by Nikhil T Awatade 1, Peter A B Wark 1, 2, Andrew S L Chan 3, 4, S M Abdullah Al Mamun 5, Nurul Yaqeen Mohd Esa 6, Kazuto Matsunaga 7, Chin Kook Rhee 8, Philip M Hansbro 1, 9, Sukhwinder Singh Sohal 10, *, and on behalf of the Asian Pacific Society of Respirology (APSR) COPD Assembly.

1. COPD a Risk Factor for COVID-19

COPD as a Risk Factor for Infection and Poor Outcomes

Chronic obstructive pulmonary disease (COPD) patients and their respiratory cells, as well as animal models of experimental COPD, are more susceptible to respiratory viral infection and viral-induced exacerbations caused by influenza, rhinoviruses, and seasonal coronaviruses [1,2,3,4,5,6,7]. It has been reported that around 50% of COPD exacerbations are caused by respiratory viral infections [8], which suggests that SARS-CoV-2 may also cause exacerbations in COPD patients. Furthermore, the incidence of hospitalization and disease severity in patients with prior respiratory diseases, such as COPD, are much higher in patients with COVID-19 than with seasonal influenza [9]. This suggests that the healthcare burden associated with SARS-CoV-2-induced exacerbations in chronic respiratory diseases, such as COPD, will far outweigh the burden induced by other more established respiratory viruses [10,11,12].

It is likely that there will be unique factors that could influence the course of COVID-19 in Asia [13,14,15]. These effects are likely to be broad, encompassing population demographics, genetics, and socio-economic factors, as well as smoking and indoor and outdoor air-pollution [16,17,18,19,20]. An important question is whether individuals with COPD are at higher risk of acquiring SARS-CoV-2 infection and/or experiencing more severe clinical COVID-19 disease. To address these concerns, we conducted a PubMed search and found 66 manuscripts on COPD and infection with COVID-19, of which 38 were associated with epidemiology or prognosis, 21 with mechanisms, and 7 with management of the disease (Table 1).

Table 1. Summary of COPD studies. ND: Not defined.

2. COPD and Susceptibility to COVID-19

A systematic review was conducted to evaluate the prevalence and mortality of chronic lung disease among COVID-19 patients. The review included 26 studies from China and three from the United States [31]. The pooled prevalences of lung comorbidities including asthma, COPD, and lung cancer were 3% (95% CI = 0–14), 2.2% (95% CI = 0.02–0.03), and 2.1% (95% CI = 0.00–0.21), respectively [31]. However, all of the studies included in the review were hospital-based, which may have resulted in a selection bias towards more severe disease. The authors did not claim that individuals with asthma or COPD were over-represented in these populations. This could indicate that there is no increased susceptibility to SARS-CoV-2 infection or it may reflect community behavioral change, as people with COPD have been advised of their susceptibility to viral infection in the past and throughout the pandemic. They may, therefore, benefit more from social isolation. Notably, the only published community-based screening study was from Iceland, and they did not assess co-morbid diseases [32]. Hence, the prevalence of COVID-19 in COPD patients will remain unknown until community-based screening studies are conducted that identify the role of chronic co-morbidities and susceptibility to COVID-19.

There is a theoretical basis and emerging clinical evidence suggesting that COVID-19 results in worse clinical outcomes for COPD patients compared to non-COPD patients. Angiotensin converting enzyme 2 (ACE2) is the main host cell receptor for SARS-CoV-2, playing a crucial role in the virus’s entry into the cell and causing infection [33]. ACE2 levels are upregulated in the small airway epithelium and alveoli in older males and in COPD patients [34,35,36,37,38,39,40,41,42]. When combined with impaired innate and adaptive immune responses in COPD patients, which can delay respiratory virus clearance [37,40], it is biologically plausible that SARS-CoV-2 may more readily propagate in the lungs of COPD patients, resulting in more severe COVID-19. Indeed, poor outcomes post SARS-CoV-2 infection have been linked with COPD patients and current smokers [3,43,44].

Reference [26] conducted a retrospective evaluation of the impact of medical co-morbidities on the risk of serious adverse outcomes in COVID-19 patients in China. They found that a greater number of co-morbidities was associated with worse clinical outcomes, and among patients with various types of co-morbidities, COPD patients had the highest hazard ratio of 2.681 for the composite endpoint of admission to the intensive care unit, invasive ventilation, or death after adjusting for age and cigarette smoking status.

In another retrospective cohort study conducted in Republic of Korea, [22] examined 4610 patients infected with SARS-CoV-2 virus and found that those with COPD were more likely to require admission to the intensive care unit (7.1% vs. 3.7%) and mechanical ventilation (5.7% vs. 2.4%) than patients without COPD. Multi-variate analyses demonstrated that COPD was a significant independent risk factor for all-cause mortality after adjustment for age, sex, and the Charlson Comorbidity Index score (OR = 1.80, 95% CI = 1.11–2.93). However, COPD was not found to be a risk factor for respiratory failure. COPD patients had the most co-morbidities, with hypertension being the most common. The pre-existing severity of COPD did not appear to influence the clinical outcomes of COVID-19, including length of hospital stay, need for intensive care, respiratory failure, or all-cause mortality; however, the number of patients with severe COPD defined by ICD-10 code (International Classification of Diseases) without spirometry confirmation was relatively small.

