key: cord-275858-46jzw94p
authors: Leung, Janice M.; Niikura, Masahiro; Yang, Cheng Wei Tony; Sin, Don D.
title: COVID-19 and COPD
date: 2020-08-13
journal: Eur Respir J
DOI: 10.1183/13993003.02108-2020
sha: 
doc_id: 275858
cord_uid: 46jzw94p

COPD patients have increased risk of severe pneumonia and poor outcomes when they develop COVID-19. This may be related to poor underlying lung reserves or increased expression of ACE-2 receptor in small airways. https://bit.ly/37dSB8l

Nonetheless, there is increasing evidence that COPD may be a risk factor for more severe COVID-19 disease [57] . An analysis of comorbidities in 1590 COVID-19 patients across China found that COPD carried an odds ratio of 2.681 (95% CI 1.424-5.048; p=0.002) for ICU admission, mechanical ventilation or death, even after adjustment for age and smoking [13] ; 62.5% of severe cases had a history of COPD (compared with only 15.3% in non-severe cases) and 25% of those who died were COPD patients (compared with only 2.8% in those who survived). In a multicentre Chinese study, COPD patients made up 15.7% of the critically ill patients, but only 2.3% of moderately ill patients ( p<0.001) [16] . Other studies have found similar, if statistically weaker, differences in COPD rates between ICU admissions and non-ICU admissions (8.3% versus 1.0%; p=0.054) [10] , severe and non-severe cases (4.8% versus 1.4%; p=0.026) [17] , and between non-survivors and survivors (7% versus 1%; p=0.047) [11] .

Why COPD patients appear to suffer worse outcomes upon contracting COVID-19 (even if their risk of contracting to begin with may not be high) is worth some speculation. First, recent evidence that COPD patients and smokers may display the machinery required for SARS-CoV-2 cellular entry differently has come to light. Similar to SARS-CoV (which was responsible for the 2002-2003 SARS pandemic) [58] , SARS-CoV-2 bears an envelope spike protein that is primed by the cellular serine protease TMPRSS2 to facilitate fusion of the virus with the cell's angiotensin-converting enzyme 2 (ACE-2) receptor and subsequent cell entry (figure 1) [59] [60] [61] [62] . Our group has recently demonstrated that in three separate cohorts with available gene expression profiles from bronchial epithelial cells, ACE-2 expression was significantly elevated in COPD patients compared to control subjects [63] . Current smoking was also associated with higher ACE-2 expression compared with former and never smokers, an observation which has subsequently been validated by other groups in separate cohorts of lung tissue and airway epithelial samples [64] [65] [66] and supported by additional evidence linking ACE-2 expression with nicotine exposure [67, 68] . It is important to note, though, that ACE-2 expression alone has not been shown yet to confer increased susceptibility or increased severity of disease. Moreover, the relatively low expression of ACE-2 in the bronchial epithelium in comparison to the nasal epithelium [69] has unclear implications for disease susceptibility in patients with predominantly small airways pathology. The management of COPD patients during the COVID-19 pandemic Two challenges of clinical care in COPD have emerged during this pandemic: 1) whether the usual algorithms of pharmaceutical management in COPD still apply and 2) how to weather the dramatic curtailments in non-pharmaceutical interventions this pandemic has wrought. Although our understanding of COVID-19 has substantially increased in a short period of time, these problems have largely been the domain of expert opinion rather than being guided by rigorous scientific evidence.

Questions remain about the effects of common respiratory medications used by our COPD patients such as inhaled (ICS) and systemic corticosteroids, short-and long-acting β 2 -agonists, and short-and long-acting muscarinic antagonists in either mitigating or exacerbating COVID-19 infections. The epidemiological data emerging from China and other early epicentres have not yet provided the necessary granularity required to determine whether these medications are harmful or beneficial in COVID-19 patients with COPD. PETERS et al.

[70], however, have recently shown that ACE-2 expression in airway epithelial cells obtained from asthmatic patients was decreased in those taking ICS compared to those who were not on ICS, raising the possibility that ICS exposure could decrease viral entry. Whether the same relationship holds true in the COPD airway, in which the predisposition to pneumonia following ICS use is well-documented, has not yet been established. For now, in the absence of data demonstrating definitive [105] to show ACE2 expression, with the respiratory system highlighted in red. c) The renin-angiotensin system (RAS) and the proposed SARS-CoV-2 action. The generation of angiotensin II from angiotensin I by angiotensin-converting enzyme (ACE) induces vasoconstriction of blood vessels and pro-inflammatory effects through the binding of angiotensin II receptor type 1 (AT 1 R), while the receptor type 2 (AT 2 R) may negatively regulate this pathway. ACE inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) are very successful anti-hypertensives by promoting vasodilation of blood vessels. ACE-2 inhibits the activity of angiotensin II by converting angiotensin I to angiotensin 1-9 and angiotensin II to angiotensin 1-7, which binds to the MAS1 proto-oncogene (Mas) receptor with anti-inflammatory effects. Upon SARS-CoV-2 binding to ACE-2, there is a shift in the ACE/ACE-2 balance towards a predominance of ACE, resulting in increased pro-inflammatory effects and tissue damage.

