COVID-19 is a global pandemic that has rapidly spread worldwide since reported in December 2019. A negative nucleic acid test of SARS-CoV-2 is the standard for a cure of COVID-19. To investigate the timeline of RNA negative conversion of COVID-19 patients, this study retrospectively analyzed clinical characteristics in a cohort of mild/moderate hospitalized patients in Chongqing, China. We found that fever, nausea, diarrhea, and abnormalities in chest CT were correlated to a prolonged NCT of SARS-CoV-2 RNA. More importantly, fever and nausea were the independent factors predicting NCT of mild/moderate COVID-19 patients.
Fever, a respiratory manifestation, is the most commonly reported symptom in patients infected with SARS-CoV-2 [14, 15]. Accordingly, fever may be a clinical sign of poor prognosis in patients and response to the release of inflammatory mediators such as cytokines and chemokines [16] [17]. These inflammatory mediators cause tissue damage and organ dysfunction by stimulating toxic oxygen derivatives suggesting that the NCT of SARS-CoV-2 RNA may be prolonged in patients [18, 19].
Chest CT has a high sensitivity to detect lung abnormalities, which is quite helpful in the early diagnosis of the disease. The “Diagnosis and Treatment Scheme for Coronavirus Disease (Trial Version 7)” recommended that a CT examination serves as the diagnostic basis for COVID-19. For chest imaging in patients with COVID-19, the early manifestation was multiple plaque shadows and interstitial changes. The later development was multiple ground glass shadows and infiltration shadows in both lungs. In severe cases, lung consolidation can occur, presenting as “white lung,” which may be related to the immunopathology. Most studies have suggested that a dysregulated/exuberant innate responses are the primary cause of coronavirus-mediated pathology [20]. Many cytokines or chemokines are involved in the immune storm after the infection of coronavirus,which eventually leads to lung injury and acute respiratory distress syndrome [21]. The improvement of chest CT was after that of body temperature. Still, it preceded the negative conversion of nucleic acid tests, suggesting that abnormalities in chest CT could indirectly reflect the persistence of SARS-CoV-2 RNA in patients with COVID-19. Our study found that abnormalities in chest CT could prolong the NCT of patients with COVID-19. Therefore, the improvement of chest CT as soon as possible has an essential effect on shortening NCT in patients with COVID-19 and promoting patients to be discharged more rapidly.
Although COVID-19 most commonly presents with respiratory symptoms, such as cough and shortness of breath [14, 22, 23], there is evidence that the illness can also present with nonrespiratory symptoms, most notably digestive symptoms such as diarrhea, diminished appetite, nausea, and vomiting [24–26]. Diarrhea appeared to be the most common GI complaint [27], followed by nausea and vomiting [22]. SARS-CoV-2 RNA was detected in stool samples from COVID-19 patients for the first time, first reported in the United States [28]. Viral RNA was still positive in gastrointestinal specimens even after levels could not be detected in respiratory samples [27], implying direct infectivity of the virus on the intestinal tract. Current research shows that the primary target organ of COVID-19 is the lung, but clinical evidence suggests that the gastrointestinal tract may be another viral target organ.
The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) has been found in both upper and lower gastrointestinal tract where its expression level was nearly 100 times higher than that of respiratory organs [29, 30]. Patients with symptoms of the digestive system have more viruses in their gut [10], and maybe more likely to cause direct damage to the intestinal mucosa. Our research found that digestive symptoms, including nausea and diarrhea, are the factors of NCT of COVID-19 patients, suggesting that patients with gastrointestinal symptoms should seek medical care to avoid delayed diagnosis and prolong treatment time.
Chinese experts recommend that patients diagnosed as mild, moderate, and severe cases of COVID-19 pneumonia and without contraindications to chloroquine, be treated with 500 mg of chloroquine twice a day for ten days[31]. In our study, when SARS-CoV-2 RNA was still detectable after 19 days of drug combination therapy, chloroquine was added to the antiviral treatment. Thirteen patients were treated with chloroquine and a median duration of viral shedding of 6.0 (IQR: 5.0–7.0) days. Therefore, these results suggest that chloroquine may play a role in reducing viral load and shortening the time of virus negative transition. Other studies have also confirmed the role of chloroquine in promoting virus negative conversion and shortening the disease course. Other studies have also confirmed the role of chloroquine in promoting virus negative conversion, shortening the course of the disease [11] and reducing/eliminating viral load in COVID-19 patients [32]. However, we did not conduct a randomized controlled study to evaluate the efficacy of chloroquine and most infections with COVID-19 were self-limited, about 15% of infected adults developed severe pneumonia that required treatment [22, 33], the numerical reduction in time to clinical improvement in those treated with chloroquine requires confirmation in more extensive studies.
There are several limitations to our study. First, the sample size of this study is not large enough. Second, we have not conducted randomized controlled trials, so we cannot determine the therapeutic effect of chloroquine on COVID-19 and its impact on shortening the time of negative viral conversion.