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Recovery of functional fitness, lung function, and immune function in healthcare workers with nonsevere and severe COVID-19 at 13 months after discharge from the hospital: a prospective cohort study

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    Lijuan Xiong
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    Department of Nosocomial Infection Management, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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    Qian Li
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    Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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    Xiongjing Cao
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    Department of Nosocomial Infection Management, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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    Huangguo Xiong
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    Department of Nosocomial Infection Management, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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    Ming Huang
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    State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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    Fengwen Yang
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    Evidence-Based Medicine Center, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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  • Daquan Meng
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    Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Mei Zhou
    Affiliations
    Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Yanzhao Zhang
    Affiliations
    Department of Rehabilitation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Yunzhou Fan
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    Department of Nosocomial Infection Management, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Liang Tang
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    Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Yang Jin
    Affiliations
    Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Author Footnotes
    † Contributed equally
    Jiahong Xia
    Correspondence
    Jiahong Xia, Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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    Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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    Yu Hu
    Correspondence
    Corresponding authors: Yu Hu, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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    † Contributed equally
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    Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Open AccessPublished:July 02, 2022DOI:https://doi.org/10.1016/j.ijid.2022.06.052

      Highlights

      • COVID-19 can cause a series of clinical symptoms.
      • The lung is the organ most affected by infection of SARS-CoV-2.
      • Interventions should be implemented to help recovery of healthcare workers with COVID-19.

      Abstract

      Objectives

      This study aimed to evaluate the recovery of functional fitness, lung function, and immune function in healthcare workers (HCWs) with nonsevere and severe COVID-19 at 13 months after discharge from the hospital.

      Methods

      The participants of “Rehabilitation Care Project for Medical Staff Infected with COVID-19” underwent a functional fitness test (muscle strength, flexibility, and agility/dynamic balance), lung function test, and immune function test (including cytokines and lymphocyte subsets) at 13 months after discharge.

      Results

      The project included 779 HCWs (316 nonsevere COVID-19 and 463 severe COVID-19). This study found that 29.1% (130/446) of the HCWs have not yet recovered their functional fitness. The most affected lung function indicator was lung perfusion capacity (34% with diffusion capacity for carbon monoxide-single breath <80%). The increase of interleukin-6 (64/534, 12.0%) and natural killer cells (44/534, 8.2%) and the decrease of CD3+ T cells (58/534, 10.9%) and CD4+ T cells (26/534, 4.9%) still existed at 13 months after discharge. No significant difference was found in the HCWs with nonsevere and severe COVID-19 regarding recovery of functional fitness, lung function, and immune function at 13 months after discharge.

      Conclusion

      The majority of Chinese HCWs with COVID-19 had recovered their functional fitness, lung function, and immune function, and the recovery status in HCWs with severe COVID-19 is no worse than that in HCWs with nonsevere COVID-19 at 13 months after discharge from the hospital.

      Keywords

      Introduction

      COVID-19 refers to an acute respiratory infectious disease caused by SARS-CoV-2, which can cause a series of clinical symptoms, such as fever, fatigue, dry cough, dyspnea, shortness of breath, shock, and multiorgan dysfunction. As of June 17, 2022, the World Health Organization reports 535,863,950 confirmed cases of COVID-19 and 6,314,972 deaths (

      World Health Organization. WHO Coronavirus (COVID-19) Dashboard, https://www.who.int/, 2022 (accessed on 18 June 2022).

      ). Between December 2019 and February 2020, 3019 healthcare workers (HCWs) (1716 confirmed cases) in China were found to be affected by SARS-CoV-2 (
      Epidemiology Working Group for NCIP Epidemic Response
      Chinese Center for Disease Control and Prevention. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China.
      ). Wuhan (17.7%) and Hubei Province (10.4%), where the patients were first diagnosed, had the highest proportion of patients with severe COVID-19 in the whole country (
      Epidemiology Working Group for NCIP Epidemic Response
      Chinese Center for Disease Control and Prevention. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China.
      ).
      At present, few studies focused on the health consequences, including symptoms (
      • Havervall S
      • Rosell A
      • Phillipson M
      • Mangsbo SM
      • Nilsson P
      • Hober S
      • Thålin C.
      Symptoms and functional impairment assessed 8 months after mild COVID-19 among health care workers.
      ), SARS-CoV-2 seroprevalence (
      • Moncunill G
      • Mayor A
      • Santano R
      • Jiménez A
      • Vidal M
      • Tortajada M
      • et al.
      SARS-CoV-2 seroprevalence and antibody kinetics among health care workers in a Spanish Hospital after 3 months of follow-up.
      ), and antibodies (
      • Egbert ER
      • Xiao S
      • Colantuoni E
      • Caturegli P
      • Gadala A
      • Milstone AM
      • et al.
      Durability of spike immunoglobin G antibodies to SARS-CoV-2 among health care workers with prior infection.
      ) in HCWs with COVID-19 after they were discharged from the hospital. A study in China followed up HCWs with COVID-19 for 3 months after discharge; it suggested that 69 (91%) of the HCWs with COVID-19 had returned to their original work, 82% of the HCWs’ lung high-resolution computed tomography returned to normal, and 42% of the HCWs had mild pulmonary function abnormalities (
      • Liang L
      • Yang B
      • Jiang N
      • Fu W
      • He X
      • Zhou Y
      • Ma WL
      • Wang X.
      Three-month follow-up study of survivors of coronavirus disease 2019 after discharge.
      ). Our previous study reported dynamic changes in functional fitness and immunologic indicators within 1 year after discharge in HCWs with severe COVID-19 (
      • Xiong L
      • Li Q
      • Cao X
      • Xiong H
      • Huang M
      • Yang F
      • et al.
      Dynamic changes of functional fitness, antibodies to SARS-CoV-2 and immunological indicators within 1 year after discharge in Chinese health care workers with severe COVID-19: a cohort study.
      ). There were also other studies revealing recovery of functional fitness (
      • Paz LES
      • Bezerra BJDS
      • Pereira TMM
      • da Silva WE.
      COVID-19. the importance of physical therapy in the recovery of workers' health.
      ), lung function (
      • 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.
      ), and immune function (
      • Qin C
      • Zhou L
      • Hu Z
      • Zhang S
      • Yang S
      • Tao Y
      • et al.
      Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China.
      ;
      • Wan S
      • Yi Q
      • Fan S
      • Lv J
      • Zhang X
      • Guo L
      • et al.
      Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID-19) infected patients.
      ) in patients with COVID-19. However, most of these studies were not carried out on HCWs with COVID-19, and few of them had compared the recovery status in patients with nonsevere and severe COVID-19 after discharge. In the fight against COVID-19, HCWs with COVID-19 had made huge sacrifices. It is of great public health significance to pay attention to their health status after discharge from the hospital and implement individualized interventions to help the recovery of the target population. So far, the health consequences of HCWs with COVID-19 at 13 months after discharge from the hospital remain unclear.
      Therefore, this study aimed to evaluate the recovery of functional fitness, lung function, and immune function in HCWs with COVID-19 at 13 months after hospital discharge and compare the recovery status of nonsevere and severe groups.

