Lung function during and after acute respiratory infection in COVID-19 positive and negative outpatients

To the Editor:

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been associated with prolonged post-acute symptoms in at least 10% of patients [1, 2]. The majority of published data evaluates hospitalised patients with severe SARS-CoV-2 disease (COVID-19) with symptoms and pulmonary function defects several months after discharge [1]. Most of the infected subjects develop mild symptoms and are treated as outpatients. Though they are also reported to suffer from prolonged symptoms, their lung function is studied far less. Furthermore, the prolonged symptoms and objectively measurable findings are usually not compared to a group suffering from airway infection caused by other pathogens [2]. As spirometry and other aerosol-producing procedures are minimised during the pandemic, there are no reports on lung function during acute COVID-19.

Forced oscillation technique (FOT) or airwave oscillometry (AOS) is a non-invasive and effort-independent method to measure airway resistance and airway reactance, enabling safe and admissible evaluation of pulmonary function [3] without producing possibly infective aerosols. FOT has been used in three previous studies to show small airway impairment one to six months after discharge in subjects who have recovered from severe COVID-19 [4–6].

Our aim was to evaluate and compare symptoms and pulmonary function at the time of acute infection (visit one) and after two months of follow-up (visit two) in outpatients with mild respiratory infection that were either RT-PCR-positive (cases) or RT-PCR-negative (controls) for SARS-CoV-2.

The final study population consisted of two clinical series, namely 43 cases and 39 controls, who took part in the CANNAS-study in Tampere, Finland from January 15th to August 18th, 2021 (R20090, NCT04728919). Cases were recruited during contact tracing phone call. Age-matched (±5 years) and gender-matched controls were recruited among subjects tested for SARS-CoV-2 due to acute respiratory infection but who later received a negative test result and gave their contact information (n=138) at local testing sites; 102 people were contacted, 43 matched controls were recruited and after drop-outs 39 subjects were included. The exclusion criteria were absence of respiratory symptoms, onset of symptoms over ten days ago, pregnancy or breastfeeding, previous vaccination against COVID-19 and inability to arrive at the study site without exposing others.

A standard nasopharyngeal swab sample was obtained and three target genes were analysed by the SARS-CoV-2 RT-PCR protocol (Seegene Inc., Seoul, South Korea). Lung function was measured with AOS (TremoFlo C-100, Thorasys, Montreal, Canada) at both visits and with spirometry (Medikro Pro, Medikro Oy, Kuopio, Finland) at the follow-up visit, according to international standards [7–9], using international and Finnish reference values [10, 11]. The visual analogue scale (VAS) from “none” (0 mm) to “worst possible” (100 mm) was used to score different symptoms at both visits. Due to skewed distributions (Kolmogorov-Smirnov test), medians (interquartile range) were used to describe the data.

The results are presented in the table 1. Cases and controls did not differ in their demographics. None of the subjects used leukotriene antagonists. Systemic corticosteroids were used only by one subject for a nonidentifiable reason before the control visit (normal AOS and spirometry). Inhaled corticosteroids were used by 5% of cases (only one of them had the diagnosis of asthma) and 3% of controls (p=1). The median time from visit one to follow-up was 59 (56–64) versus 56 (53–67) days, p=0.496, in cases and controls, respectively.

Small airways resistance (R5-20) and area of reactance (AX) were significantly higher in cases during infection (visit one) in comparison to controls, indicating impairment of the peripheral lung. In both cases and controls, there was a small but statistically significant impairment in these parameters from visit one to two (table 1). Proportions of subjects with abnormal results in each oscillometry variable (z-score<−1.65) were small, and there were no differences between the cases and controls at either visit. Spirometry results at follow-up were similar between the groups. Some of the subjects in both groups had spirometry values below the lower limit of normal (z-score<1.65) (7.7% versus 14.3% in FVC, p=0.477; 12.8% versus 17.1% in FEV₁, p=0.654; 20.5% versus 14.2% in FEV₁/FVC, p=0.554, in cases and controls respectively) but there was no difference between the groups.

During acute infection, cases had higher symptom scores in terms of decreased senses of smell and/or taste, fatigue, coughing, the need to blow their noses and dyspnoea (table 1). There was a significant decrease in symptoms in both groups at the follow-up and no significant difference between the groups.

This is the first study to evaluate outpatient lung function at the acute phase of COVID-19 infection and we had a control group suffering from respiratory infection caused by other pathogens. At the acute phase, cases had on average poorer peripheral lung function (R5-R20 and AX) in comparison to controls, yet the proportion of abnormal results was low. Although subjects recovering from severe COVID-19 infection may have impaired diffusing capacity, restriction or obstruction [12], our results suggest that mild COVID-19 infection does not impair lung function after two months of follow-up when compared to other mild respiratory infections. There were some subjects with lung function below the lower limit of normal, but this is understandable since, by definition, 5% of healthy subjects have abnormal values of each parameter, and our study also included subjects with asthma, a history of smoking (possible undiagnosed chronic obstruction) and obese people with pulmonary restriction. However, the proportion of cases with FEV₁/FVC below lower limit of normal was unexpectedly high (20.5%), but as we do not know their lung function before infection, we do not know if this is because of COVID-19 or undiagnosed prior lung disease. The important finding is that the proportion of abnormal values did not differ between the cases and controls and none of the subjects had FEV₁/FVC<0.70.

Interestingly, the trend of change in our data was slightly worse in R5, R5-20, AX and X5 in both groups. This might implicate airway damage after infection [4]. Again, there were no differences between cases and controls, suggesting that mild COVID-19 does not differ from other airway infections in this regard.

COVID-19 patients were more symptomatic than the controls at the acute phase, with the greatest differences being a decreased sense of taste and/or smell, and fatigue, which align with previous results [13, 14]. Both groups had very low levels of symptoms at control visit and there was no difference between the groups suggesting that long-lasting sequelae are not frequent in subjects with mild COVID treated as outpatients.

The study sample is representative of non-vaccinated adult Finnish outpatients with mild RTI, albeit the participation might have been more tempting to people with pulmonary or other health concerns. Measurements at visit one were taken days after the onset of symptoms, not necessarily depicting the culmination of the disease. However, the groups were comparable by background characteristics. The sample size was based on a 90% power with an alpha-error of 5% to find a between-group difference in any continuous variable that was at least 75% of the standard deviation. Thus, we cannot rule out minor differences between the groups.

In conclusion, outpatients with mild COVID-19 had poorer peripheral lung function in comparison to those with other acute respiratory infections, but there were no differences in lung function or symptoms after two months of follow-up, suggesting that possible long-standing symptoms after mild COVID-19 may not be due to physical changes in the airways.