key: cord-0893702-xn7anxj6
authors: Olloquequi, Jordi
title: COVID‐19 Susceptibility in chronic obstructive pulmonary disease
date: 2020-08-11
journal: Eur J Clin Invest
DOI: 10.1111/eci.13382
sha: 569a49b711f9b7cbc9ffbb2871ba477e529f2198
doc_id: 893702
cord_uid: xn7anxj6

In the middle of December 2019, Chinese health authorities detected a series of pneumonia cases caused by an unknown agent in Wuhan, the capital of Hubei province. The causative agent was soon identified as a new strain of human‐infecting coronavirus(1), firstly named 2019 novel coronavirus (2019‐nCoV) and later renamed as severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). The infection disease caused by SARS‐CoV‐2, known as coronavirus disease 2019 (COVID‐19), varied from asymptomatic or common cold‐like symptoms such as dry cough, fever and tiredness to severe dyspnea and respiratory failure(2).

In the middle of December 2019, Chinese health authorities detected a series of pneumonia cases caused by an unknown agent in Wuhan, the capital of Hubei province. The causative agent was soon identified as a new strain of human-infecting coronavirus 1 , firstly named 2019 novel coronavirus (2019-nCoV) and later renamed as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection disease caused by SARS-CoV-2, known as coronavirus disease 2019 (COVID-19), varied from asymptomatic or common cold-like symptoms such as dry cough, fever and tiredness to severe dyspnea and respiratory failure 2 . This initial outbreak alarmingly spread through China and other countries, and barely three months later, the World Health Organization (WHO) formally declared COVID-19 a global pandemic 3 . As of August 3, there have been more than 18,365,000 cases and 695,048 deaths by COVID-19 worldwide 4 .

Like in other infectious diseases, certain population groups have been reported to suffer a higher risk of severe clinical course of COVID-19. Among them, patients with hypertension and diabetes seem the most significant, comprising the 23.7% and 16.2% of patients in critical conditions, respectively 5, 6 . To a lesser extent, patients with coronary heart disease and cerebrovascular disease have also been repeatedly reported in severe cases, while older adults are the age group with highest mortality rates by COVID-19 7, 8 

This article is protected by copyright. All rights reserved reasonable to expect that patients with chronic respiratory diseases are also in the population risk group. Indeed, WHO acknowledges that conditions that increase oxygen needs or reduce the ability of the body to use it properly will put patients at higher risk of serious lung conditions such as pneumonia 9 .

Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability globally, characterized by persistent respiratory symptoms and airflow limitation due to airway inflammation and/or alveolar abnormalities 10 . The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recognizes COPD patients amongst the worst affected by COVID-19 11 . In the present review, the available evidence pointing to COPD patients as more prone to suffer a severe COVID-19 clinical course is discussed, and the pathophysiological mechanisms linking both diseases are explained ( Figure 1 ).

COPD emerges from a complex interaction between genetic predisposition and environmental factors. While over 97 independent genetic associations with lung parameters defining COPD and with COPD risk have been described 12 , cigarette smoking is by far the main environmental risk factor for COPD. Hence, between 15 and 50% of smokers develop COPD, whereas 80 to 90% of COPD patients are smokers or ex-smokers 13, 14 . To date, no definitive evidence on whether ever-smokers are at an increased risk of COVID-19. However, WHO argues that tobacco users may be at higher risk of SARS-CoV-2 infection, since smoking implies repetitive hand-to-face contact and often sharing of mouth pieces and hoses, all of which could facilitate the virus entry 9 . In turn, a recent study on 1,099 COVID-19 patients reported that 12.7% of current smokers died or suffered a severe clinical condition compared to only 4.7% among never-smokers 15 . Moreover, 16.9% of severe cases were eversmokers compared to 11.8% of milder cases 15 . In this sense, a recent systematic review by Vardavas and Nikitara concluded that smoking is most likely associated with negative progression and adverse outcomes of COVID-19 16 . On the other hand, a meta-analysis conducted by Lippi and Henry based on data from Chinese patients suggests that active smoking is not significantly associated with COVID-19 severity 17 .