      Methods

      Study design and participants

      The participants were from the “Rehabilitation Care Project for Medical Staff Infected with COVID-19” in China, which the Chinese Academy of Engineering and Tencent Charity Foundation launched (
      • Xiong L
      • Li Q
      • Cao X
      • Xiong H
      • Huang M
      • Yang F
      • et al.
      Dynamic changes of functional fitness, antibodies to SARS-CoV-2 and immunological indicators within 1 year after discharge in Chinese health care workers with severe COVID-19: a cohort study.
      ). The participants were HCWs with COVID-19 in Hubei Province (including the provincial capital city, Wuhan, and its surrounding cities). The HCWs with COVID-19 agreed to participate in the project through the information platform of “Rehabilitation Care Project for Medical Staff Infected with COVID-19” and were followed up on the health consequences after discharge from the hospital. The health consequences that the project mainly focused on included psychologic evaluation, a survey of persistent symptoms, lung function evaluation, and physical examinations. From June 2020 to March 2021, the project included a total of 779 HCWs (316 nonsevere and 463 severe COVID-19). All HCWs were contacted through the platform and/or by telephone to participate in follow-up visits (5, 8, 11, and 13 months after discharge) in Union Hospital (Tongji Medical College, Huazhong University of Science and Technology). Currently, the longest follow-up period for the HCWs is 13 months after discharge.
      Regarding follow-up visits at 13 months after discharge, all HCWs participating in this project were asked to take physical examinations (any time between March 11, 2021 and March 19, 2021) and complete the functional fitness, lung function, and immune function tests at Union Hospital (Tongji Medical College, Huazhong University of Science and Technology). For HCWs with abnormal results of physical examinations, experts will be arranged to develop personalized rehabilitation plans to speed recovery.
      In this study, HCWs of “Rehabilitation Care Project for Medical Staff Infected with COVID-19” who completed any follow-up visits (including functional fitness test, lung function test, and immune function test) between March 11, 2021, and March 19, 2021, were included in the analyses.
      The disease severity and the standards of discharge were evaluated according to the recommendations by the National Health Commission (
      China National Health Commission
      Chinese clinical guidance for COVID-19 pneumonia diagnosis and treatment.
      ). The severity of the disease was divided into four types, including mild (with mild clinical symptoms but without pneumonia manifestations in imaging examination), moderate (with fever, respiratory symptoms, etc., and with pneumonia manifestations in imaging examination), severe (meeting at least one of the following criteria: shortness of breath, RR ≥30 beats/min; the oxygen saturation ≤93%; PaO2/FiO2 ≤300 mmHg in the resting state), and critical (meeting at least one of the following criteria: respiratory failure requiring mechanical ventilation, shock, combined with other organ failure requiring intensive care unit [ICU] monitoring and treatment). In this study, the HCWs with severe or critical COVID-19 were assigned to the severe group, and the HCWs with mild or moderate COVID-19 were assigned to the nonsevere group. The standards of discharge included (i) no fever for three consecutive days, (ii) improved respiratory symptoms, (iii) obvious resolution and recovery of an acute lesion in lung computed tomography scanning, and (iv) two negative results of SARS-CoV-2 tests 24 hours apart.
      According to the principles of the Declaration of Helsinki, this research was approved by the ethics committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. All HCWs signed written informed consents at enrollment.

      Data collection

      Information on demographic and clinical characteristics of the participants was obtained at enrollment through the information platform of “Rehabilitation Care Project for Medical Staff Infected with COVID-19”.
      The functional fitness test was performed by doctors in the Department of Rehabilitation of Union Hospital (Tongji Medical College, Huazhong University of Science and Technology). The Senior Fitness Test (SFT) could comprehensively reflect the physical recovery status of the participants in the aspects of muscle strength, flexibility, and agility/dynamic balance. Previous literature showed that SFT could also be applied to other age groups beyond the elderly (
      • Boshnjaku A
      • Bahtiri A
      • Feka K
      • Krasniqi E
      • Tschan H
      • Wessner B.
      Test-retest reliability data of functional performance, strength, peak torque and body composition assessments in two different age groups of Kosovan adults.
      ); therefore, this study used SFT to assess the functional fitness status. In this study, the SFT included evaluation of muscle strength (grip strength test, 30-second elbow flexion test, 30-second chair stand, and 2-minute step test), flexibility (back scratch test and chair sit-and-reach test), and agility/dynamic balance (functional reach test and the Y balance test) (
      • Rikli RE
      • Jones CJ.
      Development and validation of a functional fitness test for community-residing older adults.
      ). According to literature and policy documents, there are normal ranges for evaluation of muscle strength and agility/dynamic balance (
      • Nogueira MA
      • Almeida TDN
      • Andrade GS
      • Ribeiro AS
      • Rêgo AS
      • Dias RDS
      • et al.
      Reliability and accuracy of 2-minute step test in active and sedentary lean adults.
      ; ). Therefore, if a HCW's score in any muscle strength and agility/dynamic balance test is out of the normal ranges, it was recorded that they had not recovered their functional fitness by the doctors.
      The lung function test was performed by doctors at the NHC Key Laboratory of Pulmonary Diseases of Union Hospital (Tongji Medical College, Huazhong University of Science and Technology). The tests were performed with the Masterscreen pneumotachograph system (CareFusion, Hoechberg, Germany), and the diagnoses were based on the recommendations by the American Thoracic Society (
      • 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 immunologic indicators of the HCWs were measured at the Department of Clinical Laboratory of Union Hospital (Tongji Medical College, Huazhong University of Science and Technology). The levels of cytokine profile, including interferon-γ, interleukin (IL)-10, IL-2, IL-4, IL-6, and tumor necrosis factor-α were quantified by BD cytometric bead array analysis, using the BD™ Cytometric Bead Array Human Th1/Th2 cytokine kit. The relative numbers of lymphocyte subsets, including B cells, CD3+ T cells, CD4+ T cells, CD8+ T cells, natural killer (NK) cells and CD4+/CD8+ cell ratio were detected with flow cytometry (BD FACSCanto™, BD Biosciences), and data of lymphocyte subsets were analyzed with FCAP software (version 3.0).

