Chronic obstructive lung diseases as a risk factor for severe COVID-19 (review)

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Abstract

The review presents meta-analyses and original studies data of severe outcomes of COVID-19 infection in patients with chronic obstructive pulmonary disease.

The main risk factors for the severe course of COVID-19 in many studies have been identified as follows: age over 65 years, chronic lung diseases, systemic arterial hypertension, cardiovascular diseases, diabetes mellitus, immunosuppression, chronic kidney and liver diseases. It was shown that patients with concomitant respiratory diseases were 4.2 times more likely to have a severe course of COVID-19 (OR 4.21; 95% CI 2.9–6.0), especially in patients with chronic obstructive pulmonary disease (OR 5.8, 95% CI 3.9–8.5). Patients with bronchial asthma also more often received mechanical ventilation (OR 1.58; 95% CI 1.02–2.44; p = 0.04), treatment in intensive care units (OR 1.58; 95% CI 1.09–2.29; p = 0.02), had longer hospital stays (OR 1.30; 95% CI 1.09–1.55; р < 0.003) and higher mortality (OR 1.53; 95 % CI 1.01–2.33; p = 0.04) compared with COVID-19 patients without asthma or other chronic obstructive pulmonary diseases. Another factor contributing to severe outcomes of COVID-19 is tobacco use, which increases the risk of severe disease, hospitalization and poor outcomes.

Patients with chronic obstructive pulmonary diseases, especially smokers, were more likely to have a severe COVID-19 and adverse outcomes of this disease, which must be taken into account when prescribing treatment for coronavirus infection.

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Coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first registered in December 2019 in China and has spread rapidly worldwide. By April 2020, more than 3 million cases and 208,516 lethal outcomes were registered [4, 21].

Globally, scientists and doctors were searching for methods of diagnosing and treating this disease and factors leading to an adverse outcome. By September 2022, 301,485 articles were yielded when using the keyword “COVID-19” in PubMed, including 2640 meta-analyses, and there were 30,747 articles in the Russian Science Citation Index.

Concomitant diseases represent one of the factors of severe clinical course and its adverse outcomes in patients with COVID-19. For example, in a study conducted in Mexico, patients with COVID-19 with three or more comorbidities had a higher risk of hospitalization [odds ratio (OR) = 3.1; 95% confidence interval (CI) 2.7–3.7], pneumonia (OR = 3.02; 95% CI 2.6–3.5), hospitalisations in intensive care units (OR = 2; 95% CI 1.5–2.7), and mortality (OR = 3.5; 95% CI 2.9–4.2) than patients with one or two comorbidities and patients without them [22].

Age over 65 years, chronic lung diseases, systemic arterial hypertension, cardiovascular diseases, diabetes mellitus, immunosuppression, and chronic kidney and liver diseases are risk factors for severe COVID-19 [8, 22]. Patients with obesity more often have adverse outcomes and severe disease course [22]. A study reported that patients with a body mass index of >30 kg/m2 had the highest levels of C-reactive protein and humoral endotoxin-binding factors [12] because excess body weight leads to an increase in the endotoxin translocation from the intestine to the lymphatic system and into the blood and to the maintenance of systemic inflammation in patients with COVID-19 [12].

In other clinical studies, increased risks of a more severe course of COVID-19 are noted in men, older people and senile age, and individuals with cardiovascular diseases [15, 18, 29, 31, 33].

A meta-analysis conducted in 2020 [25] presented the first data (22 studies) on 13,184 patients with COVID-19, most of whom lived in China. Patients with COVID-19 were included in the severe outcome group if their clinical symptoms worsened, they required intensive care, or they died. Compared with the non-severe outcome group, the severe group was older with male predominance (63% versus 51%) [25] and had a higher prevalence of chronic obstructive pulmonary disease (COPD; 12% versus 4%) [25]. The meta-analysis results showed that the probability of severe COVID-19 outcomes was significantly higher in patients with respiratory comorbidities (OR 4.21; 95% CI 2.9–6.0). No significant heterogeneity was found in the study. The risks of a severe course were the highest in patients with COPD (OR 5.8; 95% CI 3.9–8.5) [25].