In spite of this contradictory data, the deleterious effects of cigarette smoking on lung defenses are wellknown 18,19 . Smoking impairs the mucociliary clearance, alters humoral response to antigens and affects alveolar macrophages responsiveness, thus increasing the susceptibility to respiratory infections 20-22 . Moreover, it has also been reported that cigarette smoking decreases the number and cytotoxic activity of natural killer (NK) cells, one of the main lines of defense against viral infections 23,24 . It is not strange, thus, to find increased death rates

This article is protected by copyright. All rights reserved from influenza and pneumonia among smokers 25,26 . Cigarette smoking is also associated with a systemic inflammatory pattern 27 . Importantly, it has been shown that the immune changes found in COPD patients are an amplification of those present in smokers who do not develop COPD 28,29 . In addition, these pulmonary and systemic alterations persist after smoking cessation 30,31 . Hence, an impaired response against SARS-CoV-2 or other pathogens could be expected despite current smoking status in COPD patients. Although the molecular basis for the amplification and "chronification" of these alterations remains obscure, it is accepted that both genetic and epigenetic factors are involved 28 . In this sense, a recent study from Mostafaei and colleagues used machinebased learning algorithms to find novel genes associated with COPD 32 . They identified 44 candidate genes whose expression was significantly regulated by smoking and/or COPD. Among the most significant, the authors stressed the novel PRKAR2B gene, which encodes an important protein kinase in cAMP signaling, a protective factor in the lung and COPD. Interestingly, PRKAR2B expression was significantly downregulated in COPD patients who smoked more than 50 packs per year 32 .

In addition to cigarette smoking, other risk factors for COPD development could also be related with COVID-19 incidence and prognosis. For instance, exposure to smoke coming from biomass burning (biomass smoke, BS), which affects 3 billion people worldwide, has also been recognized as one of the main risk factors for COPD, especially among non-smokers 33 . Importantly, like tobacco smoke (TS), BS has been shown to alter pulmonary defenses, and this effect could conceivably also be enhanced and sustained in COPD patients 34 . In this regard, although COPD caused by BS and TS present some differential hallmarks, patients with double exposure have worse blood oxygenation 35 . In any case, the impact of BS on lungs is supported by several epidemiological studies reporting increased risks of acute respiratory infections (ARIs) in people exposed to this environmental pollutant 36,37 . Also, in vitro studies confirm that BS exposure alters or impairs antiviral response of lung cells 38,39 . Although no study is available yet on the risk of SARS-CoV-2 infection and BS exposure, a recent report from investigators of University of Harvard reported an increased mortality rate by COVID-19 associated to long-term exposure to PM 2.5 , one of the main components of BS 40 .

Suffering from respiratory infections during childhood also been long recognized as a risk factor for COPD development 41 . However, whether this infancy infections are involved in COPD development per se or are a consequence of previous factors determining an impaired lung function is a subject of debate. Hence, although it has been reported that respiratory syncytial virus infection (RSV) or a history of pneumonia during childhood

This article is protected by copyright. All rights reserved are associated to impaired lung function and risk of developing COPD 42-44 , it has also been demonstrated that people born with a diminished airway function are more likely to suffer COPD symptoms and subsequent viral infections [45] [46] [47] . In any case, there is no doubt that subjects who develop COPD are at an increased risk of suffering respiratory infections, a matter of importance in the context of COVID-19 pandemics. This subject is discussed in the next section.

Although COPD is mainly a chronic disease, a substantial number of patients suffer from exacerbations, defined as acute and sustained worsenings of the patient's condition from stable state and beyond normal day-to-day variations, requiring medication changes or hospitalization 48 . Exacerbations arise from several risk factors and triggers, being viral infections one of the most important causes 49 . Hence, viruses are responsible for a half to two-thirds of COPD exacerbations 50 , while these pathogens are also identified in over 10% of all stable COPD patients, being associated to worse clinical outcomes 51 . Picornaviruses, influenza A, RSV and parainfluenza are among the most detected viruses in COPD exacerbations 52 . Regarding the incidence of coronaviruses infection in COPD patients, the available data is scarce. Notwithstanding, a study assessing the presence of SARS-CoV through RT-PCR in 141 patients with mild to moderate COPD reported no trace of infection 53 . By contrast, another study reported presence of coronavirus in 5.9% of stable COPD patients 54 , whereas several coronaviruses were associated to multiple respiratory and systemic symptoms, as well as with hospitalizations, in a cohort of 2,215 COPD patients 55 .

The fact that COPD patients could be more susceptible to respiratory infections is sustained by mounting evidence. Thus, in vitro and in vivo studies have demonstrated that patients with COPD have increased viral titer and copy numbers after rhinovirus infection than control subjects [56] [57] [58] . Moreover, an upregulation of intercellular adhesion molecule-1 (ICAM-1), which is the rhinovirus major group receptor, has been reported in airways and parenchyma of COPD patients 59, 60 . Likewise, Seys and co-workers showed an upregulated expression of dipeptidyl peptidase IV (DPP4), a type II transmembrane glycoprotein that serves as receptor for Middle East Respiratory Syndrome coronavirus (MERS-CoV), in COPD patients 61 . Interestingly, both DPP4 mRNA and protein levels were inversely correlated with lung function and diffusing capacity. The authors concluded that increased DPP4 expression could partially explain why COPD patients are more susceptible to MERS-CoV 61 .

