COVID-19 and COPD: lessons beyond the pandemic

Abstract

Early in the COVID pandemic there were concerns about the outcomes for patients with COPD who developed COVID-19. Although the pandemic has made the diagnosis and routine management of COPD more difficult, the risk of patients developing COVID or of having poor outcomes is less than anticipated and there have been some unexpected findings that may lead to significant improvements in the management of COPD in future.

The theme for World COPD Day on November 17, 2021, is “Healthy Lungs: Never More Important.” The aim is to highlight that, even during the COVID-19 pandemic, chronic obstructive pulmonary disease (COPD) remains one of the three leading causes of death worldwide, as well as emphasizing the importance of healthy lungs not only for COPD but for many other conditions. The pandemic has undoubtedly made the diagnosis and routine management of COPD more difficult, and there was concern about the outcomes for patients with COPD who develop COVID-19. The 2021 Global initiative for the management of chronic Obstructive Lung Disease (GOLD) Report on the management of COPD (1) addressed the issue of COVID-19 and COPD (2). Since the Report was published, evidence on the risks patients with COPD face and the efficacy and safety of current maintenance therapies, particularly inhaled corticosteroids (ICS), has continued to emerge, although the key messages remain unchanged. Surprisingly, the pandemic has also led to insights that may have long-term benefits for patients with COPD. A number of studies around the world have shown that exacerbation rates have fallen by up to 50% during the pandemic (3). Understanding the factors responsible for this reduction, and exploring how they could be used in future, offers significant hope for patients with COPD.

At the start of the pandemic, patients with chronic respiratory diseases, including COPD, were anxious about developing COVID-19, worried about being denied care, about coping with the symptoms, and dying (4). Clinicians were also concerned about the vulnerability of these patients, and social distancing and protective self-isolation were introduced to reduce the risks. However, the evidence suggests that patients with COPD do not seem to be at greatly increased risk of infection with SARS-CoV-2, possibly reflecting the effects of maintenance therapy, as well as the effect of the protective strategies (5).

Having chronic respiratory disease is an independent risk factor for testing positive for SARS-CoV-2, but the risk is small compared with other factors such as age or obesity (6). Some studies, particularly those early in the pandemic, found a lower prevalence of COPD among people admitted to hospital with COVID-19 than would be expected from population prevalence (5, 7, 8). However, more recent and better designed studies do show that having COPD is an independent risk factor for hospital admission with COVID-19, although the additional risk is again modest. For example, in a study of a primary care cohort of 8.28 million patients, the adjusted hazard ratio for admission for patients with COPD was 1.54 [95% confidence interval (CI) 1.45–1.63] (9). COPD has also been reported to independently increase the risk of severe disease or death in some series (8–15) but not all (6, 16–18). These findings suggest that the risks are less than might be expected, and it is possible that this could be due to their maintenance therapy, particularly ICS, mitigating these risks (5).

ICS have an overall protective effect against exacerbations in patients with COPD with a history of exacerbations; however, their use in COPD is associated with an increased risk of upper respiratory tract infections (19), a higher prevalence of pneumonia (20), and a change in the lung microbiome, although not a change in respiratory virus detection (21). These effects led to concern about their effects during the pandemic; however, there are theoretical reasons why ICS may be beneficial in SARS-CoV-2 infection (22). Although in vitro studies have suggested that corticosteroids may impair antiviral innate immune responses (23, 24) and that ICS use impairs innate and acquired antiviral immune responses to rhinovirus leading to delayed virus clearance (25), ICS appear to protect against some virus infections, including those due to coronavirus. In vitro studies have shown direct antiviral effects of ciclesonide (26) and budesonide on SARS-CoV-2 (27). In contrast, patients with COVID treated with medium- and high-dose systemic corticosteroid therapy have been found to have delayed virus clearance in some studies (28, 29) but not all (30). Inhaled and systemic corticosteroids have differential effects on eosinophils in peripheral blood and induced sputum (31) and ICS appear to have a greater local anti-inflammatory effect in airways (32), perhaps as a result of differences in tissue penetration at the mucosal level, topical steroid potency, and half-life. Corticosteroids may, therefore, have different effects on SARS-CoV-2 according to whether they are inhaled or administered systemically.

ICS may also affect susceptibility to COVID through effects on angiotensin-converting enzyme 2 (ACE2) expression in the airways. The spike protein of the SARS-CoV-2 binds to ACE2 during viral attachment to host cells (33). Differences in the expression of ACE2 may modulate the individual susceptibility to and clinical course of SARS-CoV-2 infection. ACE2 mRNA expression is increased in COPD (22, 34, 35); however, it is reduced by ICS use (34, 36, 37), possibly through suppression of type I interferon (38).

