Post-discharge spirometry evaluation in patients recovering from moderate-to-critical COVID-19: a cross-sectional study

Understanding the prevalence of abnormal lung function and its associated factors among patients recovering from COVID-19 is crucial for enhancing post-COVID care strategies. This study primarily aimed to determine the prevalence and types of spirometry abnormalities among post-COVID-19 patients in Malaysia, with a secondary objective of identifying its associated factors. Conducted at the COVID-19 Research Clinic, Faculty of Medicine, University Technology MARA, from March 2021 to December 2022, this study included patients at least three months post-discharge from hospitals following moderate-to-critical COVID-19. Of 408 patients studied, abnormal spirometry was found in 46.8%, with 28.4% exhibiting a restrictive pattern, 17.4% showing preserved ratio impaired spirometry (PRISm), and 1.0% displaying an obstructive pattern. Factors independently associated with abnormal spirometry included consolidation on chest X-ray (OR 8.1, 95% CI 1.75–37.42, p = 0.008), underlying cardiovascular disease (OR 3.5, 95% CI 1.19–10.47, p = 0.023), ground-glass opacity on chest X-ray (OR 2.6, 95% CI 1.52–4.30, p < 0.001), and oxygen desaturation during the 6-min walk test (OR 1.9, 95% CI 1.20–3.06, p = 0.007). This study highlights that patients recovering from moderate-to-critical COVID-19 often exhibit abnormal spirometry, notably a restrictive pattern and PRISm. Routine spirometry screening for high-risk patients is recommended.

1. Demographic, clinical, and hospitalization data: Demographic, clinical, and hospitalization data were gathered through face-to-face interviews and the electronic records.Demographic information included age, gender, and ethnicity, while clinical details included smoking status and the presence of underlying chronic diseases.Hospitalization data included the duration of illness before admission, length of hospital stays, COVID-19 severity at presentation, the most severe COVID-19 episode during hospitalization, pharmacotherapy administered, respiratory support provided, the occurrence of respiratory complications, and details regarding intensive care unit (ICU) admission, including its length of stay.

Patients reported outcomes (PROs):
Patients were instructed to independently complete the modified Medical Research Council (mMRC) dyspnea scale and the post-COVID-19 Functional Status (PCFS) scale with minimal assistance from investigators.The mMRC and PCFS were interpreted as per the original validation of the questionnaire 20,21 .A higher score indicates a greater degree of symptom severity and impairment, respectively.

Lung function tests:
Spirometry was conducted using SpiroUSB™ (Vyaire Medical, Chicago, IL) to obtain dynamic lung volumes, including the forced expiratory volume in one second (FEV 1 ) and forced vital capacity (FVC).The cut-off value of ≥ 80% of the predicted was deemed normal for both parameters.Spirometry results were categorized into four groups: normal spirometry-normal FEV 1 , normal FVC, and FEV 1 /FVC > 0.7; restrictive pattern-reduced or normal FEV 1 , reduced FVC, and FEV 1 /FVC > 0.7; obstructive pattern-reduced FEV 1 , reduced or normal FVC, and FEV 1 /FVC < 0.7; and preserved ratio impaired spirometry (PRISm)-reduced FEV 1 , normal FVC¸ and FEV 1 /FVC > 0.7 22,23 .For patients with an obstructive pattern, post-bronchodilator spirometry was performed to identify reversible airflow obstruction.Those with a restrictive pattern were scheduled for static lung volumes and diffusion capacity measurement within two weeks using PFT Vyntus Bodybox™ (Vyaire Medical, Chicago, IL).The parameters measured included residual volume (RV), total lung capacity (TLC), diffusion capacity for carbon monoxide (DLCO), and carbon monoxide transfer coefficient (DLCO/Va).All lung function tests were conducted by certified respiratory technicians following the American Thoracic Society (ATS) and European Respiratory Society guidelines 24,25 .

Cardiopulmonary functional tests:
Patients underwent a 6-min walk test (6MWT) under the guidance of a certified respiratory physiotherapist, following the ATS guideline 26 .Their pulses and oxygen saturation were continuously monitored using the Nonin® WristOx2 ™ 3150 Bluetooth Pulse Oximeter.A 1-min sit-to-stand test (1MSTS) guided by the same respiratory physiotherapist followed and in accordance with the procedure outlined in a previous study 27 .Both assessments utilized a digital stopwatch for time measurement, and the Borg scale was employed to assess the severity of dyspnea and fatigue.Both tests were sensitive for respiratory diseases but not specific for abnormal spirometry 26,27 .

