To the best of our knowledge, this is the first prospective study that sequentially evaluated respiratory symptoms, pulmonary function measures, chest CT findings, and exercise capacity in patients with COVID-19 from 1- to 6- month after hospital discharge. This cohort study shows the respiratory symptoms and pulmonary function to gradually improve in most patients after COVID-19 infection. But chest CT images and 6MWD were still impaired compared to healthy control subjects. Abnormal CT scores at 6-month follow-up were independently associated with steroid administration during hospitalization.
Same as the other pneumonias, fever, cough and dyspnea are the main presenting symptoms among those who become hospitalized. In general, these symptoms gradually improved as patients recovered from the acute illness. Similar results were demonstrated in other pneumonia and ARDS follow-up studies[23, 24]. In a retrospective cohort, 26% of 51 patients with common COVID-19 had cough (8), throat discomfort (3) and sputum (2) at 4-weeks after hospital discharge[25]. Our study cohort showed higher portion of discharged patients to have respiratory symptoms at 1 month, which decreased to 30% at 3 months and still present at 6 months. However, higher prevalence of persistent symptoms was reported at 3 months after mild SARS-CoV-2 infection[18]. Fatigue or muscle weakness were reported in more than 60% of 1733 survivors in Jin Yin-tan Hospital at 6 months; anxiety or depression was reported nearly 25% of them[19]. The significant differences between our observations and these other studies might reflect psychosocial effects associated with COVID-19 and its aftermath, which are issues that warrant for further investigations and follow-up studies.
Similar to previous SARS reports, mild pulmonary function abnormalities and residual CT abnormalities were seen in 10%-40% of our patients at 6-month follow-up. This might explain the persistent cough and dyspnea noted in these patients after discharge. A recent study reported 110 discharged patients with COVID-19 including 17% severe disease patients [26], pulmonary function defects were detected in FEV1% in 15 (13.6%), FVC% in 10 (9.1%), which is similar to our findings. Furthermore, that study showed impairment of DLco in nearly 50% of patients and a significant difference in diffusing-capacity measurements among the different groups of disease severity. There were no significant differences among the survivors with different severity pneumonias in regard to other pulmonary function measures (e.g. FEV1, FVC, FEV1/FVC). Similarly, about 15% of 55 SARS patients in Hongkong were found to have a restrictive defect and 50% of them manifested impaired diffusion capacity after 2-year recovery period[14]. Compared to the study on SARS, pulmonary function impairment was less affected in our cohort of COVID-19 patients.
Recent autopsy study found that include diffuse alveolar damage, hyaline membrane formation, thrombi within the small pulmonary arteries, alveolar septal fibrous proliferation, and organizing pneumonia with fibrosis to be involved in pathogenesis of COVID-19 infection[27, 28]. Therefore, regarding to the secondary pulmonary fibrosis resulting from this injury, diffusion capacity would be expected to be more affected compared to lung volume in most patients[26]. Thus, it would be preferable to combine FEV1 with DLCO in detecting pulmonary function impairment in recovered COVID-19 patients.
The importance of chest CT images for the diagnosis of COVID-19 infection at early stage and assessment the treatment effects has been widely reported[29]. Liu et al. found that the pulmonary parenchymal abnormalities on CT scans due to COVID-19 could be reversible for the common COVID-19 patients after 4-week discharge[25]. Although most patients in this study manifested significantly improved CT scores, pulmonary abnormalities were still present in almost 40% of them at 6 months. The lung damage in COVID-19 was reported to be associated with a cytokine storm induced by SARS-CoV-2, which might be similar to that of SARS-CoV[30]. Wang et al investigated 12 recovered patients with SARS in Taiwan, over 80% of whom still manifested HRCT abnormalities at 60 days after discharge. Moreover, the HRCT scores were increased and correlated with increased cellularity of bronchoalveolar lavage fluid (BALF)[31]. Thus, persistence of lung inflammation during the early recovery period might be associated with the delayed resolution of SARS. As several studies on SARS reported, radiologic abnormalities were rather common among the survivors, accounting for about 80% and 30% of patients at 6-months and 1- year follow-up, respectively[32–34]. Compared with SARS, COVID-19 appears to be associated with a more prompt resolution? on chest CT images during the recovery phase in this study. According to a recent observation, 30 patients with post-COVID-19 interstitial lung changes received steroid treatment, resulting in relative increase in transfer factor and FVC with significant symptomatic and radiological improvement[35]. However, the residual lung damage as well as fibrosis of severe post-COVID-19 patients are still challenging for physicians in the setting of increasing numbers of survivors worldwide.
Previous studies have shown that 6MWD was substantially lower among ARDS and SARS survivors[36, 37]. The 6MWD of 97 survivors in Hong Kong was 464 m (SD, 87 m) at 3 months and 502m (SD 97 m)[37].The 6MWD was significantly reduced in our patients at 1 month when compared to the corresponding matched healthy subjects, and gradually recovered at 3-month follow-up. The performance in our cohort was better than that of SARS survivors in Hong Kong. The 500m distance of our 6MWD at 1 month was similar as that of SARS at 6 months after discharge. These observations seem to indicate relatively prompt recovery of COVID-19 patients compared to those with SARS. But there was no significant improvement in 6MWD after that until 6 months. Given the relatively well-preserved lung function in most of our patients, the reduced 6MWD may be related to extrapulmonary factors such as physical deconditioning and psychological effects[19]. It appears that post-COVID-19 clinic and rehabilitation program might be urgently needed in the pandemic area of COVID-19.
Steroids have been widely prescribed in patients with severe viral pneumonias in recent decades although the role of this treatment remains controversial[38–40]. During the 2003 SARS outbreak in Hong Kong, steroids were associated with better prognosis but associated with a higher rate of secondary infections[39]. In a controlled, open-label trial in 6,425 UK patients hospitalized with COVID-19, the use of low-dose dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone[7]. However, there was still concern that anti-inflammatory effects of steroids might lead to slower resolution of pneumonia as reflected in our results. Thus, it would be of interest to perform additional studies on the long-term outcome to determine the optimal timing, duration, and dose of steroid therapy in the treatment of patients with COVID-19.
There are several limitations of this study. Firstly, the number of patients in this cohort enrolled from a single center was relatively modest which might cause potential bias. Secondly, diffusing capacity was not measured in this study due to concerns regarding potential transmission during PFT performance. However, significantly decreased pulmonary gas exchange can be assessed by pulse oxygen oximetry. In this case-series, all the patients underwent 6MWT successfully and manifested oxygen saturation above 93% at room air at 3 months and 6 months. In addition, psychological evaluations were not performed to assess psycho-behavioral problems of anxiety and/or depression in this cohort. Investigating of the long-term sequelae of COVID-19 survivors in the physical and psychological domains will provide additional insights.