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Follow-up study on COVID-19 survivors one year after discharge from hospital

Open AccessPublished:September 11, 2021DOI:https://doi.org/10.1016/j.ijid.2021.09.017

      Highlights

      • The prevalence of muscle fatigue and insomnia up to 1 year after COVID-19 was high
      • The prevalence of anxiety or depression up to 1 year after COVID-19 was high
      • Survivors with radiological anomalies were older
      • Survivors with impairment of DLCO had higher urea nitrogen levels
      • The levels of SARS-CoV-2 NAb and IgG at 1 year after discharge were decreased

      Abstract

      Objective

      To evaluate the long-term consequences of COVID-19 survivors one year after recovery, and to identify the risk factors associated with abnormal patterns in chest imaging manifestations or impaired lung function.

      Methods

      COVID-19 patients were recruited and prospectively followed up with symptoms, health-related quality of life, psychological questionnaires, 6-minute walking test, chest computed tomography (CT), pulmonary function tests, and blood tests. Multivariable logistic regression models were used to evaluate the association between the clinical characteristics and chest CT abnormalities or pulmonary function.

      Results

      Ninety-four patients with COVID-19 were recruited between January 16 and February 6, 2021. Muscle fatigue and insomnia were the most common symptoms. Chest CT scans were abnormal in 71.28% of participants. The results of multivariable regression showed an increased odds in age. Ten patients had diffusing capacity of the lung for carbon monoxide (DLCO) impairment. Urea nitrogen concentration on admission was significantly associated with impaired DLCO. IgG levels and neutralizing activity were significantly lower compared with those in the early phase.

      Conclusions

      One year after hospitalization for COVID-19, a cohort of survivors were mainly troubled with muscle fatigue and insomnia. Pulmonary structural abnormalities and pulmonary diffusion capacities were highly prevalent in surviving COVID-19 patients. It is necessary to intervene in the main target population for long-term recovery.

      Keywords

      Introduction

      The coronavirus disease 2019 (COVID-19) pandemic, arising from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in more than 190 million confirmed cases and more than 4.0 million deaths (

      WHO. WHO Coronavirus (COVID-19) Dashboard. Accessed July 20, 2021. https://covid19.who.int/.

      ). Survivors with COVID-19 are frequently reported to have persistent symptoms, and pulmonary function and psychological problems. It is challenging and necessary to evaluate the long-term sequelae of COVID-19.
      Persistent pulmonary function impairment and health status were demonstrated in SARS survivors up to 1 year following hospital discharge (
      • Hui DS
      • Wong KT
      • Ko FW
      • Tam LS
      • Chan DP
      • Woo J
      • et al.
      The 1-year impact of severe acute respiratory syndrome on pulmonary function, exercise capacity, and quality of life in a cohort of survivors.
      ;
      • Ong KC
      • Ng AW
      • Lee LS
      • Kaw G
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      1-year pulmonary function and health status in survivors of severe acute respiratory syndrome.
      ;
      • Ruhl AP
      • Huang M
      • Colantuoni E
      • Karmarkar T
      • Dinglas VD
      • Hopkins RO
      • et al.
      Healthcare utilization and costs in ARDS survivors: a 1-year longitudinal national US multicenter study.
      ). Higher titers of antibodies against SARS, MERS, and H7N9 continued to persist for 1 year (
      • Choe PG
      • Perera R
      • Park WB
      • Song KH
      • Bang JH
      • Kim ES
      • et al.
      MERS-CoV Antibody Responses 1 Year after Symptom Onset, South Korea, 2015.
      ;
      • Ma MJ
      • Liu C
      • Wu MN
      • Zhao T
      • Wang GL
      • Yang Y
      • et al.
      Influenza A(H7N9) Virus Antibody Responses in Survivors 1 Year after Infection, China, 2017.
      ;
      • Xie L
      • Liu Y
      • Fan B
      • Xiao Y
      • Tian Q
      • Chen L
      • et al.
      Dynamic changes of serum SARS-coronavirus IgG, pulmonary function and radiography in patients recovering from SARS after hospital discharge.
      ). There are several reports of long-term consequences of COVID-19 at 3 months and 6 months after discharge (

      Gonzalez J, Benitez ID, Carmona P, Santisteve S, Monge A, Moncusi-Moix A, et al. Pulmonary Function and Radiological Features in Survivors of Critical Covid-19: A 3-Month Prospective Cohort. Chest 2021.

      ;
      • Huang C
      • Huang L
      • Wang Y
      • Li X
      • Ren L
      • Gu X
      • et al.
      6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.
      ;
      • Qin W
      • Chen S
      • Zhang Y
      • Dong F
      • Zhang Z
      • Hu B
      • et al.
      Diffusion capacity abnormalities for Carbon Monoxide in patients with COVID-19 at three-month follow-up.
      ;
      • Tarsitani L
      • Vassalini P
      • Koukopoulos A
      • Borrazzo C
      • Alessi F
      • Di Nicolantonio C
      • et al.
      Post-traumatic Stress Disorder among COVID-19 survivors at 3-month follow-up after hospital discharge.
      ;
      • Zhao YM
      • Shang YM
      • Song WB
      • Li QQ
      • Xie H
      • Xu QF
      • et al.
      Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery.
      ), but the prevalence and severity of the long-term sequelae of COVID-19 have remained largely unknown.
      This study systematically assessed the long-term health consequences of COVID-19 survivors 1 year after discharge. Participants in this study underwent an evaluation of health status, involving the 36-Item Short-Form Health Survey (SF-36), the 14-item Hamilton Anxiety Rating Scale (HAMA-14), the 24-item Hamilton Depression Rating Scale (HAMD-24), the modified British Medical Research Council (mMRC), and 6-minute walking test (6MWT). The characterization of chest computed tomography (CT), lung function, and titers of antibodies were also examined.

      Materials and Methods

      Study design and participants

      This prospective observational study included six cohorts of adult inpatients (aged ≥ 18 years). All adult patients with laboratory-confirmed SARS-CoV-2 infection, and subsequently admitted to the designated local hospitals in Henan Province, were enrolled. This study was approved by the Institutional Review Board of the relevant centers. All participants remained anonymous, and written informed consent was obtained. This study was registered with the Chinese Clinical Trial Registry, ChiCTR2000033186. The World Health Organization's (WHO) interim guidance diagnosis for adults with COVID-19 was used (

      WHO. Clinical management of COVID-19: interim guidance, 27 May 2020. https://apps.who.int/iris/handle/10665/332196.

      ).

