A study on changes in lung function, neutralizing antibodies, and symptoms of adult patients hospitalized with COVID-19

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Korean J Intern Med. 2023;38(1):101-112

Publication date (electronic) : 2022 October 25

doi : https://doi.org/10.3904/kjim.2022.050

Moon Seong Baek^1,*, Seong-Ho Choi^2,*, Won-Young Kim¹, Min-Chul Kim², Eun-Jeong Joo³, Mi Suk Lee⁴, Hyun Ah Kim⁵, Sook In Jung⁶, Yu Shi Nae⁷, Bongyoung Kim⁸, Yaeji Lim⁹, Jin-Won Chung²

¹Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea

²Division of Infectious Diseases, Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea

³Division of Infectious Diseases, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

⁴Division of Infectious Diseases, Department of Internal Medicine, Kyung Hee University Hospital, College of Medicine, Kyung Hee University, Seoul, Korea

⁵Department of Infectious Diseases, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Korea

⁶Department of Infectious Diseases, Chonnam National University Medical School, Gwangju, Korea

⁷Division of Infectious Diseases, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea

⁸Division of Infectious Diseases, Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Korea

⁹Department of Applied Statistics, Chung-Ang University, Seoul, Korea

Correspondence to Jin-Won Chung, M.D., Division of Infectious Diseases, Department of Internal Medicine, Chung-Ang University Hospital, 102 Heukseok-ro, Dongjak-gu, Seoul 06973, Korea, Tel: +82-2-6299-1420, Fax: +82-2-825-7571, E-mail: drjwchung@cau.ac.kr

^*

These authors contributed equally to this work.

Received 2022 February 8; Revised 2022 April 30; Accepted 2022 July 18.

Abstract

Graphical abstract

INTRODUCTION

Since the first reported severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Wuhan, China in December 2019, the number of people infected with coronavirus disease 2019 (COVID-19) has exceeded 200 million worldwide [1]. Although the number of COVID-19 survivors is increasing despite an increase in confirmed COVID-19 cases, survivors are still in a fragile state even after hospital discharge, which can place additional burdens on healthcare systems around the world. According to Donnelly et al. [2], 19.9% of patients discharged after hospitalization for COVID-19 were readmitted, and 9.1% died within 60 days. Furthermore, readmission and mortality rates at 140 days post-COVID-19 were 29% and 12%, respectively [3]. Therefore, the long-term health effects associated with COVID-19 must be evaluated.

Long COVID syndrome refers to new or ongoing symptoms 4 weeks or more after the onset of acute COVID-19 that persist for 12 weeks or more [4,5]. Because COVID-19 affects multiple organ systems, the long-term effects of COVID-19 can involve symptoms such as fatigue, headaches, and hair loss [6,7]. In a cohort study of 273,618 COVID-19 survivors, post-COVID-19 syndrome affected 36.6% of patients for between 3 and 6 months. Common symptoms included abnormal respiration (7.9%) and fatigue (5.9%) [8].

Recently, 1-year follow-up studies have been conducted for clinical characteristics and pulmonary sequelae after initial SARS-CoV-2 infection [9–11], which showed that muscle fatigue was common (39%) and that 43% of COVID-19 survivors experienced symptoms of depression. Additionally, diffusion impairment on spirometry and abnormal computed tomography (CT) findings were observed in 14.3% and 25.4% of subjects, respectively.

There is, therefore, a need for multidisciplinary care for COVID-19 survivors [6], as the long-term sequelae of COVID-19 may place a significant burden on the healthcare system [12]. Although there are growing concerns regarding the long-term health outcomes for COVID-19 survivors, these consequences remain largely unknown. Therefore, we aimed to identify changes in COVID-19-related symptoms and pulmonary sequelae using spirometry, chest CT and neutralizing antibody measurements in COVID-19 patients after discharge.

METHODS

RESULTS

Residual symptoms after COVID-19

An investigation of residual symptoms after COVID-19 is presented in Table 1. Of the 84 patients who participated in the investigation, 72 were investigated once and 12 were studied twice. In the periods of 20–90, 91–180, and 181–360 days after the onset of symptoms, 45, 36, and 15 patients were investigated, respectively. Acute symptoms such as cough, sputum, myalgia, fatigue, nausea or vomiting, and diarrhea are rarely observed after 6 months. However, lung-related symptoms such as chest discomfort and dyspnea were observed in 20% to 30% of cases, even after 6 months. Dermatologic symptoms such as rash, urticaria, and hair loss were observed in 10% to 30% of subjects after 6 months. The proportion of participants who complained of socioeconomic problems did not decrease over time. Even after 6 months, 40.0% (6/15) and 26.7% (4/15) of patients experienced financial loss and emotional distress, respectively.

