Abstract: Background: The proportion of recurrences after discharge among patients with coronavirus disease 2019 (COVID-19) was reported to be between 9.1% and 31.0%. Little is known about this issue, however, so we performed a meta-analysis to summarize the demographical, clinical, and laboratorial characteristics of non-recurrence and recurrence groups. Methods: Comprehensive searches were conducted using eight electronic databases. Data regarding the demographic, clinical, and laboratorial characteristics of both recurrence and non-recurrence groups were extracted, and quantitative and qualitative analyses were conducted. Results: Ten studies involving 2071 COVID-19 cases were included in this analysis. The proportion of recurrence cases involving patients with COVID-19 was 17.65% (between 12.38% and 25.16%) while older patients were more likely to experience recurrence (weighted mean difference (WMD)=1.67, range between 0.08 and 3.26). The time from discharge to recurrence was 13.38 d (between 12.08 and 14.69 d). Patients were categorized as having moderate severity (odds ratio (OR)=2.69, range between 1.30 and 5.58), while those with clinical symptoms including cough (OR=5.52, range between 3.18 and 9.60), sputum production (OR=5.10, range between 2.60 and 9.97), headache (OR=3.57, range between 1.36 and 9.35), and dizziness (OR=3.17, range between 1.12 and 8.96) were more likely to be associated with recurrence. Patients presenting with bilateral pulmonary infiltration and decreased leucocyte, platelet, and CD4⁺ T counts were at risk of COVID-19 recurrence (OR=1.71, range between 1.07 and 2.75; WMD=−1.06, range between −1.55 and −0.57, WMD=−40.39, range between −80.20 and −0.48, and WMD=−55.26, range between −105.92 and −4.60, respectively). Conclusions: The main factors associated with the recurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after hospital discharge were older age, moderate severity, bilateral pulmonary infiltration, laboratory findings including decreased leucocytes, platelets, and CD4⁺ T counts, and clinical symptoms including cough, sputum production, headache, and dizziness. These factors can be considered warning indicators for the recurrence of SARS-CoV-2 and might help the development of specific management strategies.

新型冠状病毒肺炎患者出院后SARS-CoV-2复阳的危险因素:系统评价和meta分析

[1]Ades AE, Lu G, Higgins JPT, 2005. The interpretation of random-effects meta-analysis in decision models. Med Decis Making, 25(6):646-654.

[2]Ahmad I, Rathore F, 2020. Neurological manifestations and complications of COVID-19: a literature review. J Clin Neurosci, 77:8-12.

[3]Altmann DM, Boyton RJ, 2020. SARS-CoV-2 T cell immunity: specificity, function, durability, and role in protection. Sci Immunol, 5(49):eabd6160.

[4]An JH, Liao XJ, Xiao TY, et al., 2020. Clinical characteristics of the recovered COVID-19 patients with re-detectable positive RNA test. Ann Transl Med, 8(17):1-12.

[5]https://doi.org/10.21037/atm-20-5602

[6]Bellesi S, Metafuni E, Hohaus S, et al., 2020. Increased CD95 (Fas) and PD-1 expression in peripheral blood T lymphocytes in COVID-19 patients. Br J Haematol, 191(2):207-211.

[7]Cai JH, Xu J, Lin DJ, et al., 2020. A case series of children with 2019 novel coronavirus infection: clinical and epidemiological features. Clin Infect Dis, 71(6):1547-1551.

[8]Cauchemez S, van Kerkhove MD, Riley S, et al., 2013. Transmission scenarios for Middle East respiratory syndrome coronavirus (MERS-CoV) and how to tell them apart. Euro Surveill, 18(24):20503.

[9]Chen DB, Xu WX, Lei ZY, et al., 2020. Recurrence of positive SARS-CoV-2 RNA in COVID-19: a case report. Int J Infect Dis, 93:297-299.

