key: cord-0950592-337dcla2
authors: Sanchez-Ramirez, Diana C.; Mackey, Denise
title: Underlying respiratory diseases, specifically COPD, and smoking are associated with severe COVID-19 outcomes: A systematic review and meta-analysis
date: 2020-07-30
journal: Respir Med
DOI: 10.1016/j.rmed.2020.106096
sha: 4067f0afaaf777a194edfd2f5d56c71ee81dada2
doc_id: 950592
cord_uid: 337dcla2

BACKGROUND: An outbreak of Corona Virus Disease 2019 (COVID-19) has spread rapidly reaching over 3 million of confirmed cases worldwide. The association of respiratory diseases and smoking, both highly prevalent globally, with COVID-19 severity has not been elucidated. Given the gap in the evidence and the growing prevalence of COVID-19, the objective of this study was to explore the association of underlying respiratory diseases and smoking with severe outcomes in patients with COVID-19 infection. METHODS: A systematic search was performed to identify studies reporting prevalence of respiratory diseases and/or smoking in relation with disease severity in patients with confirm COVID-19, published between January 1 to April 15, 2020 in English language. Pooled odds-ratio (OR) and 95% confidence intervals (95% CI) were calculated. FINDINGS: Twenty two studies met the inclusion criteria. All the studies presented data of 13,184 COVID-19 patients (55% males). Patients with severe outcomes were older and a larger percentage were males compared with the non-severe. Pooled analysis showed that prevalence of respiratory diseases (OR 4.21; 95% CI, 2.9–6.0) and smoking (current smoking OR 1.98; 95% CI, 1.16–3.39 and former smoking OR 3.46; 95% CI, 2.46–4.85) were significantly associated with severe COVID-19 outcomes. INTERPRETATION: Results suggested that underlying respiratory diseases, specifically COPD, and smoking were associated with severe COVID-19 outcomes. These findings may support the planning of preventive interventions and could contribute to improvements in the assessment and management of patient risk factors in clinical practice, leading to the mitigation of severe outcomes in patients with COVID-19 infection.

An outbreak of Corona Virus Disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was identified in Wuhan, China in December 2019. Currently, the disease has spread rapidly worldwide reaching over 3 million of confirmed cases, including 208,516 deaths as of April 27, 2020 [1] .

Unique clinical features identified within the confirmed cases included a higher proportion of males, older adults and people with underlying comorbidities [2] [3] [4] [5] . Preliminary studies reported severe COVID-19 outcomes in patients with underlying cardiovascular diseases, arterial hypertension and diabetes [2, 6] . It was also suggested that presence of underlying respiratory diseases in general may contribute to severe COVID-19 outcomes [7] , however, this association has not been elucidated and specific respiratory diseases have not been explored.

In addition, emerging literature indicates that smokers may have more severe COVID-19

infections than non-smokers [8] . However, a recently meta-analysis did not find a significant association between active smoking and severe COVID-19 [9] .

Respiratory diseases and smoking are highly prevalent worldwide. More specifically, reports indicate that about 65 million people suffer from chronic obstructive pulmonary disease (COPD), 334 million people suffer from asthma, and over 10 million people developed tuberculosis in 2015 [10] . It was estimated that one-in-five (20%) adults in the world smoke tobacco [11] , which is also a recognized risk factor for respiratory diseases.

The association of respiratory diseases and smoking, both highly prevalent globally, with severe COVID-19 outcomes has not been elucidated. Given the gap in the evidence and the growing prevalence of COVID-19, the objective of this article was to explore the association of underlying respiratory diseases and smoking with severe outcomes in patients with infection. Results of this study may support the development of preventive and clinical interventions leading to mitigate severe outcomes in patients with COVID-19.

We incorporated PRIMA guidelines through our review. A systematic search was conducted in the electronic bibliographic databases of PubMed, Web of Sciences, and Ovid MEDLINE. The key words and strategy used were: (('COVID-19' OR 'COVID 19' OR 'Novel coronavirus' OR 'SARS-CoV-2' OR 'coronavirus 2019' OR '2019-nCoV' OR 'coronavirus disease 2019') AND (('comorbidities' OR 'clinical characteristics' OR 'characteristics' OR epidemiology) OR ('smoking' OR 'tobacco' OR 'risk factors' OR 'smoker'))). The search was limited to journal articles published in 2020 (January 1 to April 15). We examined the reference lists of articles to identify additional studies.

