key: cord-0915127-x0mjbj6f
authors: Boutou, Afroditi K.; Georgopoulou, Athina; Pitsiou, Georgia; Stanopoulos, Ioannis; Kontakiotis, Theodoros; Kioumis, Ioannis
title: Changes in the respiratory function of COVID‐19 survivors during follow‐up: A novel respiratory disorder on the rise?
date: 2021-05-17
journal: Int J Clin Pract
DOI: 10.1111/ijcp.14301
sha: bba5843749aeb2ab0073d978a9475312cbddfdb6
doc_id: 915127
cord_uid: x0mjbj6f

BACKGROUND: The Human Coronavirus Disease 2019 (COVID‐19) is a highly contagious respiratory disorder that may result in acute respiratory distress syndrome. The aim of this review was to investigate the incidence and type of respiratory function abnormalities during the follow‐up of patients who recovered from COVID‐19. METHODS: A systematic search of MEDLINE was conducted, utilising various term combinations. Studies that assessed any respiratory function parameter during the re‐evaluation of patients who recovered from COVID‐19 and were published as full‐text articles in English are included in this review. RESULTS: Amongst 183 articles initially retrieved, 8 fulfilled the criteria and were included in this review; they involved a total of 341 adult patients. Four were retrospective studies, one was a prospective cohort study, one was a randomised control trial and two were case reports/case series. The follow‐up time ranged from 1 month since symptom onset to 3 months after discharge. The most frequent abnormality was reduced lung diffusion for carbon monoxide (DLCO), followed by a restrictive pattern. Other findings are the lack of resting hypoxemia, the reduced respiratory muscle strength and the decreased exercise capacity, although relative data are extremely limited. CONCLUSION: Patients who recovered from COVID‐19 present with abnormal respiratory function at short‐term follow‐up, mainly with reduced lung diffusion and a restrictive pattern. However, results are currently very limited in order safe conclusions to be made, regarding the exact incidence of these abnormalities and whether they may be temporary or permanent.

H 1 N 1 influenza 7 indicated that respiratory function abnormalities and exercise capacity impairment may persist for long during follow-up. However, studies that have compared SARS-CoV-2 to influenza infection concluded that COVID-19, besides similarities, has also several distinct features from influenza; these differences refer to underlying pathophysiologic processes (endothelialitis, interferonγ mediation of host-immune response and lymphopenia 8 ) , patient characteristics (COVID-19 patients are older but probably with less comorbidities and lower prevalence of respiratory disorders, compared to the ones with influenza 9,10 ), clinical course (the fraction of severe and critical infection and the risk ratio for most respiratory and non-respiratory complications amongst patients with COVID-19 is significantly higher, compared to what is observed for influenza infection 9,10 ), imaging presentation (ground-glass opacities are probably more often amongst COVID-19 compared to influenza patients 11 ) and prognosis. Since influenza infection cannot serve as an accurate model for COVID-19, 8 one can hypothesise that the short and long-term respiratory function abnormalities of COVID-19 patients cannot be predicted by published data on other severe respiratory infections. To the authors' knowledge, no other study has yet reviewed published literature regarding the potential functional abnormalities during short-term follow-up of patients who recovered from COVID-19 disorder. However, such an approach could provide valuable information regarding disease outcomes and prognosis and offer further data towards the optimisation of follow-up.

Based on the aforementioned, the aim of this review is to summarise the available published data regarding the potential changes in: (a) respiratory function parameters, that is spirometric variables, lung volumes, lung diffusion for carbon monoxide and respiratory muscle strength, (b) arterial blood gases and (c) exercise capacity, during the follow-up re-evaluation of patients who were hospitalised and discharged because of COVID-19 disease.

A search of MEDLINE (December 2019-August 2020) was conducted. We used the terms "covid 19," "SARS-CoV-2," "respiratory function," "pulmonary function," "spirometry," "diffusion," "exercise capacity," "6-minute walking test," "functional capacity," "functional assessment," "follow-up," and "longitudinal" in various combinations.

The reference list of all relative articles was also reviewed by the authors, in order for further studies to be identified. Studies that assessed any respiratory function parameter during follow-up reevaluation amongst discharged COVID-19 patients and were published as full-text articles in English are included in this review.

Amongst the 183 studies initially identified, 8 fulfilled the criteria and are reported in this review (Table 1) . These studies were all conducted in adults and they included a total of 341 patients (55.7% males; age range: 19-79 years). Four were retrospective studies, one was a prospective cohort study, one was a randomised control trial and two were cases series/case reports. The follow-up time ranged from 1 month since symptom onset to 3 months after discharge. Six studies were conducted in China, one in France and one in Italy.