Reference [23] conducted a retrospective study of COPD patients during the COVID-19 pandemic in Hubei, China, from December 2019 to March 2020. Among the 489 enrolled COPD patients, only two (0.41%) were diagnosed with confirmed COVID-19. Although the rates of acute exacerbations and hospitalization decreased during this period, the COPD mortality rate was significantly higher (2.86% vs. 0.65%). The authors also retroactively analyzed the characteristics of 821 patients with confirmed COVID-19, of whom 4.5% had pre-existing COPD. Patients with pre-existing COPD who died from COVID-19 had higher rates of coronary artery and cerebrovascular disease. The study concluded that pre-existing COPD was a risk factor for all-cause mortality in COVID-19 patients, and that the presence of COPD was associated with higher risk of all-cause mortality compared to COVID-19 patients without COPD.

Reference [45] conducted a systematic review and meta-analysis of 59 studies on the association between COPD and poor outcomes in COVID-19. The study found that COPD was associated with increased risks of hospitalization (OR = 4.23, 95% CI = 3.65–4.90, p < 0.0001), admission to the intensive care unit (OR = 1.35, 95% CI = 1.02–1.78, p = 0.03), and mortality (OR = 2.47, 95% CI = 2.18–2.79, p < 0.0001). However, the study also identified several important limitations of the studies, including their retrospective study design, relatively small sample sizes, and reliance on data obtained from single centers or regions. Furthermore, few studies examined the effects of COPD on COVID-19 outcomes as their primary endpoint, and the identification of COPD often relied on self-reporting or physician diagnosis, which may have introduced bias. Additionally, the impact of COPD could have been confounded by a range of demographic factors or co-morbidities.

A large study from the UK assessed the links between chronic respiratory diseases, including COPD, and COVID-19. They reviewed the links between >8.2 million people, including ~14,500 patients hospitalized for COVID-19, >1500 patients who progressed to the intensive care unit, and almost 6000 deaths. This study demonstrated that COPD patients were at increased risk of hospitalization and death (both HR = 1.54) [24]. Another US study of >11,000 patients hospitalized for COVID-19 also showed that COPD patients had higher mortality (HR = 1.27; 95% CI = 1.02–1.58), and COPD was the co-morbidity most highly associated with mortality, although obesity, diabetes, and hypertension were also independent predictors [25]. A large retrospective cohort study from China with >39,000 COVID-19 patients showed that after adjustment for age, sex, and other systemic co-morbidities, COPD (OR = 1.71; 95% CI = 1.44–2.03) and asthma (OR = 1.45; 95% CI = 1.05–1.98) but not bronchiectasis patients were more likely to reach to the composite endpoint of needing invasive ventilation, admission to the intensive care unit, or death within 30 days after hospitalization from COVID-19 [21]. Data from a New York cohort (13, 442 patients with COVID-19 attending the emergency department) showed that COPD was linked with higher risks of hospitalization (RR = 1.77; 95% CI = 1.67–1.87) and mortality (RR = 1.08; 95% CI = 0.88–1.33) [27]. Comparable results were documented in an Italian study of 1044 hospitalized patients, where increased risk of severe respiratory failure (RR = 1.81; 95% CI 1.03–3.2) was observed amongst COPD patients [28]. Data from >20,000 patients hospitalized with COVID-19 in The International Severe Acute Respiratory and Emerging Infection Consortium study showed that COPD was linked with high mortality risk (HR = 1.17; 95% CI = 1.09–1.27) [29].

The majority of studies have found that patients with pre-existing COPD and COVID-19 have worse clinical outcomes [30,46] or higher mortality risk [21]. However, biases inherent in retrospective cohort studies may have influenced these results, and prospective evaluation is necessary. Additionally, the long-term effects of COVID-19 among patients with pre-existing COPD are still largely unknown [43]. In those who have COVID-19 and seek medical attention due to illness, the role of co-morbidities such as COPD is clearer. A systematic review and meta-analysis was conducted to assess the associations of epidemiological co-morbidities with severity and prognosis, of which 61 studies with >10,000 COVID-19 cases were included. COPD was found to contribute to acute disease severity (RR = 4.20; 95% CI = 2.82–6.25), the need for admission to an intensive care unit (RR = 5.61, 95% CI = 2.68–11.76), the composite endpoint of worse clinical outcome (RR = 8.52; 95% CI = 4.36–16.65), the need for invasive ventilation (RR = 6.53; 95% CI = 2.70–15.84), and disease progression (RR = 7.48; 95% CI = 1.60–35.05) [47].

3. Acute COVID-19 Problems in COPD Patients and Management

4. Post COVID-19 Syndrome

5. Conclusions

The balance of evidence strongly suggests that COPD patients are more susceptible to contracting COVID-19, developing severe acute disease, and have worse clinical outcomes. However, the heterogeneity of the COPD population across different countries with varying proportions of co-morbidities may complicate assessing the net effect of COPD on COVID-19-related outcomes due to variability in testing and admission strategies. Additionally, individuals with COPD who have pre-existing exercise intolerance and cardiovascular morbidities are more likely to experience a complicated recovery, placing them at greater risk during the COVID-19 pandemic.

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