https://doi.org/10.1183/13993003.02108-2020 harm or benefit, ICS and other long-acting inhalers should not be routinely withdrawn nor should their use be escalated as a preventative measure for COPD patients during this pandemic [71] .

Of greater concern is the use of systemic corticosteroids, the backbone of COPD exacerbation treatment. On balance, the historical evidence for systemic corticosteroids in viral pandemics has not been entirely favourable. Lessons from the SARS and Middle East respiratory syndrome (MERS) pandemics suggest potential harm, in fact. In SARS, while the majority of studies were inconclusive, four studies showed harm, including delayed viral clearance and increased rates of psychosis [72] . In MERS, corticosteroid use was associated with increased mortality [73] and delayed viral clearance [74] . So far, the most promising preliminary data on corticosteroids and COVID-19 are from a randomised controlled trial of dexamethasone (RECOVERY) performed in the UK, which demonstrated a one-third reduction in mortality [75] . Published data, however, are derived from small retrospective studies and appear mixed, with two studies showing no benefit [76, 77] and two studies showing improvements in rates of death and escalation of care [78, 79] . Because of the results of the RECOVERY trial, however, it is likely that dexamethasone will become standard of care treatment for COVID-19 patients including those with COPD.

The impact of the pandemic has been keenly felt by COPD patients in myriad aspects of their lives. Face-to-face clinic visits with their physicians have been curtailed, as have pulmonary rehabilitation sessions and COPD home visit programmes. Patients who may have normally presented to the hospital during an exacerbation might choose to stay home for fear of exposure, resulting in delayed care, as has occurred in other conditions like myocardial infarction [80, 81] . The long-term effects of this pause in routine care have yet to be measured. For now, healthcare systems have had to adapt to these conditions by augmenting telehealth and virtual visits. Fortunately, multiple randomised controlled trials assessing telehealth for COPD patients have demonstrated its feasibility and at least non-inferiority to usual care when it comes to exacerbations, hospitalisations and quality of life [82] [83] [84] [85] [86] . Moreover, online pulmonary rehabilitation programmes appear to be as effective as in-person sessions [87] [88] [89] . In the event that social distancing measures remain in place for many more months, we advocate for the establishment of these virtual programmes to ensure our patient population can continue to receive optimal care.

Specifically, we will have to address the following questions on COVID-19 as they pertain to COPD:

• Does the burden of disease, clinical manifestations, and outcomes of COVID-19 in COPD patients differ from the general population and if so, how? • Given the multiple phenotypes associated with the term "COPD" (i.e. frequent exacerbators, emphysema-predominant, eosinophilic-predominant, asthma overlap), does COVID-19 infection in each of these phenotypes present and behave differently? • Are routine medications used in COPD such as inhaled and systemic corticosteroids, β 2 -agonists, muscarinic antagonists and chronic azithromycin protective or harmful in the setting of COVID-19 infection? • What will the impact of post-COVID-19 infection disability be in COPD patients and what resources will be required to adequately support the transition of COPD patients from the hospital to home after COVID-19? • How can we manipulate the unique airway pathology of COPD patients and the ACE-2 system to identify novel therapeutics? • What is the role of inhaled substances (e.g. tobacco, cannabis and e-cigarettes) and air pollution in increasing the susceptibility of COPD patients to COVID-19? • What can we learn from the experience of virtual care to COPD patients during this pandemic that can be applied in future scenarios to reach isolated patient populations and resource limited settings?

These research questions can best be answered by developing standards for transparent data reporting across the globe and harnessing the power of international networks that can quickly collate the data of COVID-19 COPD patients. Similarly, the efforts of translational research scientists at the laboratory bench who are working to characterise the pathophysiology of COVID-19 infections in the airway are critical to developing new therapies for a world in which there are currently very few.

Regeneron, grants and personal fees for lectures from Boehringer Ingelheim and AstraZeneca, personal fees for lectures and advisory board work from Novartis, outside the submitted work

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