The majority of patients had normal spirometry at follow-up; however, when pulmonary function was abnormal, the restrictive pattern was more frequent than the obstructive one, amongst COVID-19

survivors. In the study of Huag et al, 1 57 patients with no history of respiratory disease who underwent rehabilitation were retrospectively evaluated a month after hospital discharge. The patient group means of forced expiratory volume in 1 second (FEV 1 ), forced vital capacity (FVC), Tiffeneau index (FEV 1 /FVC) and total lung capacity (TLC) were normal. However, impairments in FEV 1 , FVC and TLC were present amongst 8.8%, 10.5% and 12.5% of patients, respectively, while a low Tiffeneau index compatible with obstructive disorder (<70) was present in one patient with smoking history.

Interestingly, TLC was the only lung volume measurement that differed between patients who recovered from mild or severe (as defined by the presence of respiratory failure or shock or need for ICU monitor and treatment) disease. 1 TLC also correlated with the total severity score in the worst chest CT, but not in the follow-up CT. 

• Patients that recovered from COVID-19 present with abnormal respiratory function at short term follow-up, mainly a restrictive pattern and impaired diffusion.

• Data is scarce regarding whether these abnormalities may be permanent or temporary and for how long they may insist, thus longitudinal follow-up studies are needed to draw safe conclusions.

follow-up FEV 1 and FEV 1 /FVC were not different than LLN and ULN correspondingly, but FVC remained reduced, indicating a partially persistent pattern of respiratory restriction. 12 Similarly, in an evaluation of 50 discharged non-critical patients 1 month after symptom onset, the majority of patients had mild impairments of pulmonary function and mean group FEV 1 %, FVC%, FEV 1 /FVC and TLC% predicted values were normal. 13 Nevertheless, when the patterns of pulmonary function were evaluated, 28% of patients presented with a restrictive pattern (with or without diffusion abnormalities). This percentage increased up to 51% amongst patients who had presented with severe pneumonia, involving >50% of parenchyma extent; the clinical severity of the disease course, though, was not associated with differences in pulmonary function variables. 13 The longest follow-up evaluation was conducted in the study of Zhao et al, which included 55 eligible patients with non-critical COVID-19 disease who had been discharged from the hospital. 14 In this study, almost one out of four patients still presented with a pulmonary function abnormality during the 3-month follow-up; a restrictive pattern was present amongst 10.9%, an obstructive pattern amongst 9.1% a mixed pattern in 5.5% of individuals, while small airway dysfunction was present in almost 13% of participants, although authors do not report the exact variables that were chosen to indicate airway dysfunction. No correlation was found, though, between FEV 1 %, FVC%, TLC% predicted values and the extent of chest X-ray findings. 14 In the larger study in the field, Mo et al evaluated 110 discharged patients within a month after symptom onset; approximately 9% had reduced FVC, 13.6% reduced FEV 1 , while in 5% of patients FEV 1 / FVC was <70. 15 The most frequent lung volume abnormality was reduced TLC; it was present amongst 25% of the total patient group, while almost half of these cases were found amongst those who had recovered from severe disease. In this study, clinical severe cases presented with significantly lower TLC% predicted, suggesting a greater impairment of respiratory function amongst those patients.

However, Mo et al did not report the extent of parenchyma involvement according to thorax computed tomography (CT) findings and its potential association to spirometric variables, while the spirometric evaluation was conducted quite early in the course of the disease that is 1 month after symptom onset. In another small study, You et al confirmed that the majority of patients who recovered from COVID-19 presented with normal pulmonary function approximately 5-6 weeks after discharge.

Amongst the 18 patients evaluated though, the most common spirometric abnormality was small airway dysfunction which was present in one-third of the participants, while 16.7% presented either an obstructive or a restrictive pattern. 16 

The most common pulmonary function abnormality encountered during patient follow-up is the impairment of diffusion capacity for carbon monoxide (DLCO), which can be either isolated or in combination with a restrictive pattern. 

Currently, the only available data on respiratory muscle function during follow-up of COVID-19 patients come from the study of 

There are extremely limited data regarding the exercise capacity of COVID-19 patients after recovery. In the study of Huang et al, the mean 6-minute walking distance (6MWD) at 1 month of follow-up was approximately 562 m; however, patients with severe disease were presented with significantly shorter 6MWD than the nonsevere ones (517.43 ± 44.55 m vs 573.52 ± 38.38 m; P = .012). 1 When the % predicted values were evaluated, the severe cases reached only 88.4% of predicted values, which is significantly lower than the non-severe cases, indicating a significant decrease in shortterm exercise capacity amongst them.

