On December 31, 2019, a cluster of pneumonia of unknown cause was reported in Wuhan, Hubei province of China, and ten days later a novel coronavirus (SARS-CoV-2) was identified.1 Although control measures were applied locally, the spread of infection increased and the World Health Organization (WHO) declared a global health emergency.2

Previous studies3,4 have identified several clinical features of patients with this new disease named as COVID-19. The majority of patients seem to have mild disease, but about 20% will progress to severe disease, including pneumonia, respiratory failure, need of mechanical ventilation and even death.

Several studies1,5–7 showed that patients with comorbidity, infected with SARS-CoV-2, might have a poorer prognosis. Cardiovascular disease, malignancy, hypertension, diabetes, cerebrovascular disease and renal disease8 were risk factors in COVID-19 patients.9 Age is another risk factor and older patients tend to have more complications.10,11

Prevalence of lung diseases has grown globally and nearly 545 million individuals currently live with a chronic respiratory condition, representing 7.4% of the world's population.12 Since the emergence of COVID-19 several studies3,4,7 have highlighted a low frequency of respiratory patients hospitalized for infection by SARS-CoV-2. However, it appears that respiratory patients are at greater risk of severe complications and even death.13–15

The aim of our study is to analyze the prevalence, clinical profile and complications of COVID-19 patients admitted to hospital with prior lung disease in a multicenter international cohort.

This is a multinational, retrospective clinical cohort study and to date is one of the largest research studies exploring the effect of previous lung disorders in COVID-19 patients admitted to a hospital. In our registry, 1271 patients (22%) had a respiratory disease upon admission, and having a prior diagnosis of lung disease is a risk factor for a worse prognosis and even death.

Early studies3–5 showed that the majority of infected patients would have a mild disease, however some of them will develop a severe disease, and comorbidities play a major, modifying role. Surprisingly, patients with chronic respiratory disease were underrepresented as compared with other comorbidities as cerebrovascular or cardiovascular disease. Huang3 presented a series of 41 patients with 13 of them admitted to ICU. One third had any comorbidity, such as diabetes (20%), hypertension (15%) and only 1 patient had a previous lung disease.

Similar prevalence were extracted from Guan,4 where only 12 patients (1%) had COPD, but half of them were admitted to ICU, mechanically ventilated or died. In a series of 138 patients, Wang5 described a 2.9% prevalence of COPD in their study but again, 8.3% of patients admitted to ICU had previous lung diseases. In a larger study, Guan7 analyzed the impact of comorbidities in 1590 patients. They found that only 1.5% had COPD, with no data about other respiratory disorders such as asthma or ILD. Unexpectedly only 7% of their patients were exposed to tobacco (current or former). Mortality rate of COPD patients was 25% with an HR of 2.68, after adjusting for age and sex, to reach any of the composite end points (ICU admission, mechanical ventilation or dead). In another study11 from China, about risk factors associated with acute respiratory distress syndrome, only 5 patients (2.5%) had chronic lung disease.

These figures about prevalence of previous respiratory diseases in COVID-19 patients admitted to hospital change when we analyze data from elderly patients or from western countries. In a study17 of 339 patients older than 60 years, there were 6.2% COPD patients, with a HR of 2.24 for complications. Fatal cases were almost 20% and 17% of them had COPD. A study18 from the New York City area showed that the most common comorbidities were hypertension, diabetes and obesity, but they also collected data in chronic respiratory diseases and 9% of patients had asthma, 4.5% had COPD and 2.9% had obstructive sleep apnea.

Angiotensin converting enzyme II (ACE2) was described as a cell entry receptor for the coronavirus responsible of SARS.19 With the outbreak of COVID-19, researchers20 confirmed that SARS-CoV-2 uses the same ACE2 receptor. Analysis21 of resected lung tissue specimens obtained from smokers with COPD, “healthy” smokers and non-smokers showed an increase of ACE2 gene expression in the epithelial cells of COPD vs. control and of current smokers vs. never smokers. Moreover, there was a significant inverse relationship between ACE2 gene expression and FEV1%. This up-regulation may predispose COPD patients or smokers to increased risk of COVID-19 disease.

Coronaviruses have been related to acute exacerbations of COPD. In a cohort22 of 200 patients from the United States and Europe, bacterial taxa and virus were studied in stable state and during an exacerbation event. Coronavirus was detected in 5% of sputum samples and it was associated with an acute event and also with frequent exacerbations. A retrospective analysis23 in COPD patients showed that coronavirus ranked as the third cause, after influenza A, and respiratory syncytial virus, for emergency department visits and hospitalizations.

