In a Commentary on EBioMedicine researchers of Icahn School of Medicine at Mount Sinai, New York try to solve the enigma between dead viral particles testing or real clinical reinfection.

Nine months after the first reports describing a novel corona virus (Severe Acute Respiratory Syndrome coronavirus 2, SARS-CoV-2) causing severe disease in humans (coronavirus Disease 2019, COVID19), and with over 47 million infected individuals worldwide, questions regarding the clinical relevance and public health implications of SARS-CoV-2 viral shedding remain unanswered.

In an article of EBioMedicine, Dr. Changwen Ke and colleagues report that, in a subset of COVID-19 patients, SARS-CoV-2 nucleic acid can be
detected intermittently in nasopharyngeal specimens despite symptom resolution. In this specific study setting, hospitalised COVID19 patients who were discharged after symptom improvement and whose respiratory or digestive tract specimens tested negative twice using nucleic acid amplification testing (NAAT), were monitored in a hotel setting for an additional two-week period under strict quarantine and social distancing measures. During this post-hospital discharge but continued isolation period, 14% of the COVID-19 survivors, all of whom had mounted neutralizing SARS-CoV-2 antibody responses, again tested positive by NAAT.

Younger patients with milder initial COVID-19 manifestations were more likely to experience such recurrences, even though the antibody titers were
comparable between patient groups with and without late detection
of SARS-CoV-2 genetic material. Thus, in some individuals, neutralizing immune responses did not eliminate intermittent detection of viral nucleic acids in the upper respiratory tract. Importantly, attempts to grow infectious virus or obtain complete viral genome sequences from these “re-positive” patients failed, suggesting that the NAAT positivity may represent degraded genetic material rather than intact viruses.

Most immune competent patients clear the virus within a few weeks, but several reports indicate that prolonged NAAT positivity (often referred to as “viral shedding”) can persist weeks after the resolution of the clinical symptoms. Of note, in a subgroup of COVID-19 survivors, NAAT positivity is associated with lingering sequelae, often in the presence of a humoral immune response, but it remains unclear whether these long-term medical conditions are due to the presence of the (replication-competent) virus or caused by dysregulation and tissue damage triggered by the initial acute viral infection.

Considerable uncertainty remains whether or not such findings translate into infectiousness and transmissibility, but the findings presented in this article show that intermittent NAAT positivity may be observed without detectable production of infectious virus. It is conceivable that in the absence of an efficient immune response (e.g., chemotherapy, post-transplant, or other immunodeficiency), prolonged viral shedding may, indeed, reflect intact, infectious virus.

Conclusions regarding re-infection can, however, only be drawn if supported by complete genome information for virus from specimens collected during both the initial and the subsequent infectious episodes, e.g. indicating that the disease-causing viral strains belong to different clades. Currently, difficulties in recovering biospecimens pertinent to an earlier acute infection, and the possibility of being re-infected with a viral strain too genetically similar to distinguish with certainty remain hurdles that need to be overcome when investigating putative re-infection cases.