Radio-imaging:
All patients underwent a standard posterior-anterior chest X-ray examination.Only those demonstrating a restrictive pattern in spirometry were scheduled for high-resolution computed tomography (HRCT) of the lungs within one month.Two radiologists, blinded to patients' information, independently reviewed the chest X-ray images to identify consolidation, ground-glass opacity (GGO), and lung parenchymal reticulation which were commonly reported in previous COVID-19 literature [28][29][30][31] .On a chest X-ray, consolidation was defined as a homogeneous opacification that obscures airway walls and blood vessels; GGO was defined as a hazy lung radiopacity with indistinct pulmonary vessel edges; and reticulation was defined as a collection of numerous small linear opacities, according to the Fleischner Society Glossary 32 .HRCT images, when available, were also reviewed to detect these findings, as well as organizing pneumonia (OP) and other relevant abnormalities such as lung nodules, atelectasis, pleural effusion or thickening, diaphragmatic elevation, cardiomegaly, and fractures, if present.To prevent cross-referencing, all chest X-ray images were reported before any HRCT evaluations were conducted.The two radiologists did not refer to the chest X-ray results when reporting the HRCT images, and vice versa.The reporting of HRCT scans was done randomly, so the radiologists who reported the HRCT might not be the same one who evaluated the chest X-ray.Lung involvement severity was assessed using the CT-score method developed by Kunhua Li et al 33 .Each lobe received a score ranging from 0 to 5 based on its level of involvement: 0 (0%), 1 (< 5%), 2 (5-25%), 3 (26-49%), 4 (50-75%), and 5 (> 75%).The total score, representing cumulative involvement across all lobes, ranged from 0 to 25 points.

Statistical analyses
Categorical variables are presented as percentages, while continuous variables are presented as mean ± standard deviation (SD).Patients were categorized into those with normal versus those with abnormal spirometry for two-group comparisons, as well as normal versus restrictive pattern or PRISm/obstructive pattern spirometry for three-group comparisons.Between-group differences were assessed using an independent t-test for continuous variables and a Chi-Square test for categorical variables.A two-sided p-value of less than 0.05 was considered statistically significant.
For multivariate analyses, variables exhibiting significant two-sided p-values in the univariate analyses were included as covariates in binary logistic regression and multinomial logistic regression.The latter analysis excluded variables showing multicollinearity (variance inflation factor > 5).The analysis aimed to derive odds ratios (OR), 95% confidence intervals (95% CI), and two-sided p-values.Statistical analysis was conducted using the Statistical Package for the Social Sciences (SPSS for Windows version 25.0, SPSS Inc, Chicago, IL, USA).

Sociodemographic and clinical characteristics
A total of 408 patients were included in the study (Fig. 1).The sociodemographic and clinical characteristics of these patients are presented in Table 1.The mean age of the patients was 51.6 ± 13.32 years.The majority were

Findings on body plethysmography, diffusion capacity, and HRCT of the lungs
Eighty-nine patients underwent body plethysmography and diffusion capacity assessment, revealing a mean RV of 57.8 ± 39.08% predicted, a mean TLC of 65.1 ± 13.25% predicted, a mean DLCO of 62.5 ± 13.94% predicted, Table 1.Demographic and clinical data of the patients.In italic: only the number of patients with the respective underlying chronic diseases is presented; *, the p-value for differences between patients with normal and abnormal spirometry; #, the p-value for differences between patients with normal, restrictive pattern, and PRISm and obstructive pattern spirometry.

