Six-month follow-up of functional status in discharged patients with coronavirus disease 2019

Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was firstly reported in Wuhan, China in December 2019 [1]. As of 9 September 2021, the COVID-19 pandemic has spread worldwide, affecting more than 220 million people and killing over four millions lives [2]. Aggregating studies have shown that most SARS-CoV-2 infection was mild and moderate, which seems to have a positive recovery rate [3‐5]. Previous studies with short-term follow-up data showed that a few discharged COVID-19 patients were re-positive for SARS-nCoV-2 detected by reverse transcription-polymerase chain reaction (RT-PCR) analysis [6, 7]. Moreover, in addition to physical damage, some COVID-19 patients may suffer from psychological impairment including sleep disorder, depression and anxiety after discharge [8, 9]. Previous studies also showed that discharged COVID-19 patients might have incompletely absorbed computed tomography (CT) findings, and some may develop residual pulmonary fibrosis [10, 11]. Moreover, a retrospective study showed that more than half of the COVID-19 patients in the early convalescence phase had impaired diffusing-capacity, lower respiratory muscle strength, and lung imaging abnormalities [12]. Patients with other coronavirus infection like severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS) may have long-term persistent radiographic abnormalities in their lungs [13, 14]. It is reasonable to imagine that some COVID-19 patients may have adverse functional outcomes despite recovery. To our knowledge, the follow-up advice for those testing positive for COVID-19 is lacking, and the long-term functional status in COVID-19 survivors remains poorly understood. We aimed to describe a six-month follow-up of the functional status of COVID-19 patients after discharge in this retrospective cohort study.

We consecutively enrolled a total of 164 patients with laboratory-confirmed COVID-19 between 15 February and 14 March 2020. After excluding seven non-survivors and 53 lost to follow-up or did not undergo the PCFS interview, 104 patients (53 [50.9%] male) with a median age of 62 (IQR 54–70] participated in the follow-up. Patients with and without the PCFS interview were similar in age (63 [54–70] vs 62 [52–69], p = 0.493), to be male (53 [51.0%] vs 24 [45.3%], p = 0.501), and admission delay (13 [7–20] days vs 14 [9–21], p = 0.157). After further excluding three (2.9%) patients with grade 3 and six (5.8%) patients with grade 4 at baseline, we included 95 patients with a baseline PCFS = 0 in the final analysis (Fig. 1).

Table 2 shows the demographics and clinical characteristics of the study population. The inter-rater reliability for baseline PCFS interview was 0.68 (95% CI 0.46–0.90); for PCFS interview 6-month after discharge 0.79 (95% CI 0.65–0.93). All patients had no recurrence of symptoms or radiological findings, and there were no reported new stroke events or other major illness or death during 6-month follow-up. At 6-month follow-up, 67 (70.5%) patients had a complete functional outcome (grade 0), 9 (9.5%) had a negligible limited function (grade 1), 12 (12.6%) had a mild limited function (grade 2), and 7 (7.4%) had moderate limited function (grade 3). The differences in the demographics and clinical characteristics between patients with PCFS = 0 and PCFS > 0 at 6-month follow-up are shown in Table 3. Compared to those with PCFS = 0, patients with PCFS > 0 trended to be younger (60 [49–69] vs 64 [56–69], p = 0.164), more likely to had onset symptoms of muscle or joint pain (9 [32.1%] vs 7 [10.4%], p = 0.01), and had shorter onset-admission delay (9 days [6–18] vs 14 [10–20], p = 0.04).

In univariable logistic regression analysis, onset symptoms of muscle or joint pain (unadjusted OR 4.06, 95% CI 1.33–12.37) were associated with an increased risk of having a PCFS > 0 at 6-month follow-up. We found a negative association between the onset-admission delay and a PCFS > 0 at six-month follow-up (unadjusted OR 0.95, 95% CI 0.89–1.00). After adjustment for age, onset symptoms of muscle or joint pain (adjusted OR 4.07 95% CI 1.32–12.54, p = 0.015) remained significantly associated with an increased risk of having a PCFS > 0 at 6-month follow-up. In the multivariable regression analysis, onset symptoms of muscle or joint pain remained significantly associated with an increased risk of incomplete functional status (adjusted OR 3.39 95% CI 1.06–10.81, p = 0.039). The association between the onset-admission delay and having a PCFS > 0 was lost in the multivariable regression model (Table 4).