      Statistical analysis

      Median and interquartile range and number (%) were used to describe continuous and categoric covariates, respectively. The Mann-Whitney U test, Wilcoxon signed-rank test, t-test, χ2, and Fisher's exact test were applied where appropriate. Multivariate linear regression models were used to analyze disease severity associations with functional fitness. Multivariable adjusted logistic regression models were applied to investigate disease severity and lung function relationships. The covariates of age, sex, education, roles in work, body mass index (BMI), smoking habit, and comorbidities were adjusted in the models. The analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). A two-sided P-value lower than 0.05 was considered statistically significant.

      Results

      Characteristics of the HCWs

      From June 2020 to March 2021, the cohort recruited a total of 779 HCWs in Hubei Province. All the follow-up visits were completed between March 11, 2021, and March 19, 2021. The median number of hospital discharge days was 387.4 (376.3, 396.3) (approximately 13 months). Among the 779 HCWs, 222 HCWs missed follow-up visits at 13 months after discharge. Among the remaining 557 HCWs, 111 HCWs declined functional fitness test, 254 HCWs declined lung function test, and 23 HCWs declined immune function test. The final sample sizes of participants who underwent functional fitness, lung function, and immune function tests (including cytokines and lymphocyte subsets) were 446, 303, and 534, respectively (Figure 1).
      Figure 1
      Figure 1Flow chart of this study.
      HCWs: healthcare workers
      The demographic and clinical characteristics of 779 HCWs according to disease severity are presented in Table 1. The HCWs’ median age was 35.0 (30.0-43.0) years, median BMI was 22.8 (20.8-25.2) kg/m2; 77% of the HCWs were female (601/779), and 59% (445/755) of the HCWs were nurses. The HCWs with severe COVID-19 were older, had higher BMI, lower education status, less likely to be nurses, more likely to have respiratory support, a history of ICU admission, comorbidities, and symptoms at admission than HCWs with nonsevere COVID-19.
      Table 1Characteristics of HCWs according to disease severity of COVID-19.
      CharacteristicsAll (N = 779)nonsevere (N = 316)Severe (N = 463)P
      Demographic characteristics
      Age (years)35.0 (30.0-43.0)34.0 (28.0-40.0)36.0 (31.0-45.0)<0.001
      BMI (kg/m2)22.8 (20.8-25.2)22.0 (20.0-23.8)23.4 (21.2-25.7)<0.001
      Sex (female)601 (77%)249 (79%)352 (76%)0.386
      Education (college and higher)586/732 (80%)234/288 (81%)352/444 (79%)0.019
      Location of the hospital work for0.378
       Hankou, Wuhan452 (58%)188 (59%)264 (57%)
       Wuchang, Wuhan196 (25%)79 (25%)117 (25%)
       Hanyang, Wuhan40 (5%)11 (4%)29 (6%)
       Outside Wuhan in Hubei91 (12%)38 (12%)53 (12%)
      Roles in work0.003
       Doctors184/755 (24%)72/298 (24%)112/457 (24%)
       Nurses445/755 (59%)182/298 (61%)263/457 (58%)
       Other126/755 (17%)44/298 (15%)82/457 (18%)
      Smoking habit (yes)24/756 (3%)9/300 (3%)15/456 (3%)0.016
      Time from discharge to follow-up (days)
      The sample sizes for a group of “all,” “nonsevere,” and “severe” were 557, 205, and 352.
      387.4 (379.3-393.4)386.4 (382.3-396.1)387.4 (379.1-393.3)0.271
      Clinical characteristics
      The highest respiratory support in hospital<0.001
       No supplemental oxygen278/740 (38%)159/295 (54%)119/445 (27%)
       Supplemental oxygen by nasal cannula or mask443/743 (60%)136/295 (46)307/445 (69%)
       Noninvasive or invasive mechanical ventilation19/740 (2%)0(0%)19/445 (4%)
      ICU admission (yes)20/753 (3%)1/299 (0.3%)19/454 (4%)<0.001
      Comorbidities (yes)167/747 (22%)28/298 (9%)139/449 (31%)<0.001
      Symptoms at admission
       Fatigue412 (53%)127 (60%)285 (62%)<0.001
       Fever404 (52%)119 (38%)285 (62%)<0.001
       Muscle soreness252 (32%)58 (18%)194 (42%)<0.001
       Dry cough238 (31%)79 (25%)159 (34%)0.006
       Cough232 (30%)72 (23%)160 (35%)<0.001
       Chest distress212 (27%)49 (16%)163 (35%)<0.001
       Diarrhea175 (23%)56 (18%)119 (26%)0.009
       Shortness of breath169 (22%)29 (9%)140 (30%)<0.001
       Headache147 (19%)33 (10%)114 (24%)<0.001
       Dyspnea99 (13%)7 (2%)92 (20%)<0.001
       Vomiting43 (6%)8 (3%)35 (8%)0.002
      Data are presented as n (%), n/N (%), or median (IQR).
      Abbreviations: BMI, body mass index; HCWs, healthcare workers; ICU, intensive care unit; IQR, interquartile range
      low asterisk The sample sizes for a group of “all,” “nonsevere,” and “severe” were 557, 205, and 352.