Regarding COVID-19, a recent paper by Leung and co-workers investigated the expression of angiotensin

This article is protected by copyright. All rights reserved converting enzyme II (ACE-2) in the lower tract of COPD patients 62 , since this transmembrane metallocarboxypeptidase has been shown to act as the doorway that allows SARS-CoV-2 into the lungs 63 . The authors reported that COPD patients show an increased airway gene expression of ACE-2 compared to control subjects and ACE-2 were inversely related to FEV 1 , suggesting a dose-dependent response 62 . Hence, these findings reinforce the idea of a higher risk for SARS-CoV-2 in subjects with COPD. Finally, it has been shown that viral infection may increase the number of bacteria in the lower airways and even facilitate a subsequent bacterial infection in COPD 64 . Indeed, 20 to 30% of COPD patients hospitalized for exacerbations present viruses and bacteria coinfection, and these coinfections increase the severity of the exacerbations [65] [66] [67] . Hence, one may anticipate that COPD patients with COVID-19 are at higher risk to develop a more severe pneumonia.

The increased susceptibility to respiratory infections leading to disease severity may reflect a defective immunity in COPD 68 . Indeed, both the innate response to pathogens and the role of adaptive immune system to such challenges are impaired in COPD, which can result in recurrent infections 29,69,70 .

Hence, despite increased numbers of alveolar macrophages have been reported in COPD patients, their phagocytic ability is reduced as compared to smokers without COPD [71] [72] [73] . Moreover, alveolar macrophages of patients with COPD also exhibit an altered capacity to secrete proinflammatory mediators and proteases, express surface and intracellular markers, induce oxidative stress and engulf apoptotic cells 74 . In turn, some studies have found reduced numbers and impaired maturation of dendritic cells in COPD patients [75] [76] [77] . In addition, interferon (IFN) signaling, which plays a key role in the innate antiviral response is also impaired in COPD. Thus, Mallia and co-workers reported a reduced production of IFN-β in broncoalveolar lavage (BAL) cells from subjects with COPD after rhinovirus infection 57 . Recent results from our research group also showed a significative reduction expression of IFN-β and its main transcription factor, IRF-7, in lung epithelium and alveolar macrophages of COPD patients 78 . This reduction was also observed in pulmonary mRNA levels of these immune mediators. Since IFN-β has proven to inhibit coronavirus replication 79, 80 , COPD patients could be especially susceptible in front of COVID-19.

Regarding adaptive immunity, a downregulation of the epithelial polymeric immunoglobulin receptor (pIgR) has been observed in COPD patients 81 . PIgR is essential for generation of mucosal sIgA, an effective virus-neutralizing molecule 82 , and its reduction was positively correlated to COPD's severity 81 . On another front,

This article is protected by copyright. All rights reserved CD8+ T cells are critical for respiratory viral clearance and provide protection against secondary infections 83 

influenza virus in subjects with COPD 84 . Interestingly, they found a downregulation of the T cell receptor signaling molecule CD247 (ζ-chain) in lung CD8+ of these patients compared with smokers and healthy controls.

They also observed a reduced T-cell cytotoxicity and an upregulation of programmed cell death protein-1 (PD-1), which renders immunosuppressive actions on CD8+ cells 84 . In another study, the same research group demonstrated that the impaired cytotoxic activity of CD8+ T cells was paralleled by a reduced proportion of CD4+ T cytotoxic cells in lung tissue from COPD patients 85 . In addition to cytotoxic T cells, other T subtypes seem to be altered in COPD. Regulatory T cells (Tregs) are a subtype of lymphocytes that express the transcription factor FoxP3, which, among other functions, have been shown to limit the extent of tissue damage that occurs during a virus infection 86, 87 . Importantly, COPD patients exhibit decreased numbers of pulmonary Treg cells, as well as reduced levels of FoxP3 mRNA and lung interleukin 10 secretion than controls 88 . Collectively, these findings indicate a characteristic immune dysfunction in COPD that could impact on the pulmonary anti-viral defense.