      Data collection

      Baseline and hospital stay: the clinical data of all participants were extracted from electronic medical records, including sociodemographic information, time of admission, length of hospital stay, and comorbidities. Clinical classification of COVID-19, blood routine outcomes, and therapeutics were also recorded. All data were checked by three physicians.
      12-month follow-up: follow-up consultations were conducted in the outpatient clinic of the relevant centers. Face-to-face interviews were performed by trained physicians and all participants were asked to complete a series of questionnaires. For the symptom questionnaire, participants were asked to report new symptom onset after COVID-19. All participants received 6MWT, pulmonary function tests (PFTs), and high-resolution CT of the chest.
      For general and respiratory symptoms, participants were asked to report persistent symptoms after COVID-19. Items such as fatigue, muscle weakness, joint paint, sleeping difficulties, headache, hair loss, chest pain, smell or taste disorder, myalgia, palpitations, dizziness, sore throat or difficulty swallowing, diarrhea or nausea, and skin rash were assessed. Furthermore, the Chinese versions of HAMA-14 and HAMD-24 were used to evaluate signs and symptoms of anxiety and depression (
      • Lu W
      • Wang H
      • Lin Y
      • Li L.
      Psychological status of medical workforce during the COVID-19 pandemic: A cross-sectional study.
      ). Overall, participants with HAMA scores of 0-6, 7-13 and ≥ 14 points were categorized as having no anxiety, mild/moderate anxiety, and severe anxiety, respectively (
      • Qin X
      • Sun J
      • Wang M
      • Lu X
      • Dong Q
      • Zhang L
      • et al.
      Gender differences in dysfunctional attitudes in major Depressive Disorder.
      ). The total score of HAMD was operationally categorized as follows: normal (score 0-6), mild or probable depression (score 7-17), moderate or definite depression (score 18-24), and severe depression (score ≥ 25) (
      • Zhuang X
      • Xu H
      • Fang Z
      • Xu C
      • Xue C
      • Hong X.
      Platelet serotonin and serotonin transporter as peripheral surrogates in depression and anxiety patients.
      ). The SF-36 is a well-known health-related quality of life questionnaire that comprehensively measures eight aspects to access physical and mental health: physical function (PF), role physical (RP), body pain (BP), general health perceptions (GH), vitality (VT), social function (SF), role emotional (RE), and mental health (MH) (
      • Apolone G
      • Mosconi P.
      The Italian SF-36 Health Survey: translation, validation and norming.
      ) it presents a score of 0-100, with a higher score indicating better health status.

      Chest CT acquisition and image analysis

      Each subject underwent an initial chest CT examination and follow-up examinations during a single-breath at full inspiration. All CT scans were acquired with the patients in the supine position with both limbs raised above the head. The whole-lung spiral CT scan was performed from the apex to the base of the lungs. The CT scanner models from the hospitals involved in this multicenter study were listed as following: Somatom Definition AS 128, Philips Brilliance 16, Philips Brilliance 64, and Philips Incisive 64. All images were then reconstructed with a 1.0-5.0 mm slice with the same increment.
      Two radiologists, who were blinded to the clinical information, independently reviewed and scored the CT images. When there was a divergent opinion, they made the finial decision via a view console. The radiologists assessed the following eight characteristics (
      • Guler SA
      • Ebner L
      • Beigelman C
      • Bridevaux PO
      • Brutsche M
      • Clarenbach C
      • et al.
      Pulmonary function and radiological features four months after COVID-19: first results from the national prospective observational Swiss COVID-19 lung study.
      ): ground glass opacities (GGO), consolidation, nodule, reticulation, interlobular septal thickening, crazy-paving pattern, subpleural curvilinear line, and pulmonary fibrosis. The CT score was derived from abnormal pulmonary involvement based on a 5-point scale: 0, normal; 1, < 5%; 2, 5-25%; 3, 26-50%; 4, 51-75%; 5, > 75%). A total score was eventually recorded via the addition of the score of an individual segment.

      Pulmonary function tests

      Outpatient PFTs were conducted in the Lung Function Laboratory of the Guangshan People's Hospital and Xixian People's Hospital, using MasterScreen PFT (Jaeger, Germany) or MasterScreen (Jaeger, Germany) according to ATS-ERS guidelines (
      • Graham BL
      • Steenbruggen I
      • Miller MR
      • Barjaktarevic IZ
      • Cooper BG
      • Hall GL
      • et al.
      Standardization of Spirometry 2019 Update. An Official American Thoracic Society and European Respiratory Society Technical Statement.
      ). The PFTs yielded the following parameters: forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC, FVC% pred, and diffusing capacity of the lung for carbon monoxide (DLCO).

      Dynamic changes of SARS-CoV-2 IgG, IgM, and neutralizing antibodies

      Serum IgM and IgG antibodies against the SARS-CoV-2 spike protein (S) and the nucleocapsid protein (N) were measured by the commercial kit provided by YHLO biotechnology (Catalog number, G86095M/G86095G), which has previously been described (
      • Zhao YM
      • Shang YM
      • Song WB
      • Li QQ
      • Xie H
      • Xu QF
      • et al.
      Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery.
      ). The cut-off for positivity was equal to 10.0 AU/mL for both IgM and IgG, according to the manufacturer. The SARS-CoV-2 neutralizing antibodies (NAb) were measured by the SARS-CoV-2 sVNT kit (Catalog number, L00847, GenScript), according to the manufacturer instructions (
      • Tan CW
      • Chia WN
      • Qin X
      • Liu P
      • Chen MI
      • Tiu C
      • et al.
      A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2-spike protein-protein interaction.
      ). The inhibition of the sample was proportional to the titer of the anti-SARS-CoV-2 neutralizing antibodies. There were 55 survivors (including four mild, 47 moderate, and four severe disease) (
      • Zhao YM
      • Shang YM
      • Song WB
      • Li QQ
      • Xie H
      • Xu QF
      • et al.
      Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery.
      ) at 3 months after discharge, and 67 survivors (including two mild, 30 moderate, 33 severe, and two critical cases) at 1 year after discharge who were tested for IgM, IgG, and NAb against SARS-CoV-2.

      Statistical analysis

      Categorical variables were expressed as number (percentage) and compared using the Chi-square test or Fisher exact test. Continuous data were described as mean ± SD (standard deviation), followed by paired or unpaired t-test, or Mann-Whitney test, or Wilcoxon test. Multivariable logistic regression modes were used to explore the risk factors associated with chest CT abnormalities or impaired DLCO. The correlation of different variables was analyzed using Spearman's correlation. All analyses were performed using SPSS 21.0 and GraphPad Prism 8.0. Two-sided P < 0.05 was considered as statistically significant.

      Results

      A total of 272 patients with COVID-19 were discharged from the relevant hospitals and the follow-up study was conducted from January 16 to February 6, 2021. Of these, 180 survivors did not attend follow-up study for several reasons, which are outlined in Figure 1. Finally, 94 adult participants, who included 3 cases of mild pneumonia, 48 cases of pneumonia, 41 cases of severe pneumonia, and 2 critical cases, were enrolled for questionnaire interview, chest CT, and 6MWT. For lung function test, 70 sampled patients ascertained as eligible received complete PFTs. Twenty survivors refused to complete the lung diffusion function test. Moreover, sixty-seven survivors received a blood antibody test.
      Figure 1
      Figure 1Flow chart of patients with COVID-19 at 1 year after hospital discharge between January 23 and February 27, 2020.
      *Questionnaires included general and respiratory symptoms, 36-Item Short-Form Health Survey (SF-36), 14-item Hamilton Anxiety Rating Scale (HAMA-14), 24-item Hamilton Depression Rating Scale-24 (HAMD-24), and the modified British Medical Research Council (mMRC).
      6MWT = 6-minute walking test; CT = computed tomography
      The demographics and characteristics of the study population are shown in Table S1. The mean age of these cases was 48.11 years, and 40 (42.55%) of them were females. Seven of them were former smokers or current smokers. The most common comorbidity was hypertension (16 cases, 17.02%), followed by diabetes mellitus (9 cases, 9.57%), chronic heart disease (4 cases, 4.26%), and asthma (2 cases, 2.13%). Although 11 (11.70%) survivors were transferred to ICU, none of them required invasive mechanical ventilation. The overall duration of hospital stay was (15.08 ± 5.71) days. With regard to treatment, patients were mostly treated with antibacterial agents (82.98%), interferon (81.91%), corticosteroids (30.85%), and immunoglobulins (10.64%). All patients received antiviral treatment. The median duration from symptom onset to follow-up visit was 366.0 (355.0, 376.0) days, and the median time from hospital discharge to follow-up visit was 345.0 (333.0, 349.0) days.