      Functional fitness in HCWs with nonsevere and severe COVID-19

      In this study, 446 HCWs (162 nonsevere and 284 severe COVID-19) took part in the functional fitness test; it found that 29.1% (130/446) of the HCWs have not yet recovered their functional fitness. There was no significant variance in the proportion of unrecovered HCWs between the nonsevere (30.2%, 49/162) and severe groups (28.5%, 81/284). The results of functional fitness test in HCWs according to disease severity are presented in Table 2. In the three aspects of functional fitness recovery (muscle strength, flexibility, and agility/dynamic balance), no significant difference was found in the nonsevere and severe groups (all P-values >0.05). The characteristics of the HCWs included and excluded from the analyses of functional fitness were similar (Table S1).
      Table 2Functional fitness in HCWs with nonsevere and severe COVID-19.
      CategoriesAll (N = 446)Median (IQR)β (95% CI)
      Nonsevere (N = 162)Severe (N = 189)Nonsevere (N = 114)Severe (N = 189)P
      Muscle strength test
       Grip strength test, N25.5 (21.2, 30.5)25.9 (21.4, 29.9)25.3 (21.3, 30.7)00.21 (-0.98, 1.41)0.726
       30-second elbow flexion test, n19.0 (15.0, 20.5)18.0 (15.0, 24.0)19.0 (15.0, 23.0)00.21 (-0.83, 1.24)0.693
      30-second chair stand, n17.0 (15.0, 20.5)18.0 (15.0, 21.0)17.0 (15.0, 20.0)0-0.50 (-1.50, 0.50)0.328
       2-minute step test, n93.0 (80.0, 107.0)95.0 (83.0, 108.0)92.0 (79.0, 107.0)0-1.62 (-5.60, 2.36)0.423
      Flexibility test
       Back scratch test (left)-1.0 (-8.0, 3.0)0.0 (-5.9, 3.4)-2.8 (-10.1, 2.6)0-0.76 (-2.51, 0.99)0.392
       Back scratch test (right)2.0 (-2.1, 5.0)2.5 (0.0, 5.2)1.7 (-4.3, 4.4)0-1.01 (-2.39, 0.36)0.147
       Chair sit-and-reach test, cm1.5 (-2.0, 6.5)2.3 (0.0, 7.0)1.0 (-3.5, 6.5)00.05 (-2.38, 2.48)0.969
      Agility/dynamic balance
       Functional reach test, cm27.0 (22.2, 31.0)27.0 (22.0, 30.0)27.0 (23.0, 31.0)00.51 (-0.97, 1.99)0.500
      YBT
       Anterior-L
      L-reach distance by left leg. bR-reach distance by right leg. The models adjusted for age, sex, education, roles in work, body mass index (BMI), smoking habit, and comorbidities.
      73.1 (69.0, 80.0)73.0 (69.4, 79.0)73.5 (68.0, 80.0)00.56 (-1.13, 2.26)0.512
       Posterolateral-L76.0 (70.2, 81.0)75.9 (71.0, 81.0)77.0 (70.0, 81.0)00.52 (-1.40, 2.45)0.595
       Posteromedial-L64.0 (54.9, 71.8)64.0 (56.0, 71.0)77.0 (70.0, 81.0)01.01 (-1.67, 3.71)0.460
       Anterior-Rb75.0 (69.5, 80.0)75.0 (70.5, 80.0)75.0 (69.0, 80.0)0-0.27 (-1.85, 1.31)0.731
       Posterolateral-R78.0 (71.5, 83.0)78.0 (73.0, 83.0)78.0 (71.0, 84.0)00.00 (-1.87, 1.870.999
       Posteromedial-R62.0 (54.0, 70.0)61.0 (54.0, 81.0)63.0 (54.0, 71.0)01.29 (-1.42, 3.99)0.351
      Leg length79.0 (76.8, 81.5)79.0 (76.8, 81.0)79.0 (76.8, 81.6)00.25 (-0.28, 0.77)0.358
      Composite score-L211.8 (196.6, 227.0)211.0 (197.9, 228.4)212.0 (196.5, 227.9)02.10 (-2.80, 7.00)0.400
      Composite score-R214.0 (197.0, 229.6)214.0 (197.9, 228.4)214.0 (196.0, 230.0)01.01 (-4.01, 6.03)0.692
      Ratio of composite score to leg length-L0.9 (0.8, 0.9)0.9 (0.8, 0.9)0.9 (0.8, 0.9)00.01 (-0.01, 0.02)0.533
      Ratio of composite score to leg length-R0.9 (0.8, 1.0)0.9 (0.8, 1.0)0.9 (0.8, 1.0)00.00 (-0.02, 0.02)0.931
      Abbreviations: HCWs, healthcare workers; IQR, interquartile range
      a L-reach distance by left leg. bR-reach distance by right leg.The models adjusted for age, sex, education, roles in work, body mass index (BMI), smoking habit, and comorbidities.

      Lung function in HCWs with nonsevere and severe COVID-19

      A total of 303 HCWs (114 nonsevere and 189 severe COVID-19) underwent lung function tests at 13 months after discharge. The lung function indicators of the HCWs according to disease severity are demonstrated in Table 3. This study found that the most affected indicator of lung function was lung perfusion capacity (34% with diffusion capacity for carbon monoxide [DLCO]-single breath [SB] <80%) in the HCWs. Obstruction (forced expiratory volume in one second/forced vital capacity <70%) was found in 8% and restriction (total lung capacity-SB <80%) in 6% of the HCWs. No significant variance in all indicators of lung function was found in HCWs of different disease severity (all P-values >0.05). The characteristics of the HCWs included and excluded from the analyses of lung function were similar (Table S1).
      Table 3Lung function in HCWs with nonsevere and severe COVID-19.
      CategoriesAll (N = 303)N (%)β (95% CI)
      Nonsevere (N = 114)Severe (N = 189)Nonsevere (N = 114)Severe (N = 189)P
      FEV1 <80%, % of predicted24 (8%)13 (11%)11 (6%)10.51 (0.20, 1.31)0.160
      FVC <80%, % of predicted7 (2%)4 (4%)3 (2%)10.57 (0.08, 4.29)0.583
      FEV1/FVC <70%24 (8%)9 (8%)15 (8%)11.11 (0.43, 2.84)0.827
      RV <80%, % of predicted*43 (14%)17 (15%)26 (14%)10.75 (0.36, 1.57)0.449
      TLC <80%, % of predicted18 (6%)9 (8%)9 (5%)10.51 (0.17, 1.57)0.243
      FRC <80%, % of predicted57 (19%)17 (15%)40 (21%)11.52 (0.77, 3.00)0.223
      DLCO <80%, % of predicted
      Carbon monoxide diffusion capacity was not corrected for hemoglobin. Abbreviations: DLCO, diffusion capacity for carbon monoxide; FEV1, forced expiratory volume in one second; FRC, functional residual capacity; FVC, forced vital capacity; HCWs, healthcare workers; RV, residual volume; TLC, total lung capacity. The models adjusted for age, sex, education, roles in work, body mass index, smoking habit, and comorbidities.
      102 (34%)42 (37%)60 (32%)10.71 (0.41, 1.23)0.223
      Data are presented as n (%).
      a Carbon monoxide diffusion capacity was not corrected for hemoglobin.Abbreviations: DLCO, diffusion capacity for carbon monoxide; FEV1, forced expiratory volume in one second; FRC, functional residual capacity; FVC, forced vital capacity; HCWs, healthcare workers; RV, residual volume; TLC, total lung capacity.The models adjusted for age, sex, education, roles in work, body mass index, smoking habit, and comorbidities.

