Clinical characteristics, cause analysis and infectivity of COVID‐19 nucleic acid repositive patients: A literature review

Abstract Coronavirus disease 2019 (COVID‐19) poses a serious threat to human health and lives. The virus is still spreading throughout the world, and the cumulative number of confirmed cases is increasing. After patients with COVID‐19 are treated and discharged, some have repeated clinical symptoms and become positive for nucleic acid tests a second time. Through analysis and review of the existing literature, the proportion of repositive patients in the discharged patient population and their clinical characteristics were systematically described for the first time. Furthermore, an in‐depth analysis of the causes of repositive nucleic acid tests and the potential transmission of the disease provides the basis for the management and protection of discharged patients with COVID‐19.

number of recovered cases is increasing. Further monitoring of the disease prognoses and the use of effective control measures to prevent the recurrence of the epidemic have become the main focus of the country.
Currently, patients who have had COVID-19, and were discharged from hospital after two consecutive negative nucleic acid tests for respiratory pathogens, are being readmitted as a result of being nucleic acid repositive on follow-up visits. On February 27, 2020, the Journal of the American Medical Association, a top international journal, reported that four medical personnel who had been discharged from hospital after receiving treatment for COVID-19 were found to have positive results on pharyngeal swab nucleic acid tests, 4 which causes high levels of confusion and concern among members of the public and medical staff.
However, there is currently insufficient knowledge about the characteristics of repositive patients. In the manuscript, we reviewed the proportion, characteristics, potential reasons, and infectivity of repositive COVID-19 patients to explain this phenomenon. In addition, suggestions for the prevention and control of viral reoccurrence in discharged patients are proposed.

| The proportion and clinical characteristics of repositive patients
A large national study in South Korea identified that 292 (3.3%) out of 8922 recovered patients subsequently have at least one positive test postdischarge, however, does not describe if all recovered patients were tested or if only those cases who were symptomatic were tested postdischarge. 5 In a follow-up of 172 discharged patients, 11 patients were tested positive in nasal Swab and 15 in anal swab, with a positive rate of 14.5%. The average age of these 25 patients was 28 years old, and six of them were children under 12 years old, suggesting that nucleic acid repositive patients are generally younger than other patients. On first hospitalization, fever (68%) and cough (60%) were common symptoms, all of which were mild forms. At readmission, eight patients (32%) developed a mild cough. 6 In a study by An et al., 7 38 of the 226 discharged patients had nucleic acid reactivation with a positive rate of 16.8%. The repositve patients had significant characteristics of "double lightness." When first admitted to the hospital, the patients' clinical symptoms were mild, and almost all of them were those who had had mild and common forms of the disease. Compared with the other discharged patients, their symptoms were less, and the RNA negative conversion time was earlier. Second, the repositive patients were young. Children younger than 14 years old accounted for 35% of the repositive patients, while there was only one repositive patient older than 60 years old. On the contrary, Xiao et al. 8 reported that 15 repositive patients were older than the other 55 discharged patients and their nucleic acid conversion times may have been longer.
In the published literature, there are few of large-sample statistics on the proportion of patients with viral redetectable, and the rate of viral redetectable has been reported to be as low as 3.3% and as high as 30.7% (see Table 1). However, the results of these small-sample-size studies suggest that a significant proportion of discharged patients are carriers of the virus. According to reports of the clinical characteristics of repositive patients, some patients have recurrent clinical symptoms, such as fever and cough. 6,[9][10][11][12] However, a large number of cases showed no clinical symptoms and no change in laboratory indicators or imaging findings. 3,7,8,[13][14][15][16][17][18] Furthermore, the repositive patients tended to be younger, and most of them had mild disease symptoms at the first time of admission. 6,7,13,13,18,19 Compared with other discharged patients, no clinical characteristics or indicators were found to reliably predict the risk of a patient being repositive for SARS-CoV-2, nor were any specific drugs or treatments associated with SARS-CoV-2 reactivation. However, whether there are clinical symptoms or not, such patients are admitted to hospital, provided medicine treatment, monitored for physical changes, and regularly tested for nucleic acid conversion (see Table 1).