[10]Chen J, Xu XP, Hu J, et al., 2020. Clinical course and risk factors for recurrence of positive SARS-CoV-2 RNA: a retrospective cohort study from Wuhan, China. Aging, 12(17):16675-16689.

[11]https://doi.org/10.18632/aging.103795

[12]Chen NS, Zhou M, Dong X, et al., 2020. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet, 395(10223):507-513.

[13]Cui J, Li F, Shi ZL, 2019. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol, 17(3):181-192.

[14]Guo LX, Wei D, Zhang XX, et al., 2019. Clinical features predicting mortality risk in patients with viral pneumonia: the MuLBSTA score. Front Microbiol, 10:2752.

[15]Hoang VT, Dao TL, Gautret P, 2020. Recurrence of positive SARS-CoV-2 in patients recovered from COVID-19. J Med Virol, 92(11):2366-2367.

[16]Hottz ED, Azevedo-Quintanilha IG, Palhinha L, et al., 2020. Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood, 136(11):1330-1341.

[17]Hu RJ, Jiang ZX, Gao HM, et al., 2020. Recurrent positive reverse transcriptase-polymerase chain reaction results for coronavirus disease 2019 in patients discharged from a hospital in China. JAMA Netw Open, 3(5):e2010475.

[18]Huang J, Zheng L, Li Z, et al., 2020. Recurrence of SARS-CoV-2 PCR positivity in COVID-19 patients: a single center experience and potential implications. medRxiv, preprint.

[19]Hui KPY, Cheung MC, Perera RAMP, et al., 2020. Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures. Lancet Respir Med, 8(7):687-695.

[20]Jaiswal S, Liu XB, Wei QC, et al., 2018. Effect of corticosteroids on atrial fibrillation after catheter ablation: a meta-analysis. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 19(1):57-64.

[21]Jiang ML, Li Y, Han ML, et al., 2020. Recurrent PCR positivity after hospital discharge of people with coronavirus disease 2019 (COVID-19). J Infect, 81(1):147-178.

[22]Khose S, Moore JX, Wang HE, 2020. Epidemiology of the 2020 pandemic of COVID-19 in the state of Texas: the first month of community spread. J Community Health, 45(4):696-701.

[23]Li LQ, Huang SL, 2020. Whether the repositive rate of 14% of discharged patients in guangdong is infectious is not clear. Caixin (in Chinese). http://china.caixin.com/2020-02-25/ 101520334.html

[24]Li N, Wang X, Lv TF, 2020. Prolonged SARS-CoV-2 RNA shedding: not a rare phenomenon. J Med Virol, 92(11):2286-2287.

[25]Li Q, Zhang H, Deng SY, et al., 2020. Expression and morphological analysis of peripheral blood lymphocytes subsets in patients with 2019 noval coronavirus. Chongqing Med, online (in Chinese).

[26]Li TS, Lu HZ, Zhang WH, 2020. Clinical observation and management of COVID-19 patients. Emerg Microbes Infect, 9(1):687-690.

[27]Li YJ, Hu YY, Yu YY, et al., 2020. Positive result of Sars-Cov-2 in faeces and sputum from discharged patient with COVID-19 in Yiwu, China. J Med Virol, 92(10):1938-1947.

[28]Lippi G, Plebani M, Henry BM, 2020. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis. Clin Chim Acta, 506:145-148.

[29]Liu S, Zhi YX, Ying S, 2020. COVID-19 and asthma: reflection during the pandemic. Clin Rev Allergy Immunol, 59(1):78-88.

[30]Liu W, Tao ZW, Wang L, et al., 2020. Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease. Chin Med J, 133(9):1032-1038.

[31]Luo DH, Wan X, Liu JM, et al., 2018. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods in Med Res, 27(6):1785-1805.