The systematic search retrieved 1203 references. After removing duplicates, two researchers (DS and DM) screened 497 titles and abstracts and 33 read full text articles. Both researchers independently reviewed the articles, before coming to a consensus opinion, to include 22 publications that met the inclusion criteria ( Figure 1 ). The main reasons for study exclusion included: 1) the study did not provide prevalence of comorbidities or smoking in patients with COVID-19; 2) prevalence of comorbidities in patients with COVID-19 was grouped in one variable and specific information on respiratory diseases was not available, and history of smoking was not included; 3) COVID-19 disease severity in relation with the prevalence of chronic respiratory diseases or smoking was not presented; and 4) the full text of the study was not in the English language. A total of 22 publications met the inclusion criteria of: 1) describe COVID-19 severity in relation with prevalence of chronic respiratory diseases and/or smoking;

2) the publication was not a meta-analysis or systematic review; and 3) full text of the study was available in English language.

The information of the 22 articles was synthesized in Table 1 , which presented: 1) author(s)' name and title of the study; 2) country of the study; 3) number of cases included and setting of data collection; 4) definition of the study for severe and non-severe COVID-19 outcomes and number of patients in each group. Severe COVID-19 outcomes included cases admitted to the ICU, reported as death or non-survivors, worsened during hospitalization, or identified as severe or critical using guidelines by the National Health Commission, the American Thoracic Society or the Chinese National Health Committee. Non-severe outcomes included cases who presented mild to moderated symptoms, were not hospitalized or hospitalized but non-ICU, survived, recovered, remained stable during hospitalization, or identified as non-severe based on guidelines by the National Health Commission, the American Thoracic Society or the Chinese National Health Committee; 5) age and gender of the patients studied; 6) number of underlying respiratory diseases among patients with severe and non-severe outcomes; and 7) number of smokers (current and/or former) with severe and non-severe COVID-19 outcomes.

The Review Manager (RevMan; version 5.3; Copenhagen, Denmark) software was used to pool the individual included studies. The analysis is presented as ORs based on the likelihood of severe COVID-19 outcome in patients with underlying respiratory diseases and history of smoking compared with patients without those potential risk factors using random-effects methods. To investigate heterogeneity between studies, the authors used the I2 index which describes the percentage of variation across the studies in the pooled analysis that is due to inconsistency rather than by chance. A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity.

This review included 22 publications that described severe COVID-19 outcomes in relation with the prevalence of chronic respiratory diseases and/or smoking (Table 1) [2, 19, 24] or died [12-15, 26, 28, 32] . Compared with the non-severe outcome group, patients in the severe outcome group were older and a larger percentage of them were males (63% vs 51%).

Twenty one studies [2, [12] [13] [14] [15] [16] [17] [18] [19] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] reported prevalence of respiratory diseases in patients with COVID-19 (n=12,976). COPD was the main respiratory disease documented in the studies, [2, 13, 16-19, 21-23, 25, 26, 29-31] one study also reported pulmonary tuberculosis and asthma [29] , and others reported respiratory comorbidities using terms such as respiratory system diseases, chronic lung diseases, lung disease, or pulmonary diseases. A higher prevalence of respiratory diseases (12%) was found in patients with severe COVID-19 outcomes compared with the non-severe outcomes group (4%). The results of the meta-analysis ( Figure 2 ) showed that patients with underlying respiratory diseases had a significantly higher odds of severe COVID-19 outcomes when data from the individual studies were pooled (OR 4.21; 95% CI, 2.9-6.0). No significant study heterogeneity (I2, 35%, p=0.06) was evident. A separate sensitivity analysis showed that patients with underlying COPD had higher odds of having severe-19 outcomes (OR 5.8; 95% CI, 3.9-8.5).

Thirteen studies [14, 16, 18-20, 22-25, 28-30, 32 ] reported prevalence of current smoking (n=9440 patients) and four of them [14, 18, 24 , 29] also reported prevalence of former smoking (n=8136 patients). Prevalence of current and former smoking was higher in patients with severe COVID-19 outcomes (13% and 6%) than in non-severe outcomes (6% and 3%). Individual and pooled results for prevalence of current and former smoking are presented in Figure 3 and 4, respectively. The results of the meta-analysis showed that smokers (current smokers OR 1.98; 95% CI, 1.16-3.39 and former smokers OR 3.46; 95% CI, 2.46-4.85) had significantly higher odds of severe COVID-19 outcomes. The analysis showed high heterogeneity for estimates of current smoking (I2, 52%, p=0.02), but no significant study heterogeneity (I2, 0%, p=0.43) was evident for estimates of former smoking.

This literature review and meta-analysis compiles evidence from 22 studies that provide information on patients' underlying respiratory diseases and smoking in relation to COVID-19 severity. Results of the pooled analysis show that prevalence of underlying respiratory diseases was a significant predictor for severe COVID-19 outcomes. Results of this study align with a previous smaller meta-analysis (four studies) which reported significant respiratory system diseases in severe COVID-19 patients compared with non-severe (OR 2.46, 95% CI: 1.76-3.44) (7) . However, our review gathered a larger number of recent publications relevant to the topic and showed a stronger association (OR 4.21, 95% CI: 2.9-6.0).

