key: cord-0778634-coaain16 authors: Hong, Lu-Xiao; Liu, Lian; Lin, Aifen; Yan, Wei-Hua title: Risk factors for SARS-CoV-2 re-positivity in COVID-19 patients after discharge date: 2021-03-12 journal: Int Immunopharmacol DOI: 10.1016/j.intimp.2021.107579 sha: 6a4d3381605a578e01bc0078ad15a510ce7258da doc_id: 778634 cord_uid: coaain16 Objective Re-positivity of SARS-CoV-2 in discharged COVID-19 patients have been reported; however, early risk factors for SARS-CoV-2 re-positivity evaluation are limited. Methods This is a prospective study, a total of 145 COVID-19 patients were treated and all discharged according to the guideline criteria by Mar 11th 2020. After discharge, clinical visits and viral RT-PCR tests by the second and fourth week follow-up were carried-out. Patient demographic and clinical characteristics and laboratory data on admission and discharge were retrieved, and predictive factors for SARS-CoV-2 re-positivity were analyzed. Results 13 out of 145 (9.0%) COVID-19 patients were confirmed re-positivity of SARS-CoV-2 by RT-PCR test. The median interval between disease onset to recurrence was 38 days. SARS-CoV-2 re-positive cases were of significantly longer virus shedding duration, notably higher body temperature, heart rate and lower TNF-α and IgG levels on admission. Covariate logistic regression analysis revealed virus shedding duration and IgG levels are independent risk factors for SARS-CoV-2 return positive after discharge. Conclusion Longer viral shedding duration and lower IgG levels are risk factors for re-positivity of SARS-CoV-2 for discharged COVID-19 patients. The Coronavirus disease 2019 pandemic is still threatening since December 2019. Great efforts such as quarantine policies and medical cares have been taken to contain the pandemic spreading [1] . Among different cohorts studied in previous studies, the proportion of patients with SARS-CoV-2 re-positivity after discharge varies from 2.4% to 69.2% [3] . Du et al. [6] reported that 3 out of 126 (2.4%) COVID-19 patients were tested re-positivity of SARS-CoV-2 but asymptomatic after their discharge. In a rather limited size, only 13 cases of Iranian COVID-19 patients, Habibzadeh et al. [7] found 9 (69.2%) of them were SARS-CoV-2 re-positive. In South Korea, with a larger cohort of 8922 COVID-19 patients, 2923 (3.3%) were confirmed to be re-positivity of SARS-CoV-2 [8]. Though most of the recurrence of SARS-CoV-2 among COVID-19 cases after discharge are asymptomatic, public concerns on risk of infectious potential from these recovered COVID-19 patients with SARS-CoV-2 re-positivity is reasonable, as human-to-human transmission of SARS-CoV-2 from asymptomatic patients was emphasized in previous studies [9, 10]. However, early predictive risk factors for re-positivity of SARS-CoV-2 after discharge are unavailable yet. In this prospective study, among 145 discharged COVID-19 patients, SARS-CoV-2 RT-PCR tests by the second and fourth week during follow-up were carried-out, 13 of them were confirmed to be SARS-CoV-2 re-positive. Patient demographic and clinical characteristics and laboratory data on admission were retrieved, and risk factors for SARS-CoV-2 re-positivity were evaluated. From 19 th January 2020, 145 consecutive laboratory confirmed COVID-19 cases were hospitalized and treated at our officially designated medical center for COVID- Continuous variables were presented as median and range or meanstandard deviation (SD), and comparison between groups were analyzed with Mann-Whitney U test. Categorical variables were presented as as counts and percentages, and difference between groups were analyzed with χ 2 test. Covariate binary logistic regression analysis with forward conditional method (co-variables with p<0.200 were included) glucocorticoids treatments were prescribed to 47 patients. All of them were discharged by Mar 11 th 2020. By May 26 th , 13 out of these 145 patients (9.0%; 7 male and 6 female; median age: 54 years) were re-admitted to our hospital due to re-positivity of SARS-CoV-2 during follow-up viral test, but all of them without COVID-19 symptoms. Of them, 12 patients whose SARS-CoV-2 returned to be positive by the 1 st follow-up and one patient by the 2 nd follow-up viral test after discharge. Among 13 COVID-19 patients with SARS-CoV-2 re-positivity, the median interval from symptom onset to SARS-CoV-2 re-positivity is 38 days (range: 26 days to 65 days). The detail clinical features on admission of these COVID-19 patients with SARS-CoV-2 negative and re-positivity after discharge