Finally, it is noteworthy that the impaired immune response is not only restricted to pulmonary cells of COPD patients. Interestingly, a recent paper by Agarwal and co-workers have demonstrated that human peripheral blood mononuclear cells (PBMC) from COPD patients have a reduced ability to metabolize carbohydrate or fatty acids, suggesting a metabolic impairment in systemic immune cells in COPD 89 . Moreover, the neutrophil-to-lymphocyte ratio (NLR) is increased both in stable and exacerbated COPD patients 35, 90 .This is particularly relevant, since a recent paper by Liu and coworkers has shown that NLR is an independent risk factor for the in-hospital mortality for COVID-19 91 . The study, which was performed on 245 COVID-19 patients, reported that subject in the highest tertile had a 15.04-fold higher risk of mortality (OR= 16.04; 95% CI, 1.14 to 224.95; P = 0.0395) after adjustment for potential confounders, when compared with patients in the lowest tertile 91 .

So far, information on COVID-19 incidence and clinical course on COPD patients is scarce. A recent metaanalysis by Lippi and Henry have reported that COPD is associated with a significant, over five-fold risk of severe COVID-19 infection 92 . However, the reported prevalence of COPD in patients diagnosed with COVID-19 is surprisingly low. Hence, the prevalence of chronic respiratory disease and COPD in two cohorts of Chinese

This article is protected by copyright. All rights reserved COVID-19 patients has been only 2.4% (44,672 patients studied) 93 and 1.4% (140 patients studied) 94 , respectively. Moreover, in the USA population, chronic respiratory diseases were comorbidities in 8.5% of COVID-19 patients 95 . In this regard, a group of investigators leaded by Dr. Àlvar Agustí recently published a paper suggesting that the use inhaled corticosteroids could reduce the risk of infection or of developing COVID-19 symptoms, since previous in-vitro studies have shown that these drugs are capable of suppressing coronavirus replication 96 . The same authors, however, warned about the fact that systemic corticosteroids were counterproductive to treat SARS 96, 97 . In this respect, it has also been shown that fluticasone propionate, an inhaled corticosteroid, impairs innate and acquired antiviral immune responses leading to delayed virus clearance and increases pulmonary bacterial load during virus-induced exacerbations in a murine model of COPD exacerbation 98 .

In six months, the COVID-19 pandemic has spread to more than 200 countries and now the main focus of infection is centered in North and South America. Consequently, governments and institutions work relentlessly to stop the spread of the SARS-CoV-2 worldwide, while trying to manage the sanitary, economic and social crisis we are facing. Since a vaccine against this coronavirus has not yet been discovered, the most important thing is to take steps to stop its spread and to protect those people at highest risk of infection or developing a more serious clinical course.

While hypertension and diabetes are the two comorbidities most clearly related to COVID-19 susceptibility, available data regarding COPD is contradictory. It is probable that COPD-patients are underrepresented in intensive care settings due to their pre-existing poor prognosis and decisions to limit the treatment to palliative care in situations of poor prognosis. Peoples in risk groups are advised to self-isolate, and most severe COPD-patients most probably do not move out of their homes due to the limits of the disease for their performance in general. Therefore, the incidence of COVID-19 may be lower in COPD-patients.

Nevertheless, substantial evidence points to COPD patients as a particularly susceptible group to SARS-CoV-2 infection and to a worst prognostic. Indeed, most COPD patients are or, at least, have been exposed to noxious gases or pollutants capable of altering pulmonary defenses during many years. Also, the immune dysfunction observed in COPD may cause increased susceptibility to respiratory viral infections and an impaired inflammatory response against these challenges. Finally, it is noteworthy that SARS survivors showed a

This article is protected by copyright. All rights reserved significative impairment of pulmonary function months after recovery 99 . If the same is confirmed for COVID-19 patients, a serious impact in the clinical course and quality of life in those with COPD as comorbidity could be expected, since they already have a diminished lung function. In any case, more research in larger patient groups will bring more data on COPD and COVID-19 severity and associations of immune dysfunction in COPD with COVID-19 risk. It would be important to know whether the patients are more prone for severe infection due to impaired immune responses and whether the clinical picture of the disease and the cytokine storm differ in these patients. Also, genotyping and complete phenotyping (including serological, radiological and histopathological assessment) will help to understand the mechanistic insights of the susceptibility to COVID-19 100 .

In light of all these facts, COPD patients should be considered as a high-risk group in COVID-19. Hence, sanitary authorities must apply specific mechanisms to monitor and assess patients with COPD in the context of the current pandemic.

None to declare.

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The author would like to thank Dr. Jack White for helping with the literature revision and Ms. Marta Chmielewska for linguistic advice.

This article is protected by copyright. All rights reserved

This article is protected by copyright. All rights reserved