Respiratory diseases were reported using a general variable which may potentially group various conditions or specifically refer to COPD. Information on other respiratory diseases was lacking except for one study that reported prevalence of COPD, asthma and secondary pulmonary TB [29] . Consequently, questions arise around the reasons leading to a lack of information on prevalence of respiratory diseases, other than COPD, and COVID-19 severity in the literature. It has been found that COPD is not infrequently misclassified due to underutilization of confirmatory spirometry and to the healthcare professional performing the diagnostic assessment [33, 34] . However, it is also possible that other respiratory diseases were underdiagnosed or not appropriately documented in the databases, which is unlikely because this information was missing across most of the studies including the report from the Centre for Disease Control (CDC) in the United States [24] . Another possibility may be that prevalence of other respiratory diseases may not be associated with severe COVID-19 outcomes due to their specific immune response and/or undergoing pharmacological treatment [35] . For example, asthma treatment usually involves the use of bronchodilators and inhaled corticosteroids which have shown to suppress coronavirus replication and cytokine production in in-vitro models [36, 37] . Overall, the relationship of COVID-19 severity with specific respiratory diseases, besides COPD, (e.g. asthma, pulmonary TB pulmonary fibrosis, etc.) and their causal mechanisms require further investigation.

Severe COVID-19 outcomes were significantly associated with current and former smoking. It is suggested that smoking may play a role in angiotensin converting enzyme 2 (ACE2) modulation [38] , which is the reported host receptor of the virus responsible for COVID-19 [39, 40] . A dosedependent increase in ACE2 expression according to smoke exposure was found in rodent and human lungs [41] . Although incidence of COVID-19 appear to be lower in patients with smoking history [18, 29] , smoking seems to be associated with worse outcomes. A recent publication suggested that smokers susceptibility to severe SARS-CoV-2 infections could be at least partially explained by the response of ACE2 expression to inflammatory signaling, which can be upregulated by viral infections [41] . Furthermore, increased ACE2 expression has been observed in COPD which is a respiratory disease strongly associated with prior cigarette exposure and severe COVID-19 outcomes [41]. However, additional studies will be required to clarify the association of smoking, COPD and ACE2 levels on the clinical course of COVID-19.

Results of this study differed from a previous meta-analysis concluding that active smoking does not apparently seem to be significantly associated with enhanced risk of progression towards severe disease outcomes in COVID-19 [9] . Discrepancy in the conclusions of the metaanalyses could be due to the large number of studies identified (5 vs 13) in this review, some of them with larger sample sizes.

It is important to note that in this study former and current smoking were associated with severe COVID-19 outcomes. This aligns with existing evidence suggesting that all levels of smoking including the exposure of former smokers and low-intensity current smokers are likely to be associated with lasting and progressive lung damage [42] . Pooled analysis showed higher odds of severe COVID-19 outcomes in former smokers compared with current smokers. It is possible that differences in the strength of association may be explained by: 1) the characteristics of the studies such as data collected (e.g. variables definition and time elapsed since the person quitted smoking); 2) the number of studies (4 vs 13) and sample sizes included;

3) specific immune responses in former and current smokers, and/or 4) the group of former smokers could be comprised of patients with more advanced COPD than the current smokers.

Results suggested that underlying respiratory diseases, specifically COPD, and smoking increase the odds of having severe COVID-19 outcomes. This is an important finding considering the high There are multiple factors to consider when interpreting these findings. First, there is limited information on respiratory diseases and smoking presented in the identified studies which prevents us from drawing further conclusions regarding the specific role of each risk factor in the development of severe COVID-19 outcomes. Evidence suggests that there is a close relationship between COPD, cigarette exposure and ACE2 modulation that could enhance the risk for developing severe COVID-19 outcomes, however, more research is needed to clarify this association. Second, the studies identified in this review were mostly conducted in China (95%).

It is possible that factors such as prevalence of respiratory diseases and their treatment, among others, may be specific to the context. Therefore, the results of this study should be considered with caution and be re-evaluated as emerging literature from other countries become available.

Third, there is a lack of information regarding variable definition during data collection which may influence the associations studied. Fourth, a high statistics heterogeneity was found in the pooled meta-analysis of current smokers and severe vs non-severe COVID-19 outcomes. This may be related to differences in data collection and sample size (25 to 6637) across the studies included in this part of the analysis. Statistics heterogeneity was not found in the other two pooled analyses (severe vs non-severe COVID-19 outcomes in respiratory disease and former smokers).

Results suggested that underlying respiratory diseases, specifically COPD, and smoking are associated with severe COVID-19 outcomes. These findings contribute to a better 

None.

DS conceived the idea for this paper and conducted the meta-analysis. DS and DM participated in the search and selection of literature, extracted key information from the studies identified, wrote and approved the final manuscript. 

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