BACKGROUND Million people have suffered COVID-19 in Spain, being the respiratory system
the most affected in many patients. Some studies, with short follow-up periods, have
reported an impairment of respiratory function after pneumonia due to COVID-19.

COPD patients are considered a risk group for SARS-CoV-2 infection and poor prognosis in
case of COVID-19; furthermore, in them respiratory function is usually already impaired.

It is in this context that a study of the evolution of the lung function of COPD patients
who have overcome COVID-19 is proposed. It is hypothesized that COVID-19 accelerates the
deterioration of lung function in patients with COPD.

AIMS

General:

To analyze the evolution of lung function in COPD patients who have suffered mild or
moderate COVID-19, while comparing it with that of patients with COPD who have not.

Specific:

To analyze the influence of different variables, including the history of COVID-19, on
the evolution of lung function in COPD patients.

METHODS

Design:

Cohort study in patients diagnosed with COPD. Two subgroups of participants will be
distinguished:

1. COVID-19 group: Patients with COPD diagnosed with COVID-19 before recruitment or
during the study period.

2. Non-COVID-19 group: Patients with COPD who have not suffered from COVID-19 either
before or during the study

Sample size calculation:

To calculate the sample size, the dependent variable is considered the difference between
basal FEV1 (corresponding to the last spirometry recorded in the clinical history,
previous to the study start), FEV1 obtained at the first assessment, and final FEV1
(obtained at the second assessment, after one year).

Accepting an alpha risk of 0.05 and a beta risk of less than 0.2 in a bilateral contrast,
22 subjects in the first group and 88 in the second group are needed to detect a
difference equal to or greater than 30 units (assuming a common SD of 59 [Vetsbo et al,
2021], a between-groups ratio of 1:4, a correlation between the first and second
measurements of 0.75, and a loss-to-follow-up rate of 10%).

Recruitment of participants and inclusion procedure An information session will be held
at the Primary Care Centres (PCC) in the territory to advise about the study, its
characteristics and objectives. At least the person in charge of spirometry's performing
will be offered to participate as a reference research person (RRP) of the study at that
PCC.

Participants will be selected by consecutive sampling, by their reference professional
(doctor or nurse), from the study start until the expected sample size is reached.
According to guidelines recommendation, follow-up spirometry will be offered to all COPD
patients who consult their primary care team, regardless of the reason for the
consultation and as long as they have no contraindications for the test. In the same
consultation, they will be offered participation in the study, they will be informed of
the procedures and reasons for the study, and they will be given the information sheet
and informed consent sheet. If they decide to sign consent, they will be recruited by the
RRP when they come to perform forced spirometry.

RRP will then check if participants have been diagnosed of COVID-19 through any
registered test (PCR, ART and/or serology) with a positive result, and will record this
information in the ad hoc data collection book (DCB), along with socio-demographic
variables. Spirometry will be performed to participants without a history of COVID-19,
and to those with a diagnosis of COVID-19 registered more than 3 months ago; spiromètric
parameters (FEV1, FVC...) will be recorded at DCB. In participants with COVID-19
diagnosis in the previous three months, spirometry and initial evaluation will be
scheduled after 3 months of diagnosis, according to the local protocol.

First assessment In the first assessment, data will be collected from electronic medical
records (comorbidities, medications); moreover, physical examination and clinical
assessment tests will be undertaken. In PCC that have adequate facilities, the 6-minute
walk test (6MWT) will be carried out. This test is included in the monitoring of the COPD
patient, as part of the BODE index, with implications on the severity and prognosis of
the disease. If the 6MWT cannot be performed, as an alternative to the BODE index, the
BODEx index (which replaces the 6MWT for the number of COPD exacerbations in the previous
12 months) will be calculated.

Finally, RRP will give an appointment to the participants for the final evaluation, one
year later, unless they are diagnosed with COVID-19 in that period; in that case,
participants will contact with RRP for new assessment three months after COVID-19
diagnosis, and will change from the non-COVID-19 cohort subgroup to the COVID-19 cohort
subgroup Follow-up After the first spirometry and first assessment, all participants will
have a second follow-up visit. In patients who do not suffer from COVID-19 during the
follow-up period, this final visit will take place 12 months after the inclusion in the
study. In patients who present COVID-19 during follow-up, this second assessment will be
taken out 15 months after the diagnosis of COVID-19. The content of this follow-up visit
will be the same as that of the first assessment, including records of spirometric
parameters, that will allow to analyse outcome measures.

Statistical analysis A first descriptive data analysis shall be carried out, providing
absolute and relative frequencies for categorical variables, and mean, and standard
deviation (or median, and interquartile range, in case they are not distributed according
to normal distribution) for continuous variables.

Differences in successive measurements of FEV1 (baseline, initial and final) between the
subgroups with and without COVID-19 shall be compared using the ANOVA test for paired
samples, or the Kruskal-Wallis test if the FEV1 values are not distributed according to
normal law.

The influence of other variables of interest on the evolution of the FEV1 value will be
analyzed by means of mixed linear models, considering as fixed factors: background of
COVID-19 (yes/no), all those that have shown significant differences in the bivariate
analysis (possible confounding variables), and those recognized as clinically relevant;
and as random factors: patients and patient visits.

Study difficulties and limitations Due to the type of sampling, it cannot be guaranteed
that COPD patients without COVID-19 are similar to COPD with COVID-19; in any case, we
will report the comparative analysis of the study variables between the two cohort
subgroups.

As an observational study, the estimation of the contribution of the study variables to a
greater deterioration of lung function may be influenced by confounding variables that
have not been considered, and therefore not be rigorous.

Lastly, due to change of diagnostic protocol COVID-19 from March 2022 (the screening was
stopped in asymptomatic and in symptomatic but not vulnerable people, including COPD
persons), It could be that some members of the non-COVID-19 group have passed a mild,
undiagnosed COVID-19.

Expected results and relevance If a greater decrease in respiratory function is observed
in COPD patients who have suffered from COVID-19, close monitoring, and early preventive
and treatment measures could be undertaken.