[32]Medical Administration and Hospital Authority, 2020. National Health Commission’s COVID-19 Diagnosis and Treatment Protocol (Trial Version 7) (in Chinese). http://www.nhc.gov.cn/yzygj/s7652m/202003/a31191442e29474b98bfed5579d5af95.shtml

[33]National Health Commission of the People’s Republic of China, 2020. Update on COVID-19 as of 24:00, March 17 (in Chinese). http://www.nhc.gov.cn/xcs/yqtb/202003/97b96f03fa3c4e8d8d0bf536271a10c0.shtml

[34]Peters JL, Sutton AJ, Jones DR, et al., 2006. Comparison of two methods to detect publication bias in meta-analysis. JAMA, 295(6):676-680.

[35]Radzikowska U, Ding M, Tan G, et al., 2020. Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors. Allergy, 75(11):2829-2845.

[36]Remy KE, Mazer M, Striker DA, et al., 2020. Severe immunosuppression and not a cytokine storm characterizes COVID-19 infections. JCI Insight, 5(17):e140329.

[37]Rothan HA, Byrareddy SN, 2020. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun, 109:102433.

[38]Song JW, Zhang C, Fan X, et al., 2020. Immunological and inflammatory profiles in mild and severe cases of COVID-19. Nat Commun, 11(1):3410.

[39]Stang A, 2010. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol, 25(9):603-605.

[40]Wong J, Koh WC, Momin RN, et al., 2020. Probable causes and risk factors for positive SARS-CoV-2 test in recovered patients: evidence from Brunei Darussalam. J Med Virol, 92(11):2847-2851.

[41]Wu ZY, McGoogan JM, 2020. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA, 323(13):1239-1342.

[42]Xiao AT, Tong YX, Zhang S, 2020. False negative of RT-PCR and prolonged nucleic acid conversion in COVID-19: rather than recurrence. J Med Virol, 92(10):1755-1756.

[43]Xu YG, Lu YQ, 2019. Systematic review and meta-analysis of the efficacy and safety of immunosuppressive pulse therapy in the treatment of paraquat poisoning. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 20(7):588-597.

[44]Yang Y, Yang MH, Shen CG, et al., 2020. Laboratory diagnosis and monitoring the viral shedding of SARS-CoV-2 infections. Innovation, 1(3):100061.

[45]https://doi.org/j.xinn.2020.100061

[46]Ye GM, Pan ZY, Pan YB, et al., 2020. Clinical characteristics of severe acute respiratory syndrome coronavirus 2 reactivation. J Infect, 80(5):e14-e17.

[47]Yuan J, Zou RR, Zeng LJ, et al., 2020. The correlation between viral clearance and biochemical outcomes of 94 COVID-19 infected discharged patients. Inflamm Res, 69(6):599-606.

[48]Zhang BC, Zhou XY, Qiu YR, et al., 2020. Clinical characteristics of 82 cases of death from COVID-19. PLoS ONE, 15(7):e0235458.

[49]Zhao WP, Wang Y, Tang YF, et al., 2020. Characteristics of children with reactivation of SARS-CoV-2 infection after hospital discharge. Clin Pediatr, 59(9-10):929-932.

[50]Zhou L, Liu K, Liu HG, 2020. Cause analysis and treatment strategies of “recurrence” with novel coronavirus pneumonia (COVID-19) patients after discharge from hospital. Chin J Tuberc Respir Dis, 43(4):281-284 (in Chinese).

[51]Zhuo L, Wei FF, Zhou JQ, et al., 2020. Factors influencing the outcome of 34 patients with COVID-19. J Pract Med, 36(14):1861-1865 (in Chinese).

[52]List of electronic supplementary materials

[53]Table S1 Search strategy of the recurrence cases with COVID-19

[54]Fig. S1 Forest plots of meta-analysis on the proportion of the asymptomatic individuals among the COVID-19 infections

[55]Fig. S2 Forest plots of meta-analysis on clinical characteristics and laboratory findings of the recurrence cases among the COVID-19 infections

[56]Fig. S3 Funnel plot assessing publication bias in studies reporting proportion of recurrence cases among the COVID-19 patients