Is there clinical evidence for a benefit or harm of ICS during the COVID-19 pandemic? A systematic review early in the pandemic identified no clinical studies concerning the relationship between ICS use in COPD and clinical outcomes from coronavirus infections (39). A more recent study suggested that ICS use in COPD was not protective against coronavirus infection and raised the possibility that it increased the risk of developing COVID-19 (40), but the results are likely to be confounded by the indication for ICS (41). Subsequent studies from the United States, Belgium, and Korea have not shown any adverse effect of ICS use (18, 42, 43), but neither have they shown benefit, although this again may be confounded by indication. The GOLD Report concluded that there are no conclusive data to support alteration of maintenance COPD pharmacological treatment including ICS, either to reduce the risk of developing COVID-19, or conversely because of concerns that pharmacological treatment may increase the risk of developing COVID-19 (2).

Knowledge of the theoretical effects of ICS on SARS-CoV-2 infection as well as their apparent protective effects in patients with COPD has led to studies of their effects in patients who do not have COPD or any other indication for ICS therapy. The STerOids in COVID-19 Study (STOIC) trial investigated the effects of inhaled budesonide early in the course of COVID. Despite being terminated early and including fewer randomized patients than originally planned, it showed a reduction in the likelihood of needing urgent medical care and reduced time to recovery after early COVID-19 (44). However, it was not placebo controlled and the benefit of ICS was far larger than any effect seen in patients prescribed ICS for airways disease. The Platform Randomized trial of Interventions against COVID-19 in older People (PRINCIPLE) trial also investigated the effects of inhaled budesonide compared with usual care in nonhospitalized patients aged 65 yr and older and those aged 50 yr and older with comorbidities. It was also not placebo controlled; patients were aware of their treatment allocation and it relied on self-reported recovery. It showed that ICS improved time to recovery, but the effects on the objective outcomes of hospital admissions or deaths were not statistically significant (45). Most patients in the study had not been vaccinated and an important question is whether the same effect would have been seen in a fully vaccinated population. In another study, inhaled open-label ciclesonide has been shown to lead to greater SARS-CoV-2 eradication rates than standard care (46). More studies are needed, and some are ongoing, but it appears that ICS may offer benefits to older non-COPD patients with COVID-19 who are at higher risk of complications.

There is evidence of a fall in hospitalization rates for COPD during the pandemic (3, 47–50). This was not accompanied by an increase in deaths from COPD, and reductions in primary care consultations for exacerbations of COPD and COPD-related emergency department attendances were also seen (49). This suggests that the reduction was real and not an artifact due to patients avoiding hospital treatment because of concerns about catching COVID. The meta-analysis of studies reporting reductions in exacerbations by Alqahtani and colleagues (3) included data from nine countries and found a consistent reduction in hospitalization rates of a magnitude much greater than that achieved by pharmacotherapy. The reduction in exacerbations may be due to a combination of factors. Four studies have shown a reduction in respiratory viral infections in patients with exacerbations (21–23, 48, 50–52), and there is evidence for improvements in air quality as a result of lockdowns (53, 54). The meta-analysis found a weak relationship between the reduction in exacerbations and the stringency of infection control measures such as school and workplace closures, cancelation of public events, restrictions on public gatherings, stay-at-home requirements, testing policy, extent of contact tracing, and requirements for face coverings (3). There is also evidence of greater adherence to pharmacotherapy during the pandemic (55, 56), possibly as a result of anxiety about outcomes (57).

It seems likely that the reduction in exacerbations was largely due to a reduction in the spread of respiratory viruses, as a result of better hand hygiene, the use of face coverings, physical distancing, and avoiding contact with others. Maintaining measures that reduce the spread of viruses will be a challenge as they are unpopular and some also have unwanted effects. Wearing masks may generate anxiety and lead to an increased feeling of breathlessness, despite the fact they do not have a significant effect on respiratory mechanics (58, 59). Shielding and isolation also have a significant negative impact on those with COPD, leading to marked reductions in physical activity (60). Nevertheless, the observation that simple infection control measures have had such an impact on hospitalization rates challenges us to develop similar, but better tolerated, interventions to reproduce these benefits.

Although the COVID pandemic has undoubtedly caused much suffering and death, there have been some positive and unexpected findings that may lead to significant improvements in the management of COPD in future.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

D.M.G.H. drafted manuscript; D.M.G.H., C.F.V., and A.A. edited and revised manuscript; D.M.G.H., C.F.V., and A.A. approved final version of manuscript.