      Immune function in HCWs with nonsevere and severe COVID-19

      In this study, 534 HCWs (198 nonsevere and 336 severe COVID-19) participated in the immune function test. No significant difference was found in the median values of cytokines (Table 4) and lymphocyte subsets (Table 5) between the nonsevere and the severe group. This study also analyzed the distribution of various cytokines and lymphocyte subsets. The results suggested that more than 95% of the study population had normal levels of interferon-γ, IL-10, IL-2, IL-4, and TNF-α, and 12.0% (64/534) of the HCWs had elevated levels of IL-6 at 13 months after discharge from the hospital (Table 4). More than 90% of the HCWs had normal relative numbers of lymphocyte subsets (B cells, CD3+ T cells, CD4+ T cells, CD4+/CD8+ cell ratio, CD8+ T cells, and NK cells) (Table 5). At 13 months after discharge from the hospital, the decrease of CD3+ T cells (58/534, 10.9%) and CD4+ T cells (26/534, 4.9%) and elevation of NK cells (44/534, 8.2%) still existed.
      Table 4Levels of cytokines in HCWs with nonsevere and severe COVID-19.
      CategoriesAll (N = 534)Nonsevere (N = 198)Severe (N = 336)P
      IFN-γ (pg/ml)1.04 (0.96-1.16)1.04 (0.96-1.16)1.04 (0.96-1.16)0.881
       Elevated1 (0.2%)1 (0.5%)0 (0.0%)0.371
       Normal
      Data are shown as the normal ranges of the indicators. Abbreviations: HCWs, healthcare workers; IQR, interquartile range. The comparison between two groups was performed with Mann-Whitney U test.
      0.64-15.170.73-15.170.64-9.58
       Decreased0 (0.0%)0 (0.0%)0 (0.0%)
      IL-10 (pg/ml)1.25 (1.09-1.45)1.25 (1.10-1.45)1.40 (1.05-1.45)0.952
       Elevated3 (0.6%)2 (1.0%)1 (0.3%)0.559
       Normal
      Data are shown as the normal ranges of the indicators. Abbreviations: HCWs, healthcare workers; IQR, interquartile range. The comparison between two groups was performed with Mann-Whitney U test.
      0.51-3.810.66-2.550.51-3.81
       Decreased0 (0.0%)0 (0.0%)0 (0.0%)
      IL-2 (pg/ml)1.36 (1.23-1.52)1.36 (1.25-1.48)1.40 (1.23-1.52)0.271
       Elevated3 (0.6%)2 (1.0%)1 (0.3%)0.558
       Normal
      Data are shown as the normal ranges of the indicators. Abbreviations: HCWs, healthcare workers; IQR, interquartile range. The comparison between two groups was performed with Mann-Whitney U test.
      0.87-4.070.87-4.070.91-4.07
       Decreased0 (0.0%)0 (0.0%)0 (0.0%)
      IL-4 (pg/ml)1.50 (1.39-1.61)1.46 (1.35-1.61)1.50 (1.39-1.60)0.598
       Elevated1 (0.2%)1 (0.5%)0 (0.0%)0.371
       Normal
      Data are shown as the normal ranges of the indicators. Abbreviations: HCWs, healthcare workers; IQR, interquartile range. The comparison between two groups was performed with Mann-Whitney U test.
      1.02-2.601.02-2.481.04-2.60
       Decreased0 (0.0%)0 (0.0%)0 (0.0%)
      IL-6 (pg/ml)1.53 (1.20-2.55)1.51 (1.20-2.44)1.62 (1.14-2.74)0.589
       Elevated64 (12.0%)25 (12.6%)39 (11.6%)0.783
       Normal
      Data are shown as the normal ranges of the indicators. Abbreviations: HCWs, healthcare workers; IQR, interquartile range. The comparison between two groups was performed with Mann-Whitney U test.
      0.32-5.250.32-5.250.48-5.23
       Decreased0 (0.0%)0 (0.0%)0 (0.0%)
      TNF-α (pg/ml)2.58 (1.60-5.60)2.49 (1.60-6.45)2.58 (1.58-5.08)0.596
       Elevated8 (1.5%)3 (1.5%)5 (1.5%)0.980
       Normal
      Data are shown as the normal ranges of the indicators. Abbreviations: HCWs, healthcare workers; IQR, interquartile range. The comparison between two groups was performed with Mann-Whitney U test.
      0.56-21.200.56-21.200.92-20.38
       Decreased0 (0.0%)0 (0.0%)0 (0.0%)
      Data are presented as median (IQR).
      a Data are shown as the normal ranges of the indicators.Abbreviations: HCWs, healthcare workers; IQR, interquartile range.The comparison between two groups was performed with Mann-Whitney U test.
      Table 5Levels of lymphocyte subsets in HCWs with nonsevere and severe COVID-19.
      CategoriesAll (N = 534)Nonsevere (N = 198)Severe (N = 336)P
      B cells (%)9.90 (7.79-12.30)9.90 (7.85-12.08)9.90 (7.72-12.42)0.963
       Elevated12 (2.2%)5 (2.5%)7(2.1%)0.918
       Normal
      Data are shown as the normal ranges of the indicators. Abbreviations: HCWs, healthcare workers; IQR, interquartile range The continuous covariate between two groups was compared with Mann-Whitney U test. The comparison of categoric covariates between two groups was evaluated using chi-square test and Fisher's exact test.
      4.29-18.314.29-17.604.30-18.31
       Decreased15 (2.8%)6 (3.0%)9 (2.7%)
      CD3+ T cells (%)70.67 (64.37-75.92)71.17 (65.15-76.40)70.04 (63.92-75.55)0.254
       Elevated7 (1.3%)0 (0.0%)7(2.1%)0.068
       Normal
      Data are shown as the normal ranges of the indicators. Abbreviations: HCWs, healthcare workers; IQR, interquartile range The continuous covariate between two groups was compared with Mann-Whitney U test. The comparison of categoric covariates between two groups was evaluated using chi-square test and Fisher's exact test.
      58.21-83.8358.34-82.8058.21-83.83
       Decreased58 (10.9%)18 (9.1%)40 (11.9%)
      CD4+ T cells (%)35.58 (31.01-40.36)36.40 (31.49-40.10)35.02 (30.54-40.85)0.280
       Elevated11 (2.0%)3 (1.5%)8 (2.4%)0.423
       Normal
      Data are shown as the normal ranges of the indicators. Abbreviations: HCWs, healthcare workers; IQR, interquartile range The continuous covariate between two groups was compared with Mann-Whitney U test. The comparison of categoric covariates between two groups was evaluated using chi-square test and Fisher's exact test.
      25.40-51.3325.59-51.3325.40-50.41
       Decreased26 (4.9%)7 (3.5%)19 (5.7%)
      CD4+/CD8+ cell ratio1.42 (1.14-1.82)1.42 (1.18-1.77)1.42 (1.09-1.86)0.746
       Elevated22 (4.1%)8 (4.0%)14 (4.2%)0.427
       Normal
      Data are shown as the normal ranges of the indicators. Abbreviations: HCWs, healthcare workers; IQR, interquartile range The continuous covariate between two groups was compared with Mann-Whitney U test. The comparison of categoric covariates between two groups was evaluated using chi-square test and Fisher's exact test.
      0.46-2.720.61-2.720.46-2.72
       Decreased1 (0.2%)1 (0.5%)0 (0.0%)
      CD8+ T cells (%)25.20 (20.76-29.98)25.17 (21.13-29.72)23.35 (20.63-30.39)0.820
       Elevated24 (4.5%)10 (5.1%)14 (4.1%)0.793
       Normal14.24-38.4814.24-38.4814.41-38.32
       Decreased19 (3.6%)6 (3.0%)13 (3.9%)
      NK cells (%)16.89 (12.01-22.75)16.07 (11.98-23.09)17.42 (12.01-22.58)0.668
       Elevated44 (8.2%)15 (7.6%)29 (8.6%)0.852
       Normal
      Data are shown as the normal ranges of the indicators. Abbreviations: HCWs, healthcare workers; IQR, interquartile range The continuous covariate between two groups was compared with Mann-Whitney U test. The comparison of categoric covariates between two groups was evaluated using chi-square test and Fisher's exact test.
      3.51-30.444.58-29.663.51-30.44
       Decreased2 (0.4%)1 (0.5%)1 (0.3%)
      Data are presented as median (IQR) or n (%).
      a Data are shown as the normal ranges of the indicators.Abbreviations: HCWs, healthcare workers; IQR, interquartile rangeThe continuous covariate between two groups was compared with Mann-Whitney U test. The comparison of categoric covariates between two groups was evaluated using chi-square test and Fisher's exact test.
      This study compared the levels and distributions of cytokines and lymphocyte subsets in HCWs with nonsevere and severe COVID-19 and found no statistically significant differences between the two groups (all P-values >0.05). This study also compared the levels of cytokines in 152 HCWs with severe COVID-19 at 11 months and 13 months after discharge. Results showed that levels of all cytokines except IL-2 were lower at 13 months after discharge than at 11 months. Levels of IL-2 were slightly elevated within normal ranges at 13 months after discharge compared with 11 months (Table S2). The characteristics of the HCWs included and excluded from the analyses of immune function were similar (Table S1).