were shown in Table 1 . Among these discharged COVID-19 patients, patients with SARS-CoV-2 re-positivity were found to be higher body temperature (37.4℃ vs. 37.0℃, p=0.086) and heart rate (89/min vs. 82/min, p=0.061) on admission, and to be elder (54 years vs. 47 years, p=0.343) and longer hospital stays (23 days vs. 20 days, p=0.181) than those with SARS-CoV-2 remain negative after discharge. Moreover, no statistical difference was observed between the two groups in terms of corticosteroid treatment status. However, SARS-CoV-2 re-positive cases had a significantly longer virus shedding duration (17 days vs. 12 days; p=0.011; Table 1 ). On the day of admission, data revealed that discharged COVID-19 patients with To be noted, other laboratory findings were not significantly different between the two groups. Furthermore, no statistical difference was also observed for these variables on the day of discharge between the two groups (Table 2) . (Table 3) . ROC analysis results showed that the area under curve (AUC) for viral shedding duration is 0.713 (95% CI: 0.549 ~ 0.876; p = 0.012; Figure 1A) , with an optimal cut-off of 15.5 days (sensitivity: 0.714; specificity: 0.710). AUC for IgG levels is 0.704 (95% CI: 0.538 ~ 0.870; p = 0.020), with an optimal cut-off of 12.1 g/L (sensitivity: 0.609; specificity: 0.750; Figure 1B ). While the pandemic COVID-19 is still threatening the public health worldwide, a certain proportion of SARS-CoV-2 nucleic acid returned to be positive in discharged COVID-19 patients during their convalescent stage also deserves our attention [13] . The percentage of SARS-CoV-2 re-positivity in discharged COVID-19 patients varies markedly depending on the different cohorts studied, which ranges from 2.4% to 69.2%, while most patients with SARS-CoV-2 re-positivity after discharge are asymptomatic or have mild symptoms according to previous reports [6, 7, 14] . A recent systematic meta-analysis included 14 studies (13 conducted in China and one in Brunei) published between 17 th Mar 2020 and 29 th May 2020, 318 out of 2568 COVID-19 patients were experienced SARS-CoV-2 re-positivity with the pooled estimated incidence with 14.8% [15] . Authors also reported that the estimated interval between disease onset to the SARS-CoV-2 re-positivity is 35.4 days. In our study, the median interval between disease onset to the SARS-CoV-2 re-positivity is 38.0 days (range: 26.0 days ~65.0 days). Though the re-positivity of SARS-CoV-2 among discharged patients with COVID-19 is a common phenomenon, detail cause for this is unclear. In this context, several explanation for the re-positivity of SARS-CoV-2 have been addressed, which could be caused by the false RT-PCR test or environmental contamination [16] , SARS-CoV-2 reactivation [2], re-infected with the same or another SARS-CoV-2 strain [17, 18] , intermittent virus shedding or prolonged viral nucleic acid conversion [19, 20] . Fortunately, no case has been reported due to the contact with SARS-CoV-2 re-positive patients to date. However, few COVID-19 patients with re-positivity of SARS-CoV-2 do have clinical consequences. In a case report with SARS-CoV-2 re-positivity, authors supposed that a weak humoral immune response with very low anti-SARS-CoV-2 antibody may account for the virus reactivation [17] . However, a cohort with 11 out of 150 COVID-19 patients (7.3%) confirmed to be re-positive of SARS-CoV-2, no remarkable difference was observed for both prevalence and levels of IgM or IgG to SARS-CoV-2 between patients with SARS-CoV-2 re-positive and those not, indicating that humoral immune response could not be a main factor for the SARS-CoV-2 re-positivity [21] . SARS-CoV-2 re-positivity by re-infection with another SARS-CoV-2 strain also has been described. To et al. [18] revealed that a COVID-19 patient re-infected with another SARS-CoV-2 strain and became SARS-CoV-2 re-positivity after 142 days. As human-to-human transmission of SARS-CoV-2 from asymptomatic patients was emphasized in previous studies [9, 22] . However, being lack the evidence of virus isolation, whether virus replicated or reactivated, or only the 'dead virus' genetic materials remain to be investigated, the potential of infectivity can't be ignored among discharged COVID-19 patients with SARS-CoV-2 re-positivity. Thus, early predictive risk factors for re-positivity of SARS-CoV-2 after discharge could be of significance in prevention and management of the disease. Indeed, more and more studies focusing on risk factors for the prediction of SARS-CoV-2 