Table 1

Changes in various symptoms or socioeconomic problems after COVID-19

Changes in chest CT score

The baseline characteristics of the 35 subjects who underwent HRCT are presented in Table 2. In total, 15 had severity scales of 5–6 (high-severity group). There were no significant differences in age between the high- and low-severity groups (p = 0.064). However, hypertension was significantly more common in the high-severity group compared with the low-severity group (64.3% vs. 15.0%, p = 0.005) (Table 1). The overall median CT score was 6 (IQR, 2.5 to 10), with the high-severity group having a higher median CT score than the low-severity group (8 [IQR, 5.75 to 10.25] vs. 5 [IQR, 0 to 8], p = 0.010). The distribution of CT scores over time after the onset of symptoms is shown in Fig. 1A. To identify the change in CT score over time, the CT score was rearranged into 1–14, 15–60, and 61–365 days after the onset of symptoms (Fig. 1B). We calculated the ratio of changes in CT values between intervals for each patient and obtained the following median values of the ratio of change: 0.65 (the ratio of CT scores at 15–60 to 1–14 days; p = 0.003), 0.39 (the ratio of CT scores at 61–365 to 15– 60 days; p = 0.0002), and 0.20 (the ratio of CT scores at 61–365 to those in 1–14 days; p = 0.0003). These values indicate that the CT score decreases with time. When the ratio of change is divided by severity group, the value of the low-severity group is lower than the high-severity group (Fig. 2). The high-severity group showed a smaller decrease in CT score over time compared with the low-severity group (0.64 vs. 0.68 in Fig. 2A, p = 0.3115; 0.10 vs. 0.48 in Fig. 2B, p = 0.1784; 0.00 vs. 0.38, p = 0.0171), suggesting that the recovery was slower in the high-severity group.

Table 2

Baseline characteristics of 35 study participants who underwent a chest computed tomography

Figure 1

Distribution of chest computed tomography (CT) scores. (A) According to time after symptom onset of the 35 patients who were hospitalized for coronavirus disease 2019 (COVID-19) treatment but were subsequently discharged. (B) According to time after symptom onset, rearranged in three intervals (1–14, 15–60, and 61–365 days). A round hollow circle indicates the result of one CT scan and the CT score of one patient is connected by a line.

Figure 2

Box-and-whisker plot showing the ratio of change of the preceding chest computed tomography (CT) score versus the following chest CT score, classified according to the severity group. (A) Ratio of 15–60 to 1–14 days. (B) Ratio of 61–365 to 15–60 days. (C) Ratio of 61–365 to 1–14 days. Low- and high-severity groups were defined with severity scales 3–4 and 5–6, respectively.

Relationship between chest CT scores and PFT results

The results of the Spearman’s correlation analysis for the CT scores and PFTs are presented in Fig. 3. Both FVC (R² = 0.2261, p = 0.012), FEV1 (R² = 0.2580, p = 0.007), and DL_CO (R² = 0.4231, p = 0.005) were significantly negatively correlated with CT scores. Compared with the low-CT score group, the high-CT score group showed significantly lower FVC (77% vs. 86%, p = 0.031), FEV1 (81% vs. 91%, p = 0.024), and DL_CO (69.5% vs. 113%, p < 0.001) values (Fig. 4).

Figure 3

Spearman’s correlation analysis for chest computed tomography (CT) score with pulmonary function. (A) CT score versus forced vital capacity (FVC) (R² = 0.2261, p = 0.012). (B) CT score versus forced expiratory volume in 1 second (FEV1) (R² = 0.2580, p = 0.007). (C) CT score versus FEV1/FVC (R² = 0.0129, p = 0.573). (D) CT versus diffusing capacity for carbon monoxide (DL_CO) (R² = 0.4231, p = 0.005).

Figure 4

Violin plots showing pulmonary function according to computed tomography (CT) score. Compared with the low-CT score group, the high-CT score group had significantly lower forced vital capacity (FVC) (median value, 77% vs. 86%, p = 0.031), forced expiratory volume in 1 second (FEV1) (median value, 81% vs. 91%, p = 0.024), and diffusing capacity for carbon monoxide (DL_CO) (median value, 67% vs. 106%, p <0.001). ^aStatistical significance.

Change of SARS-CoV-2 antibody

SARS-CoV-2 antibody tests, including neutralizing antibodies and anti-RBD antibodies, were performed, producing 106 samples from 31 patients. When days elapsed after the onset of symptoms were divided into seven intervals (Fig. 5), the antibody titer was highest in the 22 to 60 days, and began decreasing after 120 days. From 22 to 60 days, anti-RBD antibody (RBD ELISA) titers tended to be higher in the high-severity group than in the low-severity group (1.53 vs.1.23 in 22–60 days, p = 0.0907; 1.21 vs. 0.50 in 61–120 days, p = 0.0688; 0.73 vs. 0.27 in 121–180 days, p = 0.0571), although there was no statistical significance when comparing neutralizing antibody titers.

Figure 5

Violin plots showing temporal changes in anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies according to time after symptom onset. (A) Neutralizing antibodies (NAbs). (B) Anti-receptor binding domain (RBD) antibody enzyme-linked immunosorbent assay (ELISA) test results. Low- and high-severity groups were defined as severity scales 3–4 and 5–6, respectively.