Exercise capacity was even worse in the study of Liu et al, 18 where an intervention group (that received respiratory PR after hospital discharge) was compared to a control group (that did not receive respiratory PR); in both groups mean 6MWD very low at baseline (162.7 ± 72.0 vs 155.7 ± 82.1, correspondingly) and it remained invariable in the control group at 6 weeks of follow-up (157.2 ± 71.7).

Although the latter study was conducted in elderly individuals with one or more comorbidities, it indicates that exercise capacity can markedly reduce amongst COVID-19 survivors and this reduction may insist for a long.

In this review, we summarised the existing literature regarding follow-up lung function abnormalities amongst patients who were discharged after recovering from SARS-CoV-2 infection; the most remarkable finding is that existing data are scarce, as they come from small studies which were conducted during very short-term followup. Amongst the abnormalities noted, reduced DLCO was the most frequently encountered, followed by a restrictive pattern, as they may be evident in almost half of patients during follow-up. Other interesting findings are the lack of resting hypoxemia, the reduced respiratory muscle strength and the decreased exercise capacity, although relative data are extremely limited. Respiratory restriction is far more common than obstructive abnormalities amongst these patients. The main respiratory function parameter that was found to be reduced was TLC, which was the only lung volume parameter associated with the severity of disease 15, 16 and with the extent of imaging abnormalities. 13 Since peripheral ground-glass opacities with or without pulmonary fibrosis are the main residual abnormality amongst these patients, 1 persists at follow-up. 1 Although obstructive pattern with FEV 1 /FVC <70 seems to be highly unusual amongst non-COPD patients, small airway dysfunction is a common abnormality, but of low severity.

This finding may also be explained by small airway congestion, 15 but this is a hypothesis that needs to be further tested. Whether this may also be the progress of COVID-19 survivors, remains to be studied. to optimise their long-term outcomes.

The authors declared no conflict of interest.

Afroditi K. Boutou https://orcid.org/0000-0001-7366-2038

Impact of coronavirus disease 2019 on pulmonary function in early convalescence phase

Nicotine treatment and smoking cessation in the era of COVID-19 pandemic: an interesting alliance

WHO Coronavirus Disease (COVID-19) Dashboard

Organ-specific manifestations of COVID-19 infection

Long-term clinical outcomes in survivors of severe acute respiratory syndrome and Middle East respiratory syndrome coronavirus outbreaks after hospitalisation or ICU admission: a systematic review and metaanalysis

1-year pulmonary function and health status in survivors of severe acute respiratory syndrome

Recovery of pulmonary functions, exercise capacity, and quality of life after pulmonary rehabilitation in survivors of ARDS due to severe influenza A (H1N1) pneumonitis. Influenza Other Respir Viruses

Pathogenesis of COVID-19-induced ARDS: implications for an ageing population

Risk for in-hospital complications associated with COVID-19 and influenza -Veterans Health Administration

WHO: Coronavirus disease (COVID-19): Similarities and differences with influenza

Comparison of hospitalized patients with ARDS caused by COVID-19 and H1N1

Pulmonary function in patients surviving to COVID-19 pneumonia

Functional characteristics of patients with SARS-CoV-2 pneumonia at 30 days postinfection

Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery

Abnormal pulmonary function in COVID-19 patients at time of hospital discharge

Anormal pulmonary function and residual CT abnormalities in rehabilitating COVID-19 patients after discharge

Follow-up study on pulmonary function and radiological changes in critically ill patients with COVID-19

Respiratory rehabilitation in elderly patients with COVID-19: a randomized controlled study

Silent hypoxia in patients with SARS CoV-2 infection before hospital discharge

Thin-section computed tomography manifestations during convalescence and long-term follow-up of patients with severe acute respiratory syndrome (SARS)

Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series

Diffuse alveolar damage (DAD) from coronavirus disease 2019 infection is morphologically indistinguishable from other causes of DAD

Abnormal carbon monoxide diffusion capacity in COVID-19 patients at time of hospital discharge

Examination of the carbon monoxide diffusing capacity (DL(CO)) in relation to its KCO and VA components

Diffusing capacity, specific diffusing capacity and interpretation of diffusion defects

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Six month radiological and physiological outcomes in severe acute respiratory syndrome (SARS) survivors