Time and Risk Factors of Viral Clearance in COVID-19 Patients
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a global pandemic. To mitigate the risk of viral transmission, many countries have implemented stringent criteria for hospital discharge and discontinuation of isolation, including two consecutive negative results of reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 RNA on nasopharyngeal swabs collected at least 24 hours apart. Understanding the time of viral clearance is critical for managing patient isolation and optimizing healthcare resources. However, limited data exist on the viral clearance time and its associated risk factors in COVID-19 patients. This study aims to determine the time and risk factors of viral clearance in throat swabs among COVID-19 patients, providing valuable insights into the disease’s natural history and management.
Study Design and Methodology
This retrospective observational study included patients admitted to Zhongnan Hospital of Wuhan University between January 1, 2020, and March 16, 2020, who met the World Health Organization (WHO) definition of COVID-19 and had two consecutive negative SARS-CoV-2 nucleic acid tests after treatment. The study was approved by the institutional ethics board of Zhongnan Hospital of Wuhan University (No. 2020013), and informed consent was waived due to the retrospective nature of the research.
Data collected included demographic information, comorbidities, symptoms on admission, laboratory and imaging findings, development of respiratory failure, treatments administered, time of nucleic acid negative conversion (defined as the number of days from symptom onset to the first undetectable SARS-CoV-2 viral RNA in throat swabs in two consecutive tests), and hospital length-of-stay. Statistical analyses were performed using the Kaplan-Meier method, log-rank test, and multivariate Cox regression to identify factors associated with the time of viral clearance. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated, and a two-tailed p-value < 0.05 was considered statistically significant.
Patient Characteristics and Clinical Findings
A total of 397 COVID-19 patients were included in the study. The median age was 54 years (interquartile range [IQR]: 41–64), and 45.6% (181/397) were male. Hypertension was the most common comorbidity, present in 22.2% (88/397) of patients. The most frequent symptoms on admission were fever (78.6%, 312/397), cough (55.4%, 220/397), and fatigue (35.5%, 141/397). The median time from symptom onset to SARS-CoV-2 nucleic acid negative conversion was 23.5 days (IQR: 15.8–32.3). Notably, 79.5% (248/312) of febrile patients still tested positive for SARS-CoV-2 RNA after temperature recovery. Additionally, 41.0% (128/312) and 17.9% (56/312) of patients remained RT-PCR positive at 7 and 14 days after temperature recovery, respectively. At the end of follow-up, 99.5% (395/397) of patients were discharged, and 0.5% (2/397) had died. The median hospital stay was 14 days (IQR: 10–22).
Factors Associated with Viral Clearance
Univariate analysis using the log-rank test identified several factors associated with the time of SARS-CoV-2 nucleic acid negative conversion. These included age ≥55 years (p = 0.034), development of respiratory failure (p = 0.003), lymphopenia (p < 0.001), corticosteroid therapy (p < 0.001), oseltamivir treatment (p < 0.001), and interferon-alpha treatment (p = 0.004). Multivariate Cox regression analysis revealed that age ≥55 years (HR: 0.791, 95% CI: 0.643–0.973, p = 0.026) and development of respiratory failure (HR: 0.640, 95% CI: 0.518–0.791, p < 0.001) were associated with delayed viral clearance. Conversely, lymphopenia on admission (HR: 1.543, 95% CI: 1.212–1.965, p < 0.001) and corticosteroid therapy (HR: 1.742, 95% CI: 1.310–2.316, p < 0.001) were associated with accelerated viral clearance.
Discussion
The median time of viral clearance in this study was 23.5 days, which is longer than the 10.5 days reported in a study conducted outside Wuhan. This discrepancy may be attributed to differences in healthcare resource availability and the timing of treatment initiation. The findings align with another study conducted in Wuhan, which also reported prolonged viral clearance times. The study highlights that a significant proportion of COVID-19 patients remain RT-PCR positive even after temperature recovery, underscoring the importance of nucleic acid testing in determining patient discharge and isolation discontinuation.
Older age was associated with delayed viral clearance, likely due to age-related declines in T cell function and proliferation, which impair the ability to control viral replication. The development of respiratory failure was also linked to delayed clearance, consistent with previous reports that patients with persistent viral presence tend to have more severe disease outcomes. Lymphopenia on admission was associated with rapid viral clearance, possibly due to the activation of the hypothalamic-pituitary-adrenal axis during viral infections, leading to cortisol secretion and lymphocyte redistribution to infected sites. Corticosteroid therapy was found to shorten the time of viral clearance, contrary to some studies that suggested delayed clearance with corticosteroid use. This discrepancy may be related to the timing of corticosteroid initiation, which was based on clinical indicators such as fever progression, dyspnea, and oxygen saturation levels in this study.
Limitations
This study has several limitations. First, it did not assess the time of nucleic acid negative conversion in blood, stool, or urine samples. Second, viral loads (Ct values) were not recorded, limiting the ability to correlate viral load with clearance time. Third, the study relied on RT-PCR for viral detection, which cannot distinguish between viable and non-viable virus, potentially overestimating the duration of infectivity.
Conclusion
In conclusion, this study provides valuable insights into the time and risk factors of viral clearance in COVID-19 patients. Viral clearance often occurs after temperature recovery, with older age and respiratory failure associated with delayed clearance, while lymphopenia and corticosteroid therapy are linked to accelerated clearance. These findings have important implications for patient management and public health strategies during the COVID-19 pandemic.
doi.org/10.1097/CM9.0000000000001467
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