| Cause analysis for recovered COVID-19 patients with repositive nucleic acid results
In the existing literature, strict isolation measures continue to be taken for discharged patients, and the chance of reexposure to the source of infection is very low, 7,8,11,11,17 which suggested that nucleic acid repositive patients are not reinfected with SARS-CoV-2, rather, it is likely that the virus was not completely cleared before the patients were discharged from hospital, and their previous nucleic acid test results were false negative. To ascertain why the nucleic acid results were false negative and SARS-CoV-2 is not easily cleared, the etiological and patient characteristics and laboratory tests should be analyzed in combination with the relevant literature.

| Biological characteristics of SARS-CoV-2
Since the outbreak of SARS in 2003 and MERS in 2012, the possibility of coronaviruses spreading from animals to humans has been confirmed. 20,21 SARS-CoV-2 is similar to some of the coronaviruses detected in bats but distinct from SARS-CoV and MERs-CoV. Its conserved replicase domain (ORF1a/b) has less than 90% nucleotide sequence similarity with other β-coronaviruses, thus, it is a new type of coronavirus. [22][23][24][25] Shen et al. 26 recently found a significant level of viral diversity in some infected patients, suggesting the rapid evolution of SARS-COV-2.
During the rapid development of the epidemic, the virus was prone to point mutations during human-to-human transmission. In a latest study, Yuan et al. 6 An et al. 7 Xiao et al. 8 Deng et al. 10 Wong et al. 11 Zhu et al. 12 Ye et al. 13 Li et al. 14 Cao et al. 15 Yuan et al. 18 Number Yuan et al. 6 An et al. 7 Xiao et al. 8 Deng et al. 10 Wong et al. 11 Zhu et al. 12 Ye et al. 13 Li et al. 14 Cao et al. 15 Yuan et al. 18 Clinical

| The duration of infection and condition of the patient
Most patients infected with SARS-COV-2 experience an initial asymptomatic incubation period, followed by mild, severe, and symptomatic remission. 29 The viral load may differ between patients with different disease durations. The outcome of a patient's illness is often affected by many factors. Zheng et al. 30 32 These studies suggest that after recovery from SARS-CoV-2, patients may carry protective antibodies and maintain their immunity for a long time, but the production of antibodies does not necessarily mean that the patient will not be reinfected. Bentivegna et al. 33  Guo et al. 34 found that absolute counts of CD3+ T cells, CD3+CD4+ T cells, and CD3+CD8+ T cells were significantly reduced in patients affected by viral pneumonia death. Therefore, the decreased cellular immune function may affect the development of the disease, which may be related to nucleic acid reactivation in discharged patients.

| Patient's immunity
Liu et al. 35 found that albumin is an independent risk factor for the progression of COVID-19.

| Sampling and testing methods
How closely the collection, preservation, and inspection methods follow the strict recommended standards will affect the quality of the specimens and, ultimately, the accuracy of the nucleic acid test results. In a comparative study of confirmed patients, the nucleic acid detection rate for common swabs was significantly lower than that of flocking swabs using virus preservation solution. 39 Sampling materials, volume, timing, and operation will all affect the test results, for example, throat and Therefore, some highly suspected patients are still negative for SARS-COV-2 in multiple clinical tests. In these cases, the use of more than two reagents is recommended for testing and verification.

| The virus is in other tissues
In early reports, 2-10% of patients with COVID-19 had gastrointestinal symptoms such as diarrhea, abdominal pain, and vomiting. 41,42 Recent evidence has revealed that nucleic acid was redetected in stool swabs and feces of patients with COVID-19. 43,44 Wang et al. 45 reported three discharged patients who were read-