      Symptoms, HAMA, HAMD, mMRC, and SF-36 questionnaires at 1-year follow-up

      At 1-year follow-up, 61.70% of patients (58 of 94) reported at least one symptom that did not exist before COVID-19 infection, including muscle fatigue (39.36%), insomnia (22.34%), joint paint (20.21%), headache (14.89%), hair loss (13.83%), and chest pain (13.83%) (Table 1). Eleven patients (11.70%) still experienced a smell or taste disorder. The frequency of muscle fatigue in severe/critical COVID-19 was higher than that of mild/moderate COVID-19 (P < 0.05, Table 1). According to the results (Table S2), persistent symptoms, anxiety or depression, and the mMRC dyspnea scale of COVID-19 patients had no relation to age, which was consistent with previous reports (
      • Hui DS
      • Wong KT
      • Ko FW
      • Tam LS
      • Chan DP
      • Woo J
      • et al.
      The 1-year impact of severe acute respiratory syndrome on pulmonary function, exercise capacity, and quality of life in a cohort of survivors.
      ;
      • Qin W
      • Chen S
      • Zhang Y
      • Dong F
      • Zhang Z
      • Hu B
      • et al.
      Diffusion capacity abnormalities for Carbon Monoxide in patients with COVID-19 at three-month follow-up.
      ).
      Table 1Symptoms, quality of life, and anxiety/depression questionnaires results at 1-year follow-up.
      Symptoms
      TotalMild/moderateN = 51Severe/criticalN = 43P
      Any one of the following symptoms, N (%)
      Muscle fatigue37 (39.36)15 (29.41)22 (51.16)0.032
      Insomnia21 (22.34)10 (19.61)11 (25.58)0.488
      Joint paint19 (20.21)7 (13.73)12 (27.91)0.088
      Headache14 (14.89)9 (17.65)5 (11.63)0.414
      Hair loss13 (13.83)5 (9.80)8 (18.60)0.218
      Chest pain13 (13.83)5 (9.80)8 (18.60)0.218
      Palpitations11 (11.70)6 (11.76)5 (11.63)0.984
      Smell or taste disorder11 (11.70)6 (11.76)5 (11.63)0.984
      Myalgia11 (11.70)7 (13.73)4 (9.30)0.506
      Dizziness10 (10.64)4 (7.84)6 (13.95)0.534
      Sore throat or difficulty swallowing9 (9.57)5 (9.80)4 (9.30)1.000
      Diarrhea or nausea9 (9.57)6 (11.76)3 (6.98)0.664
      Skin rash2 (2.13)2 (3.92)00.498
      QuestionnairesMild/moderateN = 51Severe/criticalN = 43P
      HAMA0.370
      No anxiety (≤ 6), N (%)55 (58.51)30 (58.82)25 (58.14)
      Mild/moderate anxiety (7-13), N (%)30 (31.91)18 (35.29)12 (27.91)
      Severe anxiety (≥ 14)9 (9.57)3 (5.88)6 (13.95)
      HAMD0.646
      Normal (≤ 6), N (%)54 (57.45)32 (62.75)22 (51.16)
      Mild/probable depression (7-17), N (%)30 (31.91)15 (29.41)15 (34.88)
      Moderate/definite depression (18-24), N (%)7 (7.45)3 (5.88)4 (9.30)
      Severe depression (≥ 25), N (%)3 (3.19)1 (1.96)2 (4.65)
      mMRC score0.344
      0, N (%)72 (76.60)41 (80.39)31 (72.09)
      ≥ 1, N (%)22 (23.40)10 (19.61)12 (27.91)
      SF-36
      Physical function (PF)95 (90, 100)95 (90, 100)95 (85, 100)0.150
      Role-physical (RP)100 (75, 100)100 (75, 100)100 (25, 100)0.037
      Body pain (BP)74 (61.75, 100)74 (52, 100)74 (64, 100)0.418
      General health perceptions (GH)66 (47, 80)65.49 ± 20.5558.88 ± 25.810.179
      Vitality (VT)75 (63.75, 90)80 (65, 90)70 (60, 85)0.108
      Social function (SF)70 (40, 80)70 (50, 80)60 (40, 80)0.740
      Role-emotional (RE)100 (66.67, 100)100 (66.67, 100)100 (66.67, 100)0.502
      Mental health (MH)76 (60, 92)76 (60, 92)76 (64, 92)0.846
      For anxiety symptoms, 30 (31.91%) patients were evaluated as mild/moderate anxiety and 9 (9.57%) patients were severe. For depression symptoms, 42.55% of patients presented altered depression scores, including mild/probable depression (30 cases, 31.91%), moderate/definite depression (7 cases, 7.45%), and severe depression (3 cases, 3.19%). Although there were 25 patients who participated in both the 3-month and 1-year follow-ups, the HAMA and HAMD scores of 25 enrolled survivors at 1-year follow-up were significantly lower than those of patients at the 3-month follow-up (Figure 2). In addition, the prevalence of mMRC score ≥ 1 was 22 (23.40%). The SF-36 revealed that PF, RP, BP, VT, RE, and MH reached the highest scores (95, 100, 74, 75, 100, and 76, respectively), while GH and SF reached the lowest scores (66 and 70, respectively).
      Figure 2
      Figure 2Comparison of the results of HAMA and HAMD scores between the 25 COVID-19 survivors at the 3-months and 1-year follow-ups.
      * P < 0.05; *** P < 0.001

