Patients received a comprehensive medical assessment with a detailed medical history. Data including demographics, persistent symptoms from surveys, and pulmonary function test results were collected during the follow-up visit. Demographic data included age, sex, body mass index (BMI), and previous cardiovascular disease risk factors for which regular pharmacological treatment was incorporated including systemic hypertension, cardiac disease, diabetes mellitus, Tobacco use (current or former smoker vs. never smoker), obesity (defined as body mass index > 30 kg/m2). Patients were asked if they received oral corticosteroids and/or anticoagulants during the disease and to recount presence or absence of symptoms at the time of the visit including: fatigue, shortness of breath on effort, cough, chest tightness, chest pain, sore throat, blocked and/or runny nose, loss of smell, loss of taste, diarrhea, abdominal pain, muscle or joint pain, headache, tachycardia, sore or red eyes, excessive sweating (over a 24hr period, including night sweats), hair loss, and weight loss [30, 31].
Spirometry and measurements of DLCO, were performed approximately four weeks following baseline symptoms through standard equipment (Easy One Pro®, NDD Medical Technologies, Switzerland). Spirometry reference equations were obtained from Hankinson (1999) . The technical quality of spirometry was adhered to per 2019 spirometry standards . The reference equations for pulmonary diffusing capacity for carbon monoxide (DLCO) was obtained from Vazquez-Garcia and colleagues . The 2017 Technical standards for DLCO were followed for technical quality .
A Fisher’s exact test compared the number males versus females being below the LLN for DLCO. A Fisher’s exact test also compared the number males versus females with a restrictive spirometric pattern as defined by the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) being ≥ LLN with the FVC being less than the LLN. The Fisher’s Exact Test would allow an examination of a sex differences in the proportion of males versus females that had abnormally low lung function. Several N-1 Chi-Squared Tests were used to determine whether the percentage of several signs and symptoms that were present post-COVID-19 were different between those with a DLCO < LLN and those with a DLCO ≥ LLN . A Benjamini-Hochberg procedure was used to control the false discovery rate , which we set to 0.05.
Binary logistic regression was performed using the Forward: Likelihood ratio method (enters independent variables one at a time) to determine the factors associated with an impaired DLCO (DLCO < LLN) in the mild post-COVID-19 patients. Cardiovascular disease (CVD) risk factors [smoking status (yes, no), high blood pressure (yes, no), cardiac arrhythmia (yes, no), obesity (yes, no)], true cardiac disease (yes, no), fatigue, dyspnoea, cough, headache, chest tightness, sore throat, persistent loss of smell (yes, no), dysfunction in the sense of taste (yes, no), conjunctivitis, blocked and/or runny nose, use of oral corticosteroids during the disease (yes, no), use of anticoagulant medications (yes, no), sex (male, female), age in z scores, height in z scores, weight in z scores, body mass index (BMI) in z scores, a restrictive spirometric pattern (forced vital capacity or FVC below the lower limit of normal, LLN, and FEV1/FVC ≥ LLN), forced expiratory volume in 1 s (FEV1) (y = yes, 0 = no), forced expiratory flow rate over the middle half of expiration (FEF25−75) in z scores and peak expiratory flow (PEF) in z scores.
Using mean data from 22 previous studies (including the current study), multiple linear regression analysis using forward selection was used to identify which of the five following factors would predict the proportion of patients who had previous COVID-19 and impaired DLCO at follow-up. The mean age (years), mean body mass index (kg/m2), mean number of days between receiving the COVID-19 diagnosis and follow-up, history of mild vs severe COVID-19 disease (i.e. patients that were either hospitalized, intubated, presented with fibrotic CT changes in the lung were labelled as 1, compared to those that were not labelled as 0), and the criteria used to define impaired DLCO (DLCO < 80% predicted labelled as 1, vs DLCO < LLN labelled as 0) were predictors used in the model.
All data were analysed by a statistical software package (IBM SPSS Statistics, Version 27, Chicago IL). A p-value of < 0.05 was used to signify statistical significance. Any case with a studentized residual ≥ 3.0 were removed from any model.