Discussion
The current study highlights that nearly half of the patients hospitalized for moderate-to-critical COVID-19 continue to show abnormal spirometry even after an average of five months after discharge.Approximately one-third of them displayed a restrictive pattern, while another one-fifth surprisingly manifested PRISm.This study identifies chest X-ray as a reliable tool for predicting abnormal spirometry and its subtypes, particularly when consolidation and GGO are present.Furthermore, the 6MWT could be a valuable tool for predicting abnormal spirometry.Although certain clinical data were also found to be useful, the 1MSTS and PROs do not add additional value to the prediction of spirometry abnormalities.A meta-analysis of seven studies, primarily conducted in China, revealed that 22.9% of patients hospitalized for COVID-19 demonstrated abnormal spirometry within three months post-discharge 34 .Among these, 15.0% exhibited a restrictive pattern while 7.9% showed an obstructive pattern 34 .A separate study in Thailand reported abnormal spirometry in 17.2% of patients hospitalized for mild-to-severe COVID-19 at sixty days post-discharge, with 9.2% having an obstructive pattern and 8.0% having a restrictive pattern 35 .In Spain and Belgium, studies reported solely a restrictive pattern among hospitalized COVID-19 patients.In the Spanish study, 14.3% of patients requiring oxygen supplementation for pneumonia exhibited this pattern at two months, 9.3% at six months, and 6.7% at twelve months 36 .In the Belgian study, 55% of patients admitted to the ICU for ARDS demonstrated a restrictive pattern at three months 37 .Compared to these other studies, our study showed a high prevalence of abnormal spirometry potentially attributed to the predominance of severe and critical COVID-19 cases among our cohort.The observation that the restrictive pattern was the most common spirometry abnormality aligns with findings in China 34 , France 38 , Spain 36 , and Belgium 37 .The increased proportion of patients with an obstructive pattern in the Thailand study, however, could be due to the non-exclusion of individuals with pre-existing lung diseases, including bronchial asthma and chronic obstructive pulmonary disease (COPD) 35 .
The majority of existing studies have focused on investigating the lung function of patients recovering from COVID-19 based on severity of illness.These studies have consistently shown that individuals with more severe illness tend to exhibit significantly lower static lung volumes and diffusion capacity, while their dynamic lung volumes in spirometry often remain preserved 8,[38][39][40][41] .To date, only a study in Thailand and China have respectively reported significantly lower dynamic lung volumes in patients with more severe illness 35,42 , while another study in the Netherlands found only FVC to be significantly lower in such cases 43 .Additional studies have shown that for individuals post-COVID-19, spirometry indices were not significantly different from the Table 3. PROs, cardiopulmonary functional tests, and chest X-ray findings of the patients.^, 404 patients performed 6MWT: 217 had normal spirometry, 187 had abnormal spirometry (114 restrictive, 73 PRISm and obstructive); + , 402 patients performed 1MSTS: 215 had normal spirometry, 187 had abnormal spirometry (114 restrictive, 73 PRISm and obstructive); *, p-value for differences between patients with normal and abnormal spirometry; #, p-value for differences between patients with normal, restrictive pattern, and PRISm and obstructive pattern spirometry.www.nature.com/scientificreports/healthy population 44 , those with other viral upper respiratory tract infections 45 , or the same cohort of patients one year before the infection 46 .A review by Thomas et al. further concluded that spirometry indices are often well-preserved in COVID-19, without being significantly affected by illness severity 47 .As far as we know, our study is the first to demonstrate no significant differences in spirometry patterns between patients with varying severity of COVID-19.
Our study identifies several factors associated with abnormal spirometry in patients recovering from COVID-19, notably abnormal chest X-ray and 6MWT during follow-up, as well as underlying cardiovascular disease.In Thailand, individuals with abnormal chest X-ray after COVID-19 had significantly lower dynamic lung volumes 35 .Additionally, chest CT abnormalities after COVID-19 were correlated with lower dynamic lung volumes and diffusion capacity among those in Austria 48 , Netherlands 40 , and China 49 , although not in France 38 .Oxygen desaturation during the 6MWT was associated with diffusion capacity impairment among post-COVID patients in the Netherlands 40 , but not in Thailand or Germany 35,50 .The relationship between lung function and mMRC scores or 6MWT in individuals post-COVID has not been extensively explored in previous studies, where these measures were assessed but not specifically analyzed for their association or correlation 36,41,51,52 .To date, only one study from Austria has reported a negative correlation between lung function and mMRC scores 48 , while another study from the Netherlands reported an association between poor lung function and oxygen desaturation in the 6MWT 40 .Additionally, two other studies, one from China and another from Belgium, found concurrent abnormalities in lung function, radio-imaging, 6MWT, and mMRC in the same cohort of post-COVID patients, suggesting a potential relationship between these factors 8,37 .Other factors associated with impaired lung function in previous studies included older age 36,46 , female gender 36 , lower body mass index 36 , underlying chronic lung disease 46 , higher inflammatory markers at presentation 36,49 , previous ARDS 37 , and shorter discharge-to-followup interval 48,51 .Corticosteroid treatment was linked to better lung function recovery 37,51 , while this was not observed with other treatment modalities 43 .Overall, our study findings are consistent with most of other studies.
Our study is the first to report PRISm in post-COVID patients.PRISm, previously known as pre-COPD, restrictive, or non-specific pattern, has a prevalence of 4.7-22.3% in the general population 53 .Recent studies indicate that it primarily affects the small airways and vessels while sparing lung parenchyma 53,54 .Two studies have shown that 25.1% and 32.6% of individuals with PRISm, respectively progress to spirometry-defined COPD in five years 55,56 .Conversely, improvement of spirometry from obstructive pattern to PRISm over time has also been observed 57 .Therefore, individuals with PRISm in this study could either indicate an improvement from airflow obstruction or an early sign of deterioration to COPD after COVID-19.Additionally, the possibility that this reflects population prevalence rather than being directly attributed to COVID-19 cannot be discounted.Future studies that prospectively following up on this patient cohort could provide a definitive answer.The high prevalence of the restrictive pattern among our patients can be explained by the aberrant wound healing typically following diffuse alveolar damage by SARS-CoV-2, leading to severe scarring and fibrosis 58 .Respiratory muscle weakness following SARS-CoV-2 infection could also be another possibility 59 .
The findings from this study have several clinical implications.First, spirometry should be routinely performed in patients post moderate-to-critical COVID-19 due to the high prevalence of abnormality.Second, when universal spirometry screening is not feasible among them, a targeted risk stratification approach considering chest X-ray, 6MWT, and specific clinical characteristics is recommended.Third, chest X-ray proves to be the most reliable screening tool for abnormal spirometry, with the additional benefits of being readily available and   Fourth, the 6MWT also emerges as a valuable screening tool for abnormal spirometry.Fifth, 1MSTS and PROs may not add significant value to the screening and should not be prioritized during follow-up.Sixth, this study suggests the potential development of a scoring system that combines these factors, providing a practical tool for clinicians to efficiently select patients for lung function tests.
The large sample size of this study allows for the generalizability of the result.It is one of the few studies in the Southeast Asia, where outcomes may differ from other parts of the world due to variations in genetic, environmental, and lifestyle factors.The study focused on patients hospitalized with moderate-to-critical COVID-19 who were more susceptible to long-term lung injuries.The comprehensive study outcomes include objective assessments like lung function, radio-imaging, and cardiopulmonary functional evaluations, alongside subjective assessments such as PROs.However, this study was conducted during the peak of the pandemic.Travel restrictions, public reluctance to visit hospitals, and constrained healthcare resources could lead to several weaknesses.First, the convenience sampling method may introduce bias.Second, not every patient can undergo examination with body plethysmography, for diffusion capacity, and with HRCT.Third, some patients who were offered these investigations defaulted.Fourth, due to practical and logistic reasons the follow-up assessments could not be conducted at a fixed interval, such as three months, six months, or twelve months post-discharge.Fifth, no spirometry was done before the COVID-19 infection to demonstrate baseline normality.Sixth, factors associated with specific abnormal spirometry patterns should be interpreted with caution, as the sample size may not be powerful enough to accurately reflect these secondary outcomes.Seventh, although patients' age and discharge-to-follow-up interval may show statistical significance in multivariate analysis, an OR of 1.0 indicates a lack of clinical significance.Eighth, the OR for ARDS could not be generated using logistic regression due to the complete separation phenomenon and the events were extremely low resulting in a lack of statistical power for the analysis.Ninth, multidimensional assessment of PROs such as HRQOL was not performed.Lastly, lung function tests were not conducted as a follow-up after the study to observe potential changes in patterns.