      Discussion

      To the best of our knowledge, this is the first study that focuses on the health consequences of patients with COVID-19 with the longest follow-up time (13 months after discharge), and the study population consisted of HCWs. This study found that at 13 months after discharge from the hospital, there was no statistically significant difference between the HCWs in nonsevere and severe groups regarding recovery of functional fitness, lung function, and immune function. The results of this study found that at 13 months after discharge, a small proportion of HCWs had not recovered their functional fitness (about 30%), had poor lung perfusion (34%), increased IL-6 and NK cells, and decreased relative numbers of CD3+ T cells and CD4 + T cells. Interventions should be implemented timely to help speed recovery in these target populations in the future.
      In this study, approximately 30% of the HCWs had not recovered their functional fitness at 13 months after discharge from the hospital. The results were consistent with the findings of an Italian study, which demonstrated that 32% of the patients were still showing impaired functional fitness up to approximately 3-6 months after infection with SARS-CoV-2 (
      • Baricich A
      • Borg MB
      • Cuneo D
      • Cadario E
      • Azzolina D
      • Balbo PE
      • et al.
      Midterm functional sequelae and implications in rehabilitation after COVID19. A cross-sectional study.
      ). The decline in functional fitness was also found in patients with SARS approximately 1-2 years after discharge from the hospital (
      • Rooney S
      • Webster A
      • Paul L.
      Systematic review of changes and recovery in physical function and fitness after severe acute respiratory syndrome-related coronavirus infection: implications for COVID-19 rehabilitation.
      ). Studies speculated that the causes of the decline in functional fitness might be related to the prolonged time of immobility (
      • Herridge MS
      • Moss M
      • Hough CL
      • Hopkins RO
      • Rice TW
      • Bienvenu OJ
      • et al.
      Recovery and outcomes after the acute respiratory distress syndrome (ARDS) in patients and their family caregivers.
      ), the impairment in lung function (
      • 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 presence of neurologic symptoms (e.g., as skeletal muscle injury) (
      • Cagnazzo F
      • Arquizan C
      • Derraz I
      • Dargazanli C
      • Lefevre PH
      • Riquelme C
      • et al.
      Neurological manifestations of patients infected with the SARS-CoV-2: a systematic review of the literature.
      ), and the inflammatory changes due to cardiac involvement (
      • Cruz Rodriguez JB
      • Lange RA
      • Mukherjee D
      Gamut of cardiac manifestations and complications of COVID-19: a contemporary review.
      ). To date, it is not clear how COVID-19 affects the functional fitness of the patients and for how long the impaired functional fitness will last. Therefore, research regarding mechanisms and a longer follow-up time should be carried out in the future. In addition, rehabilitation guidance should be provided to help their recovery.
      Our study found that up to 34% of the HCWs with COVID-19 had diffusion impairment at 13 months after discharge. Similar to the previous findings, the lung is the organ most affected by infection of SARS-COV-2. Former studies also found abnormal lung function in patients with COVID-19 after discharge or symptom onset (
      • 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.
      ;
      • Milanese M
      • Anselmo M
      • Buscaglia S
      • Garra L
      • Goretti R
      • Parodi L
      • et al.
      COVID-19 6 months after hospital discharge: pulmonary function impairment and its heterogeneity.
      ;
      • Shah AS
      • Wong AW
      • Hague CJ
      • Murphy DT
      • Johnston JC
      • Ryerson CJ
      • et al.
      A prospective study of 12-week respiratory outcomes in COVID-19-related hospitalisations.
      ). The study in Jin Yin-tan Hospital in China reported that approximately 22-56% of patients with various severity scales of COVID-19 had pulmonary diffusion abnormality (DLCO <80%, % of predicted) at 6 months after symptom onset (
      • 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 study in Italy also found that 40% of the patients with COVID-19 had DLCO impairment at 6 months after hospital discharge (
      • Milanese M
      • Anselmo M
      • Buscaglia S
      • Garra L
      • Goretti R
      • Parodi L
      • et al.
      COVID-19 6 months after hospital discharge: pulmonary function impairment and its heterogeneity.
      ). Another prospective cohort in Canada suggested that more than 50% of the patients with COVID-19 had lung function impairment at 12 weeks after symptom onset (
      • Shah AS
      • Wong AW
      • Hague CJ
      • Murphy DT
      • Johnston JC
      • Ryerson CJ
      • et al.
      A prospective study of 12-week respiratory outcomes in COVID-19-related hospitalisations.
      ). In published studies, patients with SARS (
      • Xie L
      • Liu Y
      • Xiao Y
      • Tian Q
      • Fan B
      • Zhao H
      • Chen W.
      Follow-up study on pulmonary function and lung radiographic changes in rehabilitating severe acute respiratory syndrome patients after discharge.
      ) and H1N1 (
      • Bai L
      • Gu L
      • Cao B
      • Zhai XL
      • Lu M
      • Lu Y
      • et al.
      Clinical features of pneumonia caused by 2009 influenza A(H1N1) virus in Beijing.
      ) were also found to have varying degrees of decline in lung diffusing capacity after discharge. The impairment would persist for months or years after discharge. Therefore, it is of significant importance to monitor lung function in patients with COVID-19 after discharge from the hospital for a longer period of time. In addition, effective intervention measures, such as cardiopulmonary exercise (
      • Gao Y
      • Chen R
      • Geng Q
      • Mo X
      • Zhan C
      • Jian W
      • et al.
      Cardiopulmonary exercise testing might be helpful for interpretation of impaired pulmonary function in recovered COVID-19 patients.
      ), should be practiced to help patients regain their regular lung function. Some studies speculate that the mechanisms of the decreased diffusing capacity caused by SARS-COV-2 may be related to angiotensin-converting enzyme 2, lung and multiorgan damage, and functional failure caused by cytokine storm (
      • Iwasaki M
      • Saito J
      • Zhao H
      • Sakamoto A
      • Hirota K
      • Ma D.
      Inflammation triggered by SARS-CoV-2 and ACE2 augment drives multiple organ failure of severe COVID-19: molecular mechanisms and implications.
      ;
      • Mustafa MI
      • Abdelmoneim AH
      • Mahmoud EM
      • Makhawi AM.
      Cytokine storm in COVID-19 patients, its impact on organs and potential treatment by QTY code-designed detergent-free chemokine receptors.
      ), and related mechanism research should also be further carried out.
      Patients infected with the SARS-COV-2 (
      • Qin C
      • Zhou L
      • Hu Z
      • Zhang S
      • Yang S
      • Tao Y
      • et al.
      Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China.
      ;
      • Wan S
      • Yi Q
      • Fan S
      • Lv J
      • Zhang X
      • Guo L
      • et al.
      Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID-19) infected patients.
      ), SARS-COV (
      • Huang KJ
      • Su IJ
      • Theron M
      • Wu YC
      • Lai SK
      • Liu CC
      • et al.
      An interferon-gamma-related cytokine storm in SARS patients.
      ), H7N9 (
      • Zhou J
      • Wang D
      • Gao R
      • Zhao B
      • Song J
      • Qi X
      • et al.
      Biological features of novel avian influenza A (H7N9) virus.
      ), and H5N1 (
      • Henter JI
      • Chow CB
      • Leung CW
      • Lau YL.
      Cytotoxic therapy for severe avian influenza A (H5N1) infection.
      ) were found to have increased levels of cytokines (especially IL-6), which indicated an uncontrolled systemic inflammatory reaction process and might lead to severe immune pathologic damage. Similar to the current study, a study in China demonstrated that 2 weeks after recovery, patients with COVID-19 had elevated levels of IL-6 (20.59%), IL-4 (19.12%), TNF-α (10.29%), IL-17 (2.94%), and IL-10 (1.47%); whereas levels of cytokine in healthy controls were all in normal ranges (
      • Hasichaolu ZX
      • Zhang X
      • Li X
      • Li X
      • Li D.
      Circulating cytokines and lymphocyte subsets in patients who have recovered from COVID-19.
      ). Another study in China compared the levels of cytokines in hospitalized and discharged patients with noncritical COVID-19; it reported that the levels of IL-6, TNF-α, interferon-γ, IL-2, IL-4, and IL-10 were all upregulated in the hospitalized patients (
