[Is chronic obstructive pulmonary disease a protective factor in SARS-CoV-2 infection? The importance of bronchodilator treatment].

Dear Director,

Globally, viruses play an important role in exacerbations of chronic obstructive pulmonary disease (COPD). In a systematic review of infections in patients with COPD that required hospital admission, it was observed that the rhinovirus, respiratory syncytial virus (RSV), and influenza virus were the most prevalent agents, followed by parainfluenza and coronavirus. Coronavirus is the most frequent upper respiratory tract infection and is predominant during the winter months.

In a study conducted in Spain, 26% of patients admitted during the flu season presented with COPD as a comorbidity. Other authors have reported a somewhat lower prevalence of COPD in patients with the flu (17.3%) and an even lower prevalence of COPD in patients with RSV infection (7.6%). There are also studies which have evaluated the presence of COPD as a comorbidity in other coronavirus infections such as SARS, with a rate of 6%, and MERS, with a rate of 13%.

In regard to the current SARS-CoV-2 pandemic, it was initially considered that people with chronic lung diseases could be more prone to presenting with symptoms of the infection or to developing a more severe infection. However, published case series show a low prevalence of patients with COPD: 6.6% in the United States of America, 3% in Italy, and just 1.4% in China.

This low prevalence could give rise to different interpretations. First, the strict lockdown imposed by public health authorities could explain that these patients, who are supposedly more vulnerable to SARS-CoV-2 infection, had closely followed social distancing protocols, thus decreasing the risk of contact.

Second, there could be a protective effect that is not well established in the physiopathology of chronic respiratory disease, with a different immune response that could prevent infection in these patients or condition milder symptoms. One piece of data in favor of this protection against infection can be concluded from the study by Mehta et al., which analyzes factors associated with a positive result on a SARS-CoV-2 diagnostic test in a sample of 184,772 people. Of the total number of tests, 1735 (9.4%) were positive whereas in patients with COPD, only 114 (6.4%) were positive (p  <  .001). Therefore, it seems that COPD as a comorbidity is associated with a lower probability of having COVID-19.

Third, it has been hypothesized that baseline inhaled treatments, such as inhaled corticosteroids and bronchodilators, could have a protective effect against SARS-CoV-2 infection. In vitro studies on inhaled corticosteroids (budesonide), either alone or in combination with other bronchodilators (glycopyrronium bromide and formoterol), have demonstrated a suppression of HCoV-229E coronavirus replication.

Likewise, another study on inhaled corticosteroids that included just 3 patients, conducted in Japan and without a control group, observed a lower requirement for ventilatory support. On this matter, a systematic review was recently published on the possible protective effect of inhaled corticosteroids; it was unable to establish either a beneficial or detrimental effect of this treatment. Similarly, in an Italian study on a cohort of patients with COVID-19, patients with SARS-CoV-2 infection were compared to the general population. No influence on progress related to either short- or long-term inhaled corticosteroids or beta-adrenergic agonists was noted.

Tiotropium bromide is one of the main treatments for COPD and is usually used in approximately 30% of patients treated in primary care. Recent studies have demonstrated how tiotropium reduces neutrophils and macrophages as well as IL-6 and gamma interferon levels in the airways of rats exposed to tobacco smoke and infected with the A/PR/8/34 (H1N1) influenza virus. The effect was greater than what was observed with fluticasone and roflumilast. This potential anti-inflammatory effect with cytokine inhibition in animal models could explain a greater protective effect of tiotropium versus other inhaled therapies in SARS-CoV-2 infection.

We have analyzed the prevalence of COPD in patients treated for COVID-19 in our center, specifically evaluating their baseline treatment with inhalers as a potential protective factor against SARS-CoV-2 infection.

A retrospective, observational study was carried out in the Mataró Hospital which identified patients hospitalized with a clinical and/or microbiological diagnosis of SARS-CoV-2 from March 10 to April 22, 2020. A diagnosis of COPD was established when the physician had recorded it on the medical record or when a compatible spirometry was available. Treatments with inhaled corticosteroids and anticholinergics were also recorded.

During the study period, 487 patients were identified. Of them, 78 (16%) had a clinical diagnosis and 409 (84%) had a microbiological diagnosis of SARS-CoV-2 infection. Of the patients identified, 62.2% were men. The mean age was 64.9 ± 15.1 years and the overall mortality rate was 20.5%. Of all patients, 25 had a diagnosis of COPD (5.1%), 17 of which (68%) had spirometric confirmation. Within the group of patients with COPD, the mean age was 72.7 ± 9.1 years and they had a greater mortality rate of 44%.

We compared the baseline treatment of patients with COPD in our COVID-19 cohort with other published series of patients with hospital admission due to COPD exacerbation related to other respiratory pathogens or those in stable clinical condition. We did not note any differences in the use of inhaled corticosteroids between both groups. However, the use of tiotropium was significantly lower in patients with COPD who had been hospitalized for COVID-19 in relation to other cohorts of patients with stable COPD and without SARS-CoV-2 infection and controlled in primary care (12% vs. 29.5% and 31.7%, p  <  .03) (Table 1 Table 1).

Table 1

Treatment with inhaled corticosteroids and anticholinergics in patients with COPD in series of patients hospitalized due to SARS-CoV-2, severe exacerbation of COPD, and patients in the stable phase (primary care).

	Patients	IC	AC	LTAC	Tiotropium
Severe SARS-CoV-2 infection
Boixeda et al. (Mataró Hospital)	25	16 (64)	17 (68)	11 (44)	3 (12)*
Severe COPD exacerbation
Casas-Mendez et al.14	465	293 (63)	363 (77.5)	158 (33.9)	–
Stable COPD
Morros et al.12	3837	2224 (57.9)	1763 (45)	–	1134 (29.5)*
De Oliveira et al.15	180	167 (92.8)	–	–	57 (31.7)*

The data are shown in absolute values (percentage).

AC: anticholinergics; IC: inhaled corticosteroids; COPD: chronic obstructive pulmonary disease; LTAC: long-term anticholinergics.

p <  .03.

The analysis of our cohort of patients with SARS-CoV-2 confirms a low prevalence of patients with COPD (5.1%). These patients were older (p  =  .02), had greater mortality (p  =  .03), and there was a low percentage of patients treated with tiotropium (p  =  .034).

Given the discordance in the available information, large studies are needed that evaluate the presence of COPD and baseline treatments as possible protective factors against SARS-CoV-2 infection, with special attention paid to treatment with tiotropium, which appeared to have a protective effect in our study.

Likewise, it seems necessary to evaluate different prognostic factors that allow for confirming whether presence of COPD is associated with a worse disease prognosis or if there are other confounding factors that explain this higher mortality, such as age or the establishment of therapeutic limitations related to the comorbidity itself or the healthcare resources available in the context of a pandemic.