Conclusions
Patients recovering from moderate-to-critical COVID-19 often demonstrated abnormal spirometry, particularly manifesting a restrictive pattern and PRISm.Therefore, spirometry should be routinely offered to those at higher risk of abnormalities, such as individuals with abnormal chest X-ray and 6MWT during follow-up, as well as those with underlying cardiovascular disease.PRISm represents a novel finding among post-COVID patients, warranting further follow-up to elucidate the underlying mechanism of this lung function abnormality.#, multinomial logistic regression analysis using patients with normal spirometry as reference; ^, continuous variables; !, Most severe illness during hospitalization was added as a covariate for binary logistic regression even though univariate p = 0.052; a, OR = 1.03; b, OR = 1.04; c, OR = 0.94.

Table 2 .
Hospitalization data of the patients.In italic: only the number of patients with the respective pharmacotherapy, respiratory support, and respiratory complications are presented; *, p-value for differences between patients with normal and abnormal spirometry; #, p-value for differences between patients with normal, restrictive pattern, and PRISm and obstructive pattern spirometry.

Table 4 .
Binary and multinomial logistic regression analyses to determine factors associated with abnormal spirometry results.*, binary logistic regression analysis using patients with normal spirometry as reference;

Table 5 .
Findings of body plethysmography, diffusion capacity, and HRCT of the lungs for patients with restrictive pattern spirometry.