      • Lin L
      • Luo S
      • Qin R
      • Yang M
      • Wang X
      • Yang Q
      • et al.
      Long-term infection of SARS-CoV-2 changed the body's immune status.
      ). Our previous research explored the cytokine levels in HCWs with severe COVID-19 before discharge, at 5 months, 8 months, and 11 months after discharge. The results suggested that the majority of the HCWs’ cytokine levels gradually returned to normal (showing a trend of decline) (
      • Xiong L
      • Li Q
      • Cao X
      • Xiong H
      • Huang M
      • Yang F
      • et al.
      Dynamic changes of functional fitness, antibodies to SARS-CoV-2 and immunological indicators within 1 year after discharge in Chinese health care workers with severe COVID-19: a cohort study.
      ). The cytokine levels still showed a trend of decline from 11 months to 13 months in HCWs with severe COVID-19. At 11 months after discharge, about one-third of HCWs with severe COVID-19 had elevated cytokine levels (
      • Xiong L
      • Li Q
      • Cao X
      • Xiong H
      • Huang M
      • Yang F
      • et al.
      Dynamic changes of functional fitness, antibodies to SARS-CoV-2 and immunological indicators within 1 year after discharge in Chinese health care workers with severe COVID-19: a cohort study.
      ). This study found that at 13 months after discharge, only 12% of the HCWs (including nonsevere and severe COVID-19) had increased cytokine levels (only IL-6 increased), indicating that the cytokines recovered well in the majority of the participants regardless of disease severity. This study found, for the first time, that the recovery of cytokine levels in HCWs with nonsevere and severe COVID-19 at 13 months after discharge from the hospital was similar, indicating that the immune function of HCWs with severe COVID-19 could also be recovered as well as those with nonsevere COVID-19. However, the specific mechanism is still unclear, and research should be carried out to explore the recovery process further.
      This study found that at 13 months after discharge, the relative numbers of CD3+ T cells, CD4+ T cells, and CD8+ T cells decreased and NK cells increased in HCWs regardless of disease severity. This is similar to our previous results in follow-up visits within 1 year (
      • Xiong L
      • Li Q
      • Cao X
      • Xiong H
      • Huang M
      • Yang F
      • et al.
      Dynamic changes of functional fitness, antibodies to SARS-CoV-2 and immunological indicators within 1 year after discharge in Chinese health care workers with severe COVID-19: a cohort study.
      ). However, the lymphocyte subsets at 13 months after discharge recovered better than within 1 year in HCWs. In addition to our previous study, other research indicates that the immune system gradually recovered after COVID-19 infection. A study in China found decreased levels of CD8+ T cells, CD19+ B cells, total lymphocytes, CD3+ T cells, CD4+ T cells, and CD56+ NK cells in patients with COVID-19 2 weeks after recovery (
      • Hasichaolu ZX
      • Zhang X
      • Li X
      • Li X
      • Li D.
      Circulating cytokines and lymphocyte subsets in patients who have recovered from COVID-19.
      ). Another study in China suggested that the levels of neutrophils, monocytes, NK cells, and CD4+ T cells increased. Levels of total lymphocytes and CD8+ T cells significantly decreased in discharged noncritical patients with COVID-19 than in those who were hospitalized (
      • Lin L
      • Luo S
      • Qin R
      • Yang M
      • Wang X
      • Yang Q
      • et al.
      Long-term infection of SARS-CoV-2 changed the body's immune status.
      ). Published studies showed that levels of lymphocyte subsets were significantly decreased in patients with severe COVID-19 (
      • Huang W
      • Berube J
      • McNamara M
      • Saksena S
      • Hartman M
      • Arshad T
      • Bornheimer SJ
      • O'Gorman M
      Lymphocyte subset counts in COVID-19 patients: a meta-analysis.
      ;
      • Wang F
      • Nie J
      • Wang H
      • Zhao Q
      • Xiong Y
      • Deng L
      • et al.
      Characteristics of peripheral lymphocyte subset alteration in COVID-19 Pneumonia.
      ). Lymphocytes play key roles in viral clearance in patients with COVID-19. The observed decrease of lymphocyte subsets may destroy many immune cells, inhibiting the patients’ cellular immunity. The decreases in lymphocyte subsets after recovery were evidenced to be independent predictors of disease severity and rehabilitation efficacy (
      • Akbari H
      • Tabrizi R
      • Lankarani KB
      • Aria H
      • Vakili S
      • Asadian F
      • et al.
      The role of cytokine profile and lymphocyte subsets in the severity of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis.
      ;
      • Deng Z
      • Zhang M
      • Zhu T
      • Zhili N
      • Liu Z
      • Xiang R
      • et al.
      Dynamic changes in peripheral blood lymphocyte subsets in adult patients with COVID-19.
      ;
      • Wan S
      • Yi Q
      • Fan S
      • Lv J
      • Zhang X
      • Guo L
      • et al.
      Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID-19) infected patients.
      ;
      • Wang F
      • Nie J
      • Wang H
      • Zhao Q
      • Xiong Y
      • Deng L
      • et al.
      Characteristics of peripheral lymphocyte subset alteration in COVID-19 Pneumonia.
      ). Similar T cell depletion was also observed in SAR-CoV and MERS patients (
      • Fung SY
      • Yuen KS
      • Ye ZW
      • Chan CP
      • Jin DY.
      A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses.
      ). However, the mechanisms remain unclear; although there were studies speculating that cytokine storm (
      • Zhang X
      • Tan Y
      • Ling Y
      • Lu G
      • Liu F
      • Yi Z
      • et al.
      Viral and host factors related to the clinical outcome of COVID-19.
      ), lung impairment, and virus (
      • Merad M
      • Martin JC.
      Pathological inflammation in patients with COVID-19. a key role for monocytes and macrophages.
      ) might be involved in the T cell depletion. Future mechanism studies are warranted. Studies with a longer follow-up time are also needed to investigate the impacts of COVID-19 on immune function.
      This research has several limitations. First, this study evaluated the HCWs’ functional fitness recovery from three aspects: muscle strength, flexibility, and agility/dynamic balance. Follow-up studies should also use other evaluation methods, such as the 6-minute walking test, to evaluate the HCWs’ functional fitness recovery. Second, the HCWs did not have a lung function test before infection. Therefore, it was impossible to compare with the results after infection. The number of HCWs with chronic respiratory disease was limited. However, self-reported prevalence of chronic respiratory disease might lead to underestimation. This study speculates that the majority of the HCWs’ lung function at baseline is normal. The interpretation of current results remains valid. Third, this study did not analyze the associations between computed tomography findings and lung function parameters; future studies should focus on these aspects. Fourth, due to laboratory testing methods, only the relative numbers of lymphocyte subsets were available in this study. Follow-up studies should also focus on the differences in the absolute numbers of lymphocyte subsets. Fifth, this study lacked a control group and could not assess the health status of HCWs who were not infected with COVID-19. Future studies should be conducted to compare the health status of HCWs infected and uninfected with COVID-19. Lastly, this study found no statistically significant difference in some aspects of health recovery in HCWs with nonsevere and severe COVID-19. The response rate of follow-up visits may introduce biases to the study findings. However, the characteristics of the HCWs included and excluded from the study were similar. In addition, the low proportion of ICU admission (4%) in HCWs with severe COVID-19 and the high proportion (approximately 40%) of HCWs without supplemental oxygen may also limit generalizability of the study findings to other populations. Therefore, the results achieved in the current study need to be confirmed in larger cohort studies in the future.
      At 13 months after discharge from the hospital, the health consequences of the majority of the HCWs with COVID-19 had returned to normal. The recovery of HCWs with severe COVID-19 is no worse than those with nonsevere COVID-19 in terms of functional fitness, lung function, and immune function. However, it is still necessary to implement timely interventions in helping HCWs to recover fully after discharge from the hospital.

