significant comorbidity for COVID-19 [37] .

The evidence provided by this study, based on the risk analysis of more than 8000 COVID-19 patients matched with gold standard epidemiological reports in the general population, is in contrast with the potentially misleading information provided by Lippi and Henry [38] that COPD is associated with severe forms of COVID-19. Such a discrepancy could be related with the fact that there is no consensus on the rank of severity in COVID-19 patients, and that defining whether a patient has all the features of acute respiratory distress syndrome (ARDS) instead of acute lung injury (ALI) may be difficult or impossible in non-intubated subjects [39] [40] [41] . However, it is expectable that hospitalized COVID-19 patients with asthma or COPD may result in worse outcomes than those without respiratory comorbidities.

SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE-2) as the cellular entry receptor; considering that subjects with chronic obstructive respiratory disorders, especially COPD patients, may have increased expression of ACE-2 receptor [42] , it was expected that these subjects would have been at higher risk of hospitalization. Indeed, the reduced risk of hospitalization The NOS category 'Comparability' was not included in the quality assessment due to the intrinsic nature of the included epidemiological studies, that do not have any 'non-exposed group' to compare with the 'exposed group' of COVID-19 patients.

The NOS category 'Selection' was modified to fit the intrinsic characteristics of the included epidemiological studies, that do not have any 'non-exposed group'. COVID-19: coronavirus disease 2019; NA: not available; NOS: Newcastle-Ottawa Scale. A maximum of 1 star (*) was allotted for the NOS category 'Comparability' due to the intrinsic nature of the epidemiological reports, since the 'exposed' and 'non-exposed' groups could not be perfectly matched and/or adjusted for confounders. in asthmatic and COPD patients with COVID-19 could be associated with the widespread therapeutic use in these subjects of inhaled corticosteroids (ICSs) that, recently, have been proved to be characterized by protective effect against virus infections, specifically those due to coronaviruses [43] . In this respect, recently Halpin et al. [44] published a short commentary questioning which factors could account for the fact that asthma and COPD seem under-represented across the comorbidities reported by COVID-19 patients. The proposed hypotheses included the unlikely possibility of underdiagnosis of chronic obstructive respiratory disorders and the theory that asthma and COPD may protect themselves against COVID-19 due to different immune response elicited by both chronic diseases. However, a third and most likely theory was that concerning the beneficial impact of ICSs as therapy for chronic obstructive respiratory diseases, which could reduce the infection risk and the development of symptoms related with COVID-19 [44] . This hypothesis seems to be supported by in vitro studies documenting the efficacy of ICSs alone or combined with bronchodilators in inhibiting coronavirus replication and cytokine production, but also by in vivo evidence [45] [46] [47] . Interestingly, it was demonstrated that asthmatic patients treated with ICSs present a reduced sputum cell expression of ACE-2 and transmembrane protease serine 2 (TMPRSS2), the latter considered a key player in the process of virus-cell membrane fusion [48, 49] .

In any case, the role of ICSs as preventive therapy in patients at risk of infection by Sars-CoV-2 remains unclear. Nevertheless, it is essential to systematically collect data on comorbidities and therapeutic history of patients, in order to characterize the potential benefit-risk ratio of therapy for asthma and COPD against the spread of Sars-CoV-2.

The main limitation of this study is related with the intrinsic characteristics of simple pooling approach, that fails to weight individual studies or subgroups [33] . However, considering that the analysis was performed on a very large sample size, that the selected studies were comparable with respect to designs, data collection and reporting, and that generally the NOS reported a more than acceptably quality score for the investigated studies, it is improbable that the pooled results were affected by type 1 error or bias [31] .

Since most asthmatic and COPD patients are currently treated worldwide with an ICS [50] [51] [52] [53] , this concise quantitative synthesis indirectly supports the evidence that ICSs may improve the clinical course of COVID-19, probably by modulating the mRNA expression not only of ACE-2 receptor, but also of TMPRSS2 that facilitates the viral entry into the host cells [48, 53] .

All authors were involved in the conceptualization, design, analysis, and interpretation of the data, along with the drafting and critical revising of the manuscript. The authors read and approved the final version of the manuscript.

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We thank GlaxoSmithKline (IT) for the unconditional support provided for this research. This manuscript was not funded.

This paper was not funded.

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

http://orcid.org/0000-0001-7801-5040 Luigino Calzetta http://orcid.org/0000-0003-0456-069X