Persistent SARS-CoV-2 positivity

Abstract

To the Editor: D espite many efforts in understanding the pathogenesis of coronavirus disease 2019 (COVID-19), numerous unsolved questions contribute to the increasing sense of uncertainty about this disease. A compelling problem is the management of previously infected patients with a persistent SARS-CoV-2 nasopharyngeal swab polymerase chain reaction (PCR) positivity after an appropriate period of quarantine and proved “immunization” as confirmed by seroconversion. Although PCR positivity may not drive public health concerns in terms of contagiousness, it may be detrimental for health care workers and people onwaiting lists for elective procedures or surgeries. The question that arises is:What is the biological mechanism underlying the prolonged persistence of test positivity in absence of symptoms? Considering the pathogenicity of SARS-CoV-2, three potential mechanisms have been hypothesized: (i) reinfection, (ii) residual fragments of viral RNA and (iii) genomic integration. Reinfection is not a well-defined event in COVID-19. In patients with reinfection, analysis of viral genome sequences documented that distinct isolates of SARS-CoV-2 can cause a second infection. Most cases of reinfection had worse clinical outcomes despite the absence of presumed defects of the immune system. Although the scenario can seemworrisome in terms of disease severity and spread of the virus, these data are largely biased by patient selection. Testing has indeed been performed mainly in symptomatic patients; therefore, the rate of subjects with asymptomatic recurrence of the disease remains undiagnosed in the absence of a systematic surveillance program. Recently, the entity of immune response has been evaluated in a large study conducted on 30,082 patients. The findings of this study showed that more than 90% of the screened patients with mild or moderate COVID-19 were able to mount a robust and prolonged (at least for 5 months) neutralizing antibody response (anti-spike protein) against the virus. Although it is too early to draw firm conclusions about the protective role of these antibodies, the authors of this study claimed that neutralizing antibodies may reduce the risk of reinfection or mitigate the symptoms of recurrence. Concerning the issue of viral remnants, SARS-CoV-2 nasopharyngeal swab PCR positivity does not rule out the possibility to detect genetic material without infectious potential. As in other viral infections (SARS-CoV, Middle East respiratory syndrome coronavirus, influenza virus, Ebola virus, Zika virus and measles virus), viral RNA can be detected long after the resolution of the infection. Noninfectious small fragments of viral genetic material are slowly degraded by the immune system and remain detectable on the mucosal surface for many weeks. Similarly, SARS-CoV-2 shedding has been detected for more than 2 months in adults and pediatrics. Nevertheless, persistent viral shedding paves the way to a new hypothesis and raises questions about the possibility that viral RNA may integrate into the host genetic material. On this issue, Zhang et al have recently documented in vitro that SARS-CoV-2 RNA may be reverse transcribed and integrated into human cells,