Recently, patients with COVID-19 who showed persistently positive SARS-CoV-2 nucleic acid test results despite resolved clinical symptoms have attracted a lot of attention. Li et al. reported one patient who had persistently positive SARS-CoV-2 nucleic acid test results until Day 49 after disease onset . In our study, we have reported a patient who achieved clinical recovery but showed persistently positive SARS-CoV-2 nucleic acid test results until Day 92 after disease onset, which is currently the longest reported period for positive SARS-CoV-2 nucleic acid test results. The pathogenesis of this phenomenon is unclear, and the implications of these patients being potential sources of infection require further confirmation. It may also be pertinent to further examine the subsequent management and treatment of such patients.
A study using ultra-deep sequencing of 11 patient-derived virus isolates showed that there are 33 mutations in SARS-CoV-2, of which 19 are novel mutations . Among these patients, patient number 11 showed persistent positivity for viral nucleic acids for 45 days, and 3 nucleotide mutations were found in that particular virus isolate. Subsequent experiments analyzed the replication speed and pathogenicity, and suggested that persistent nucleic acid positivity may be associated with virus mutations. Another study reported a patient with COVID-19 who died due to stroke, and the nasopharyngeal swab samples from that patient tested negative for SARS-CoV-2 in 3 continuous polymerase chain reaction tests. However, electron microscopic and immunohistochemical staining (IHC) images showed the presence of residual SARS-CoV-2 in the patient’s lungs. That study provided a new understanding of SARS-CoV-2 infection . The patient in our study tested negative for viral nucleic acids thrice in a row but tested positive during follow-up. This shows that even two consecutively negative results on the nucleic acid test cannot be used as a marker of in vivo viral clearance. This new data shows the possibility that infection may persistent after clinical recovery in COVID-19 and even evolve to chronic infection. Peripheral blood lymphocytopenia is common in patients with COVID-19, and their autopsies show lymph nodal and spleen damage, suggesting that immune system damage may be a mechanism of persistent infection. There was no significant correlation between the in vivo SARS-CoV-2 N protein antibody changes and the nucleic acid test results seen in that patient. This may be because the N antibodies are not neutralizing antibodies. Regrettably, S antibody was not monitored at that time due to limitations. In addition, the interplay between the virus and immune system may lead to immune evasion or induced immune tolerance, which may need to be analyzed by further in-depth studies. These patients do not require long-term inpatient quarantine for their post-discharge management, as their infectivity is lower. Hence, it is recommended that they should quarantine at home for an extended period and undergo periodic SARS-CoV-2 nucleic acid tests, and should be observed for adverse outcomes due to persistent viral infection.
There is still a lot of debate on whether these patients are infectious and their infectivity. Positive viral nucleic acid test results show remaining viral genetic activity in this patient, and there have been reports of infectious viruses isolated from patient samples ; however, there has been no prior report suggesting that convalescent patients who test persistently positive for viral nucleic acids may infect others or cause local outbreaks. A recent study of 262 recovered patients found that there were 38 patients who tested positive for nucleic acids after recovery, but 21 close contacts of these patients tested negative, suggesting that they were not infected . A possible explanation is that such patients are often quarantined in hospitals, and individual and social preventive measures are adopted, which causes disease transmission to be lower. Conversely, in the case of our patient, although viral nucleic acid test results for sputum samples were positive on March 17 and 24, but his nasal and oral cavities, hands, and inner surface of mask all tested negative. His personal belongings and objects in his surrounding environment, including his cell phone, bed rail, floors, and toilet bowl surfaces too tested negative, showing that the surrounding environment was not contaminated with the virus. This may be because this patient did not cough, expectorate, or show other behavior that could expel the virus from the respiratory tract, suggesting low possibility of infectivity.
As the prognoses and infectivity of patients with such persistent infection are unknown, it remains debatable whether an active search for effective antiviral treatment for such patients should be conducted. Currently, there are no drugs against the SARS-Cov-2 that have proven effective in clinical trials. Although remdesivir is considered the most promising antiviral drug, the local and overseas clinical trials have seen inconsistent results [8, 9]. This may be due to differences in selected timing for antiviral treatment, number of patients, and treatment endpoints. Our patient successively received different antiviral treatments as recommended in the Chinese guidelines, such as interferon nebulization, umifenovir, chloroquine phosphate, and convalescent phase plasma, but did not show persistent and stable negative nucleic acid test results. After he was hospitalized, he was treated with danoprevir and its booster, ritonavir, for 10 days. Subsequently, the patient tested negative for nucleic acid for three consecutive days. However, his nucleic acid test result was positive on Day 92 after discharge, showing that the aforementioned antiviral regimen did not have significant effects on the negative conversion of nucleic acid tests results. Thus, we should be vigilant for patients that may have chronic SARS-CoV-2 infection, and these patients should be closely followed up for a long period of time.
In conclusion, after patients with COVID-19 have achieved clinical recovery, a minority of patients may show positive SARS-CoV-2 nucleic acid tests results for a long period of time. This provides new directions for research on SARS-CoV-2 infection. Further studies are required to understand the pathogenesis of this phenomenon and its implications in disease transmission. Such patients require long-term follow-up to observe potential long-term adverse outcomes, and they should be quarantined. Additionally, further studies are also required to analyze potential infectivity in such cases and determine whether a search for more effective antiviral drugs or regimens that completely clear the virus is warranted.