The high contagiousness of SARS-CoV-2, localisation of the virus in the lower respiratory tract, identical clinical presentation of COVID-19, exacerbations of COPD, and the lack of pathogenetic therapy make it difficult to provide medical care to patients with COPD during a pandemic at all its stages. In addition, patients with COPD are usually diagnosed with diseases of the heart and blood vessels, which are also risk factors for the severe course of any acute respiratory infection, including COVID-19 [9]. However, COVID-19 is characterized by the influence of the virus not only on the respiratory system but also on blood vessels with the formation of microthrombi, which contribute to increased respiratory dysfunction; patients with COVID-19 had nine times more microthrombi in alveolar capillaries than patients with influenza [1, 10]. When SARS-CoV-2 enters the body, endothelial cells are activated, which induces systemic inflammation, thrombosis, and microvascular dysfunction [16]. These pathophysiological changes are hazardous for patients with cardiovascular diseases and may represent one of the causes of high mortality from COVID-19.

Another factor that contributes to the severe disease course in patients with COPD is tobacco smoking. Tobacco smoking, including passive smoking, remains the main preventable cause of premature death worldwide and the main risk factor for the occurrence of COPD, which can affect 15%–30% of smokers [7, 17]. Epidemiological studies have shown that in Russia, COPD occurs in 21.8% of patients with respiratory symptoms and15.3% of the general population [6, 14]. Moreover, 65% of smokers have pathological changes in the lungs that can cause COPD [13]. Even in those long-term smokers who consider themselves healthy, pronounced impairment of bronchial patency was registered in 15% of cases [5]. Tobacco cessation slows the deterioration of external respiration, stabilizes the clinical COPD status, and contributes to an increase in life expectancy and quality [27].

Many studies have reported that smokers had more severe COVID-19 than non-smokers, and they required intensive care and mechanical lung ventilation 2.4 times more often [11, 20, 28].

According to the World Health Organization, 1.4%–18.5% of adult patients hospitalized for COVID-19 were smokers [30]. Although several studies have demonstrated a lower percentage of smokers among patients hospitalized for COVID-19 than the general population, possible errors in these studies should be considered, which could be associated with a stringent epidemiological situation and smoking status is not always documented, especially in the absence of a pronounced nicotine withdrawal syndrome [11].

The pathogenesis of COVID-19 and its severe course are largely associated with angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) [19]. The ACE2 receptor level is increased in older individuals, male patients, and smokers [19]. Since smoking increases ACE2 expression, patients with COPD are prone to COVID-19 and are at higher risk of severe COVID-19 [20]. A dose-dependent increase in ACE2 expression depending on smoke exposure was revealed in the lungs of rodents and humans [26].

The expressions of ACE2 and TMPRSS2 in patients with asthma is comparable (or less common) to that in healthy people [19]. This may explain the lower incidence of COVID-19 (at least in 2020–2021) in patients with asthma than in patients with COPD. Moreover, data have been obtained not only on the lower incidence of COVID-19 in bronchial asthma (BA) but also on a decrease in the number of patients hospitalized for asthma exacerbation (data from a study in Japan) [19]. Therefore, clinical recommendations for the treatment of BA during a pandemic have remained the same in many countries.

Later, these results were called into question, and in 2022, a study in the USA analysed the clinical course of COVID-19 in patients with BA. During the initial data processing, indeed, no differences were detected in the severity of COVID-19 in patients with and without BA [23]. However, in the adjusted analysis (the analysis was adjusted for demographics, comorbidities, smoking status, and time of illness during the pandemic), patients with more often BA received mechanical lung ventilation (OR1.58; 95% CI 1.02–2.44; p = 0.04) and hospitalized in the intensive care unit (OR1.58; 95% CI 1.09–2.29; p = 0.02), had longer hospital stay (OR1.30; 95% CI 1.09–1.55; p < 0.003), and had higher mortality (OR1.53; 95% CI 1.01–2.33; p = 0.04) than the non-asthma cohort [23]. Inhaled corticosteroid use and eosinophilic phenotype were not found to be associated with significant differences in severe COVID-19 outcomes, although conflicting data demonstrate the suppression of coronavirus replication and cytokine production in vitro models using bronchodilators and inhaled corticosteroids [24, 32]. Comparison of the clinical course and severity of BA showed that in patients with moderate BA, the outcomes were worse than in those with severe BA [23], which requires further research to understand the role of various drugs and characteristics of the geno- and phenotypes of the disease for the prevention of severe COVID-19.