re-positivity have been released, however, conclusions remain controversial. The discrepancy across studies could be caused by heterogeneity of the cohorts, such as difference in cohort size, patient gender, age, treatment regime and physical or laboratory index included to analysis. In this context, data revealed that COVID-19 patients with younger, mild and moderate severity and higher lymphocyte counts were prone to be SARS-CoV-2 re-positive after discharge [15, 23] , while cases with elder age above 60 years, severe and higher higher lymphocyte counts were found to be SARS-CoV-2 re-positive in other studies [19, 24, 25, 26] . In our study, data showed that patients with longer viral shedding duration and lower serum IgG levels are significantly related to the recurrence of SARS-CoV-2 after discharge, but not with patient age, severity and the corticosteroid treatment. The underlying mechanisms for delayed SARS-CoV-2 shedding remain elusive. We previously reported that lower CD8+ T cells is an predictive factor for the delayed viral shedding [12] , which echoes findings that immune suppression such as excessive usage of corticosteroid for or COVID-19 treatment or immunocompromised patients whose adaptive immune function including T and B cells were impaired have been related to the prolonged viral shedding [27, 28] . In addition to laboratory findings, other clinical data such as chronic rhinosinusitis and atopy have been found to be related to an increased risk for delayed viral shedding [29] . However, no relationship was observed between the viral shedding duration and symptoms or pre-existing disorders in this study (data not shown). In summary, our findings revealed that longer viral shedding duration and lower IgG levels on admission are risk factors for re-positivity of SARS-CoV-2. Obviously, our study have several limitations. First, the major limitation is that our study is based on a rather small cohort from our single medical center, and only 13 patients Technology Bureau of Taizhou (1901ky01; 1901ky04) . This study was approved by the Ethics committee of the Taizhou Hospital of Zhejiang Province (#K20200111). Written informed consent was obtained from all patients or guardian. The authors have declared no conflict of interest. p=0.020 Mask wearing in pre-symptomatic patients prevents SARS-CoV-2 transmission: An epidemiological analysis Re-positive coronavirus disease 2019 PCR test: could it be a reinfection? New Microbes New Infect SARS-CoV-2-Positive Sputum and Feces After Conversion of Pharyngeal Samples in Patients With COVID-19 Recurrent SARS-CoV-2 RNA positivity after COVID-19: a systematic review and meta-analysis SARS-CoV-2 environmental contamination associated with persistently infected COVID-19 patients, Influenza Other Respir Recurrent pneumonia in a patient with new coronavirus infection after discharge from hospital for insufficient antibody production: a case report COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing Clinical characteristics of recovered COVID-19 patients with re-detectable positive RNA test False negative of RT-PCR and prolonged nucleic acid conversion in COVID-19: Rather than recurrence Recurrent positive SARS-CoV-2: Immune certificate may not be valid Infection and Transmission Kinetics of SARS-CoV-2 positivity of infected and recovered patients from a single center Probable causes and risk factors for positive SARS-CoV-2 test in recovered patients: Evidence from Brunei Darussalam Clinical course and risk factors for recurrence of positive SARS-CoV-2 RNA: a retrospective cohort study from Wuhan, China Prevalence and impact factors of recurrent positive SARS-CoV-2 detection in 599 hospitalized COVID-19 patients Factors associated with delayed viral shedding in COVID-19 infected patients: A retrospective small-scale study Long term SARS-CoV-2 infectiousness among three immunocompromised patients: from prolonged viral shedding to SARS-CoV-2 superinfection Declarations Author Contributions: Concept and design, manuscript drafting and statistical analysis Acquisition, analysis, or interpretation of data Funding Information This work was supported by grants from Compliance with Ethical Standards This study was approved by the Ethics committee of the Taizhou Hospital of Zhejiang Province (#K20200111) Re-positivity of SARS-CoV-2 among discharged COVID-19 patients is common. 2. Early risk factors for SARS-CoV-2 re-positivity remain elusive Longer viral shedding duration and lower IgG are risk factors for re-positivity of SARS-CoV-2