      Lung function, 6MWT, and chest CT at 1-year follow-up

      The pulmonary function, 6MWT, and chest CT results are shown in Table 2. Anomalies were noted in FEV1% predicted in 16 of 90 cases (17.78%), FEV1/FVC in 9 (10%), total lung capacity (TLC%) predicted in 4 cases (5.71%), and DLCO% predicted in 10 cases (14.29%). One year after discharge, 20% and 35.29% of mild/moderate COVID-19 patients developed impaired pulmonary diffusion capacities and abnormal chest imaging manifestations (Table 2). Lung function tests of 25 patients who participated in both the 3-month (
      • Zhao YM
      • Shang YM
      • Song WB
      • Li QQ
      • Xie H
      • Xu QF
      • et al.
      Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery.
      ) and 1-year follow-ups were collected. There was no significant difference in FVC%, FEV1% pred, FEV1/FVC, and TLC% between patients at the 3-month and 1-year follow-ups. The diffusing capacity in COVID-19 patients 1 year after discharge was higher than that at the 3-month follow-up, even though there was no significant between-group difference (Table S3). All of these results indicate that CT patterns of abnormalities may contribute to pulmonary interstitial damage. The median (IQR) distance in the exercise test was 504.00 (486.36, 540.00) meters, with a median oxygen saturation of 97%; there was no oxygen saturation < 90% (data not shown). The difference in the distance of the 6MWT between the current cohort and healthy population was calculated adjusted by sex, age, weight, and height (
      • Enright PL
      • Sherrill DL.
      Reference equations for the six-minute walk in healthy adults.
      ). The distance of the sampled participants showed a significant decrease compared with the healthy population (median: 596.45, IQR: 514.50-635.19; P < 0.0001, Table S4).
      Table 2Pulmonary function, 6MWT, and chest CT scan findings in all patients at 1-year follow-up.
      Pulmonary function
      Mild/moderate(n = 50)Severe/critical(n = 40)P
      FVC%, (n = 90)Normal range ≥ 80%101.17 ± 16.60102.59 ± 14.7199.38 ± 18.730.364
      FEV1% pred, (n = 90)Normal range ≥ 80%100.85 (87.88, 108.68)101 (88.55, 107.92)99.7 (84.88, 110.18)0.881
      ≥ 80%, N (%)74 (82.22)42 (84)32 (80)0.622
      < 80%, N (%)16 (17.78)8 (16)8 (20)
      FEV1/FVC, (n = 90)Normal range ≥ 70%79.74 (75.86, 84.23)79.37 (75.75, 85.19)79.94 (76.47, 83.22)0.951
      ≥ 70%, N (%)81 (90)46 (92)35 (87.5)0.724
      < 70%, N (%)9 (10)4 (8)5 (12.5)
      Mild/moderate(n = 35)Severe/critical(n = 35)P
      TLC%, (n = 70)Normal range ≥ 80%98.86 ± 12.24100.34 (94.9, 108)94.98 (87.1, 106.5)0.079
      ≥ 80%, N (%)66 (94.29)33 (94.29)33 (94.29)1.000
      50-80%, N (%)4 (5.71)2 (5.71)2 (5.71)
      RV%, (n = 70)Normal range ≥ 65%105.96 (93.78, 117.96)114.2 (95.3, 124.26)102.1 (89.6, 114.49)0.113
      DLCO%, (n = 70)Normal range ≥ 80%99.50 ± 18.8299.54 ± 21.6299.46 ± 15.840.856
      ≥ 80%, N (%)60 (85.71)28 (80)32 (91.43)0.172
      60-80%, N (%)10 (14.29)7 (20)3 (8.57)
      6MWT (n = 94)Mild/moderate(n = 51)Severe/critical(n = 43)P
      Distance (m)504 (486.36, 540)504 (498, 546)500 (468, 528)0.248
      Minimal oxygen saturation (%)97 (95, 98)98 (96, 99)96 (94, 98)0.001
      Chest CT (n = 94)Mild/moderate(n = 51)Severe/critical(n = 43)P
      Density
      Ground-glass, N (%)38 (40.43)18 (35.29)20 (46.51)0.270
      Volume of GGO, cm30.00 (0.00, 0.32)0.00 (0.00, 0.12)0.00 (0.00, 0.88)0.033
      Consolidation, N (%)2 (2.13)02 (4.65)0.207
      Internal structures
      Interlobular septal thickening, N (%)10 (10.64)3 (5.88)7 (16.28)0.196
      Subpleural lines, N (%)14 (14.89)6 (11.76)8 (18.60)0.353
      Nodule, N (%)28 (29.79)14 (27.45)14 (32.56)0.590
      Linear opacities, N (%)13 (13.83)9 (17.65)4 (9.30)0.243
      Lesions
      Reticulation, N (%)4 (4.26)1 (1.96)3 (6.98)0.492
      Fibrotic, N (%)8 (8.51)2 (3.92)6 (13.95)0.172
      CT score
      Score, mean (SD)1.50 (0.00, 3.25)1 (0, 2)2 (1, 6)0.002
      Number of lobes involved, median (IQR)1.50 (0.00, 3.00)1 (0, 2)2 (1, 3)0.005
      Overall, many abnormalities in chest CT were detected in 67 survivors at 1-year follow-up, including 38 with local GGO (40.43%) and two with consolidation (2.13%). GGO, nodule, and subpleural lines were the most frequent abnormalities in chest CT (40.43%, 29.79%, and 14.89%, respectively). Fibrotic lesions were observed in 13.83% of these 94 patients. The median total CT score was 1.50 (IQR 0.00-3.25) and the median number of segments involved was 1.50 (IQR 0.00-3.00). According to Table 2, survivors with severe/critical cases showed a lower level of minimal oxygen saturation in 6MWT and a significantly higher CT score (P < 0.05). Furthermore, the follow-up CT in severe/critical patients showed a greater number of involved lobes (mild/moderate patients 1 [0-2] vs. severe/critical patients 2 [1-3]; P < 0.05). Chest imaging manifestations of 25 survivors who participated in both the 3-month (
      • Zhao YM
      • Shang YM
      • Song WB
      • Li QQ
      • Xie H
      • Xu QF
      • et al.
      Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery.
      ) and 1-year follow-ups were collected. Additionally, the patients at the 3-month follow-up had higher total scores of chest CT compared with those in the late convalescence phase (Figure S1).