In the Russian Federation, among patients with cystic fibrosis (CF), the incidence of COVID-19 as of 1 August 2020, was 3.8 (0.38%) per 1,000 patients (2.1:1000 for children and 8.8:1000 for adults) [2]. Although patients with CF are at risk for severe COVID-19, the infection did not induce a significant deterioration in the underlying disease. No lethal outcomes from COVID-19 have been reported in Russian patients with CF [2]. Among adult patients with CF living in St. Petersburg and the Leningrad region, the incidence of COVID-19 was 17.85%, which was lower than that in the general population. In rare cases, the disease proceeded with a severe course. The efficiency of outpatient treatment and the absence of lethal outcomes from COVID-19 were also noted [3]. The risk factors for severe COVID-19 in patients with CF do not include advanced age, tobacco consumption, and active smoking [2, 25]. The role of self-isolation in serious illnesses such as CF should not be ruled out.

COPD and tobacco smoking increase the risk of severe disease and adverse outcomes of COVID-19. This is important for the development of preventive measures that will help improve the management of patient risk factors in clinical practise.

ADDITIONAL INFORMATION

Author contribution. Thereby, all authors made a substantial contribution to the conception of the study, acquisition, analysis, interpretation of data for the work, drafting and revising the article, final approval of the version to be published and agree to be accountable for all aspects of the study.

Competing interests. The authors declare that they have no competing interests.

Funding source. This study was not supported by any external sources of funding.

ДОПОЛНИТЕЛЬНАЯ ИНФОРМАЦИЯ

Вклад авторов. Все авторы внесли существенный вклад в разработку концепции, проведение исследования и подготовку статьи, прочли и одобрили финальную версию перед публикацией.

Конфликт интересов. Авторы декларируют отсутствие явных и потенциальных конфликтов интересов, связанных с публикацией настоящей статьи.

Источник финансирования. Авторы заявляют об отсутствии внешнего финансирования при проведении исследования.

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About the authors

Valery D. Kulikov

Research Institute of Pulmonology of the Academician I.P. Pavlov First St. Petersburg State Medical University

Author for correspondence.
Email: vdkulikov@mail.ru

PhD, MD, Leading Researcher, Research Institute of Pulmonology

Russian Federation, Saint Petersburg

Olga A. Sukhovskaya

Research Institute of Pulmonology of the Academician I.P. Pavlov First St. Petersburg State Medical University; St. Petersburg State Research Institute of Phthisiopulmonology

Email: ktc01@mail.ru

PhD, Head of Department, Research Institute of Pulmonology; Head of Centre

Russian Federation, Saint Petersburg; Saint Petersburg

Maria A. Smirnova

St. Petersburg State Research Institute of Phthisiopulmonology

Email: ktcniif@mail.ru

Therapist

Russian Federation, Saint Petersburg

Nataly A. Kuzubova

Research Institute of Pulmonology of the Academician I.P. Pavlov First St. Petersburg State Medical University

Email: kuzubova@mail.ru

PhD, MD, Deputy Director, Research Institute of Pulmonology

Russian Federation, Saint Petersburg

Olga N. Titova

Research Institute of Pulmonology of the Academician I.P. Pavlov First St. Petersburg State Medical University

Email: titovaon@spb-gmu.ru

PhD, MD, Head, Research Institute of Pulmonology

Russian Federation, Saint Petersburg

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