      Funding

      The study was supported by the Rehabilitation Care Project for Medical Staff Infected with COVID-19 in China launched by the Chinese Academy of Engineering and Tencent Foundation. The study's funder had no role in the study design, data collection, analysis, interpretation, or report writing. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

      Declarations of competing interest

      The authors have no competing interests to declare.

      Ethical approval

      According to the principles of the Declaration of Helsinki, this research was approved by the ethics committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. All HCWs signed written informed consents at enrollment.

      Availability of data and materials

      All data generated or analyzed during this study are included in this published article (and its supplementary information files). Because the cohort is still going on, we may not make the data available to others.

      Author contributions

      Hu Y, Xia J, Xiong LJ, Li Q, Cao XJ, Xiong HG, Huang M, and Yang FW designed this study. Hu Y, Xiong LJ, and Li Q were responsible for the integrity of the data and the accuracy of the data analysis. All authors had full access to all of the data in the study. Hu Y, Xia J, and Xiong LJ managed the project and provided guidance. Xiong LJ, Cao XJ, Xiong HG, Meng DQ, Zhou M, Zhang YZ, and Fan YZ collected the data. Xiong LJ, Li Q, Xiong HG, and Tang L analyzed the data. Xiong LJ and Li Q drafted the manuscript. All authors revised the manuscript and gave final approval for the version to be published.

      Appendix. Supplementary materials

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