      Comparison of clinical characteristics between normal and abnormal chest CT

      As shown in Table 3, the clinical characteristics of patients between the normal and abnormal chest CT groups were compared. Chest CT scan was performed for 94 patients and showed abnormalities in 67 survivors at 1-year follow-up. The median age for participants with abnormal CT was 52 (IQR 46-58), much older than that of the normal CT group (median: 40; IQR: 28-50). Furthermore, 79.10% of patients in the abnormal CT group had symptoms of cough, and this rate was remarkably higher than that of the normal CT group (55.56%). The median CXR peak score evaluated during hospital stay was 6.00 (IQR, 3.00-12.00) for the abnormal CT group and 2.00 (IQR, 1.00-4.00) for the normal CT group.
      Table 3Univariate analysis of predictors of abnormal CT score.
      ParametersNormal rangeNormal CT group(N = 27)Abnormal CT group(N = 67)P value
      Age≥ 1840 (28, 50)52 (46, 58)0.000
      Sex, female (%)11 (40.74)29 (43.28)0.504
      Incubation period, d5 (2, 8)5 (3, 8)0.241
      Hospital period, d12 (10, 17)15 (12, 18)0.079
      Temperature, ℃38.12 ± 0.8138.14 ± 0.680.891
      History of smoking1 (3.7)6 (8.96)0.657
      Comorbidities
      Hypertension3 (11.11)13 (19.40)0.509
      Diabetes mellitus3 (11.11)6 (8.96)1.000
      Chronic heart disease1 (3.70)3 (4.48)1.000
      Severe/critical1 (3.70)10 (14.93)0.239
      Signs and symptoms at admission
      Fever, No. (%)22 (81.48)61 (91.04)0.342
      Cough, No. (%)15 (55.56)53 (79.10)0.021
      Weakness, No. (%)9 (33.33)20 (29.85)0.741
      Chest tightness, No. (%)4 (14.81)18 (26.87)0.212
      CXR peak score2.00 (1.00, 4.00)6.00 (3.00, 12.00)0.007
      Laboratory data
      Blood routine
      Leucocyte count (× 109/L)4-105.48 (4.75, 6.36)4.97 (3.92, 6.04)0.180
      Neutrophil count (× 109/L)2-73.74 (2.29, 4.78)3.28 (2.36, 4.69)0.649
      Lymphocyte count (× 109/L)0.8-4.01.69 (1.09, 1.97)1.18 (0.91, 1.56)0.014
      NLR2.08 (1.31, 4.16)2.73 (1.73, 3.92)0.169
      Monocyte count (× 109/L)0.12-0.800.37 (0.31, 0.45)0.30 (0.19, 0.41)0.036
      Eosinophil count (× 109/L)0.02-0.500.03 (0.01, 0.10)0.01 (0.00, 0.04)0.003
      Red blood cell count (× 109/L)3.50-5.504.70 ± 0.454.56 ± 0.570.286
      Hemoglobin concentration (g/L)110-160138.78 ± 16.94135.02 ± 19.330.380
      Platelet count (× 1012/L)100-300171.22 ± 59.28169.87 ± 63.050.924
      Blood biochemistry
      AST, U/L0-4024.00 (17.00, 29.00)25.00 (19.60, 37.00)0.224
      ALT, U/L0-4018.00 (16.00, 37.10)21.60 (13.10, 40.10)0.454
      Albumin, g/L35-5542.94 ± 5.0739.25 ± 3.870.000
      TP, g/L60-8567.42 ± 4.4565.23 ± 5.830.082
      GGT, U/L0-4721.00 (15.50, 35.60)26.00 (16.00, 52.40)0.547
      ALP, U/L20-15060.00 (55.00, 76.20)61.00 (47.90, 74.50)0.655
      TBA, μmol/L0-153.50 (2.30, 5.00)2.80 (2.00, 4.40)0.652
      Total bilirubin, μmol/L0-2410.20 (7.70, 15.60)9.70 (7.40, 13.44)0.590
      Direct bilirubin, μmol/L0.00-9.502.50 (1.52, 4.90)2.92 (2.02, 4.50)0.264
      Indirect bilirubin, μmol/L0-17.17.80 (5.70, 11.20)6.70 (5.10, 9.90)0.185
      Urea nitrogen, μmol/L1700-83003.86 (2.80, 4.92)4.03 (3.33, 5.17)0.188
      Creatinine, μmol/L20.00-106.0063.00 (50.00, 75.80)69.00 (56.30, 76.00)0.245
      UA, μmol/L200-428272.10 ± 69.78239.62 ± 73.350.052
      Glucose, mmol/L3.89-6.115.45 (4.84, 6.27)5.81 (5.16, 7.23)0.131
      TG, mmol/L0.00-1.701.59 (1.00, 2.00)1.14 (0.85, 1.58)0.059
      LDH, U/L100-240171.7 (141.2, 227.0)217.2 (170.0, 268.4)0.012
      Infection-associated
      CRP, mg/L5-105.00 (2.00, 21.62)15.00 (8.00, 30.27)0.003
      Blood coagulation
      Prothrombin time, s11-1513.20 (11.70, 14.40)13.10 (11.70, 14.70)0.584
      INR0.8-1.51.06 ± 0.191.10 ± 0.180.367
      APTT, s14-2127.80 (22.00, 35.20)28.10 (22.10, 35.70)0.848
      Thrombin time, s22-3814.80 (12.40, 18.20)16.50 (12.60, 18.20)0.598
      Fibrinogen, g/L2-43.68 ± 1.183.91 ± 1.070.352
      D-dimer, μg/L0-500290.00 (130, 390)290.00 (120, 410)0.987
      Treatment
      Corticosteroids, No. (%)4 (14.81)25 (37.31)0.009
      Interferon beta, No. (%)22 (81.48)55 (82.09)1.000
      Immunoglobulins, No. (%)1 (3.7)9 (13.43)0.166
      Data are expressed as mean ± SD, median (IQR), and No. (%). Comparisons were determined by Student's t-test, Mann-Whitney U test, or χ2 test, as appropriate.
      Abbreviations: NLR, neutrophil-lymphocyte ratio; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TP, total protein; GGT, gamma-glutamyl transferase; ALP, alkaline phosphatase; TBA, total bile acids; GLO, globulin; UA, uric acid; TG, triglyceride; CRP, C-reactive protein; LDH, lactate dehydrogenase; INR, international normalized ratio; APTT, active partial thrombin time
      There were plenty of differences in laboratory findings between the normal and abnormal chest CT groups. At hospital admission, patients had decreased lymphocyte count (P = 0.014). For blood biochemistry, a lower level of albumin (P = 0.000) and higher level of LDH (P = 0.012) in patients with abnormal chest CT were evidenced compared with those in the normal CT group. The level of CRP was much higher in the abnormal CT group (P = 0.003), indicating a more serious infection. With regard to treatment, participants in the abnormal CT group were more likely to receive corticosteroids (37.31% vs 14.81%, P = 0.009) than those in the normal CT group. After multivariable adjustment, older participants showed an OR 1.080 (95% CI: 1.013, 1.153) for abnormal CT at 1-year follow-up (Table 4).
      Table 4Multivariate analysis of predictors of abnormal CT score.
      βP valueOR (95% CI)β
      Logistic regression analysis for sex, history of smoking, and symptoms of chest tightness at admission
      P value
      Logistic regression analysis for sex, history of smoking, and symptoms of chest tightness at admission
      OR (95% CI)
      Logistic regression analysis for sex, history of smoking, and symptoms of chest tightness at admission
      Cough-1.1500.0690.317 (0.092, 1.095)-1.0700.0980.343 (0.097, 1.218)
      Age0.0720.0241.075 (1.009, 1.144)0.0770.0191.080 (1.013, 1.153)
      CXR peak score0.0850.2211.089 (0.950, 1.248)0.0930.1941.097 (0.954, 1.218)
      Lymphocyte count-0.0600.6040.942 (0.756, 1.173)-0.0610.6060.941 (0.747, 1.185)
      CRP-0.0090.5570.991 (0.963, 1.021)-0.0080.5880.992 (0.963, 1.022)
      LDH-0.0010.8400.999 (0.990, 1.008)-0.0020.7410.998 (0.989, 1.008)
      Albumin-0.0940.2440.910 (0.776, 1.066)-0.0880.2900.916 (0.779, 1.078)
      Corticosteroids-1.0930.1340.335 (0.080, 1.398)-0.9690.2060.380 (0.085, 1.701)
      Abbreviations: CI, confidence interval; CXR, chest x-ray; CRP, C-reactive protein; LDH, lactate dehydrogenase
      a Logistic regression analysis for sex, history of smoking, and symptoms of chest tightness at admission