Differences in prevalence of respiratory diseases in patients admitted to a hospital for COVID-19 may have several explanations. First of all, age. Our registry is based mostly of patients from Italy and Spain, where COVID-19 patients were older (mean age 65 years) than previously published series from elsewhere. This may represent European population aging, and COPD and ILD prevalence increases with age. Second, underdiagnosis of all chronic respiratory diseases is a universal feature.12 Data from epidemiological studies24 show that COPD patients are commonly underdiagnosed due to physician unawareness, spirometry unavailability, confounding of symptoms with tobacco smokers and heart conditions, among other. Third, our registry divided patients in several categories of lung disease, which may increase attention in declaring it by the local researchers. Fourth, it may be related to a protective effect of COPD treatments, as inhaled steroids. A study from Japan25 showed a reduction of coronavirus (not SARS-CoV-2) replication and cytokine production in cultures of cells from nose and trachea after treatment with budesonide. We collected information about previous treatments in our series of patients, but no effect was found with neither the use of inhaled beta-agonists nor inhaled steroids. A recent systematic review of inhaled steroids in COVID-19 found zero trials to meta-analyse,26 no publications were identified as having data on prior ICS use in patients with SARS, MERS or COVID-19 infection. No data were available for either a qualitative or narrative answer to the review question.

Complications and mortality are increased in COVID-19 patients with comorbidities as chronic respiratory disorders. A study15 in patients admitted to intensive care units in Italy, almost three fourth of them with COPD died and it was an independent risk factor associated with mortality (HR, 1.68; 95% CI, 1.28–2.19). In our study, 30% of patients with previous lung disease died, compared with 18% of patients without respiratory diseases. Mortality in the sub-group of COPD patients was even higher, 40% of them died. They represent 16% of all declared deaths in our registry.

Contrary, patients with asthma appear not to have an increased risk of mortality. There are contradictory results regarding this issue, as a recent study27 showed that COVID-19 patients with asthma had a higher mortality rate, whilst a meta-analysis28 indicated that asthma as a comorbidity may not increase mortality.

A number of meta-analyses have explored the risk of a severe disease in patients with COPD and COVID-19. Zhao29 studied 11 case-series with a total number of 2002 patients. The pooled OR of COPD and the development of a severe form of disease were 4.38. Current smoker had an OR of 1.98. Alqahtani14 included 2473 patients in their review (14 out of 15 studies were from China). COPD patients and smokers were at higher risk of more severe disease, but prevalence rates of COPD patients were lower than in our study (2% vs. 8.3%). Our findings show that a prior diagnosis of lung disease, compared with those without respiratory diseases, is a prognostic factor for survival, after adjusting for confounders.

Predictors of mortality in patients with lung diseases pointed out some clinically relevant conclusions. Older age, use of home oxygen therapy, acute respiratory failure upon admission and elevated D-dimer were associated with an increased mortality risk. Also they had more comorbidities as diabetes, hypertension, obesity, chronic heart failure and previous immunosuppressive treatments that may explain in part an increased risk of mortality. Moreover, the use of systemic steroids during hospitalization increased the risk of dying in these patients which may be a bias effect in a more severe form of disease as a preliminary report of a study30 has shown a protective role of dexamethasone. In a Cox regression analysis, the only protective effect was found with gender (female versus male) and the use of Q/HCQ, which almost halved the hazard of dying. This last finding is controversial because results from studies are contradictory as one31 has shown no effect of Q/HCQ about mortality while another32 has presented a reduction of viral load in patients treated with Q/HCQ.

This study has several strengths, including a large size, immediacy, high data completion with relatively few missing variables, and data collection from diverse centers and countries. However, a number of potential limitations can be discussed. First, it has a retrospective observational design from several centers in 6 countries. Any source of selection or information bias, or confounding in collecting data cannot be ruled out, but at the same time give us a real view of management and prognosis of COVID-19 patients in an international scenario. Second, data is only about hospitalized patients with COVID-19, so we may lose information regarding milder forms of the disease. Third, results are based in a post hoc analysis and information generated would not be as robust as a prospective cohort or a clinical trial, so we have to consider efficacy of administered treatments with caution. Fourth, some patients with lung diseases have other comorbidities that may bias the increased risk of mortality. Others include, data collection mostly by non-pneumologists therefore without any a priori interest on respiratory disease, the universal underdiagnosis of lung diseases, absence of differential diagnosis and overlap of individual respiratory conditions. Results are on short-term mortality, so no exploration was conducted beyond 30 days post admission. Our aim was to generate hypotheses and to compare ours with other cohorts, but new studies should be done trying to analyze survival patterns and complications in patients with different lung diseases and COVID-19.

In this large, international registry, 22% of patients hospitalized for COVID-19 had a previous lung disease, being COPD the most prevalent diagnosis (8% of the registry). Having a lung disease is a risk factor for mortality in patients with infection for SARS-CoV-2 and a higher mortality is described in our cohort. Older age, male gender, home oxygen therapy, and respiratory failure on admission were associated with an increased mortality. Efforts must be done to identify these patients upon admission to set measures to improve their clinical outcomes.

JS-C had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis including any adverse effects. JS-C and IJN-G were involved in the design of the study. JBS, JACA were involved in data analysis. All authors were involved in the interpretation of the data and in the writing and critical review of the manuscript.

All authors declare no competing interests.