DISCUSSION

The main symptoms in COVID-19 survivors vary depending on the follow-up period. One month after the onset of symptoms, dyspnea was observed in over 70% of patients [17], while 8.6% of patients had dyspnea, 12.4% had anosmia, and 9.7% had fatigue after 4 months [18]. However, in a 1-year follow-up study, the main symptoms were muscle fatigue and insomnia [9]. Thus, acute COVID-19-related symptoms such as dyspnea remained in the convalescence phase, while persistent constitutional symptoms remained over a more prolonged period. In our study, several study participants reported dyspnea and chest discomfort 6 months after COVID-19 onset. The reason the COVID-19 symptoms continued for a prolonged period in this study is thought to be because only a small number of the total patients that were admitted to the study hospitals were included in this study. It is also possible that those with a relatively severe infection may have been enrolled preferentially. As mentioned earlier, various socioeconomic problems such as relationship severance or job losses persisted after discharge, meaning that socioeconomic support may be needed for COVID-19 survivors.

Several studies have described COVID-19 patients with abnormal CT findings, even after discharge of COVID-19 [10,11,19–23]. Follow-up studies have shown that residual CT abnormalities decrease over time. In a recent 1-year follow- up study, CT abnormalities persisted in 39% of subjects after 3 months, 27% after 7 months, and 25% after 1 year [11]. Total CT scores decreased from 8.2 ± 6.1 (at discharge) to 1.8 ± 3.9 (after 1 year). The residual CT abnormalities are associated with disease severity [11,21,23]. Of mechanically ventilated patients with COVID-19 who underwent 3-month follow-up CT scans, 96% showed abnormality and 91% fibrosis [21]. Huang et al. [23] reported that the median CT scores at a 6-month follow-up were higher in the high-severity group (median score of 5) than in the low-severity group (median score of 3). Consistent with these previous studies, the results of our study revealed that the CT scores steadily decreased over time, with the CT scores in the high-severity group decreasing more slowly than in the low-severity group. However, several unanswered questions remain regarding the long-term burden on the healthcare system, and whether the residual CT abnormalities persist as lung fibrotic changes [24]. Therefore, further studies on the long-term health consequences of COVID-19 are warranted.

Even after recovering from COVID-19, many patients experience poor lung function over a considerable period [9,20,23,25–31]. Abnormal DL_CO values, which indicate an impaired diffusing capacity, are particularly prevalent in COVID-19 survivors. DL_CO impairment (< 80% of the estimated value) was found in 36% to 58% of the patients after 6 months [30]. However, the proportion of patients with abnormal DL_CO gradually decreased over time (33% after 8 months and 15% after 1 year) [9,31].

Owing to the small number of patients whose DL_CO was tested, the change in DL_CO was not significant in our results. However, Orzes et al. [28] reported a significant correlation between chest CT severity score and DL_CO after 6 months (R² = 0.32, p < 0.01). Our study results showed a negative correlation with the follow-up CT score, particularly for DL_CO (% predicted) (R² = 0.42, p = 0.005). For the relationship between PFT and severity, DL_CO after 8 months was negatively correlated with severe illnesses requiring prolonged oxygen therapy [31], which was also consistent with our results. However, Zhao et al. [9] reported that persistent DL_CO impairment was 14% after 1 year regardless of the severity of the COVID-19 infection. In addition, a 3-month follow-up study showed no significant association between dyspnea and DL_CO impairment [32]. Although there was long-term impaired alveolar diffusing capacity remained, its clinical significance is uncertain. Therefore, further study is necessary regarding persistently impaired lung function.

Neutralizing antibodies decreased markedly 4 months after symptom onset (Fig. 3), which is consistent with the results of a previous study [33]. However, recent studies showed that although neutralizing antibodies decrease, they are can persist for up to 8–10 months [34,35]. It was difficult, however, to demonstrate such long-term results in our study, as the number of samples decreased markedly after 6 months. Additionally, we observed that more neutralizing antibodies were generated and decreased more slowly in cases of severe infection, which was consistent with the results of recent studies [35,36]. To further analyze the possibility of reinfection, follow-up studies on levels of neutralizing antibodies in COVID-19 patients are necessary, as well as in those who were subsequently vaccinated.

To the best of our knowledge, this is the first study in Korea to use long-term data for COVID-19, such as physical symptoms, lung function, chest CT scores, and neutralizing antibodies for SARS-CoV-2 up to 1 year after the onset of symptoms. Nonetheless, it has several limitations. First, due to the retrospective study design, some values were missing, and not all participant could be evaluated. Additionally, pre-COVID-19 baseline PFT could not be assessed. Second, selection bias is a possibility because of the small sample size. Third, the questionnaire was not a continuous follow-up of a single patient recovering from COVID-19 but rather a comparison of the responses of different patients at different times after infection. Moreover, symptoms may not have been described accurately because the questionnaire was based on participants’ responses [37].

COVID-19 is becoming increasingly endemic; hence, the long-term consequences of the disease must be further explored. In COVID-19 survivors, chest CT score, which is related to lung function, recovers over time, but recovery is slower in severely ill patients. The neutralizing antibodies in COVID-19 survivors increased and peaked after 2 months and started to decrease after 4 months. Subjects also complained of various ongoing symptoms and socioeconomic problems for several months after their initial diagnosis. More research is necessary regarding survivors’ COVID-19-related symptoms and pulmonary sequelae.

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