To be representative for patients with non-severe COVID 19, we performed a separate analysis by limited on those without severe COVID-19 (n = 82). Additional file 1: Table S1 summarizes the differences in baseline characteristics between patients with and without incomplete functional status at six-month follow-up. This separate analysis did not alter the association between joint or muscle pain and incomplete function. (unadjusted OR 4.0, 95% CI 1.21–13.18, p = 0.023, age-adjusted OR 4.14, 95% CI 1.23–13.90, p = 0.022, multivariate OR 3.46, 95% CI 0.99–12.07, p = 0.05).

The most important finding of the present study was that a small proportion of COVID-19 survivors may have an incomplete function status at a six-month follow-up after discharge. A previous study found that a considerable proportion of COVID-19 survivors without critical cases still had radiological and physiological abnormalities at three months after discharge [21]. Our study adds to findings of the previous study by incorporating insights into the functional outcome with a longer-term follow-up data. Several recently published literatures showed that a majority of COVID-19 survivors experienced COVID-19 related symptoms or functional limitations up to six months [22‐24]. Different populations and assessing methods may account for the discrepancies among different studies. For example, one study also included patients with suspect COVID-19 assessed using an online panel [24], whereas trained physicians conducted a face-to-face interview in another study [22]. More studies with a longer follow-up are needed to better understand the important question for clinicians and the public: will patients recovered from COVID-19 have long-term sequelae?

In our cohort, COVID-19 survivors with the onset symptoms of joint or muscle pain were at an increased risk of having incomplete function status at six-month after discharge. In line with our finding, a previous study of 158 hospitalized COVID-19 patients showed that the symptoms of muscle or joint pain were significantly associated with the trend of intensification of COVID-19 (3/30% vs 3/128, p = 0.048) [25]. The associated muscle pain is one of the most frequent causes of pain in SARS-nCoV-2 infection. For example, a previous meta-analysis of ten observational studies showed that nearly 36% of COVID-19 patients had myalgia as one of the most common onset symptoms [26]. Although previous studies have suggested that the onset symptoms of muscle pain do not seem to increase with COVID-19 severity [3, 16, 27], in patients with abnormal chest radiographic findings, myalgia appeared to be an important risk factor for the severity of the overall disease [28]. The upregulation of the proinflammatory cytokines such as interleukin-6 during viral infection may cause muscle and joint pain [29]. Some researchers believe that myalgia in COVID-19 patients might mirror the systematic inflammation and cytokine response [30]. As SARS-CoV-2 infection induces robust immunologic complications like cytokine storm, elevated cytokine levels such as interleukin-6, interleukin-10, and tumor necrosis factor-α might occur, especially in patients with a moderate or severe disease course [31, 32]. This hypothesis was supported by a previous observational study that showed COVID-19 patients with muscle injury had manifestations of increased inflammatory response and blood coagulation function [33]. Although our study cannot provide comparative data to determine the effects of COVID-19 on the long-term functional outcome, our findings will contribute to determining COVID-19 at initial stages and suggesting medical intervention in a timely manner.

Our data suggest that the inter-rater reliability of the PCFS interview was satisfactory. Moreover, both raters reported no significant difficulties with scale interpretation, indicating that the PCFS is a simple and feasible approach to monitor the course of symptoms and the impact of symptoms on the functional status of COVID-19 survivors. Previous studies have shown that the functional impairment checklist is reliable, valid and responsive to changes in symptom and disability as a consequence of SARS, suggesting it may provide a means of assessing health-related quality of life outcomes in a longitudinal follow-up [34].

The present study indicated that a small proportion of COVID-19 survivors may have incomplete function status at six-month follow-up, and the risk of incomplete function is higher among patients presenting at baseline with muscle or joint pain. Such patients may benefit from follow-up rehabilitation programs.