      Lung function sequelae in COVID-19 patients 1 year after hospital discharge

      Ten of 70 survivors with COVID-19 had impaired DLCO% predicted at 1-year follow-up. To figure out the differences between normal and impaired DLCO survivors, this study compared demographics, clinical characteristics, and laboratory parameters between the two groups in Table 5. It found that laboratory parameters including red blood cell count, hemoglobin concentration, ALT and TP on admission were lower in the impaired DLCO group, and the difference between the two cohorts was statistically significant. The level of urea nitrogen in the DLCO-impaired group was higher than in the DLCO-normal group. Other variables between the impaired DLCO group and normal DLCO group showed no significant difference. Finally, age, sex, and a history of smoking were imputed into the multivariable logistic regression model. It was found that the higher level of urea nitrogen at admission was associated with DLCO% predicted < 80% (OR 1.004, 95% CI 1.001-1.006, P = 0.021, Table 6).
      Table 5Univariate analysis of predictors of abnormal DLCO% predicted.
      ParametersNormal rangeDLCO normal group (N = 60)DLCO impaired group (N = 10)P value
      Age≥ 1847.33 ± 12.2948.90 ± 15.900.722
      Sex, female (%)25 (41.67)6 (60)0.461
      Incubation period, d5.00 (3.00, 7.00)4.00 (3.00, 6.00)0.494
      Hospital period, d13.00 (10.00, 18.00)16.00 (11.75, 18.00)0.337
      Temperature, ℃38.20 (37.50, 38.68)38.00 (38.00, 38.35)0.880
      History of smoking311.000
      Comorbidities
      Hypertension9 (15)3 (30)0.476
      Diabetes mellitus3 (5)1 (10)1.000
      Chronic heart disease3 (5)1 (10)1.000
      Signs and symptoms at admission
      Fever, N (%)53 (83.33)9 (90)1.000
      Cough, N (%)45 (75)8 (80)1.000
      Weakness, N (%)19 (31.67)00.089
      Chest tightness, N (%)15 (25)00.171
      CXR peak score4.00 (1.00, 12.00)6.00 (3.00, 9.00)0.602
      CXR score1.00 (0.00, 3.00)2.00 (0.00, 4.00)0.774
      Laboratory data
      Blood routine
      Leucocyte count (× 109/L)4-105.45 ± 1.854.74 ± 1.000.242
      Neutrophil count (× 109/L)2-73.73 ± 1.643.06 ± 1.130.215
      Lymphocyte count (× 109/L)0.8-4.01.23 (0.96, 1.71)1.13 (0.95, 1.64)0.724
      NLR2.72 (1.99, 4.10)2.13 (1.61, 4.08)0.470
      Monocyte count (× 109/L)0.12-0.800.33 (0.26, 0.44)0.34 (0.23, 0.46)0.968
      Eosinophil count (× 109/L)0.02-0.500.01 (0.00, 0.04)0.02 (0.01, 0.05)0.378
      Red blood cell count (× 109/L)3.50-5.504.72 ± 0.514.12 ± 0.460.001
      Hemoglobin concentration (g/L)110-160139.16 ± 18.47122.70 ± 14.580.009
      Platelet count (× 1012/L)100-300160.00 (124.00, 195.50)155.00 (124.50, 199.25)0.987
      Blood biochemistry
      AST, U/L0-4026.00 (17.08, 36.10)22.80 (19.10, 30.78)0.737
      ALT, U/L0-4020.75 (15.13, 41.38)16.50 (7.75, 22.40)0.041
      Albumin, g/L35-5541.06 ± 4.7541.64 ± 2.870.711
      TP, g/L60-8566.86 ± 5.1963.25 ± 5.340.046
      GGT, U/L0-4730.00 (16.55, 43.15)17.60 (13.00, 28.20)0.113
      TBA, μmol/L0-153.50 (2.30, 5.08)2.40 (1.98, 2.85)0.102
      Total bilirubin, μmol/L0-249.15 (7.11, 12.95)8.33 (6.15, 13.25)0.795
      Direct bilirubin, μmol/L0.00-9.502.85 (1.90, 4.58)2.30 (1.35, 2.99)0.129
      Indirect bilirubin, μmol/L0-17.16.26 (4.68, 8.38)5.57 (5.03, 10.03)0.699
      Urea nitrogen, μmol/L1700-83004024.33 ± 1183.335837.00 ± 1549.660.000
      Creatinine, μmol/L20.00-106.0065.80 ± 11.6068.73 ± 16.160.489
      UA, μmol/L200-428252.82 ± 71.61256.34 ± 75.650.887
      Glucose, mmol/L3.89-6.115.77 (5.07, 6.49)5.79 (5.33, 6.62)0.873
      TG, mmol/L0.00-1.701.12 (0.82, 1.61)1.36 (1.09, 1.71)0.343
      LDH, U/L100-240195.80(149.60-261.53)217.30(141.00-260.75)0.887
      Infection associated
      CRP, mg/L5-1011.15 (5.10, 28.53)9.45 (2.88, 23.06)0.615
      Blood coagulation
      Prothrombin time, s11-1513.20 (11.18, 14.78)14.45 (11.48, 15.55)0.373
      INR0.8-1.51.09 ± 0.211.09 ± 0.200.991
      APTT, s14-2125.10 (20.13, 28.88)28.55 (25.40, 35.63)0.055
      Thrombin time, s22-3817.65 (15.35, 24.73)14.80 (14.18, 19.13)0.113
      Fibrinogen, g/L2-43.92 ± 1.153.78 ± 1.410.730
      D-dimer, μg/L0-500225.00 (82.50, 400.00)280.00 (255.00, 360.00)0.306
      Treatment
      Corticosteroids, No. (%)20 (33.33)0 (0)0.075
      Interferon beta, No. (%)57 (95)8 (80)0.297
      Immunoglobulins, No. (%)3 (5)1 (10)1.000
      Data are expressed as mean ± SD, median (IQR), and No. (%). Comparisons were determined by Student's t-test, Mann-Whitney U test, or χ2 test, as appropriate.
      Abbreviations: NLR, neutrophil-lymphocyte ratio; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TP, total protein; GGT, gamma-glutamyl transferase; ALP, alkaline phosphatase; TBA, total bile acids; GLO, globulin; UA, uric acid; TG, triglyceride; CRP, C-reactive protein; LDH, lactate dehydrogenase; INR, international normalized ratio; APTT, active partial thrombin time
      Table 6Multivariate analysis of predictors of abnormal DLCO.
      βP valueOR (95% CI)β
      Logistic regression analysis adjusted for age, sex, and history of smoking
      P value
      Logistic regression analysis adjusted for age, sex, and history of smoking
      OR (95% CI)
      Logistic regression analysis adjusted for age, sex, and history of smoking
      Red blood cell count-4.2530.1690.014 (0.000, 6.063)-4.8840.1270.008 (0.000, 4.037)
      Hemoglobin concentration-0.0950.3180.909 (0.754, 1.096)0.0020.9871.002 (0.784, 1.281)
      ALT-0.2490.0960.780 (0.582, 1.045)-0.2270.1390.797 (0.590, 1.076)
      TP-0.1210.5230.886 (0.611, 1.285)-0.3040.1890.738 (0.468, 1.162)
      Urea nitrogen0.0040.0321.004 (1.000, 1.007)0.0030.0211.004 (1.001, 1.006)
      Abbreviations: CI, confidence interval; TP, total protein; ALT, alanine aminotransferase
      a Logistic regression analysis adjusted for age, sex, and history of smoking

      Dynamic changes of antibodies

      There were 55 and 67 survivors tested for SARS-CoV-2 IgG, IgM antibodies, and NAbs against SARS-CoV-2 at 3 months and 1 year after discharge, respectively. The negative rates of SARS-CoV-2 IgG were 7.27% and 11.94% at the 3-month and 1-year follow-ups, respectively. SARS-CoV-2 IgM became negative in 60.00% (33 of 55 patients) 3 months after discharge. At the 1-year follow-up after hospital discharge, the negative rate of IgM was 82.09% (55 of 67 patients). It was observed that the concentrations of SARS-CoV-2 IgG and IgM antibodies in the early convalescence phase were higher than those of survivors in the late convalescence phase. Application of the manufacturer's advised cut-off of 30% resulted in 47 samples (85.45%) reporting as unambiguously positive for ‘neutralization’ at the 3-month follow-up, whilst 55 of 67 participants (82.09%) who presented for follow-up displayed an efficient neutralization 1 year after hospital discharge. As shown in Figure 3, there was no difference in serum anti-S IgM level between the mild/moderate and severe/critical groups (P > 0.05) 1 year after discovery. The anti-N IgG level of participants was 29.73 (IQR: 14.92-39.56) for the mild/moderate group and 46.76 (IQR: 24.59-63.78) for the severe/critical group. A significant difference was observed between the mild/moderate and severe/critical groups (P < 0.05). The neutralizing activity in sVNT was higher than that in the severe/critical group (P < 0.05). The same phenomenon was noticed in the anti-N IgG and SARS-CoV-2 sVNT level during follow-ups of survivor patients, but not in anti-S IgM (Figure 3).
      Figure 3
      Figure 3Anti-SARS-CoV-2 IgG and IgM antibodies, and neutralizing activity kinetics in the serum of patients with SARS-CoV-2 infection. The serum of 55 participants who participated in the 3-months follow-up were collected, including 4 mild cases, 47 moderate cases, and 4 severe cases. Of 67 survivors 1 year after discovery, 2.99% (2 cases) were classified as mild, 44.78% (30 cases) moderate, 49.25% (33 cases) severe, and 2.99% (2 cases) critical. Comparison of anti-N IgG, anti-S IgM antibody concentration or neutralizing activity of patient serum in different COVID-19 groups in recovering status (mild/moderate: A, B, and C; severe/critical: D, E, and F). Distribution of anti-N IgG (D), anti-S IgM (E) antibodies, and sVNT inhibition (F) in different COVID-19 groups 1 year post discharge (I/II = mild/moderate group; III/IV = severe/critical group).
      n.s. = not significant
      * P < 0.05; ** P < 0.01; *** P < 0.001; **** P < 0.0001
      A significant correlation between the potent neutralizing activity in the SARS-CoV-2 sVNT and anti-N IgG antibodies was observed. The neutralizing activity in sVNT was not significantly correlated with the level of anti-S IgM antibodies at the 1-year follow-up (Figure 4). It is worth noting that patients produced robust NAb responses after SARS-CoV-2 infection, and the majority of antibody neutralizing activity persisted for more than 1 year after infection.
      Figure 4
      Figure 4Neutralizing activity in sVNT correlates with anti-N IgG antibodies. (A and B) Serum from 55 individuals was tested for antibodies against SARS-CoV-2 N IgG and neutralizing activity response at 3 months (A) and 1 year (B) after hospital discharge. (C and D) Serum from 55 or 67 individuals was tested for antibodies against SARS-CoV-2 S protein (IgM) and sVNT against neutralizing antibodies against SARS-CoV-2 that block the interaction with ACE2 cell surface receptor at 3 months (C) and 1 year (D) after discharge.

      Discussion

      Plenty of studies have been performed to describe the sequalae of COVID-19 survivors after hospital discharge. This study performed the first study with a duration of 1-year follow-up exploring the clinical consequences of adult patients recovering from SARS-CoV-2. It found that at 1 year after hospital discharge, a high proportion of survivors endorsed at least one symptom, particularly muscle fatigue, insomnia, and joint paint. The most striking finding was the high proportion of patients with lung injury (71.28%) and DLCO impairment (14.29%) 1 year after discharge, although the severity of COVID-19 had no relation to abnormality of CT and DLCO. The levels of SARS-CoV-2 IgG, IgM, and neutralizing activity were significantly lower than those in the early convalescence phase.
      It was found that muscle fatigue and sleep difficulties were most common even at 1 year after hospital discharge. The rates were lower than those reported in the 1-year follow-up study of SARS survivors (
      • Tansey CM
      • Louie M
      • Loeb M
      • Gold WL
      • Muller MP
      • de Jager J
      • et al.
      One-year outcomes and health care utilization in survivors of severe acute respiratory syndrome.
      ). A follow-up study of COVID-19 survivors showed that 29.5% of patients still had muscular fatigue at the 3-month follow-up (

      Gonzalez J, Benitez ID, Carmona P, Santisteve S, Monge A, Moncusi-Moix A, et al. Pulmonary Function and Radiological Features in Survivors of Critical Covid-19: A 3-Month Prospective Cohort. Chest 2021.

      ). A previous study reported that the most common 6-month consequences of COVID-19 in patients discharged from hospital were muscle fatigue (63%) and sleep difficulties (26%), whilst age was the risk factor for fatigue (
      • Huang C
      • Huang L
      • Wang Y
      • Li X
      • Ren L
      • Gu X
      • et al.
      6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.
      ). However, age had no relationship with the symptoms in COVID-19 survivors in the current study. Additionally, the results of questionnaires in this study showed that a considerable proportion of participants had persistent psychological symptoms. This is consistent with data from previous COVID-19 survivors at 1-month follow-up after hospital treatment (
      • Mazza MG
      • De Lorenzo R
      • Conte C
      • Poletti S
      • Vai B
      • Bollettini I
      • et al.
      Anxiety and depression in COVID-19 survivors: role of inflammatory and clinical predictors.
      ). The 6MWT distances were shorter than the reference values. The muscle fatigue and psychiatric consequences were likely caused by the immune response, virus infection, social isolation, a potentially fatal illness, and stigma.
      A recent meta-analysis of CT imaging of COVID-19 patients showed that 91.6% of patients showed an abnormal pattern in chest imaging manifestations, and patchy or GGO were the most common findings in the acute phase (
      • Zhu J
      • Zhong Z
      • Li H
      • Ji P
      • Pang J
      • Li B
      • et al.
      CT imaging features of 4121 patients with COVID-19: A meta-analysis.
      ). Two studies including some critical COVID-19 patients showed that the prevalence of chest CT abnormalities ranged from 80.7%-53.91% at the 3-month and 6-month follow-ups (

      Gonzalez J, Benitez ID, Carmona P, Santisteve S, Monge A, Moncusi-Moix A, et al. Pulmonary Function and Radiological Features in Survivors of Critical Covid-19: A 3-Month Prospective Cohort. Chest 2021.

      ;
      • Huang C
      • Huang L
      • Wang Y
      • Li X
      • Ren L
      • Gu X
      • et al.
      6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.
      ). A recent study found that the rate of radiological anomalies was 39% and the median of CT score was 0.0 (IQR: 0.0-1.0) 7 months after recovery (
      • Liu M
      • Lv F
      • Huang Y
      • Xiao K.
      Follow-Up Study of the Chest CT Characteristics of COVID-19 Survivors Seven Months After Recovery.
      ). The rate of radiographic anomalies and fibrosis was 71.28% and 8.51% in the current cohort. Even with the high rate of lung injury on chest imaging, the median CT score was 1.5 (IQR: 0.00, 3.25) at the 1-year follow-up. The severe/critical COVID-19 patients showed significant increases in CT abnormalities compared with the mild/moderate patients at the 1-year follow-up. Therefore, it can be inferred that chest CT imaging abnormalities caused by SARS-CoV-2 could gradually be resolved over time. Furthermore, the factor associated with lung damage on chest CT was age, which was consistent with previous studies on SARS and MERS (
      • Antonio GE
      • Wong KT
      • Hui DS
      • Wu A
      • Lee N
      • Yuen EH
      • et al.
      Thin-section CT in patients with severe acute respiratory syndrome following hospital discharge: preliminary experience.
      ;
      • Chan KS
      • Zheng JP
      • Mok YW
      • Li YM
      • Liu YN
      • Chu CM
      • et al.
      SARS: prognosis, outcome and sequelae.
      ;
      • Chang YC
      • Yu CJ
      • Chang SC
      • Galvin JR
      • Liu HM
      • Hsiao CH
      • et al.
      Pulmonary sequelae in convalescent patients after severe acute respiratory syndrome: evaluation with thin-section CT.
      ;
      • Feikin DR
      • Alraddadi B
      • Qutub M
      • Shabouni O
      • Curns A
      • Oboho IK
      • et al.
      Association of Higher MERS-CoV Virus Load with Severe Disease and Death, Saudi Arabia, 2014.
      ). It could be speculated that age might be a predictor of radiological damage in patients who have recovered from COVID-19. Whether the remaining radiological anomalies completely resolve needs to be investigated in longer-term and further large-scale studies.
      A similar phenomenon could be noticed with pulmonary function during follow-ups of survivor patients with COVID-19. At the time of hospital discharge, the findings from 110 patients with mild (n = 24), moderate (n = 67), and severe (n = 19) disease showed that DLCO anomalies were noted in 47.2% of patients (
      • Mo X
      • Jian W
      • Su Z
      • Chen M
      • Peng H
      • Peng P
      • et al.
      Abnormal pulmonary function in COVID-19 patients at time of hospital discharge.
      ). The rate of impaired DLCO remained high 6 months after discharge (34.13%), although it was lower than that at 3 months (54%) (
      • Huang C
      • Huang L
      • Wang Y
      • Li X
      • Ren L
      • Gu X
      • et al.
      6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.
      ;
      • Qin W
      • Chen S
      • Zhang Y
      • Dong F
      • Zhang Z
      • Hu B
      • et al.
      Diffusion capacity abnormalities for Carbon Monoxide in patients with COVID-19 at three-month follow-up.
      ). A recent study showed that 82% of ICU patients with ARDS secondary to COVID-19 had impaired DLCO at the 3-months follow-up (

      Gonzalez J, Benitez ID, Carmona P, Santisteve S, Monge A, Moncusi-Moix A, et al. Pulmonary Function and Radiological Features in Survivors of Critical Covid-19: A 3-Month Prospective Cohort. Chest 2021.

      ). The result of lung function assessment in this study showed that 14.29% of participants had a lung carbon monoxide diffusion dysfunction 1 year after hospital discharge; this is consistent with data from previous SARS 1-year follow-up studies (
      • Hui DS
      • Wong KT
      • Ko FW
      • Tam LS
      • Chan DP
      • Woo J
      • et al.
      The 1-year impact of severe acute respiratory syndrome on pulmonary function, exercise capacity, and quality of life in a cohort of survivors.
      ;
      • Ong KC
      • Ng AW
      • Lee LS
      • Kaw G
      • Kwek SK
      • Leow MK
      • et al.
      1-year pulmonary function and health status in survivors of severe acute respiratory syndrome.
      ). The severity of pulmonary inflammation in the acute phase might be the reason for fibroblast activation and impaired DLCO in the convalescence phase (
      • Qin W
      • Chen S
      • Zhang Y
      • Dong F
      • Zhang Z
      • Hu B
      • et al.
      Diffusion capacity abnormalities for Carbon Monoxide in patients with COVID-19 at three-month follow-up.
      ). The current study also found that the level of urea nitrogen was an independent factor of abnormal DLCO, which is in agreement with previous studies (
      • Izcovich A
      • Ragusa MA
      • Tortosa F
      • Lavena Marzio MA
      • Agnoletti C
      • Bengolea A
      • et al.
      Prognostic factors for severity and mortality in patients infected with COVID-19: A systematic review.
      ;
      • Mudatsir M
      • Fajar JK
      • Wulandari L
      • Soegiarto G
      • Ilmawan M
      • Purnamasari Y
      • et al.
      Predictors of COVID-19 severity: a systematic review and meta-analysis.
      ). Thus, this study will help clinicians and policymakers in tailoring management strategies for COVID-19 survivors to identify impaired DLCO as early as possible, and to develop better centralized management and pulmonary rehabilitation.
      Previous studies have shown that serum IgG and neutralizing antibodies against SARS-CoV and MERS-CoV can persist for an average of 2 years (
      • Cao WC
      • Liu W
      • Zhang PH
      • Zhang F
      • Richardus JH.
      Disappearance of antibodies to SARS-associated coronavirus after recovery.
      ;
      • Choe PG
      • Perera R
      • Park WB
      • Song KH
      • Bang JH
      • Kim ES
      • et al.
      MERS-CoV Antibody Responses 1 Year after Symptom Onset, South Korea, 2015.
      ;
      • Payne DC
      • Iblan I
      • Rha B
      • Alqasrawi S
      • Haddadin A
      • Al Nsour M
      • et al.
      Persistence of Antibodies against Middle East Respiratory Syndrome Coronavirus.
      ;
      • Wu LP
      • Wang NC
      • Chang YH
      • Tian XY
      • Na DY
      • Zhang LY
      • et al.
      Duration of antibody responses after severe acute respiratory syndrome.
      ). Recent studies have shown that approximately 90% of the patient cohort remained SARS-CoV-2 IgG-positive 3-6 months following symptom onset (
      • Maine GN
      • Lao KM
      • Krishnan SM
      • Afolayan-Oloye O
      • Fatemi S
      • Kumar S
      • et al.
      Longitudinal characterization of the IgM and IgG humoral response in symptomatic COVID-19 patients using the Abbott Architect.
      ;
      • Rodda LB
      • Netland J
      • Shehata L
      • Pruner KB
      • Morawski PA
      • Thouvenel CD
      • et al.
      Functional SARS-CoV-2-specific immune memory persists after mild COVID-19.
      ;
      • Zhao YM
      • Shang YM
      • Song WB
      • Li QQ
      • Xie H
      • Xu QF
      • et al.
      Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery.
      ). Regarding NAbs, 85% of patients had a high NAbs titer 3-4 months post-symptom onset (
      • Jiang XL
      • Wang GL
      • Zhao XN
      • Yan FH
      • Yao L
      • Kou ZQ
      • et al.
      Lasting antibody and T cell responses to SARS-CoV-2 in COVID-19 patients three months after infection.
      ). SARS-CoV-2 IgG titers and NAbs neutralizing activity at 1-year follow-up in recovered individuals in the current cohort exhibited a significant decrease compared with those at 3 months after hospital discharge. The current cohort found no difference in the seropositivity of the antibodies among survivors with COVID-19 between 3 months and 1 year after discharge. The decline of serum IgG and neutralizing antibodies observed in the present study indicates re-infection among recovered COVID-19 patients. Taken together, the findings from this study suggest rising antibody levels 1 year after hospital discharge in patients with COVID-19 and this will have important implications regarding monitoring the immune response against SARS-CoV-2 and establishing vaccination strategies.
      There were several limitations to this study. First, the cohort with confirmed SARS-CoV-2 infection was small, whilst a larger sample size would be more ideal for this type of study. Second, the baseline data of PFTs and 6MWT were unavailable, so it was unknown whether the observed abnormalities were already present prior to diagnosis with COVID-19. Third, since only two patients with critical COVID-19 symptoms were enrolled, further efforts are needed to assess the long-term outcomes of critical COVID-19 survivors.

      Conclusions

      In conclusion, a cohort of patients were mainly troubled with muscle fatigue, insomnia, anxiety or depression 1 year after being in hospital for COVID-19. Pulmonary structural abnormalities and functional impairment were common among those who were tested. The high level of urea nitrogen on hospital admission due to COVID-19 could effectively predict impaired DLCO after 1 year of discharge. COVID-19 elicits immune responses that persist and display functional hallmarks of antiviral immunity.

      Ethical approval and participation consent

      The study was approved by the First Affiliated Hospital of Zhengzhou University (2020-KY-61) and was registered with the Chinese Clinical Trial Registry, ChiCTR2000033186. Written informed consent was obtained from all the patients.

      Conflict of interest

      The authors declare no competing interests.

      Funding source

      The Science & Technological Project of Henan Province (No. 212102310208), The Major Project of Medical Science and Technology of Henan Province (No. SBGJ202001006) and The Youth Project of Medical Science and Technology of Henan Province (No. SBGJ202003022), Youth innovation fund of the First Affiliated Hospital of Zhengzhou University (No. YNQN2017169 and No. YNQN2017171), and Shenzhen Science and Technology Program (No. JSGG20200225153121723).

      Appendix. Supplementary materials

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