Cases and etiologies of suspected COVID-19 reactivation.

Our article outlines a perspective on COVID-19 reactivation with considerations of implored commentary on behalf of the medical community regarding open discourse about this subject. Such a topic is paramount in elucidating parameters that pertain to testing, and subsequent public health population dynamics once uneventful cases pass. We argue that what some may refer to as a reinfection or reactivation of the virus, is actually a result of prolonged shedding of the virus complemented with occasional false positives/negatives and lab errors. This article was written with the perspective of informing in addition to engage discussions that distill salient, evidence-based characterization of COVID-19. We hope to recruit fellow academics in medicine who see trends in their own respective communities about people who re-test, and to explore their clinical outcomes. © 2020 Ghali, Rico-Mesa, Nashawi, Cadena, licensee HBKU Press.

Background

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has infected approximately 4 million individuals worldwide, with 578,000 deaths reported as of July 15, 2020.[1] COVID-19 is changing the landscape of multiple components of our healthcare system, including research, public health, and the implementation of traditional clinical medicine. Scientific literature has proactively begun investigating the mechanisms by which this virus infects and the pathophysiology of its sequelae. Preliminary findings about viral dynamics have been alarming in countries such as South Korea and China,[2-3] which experienced some of the earliest interactions with COVID-19. These countries have implemented sweeping societal changes based on limited contact procedures to mitigate viral spread. However, reinfections, with rate as high as 14%, have been reported in these countries.[2] According to Ye et al., COVID-19 reactivation is observed once patients test positive for SARS-CoV-2 infection via nasal swab after being discharged. Moreover, according to them, the period where patients have negative to positive test results ranged from 4 to 17 days, suggesting that recovered patients may need further isolation and viral detection.[4] Considering the effects of loosening contact precautions or instituting more strict guidelines, it is necessary to consider the possibility that several patients considered to experience COVID-19 reactivation are likely to have false-positive test results. This manuscript aims to evaluate several cases of COVID-19 reactivation and to challenge our previously held dogmas of the COVID-19 pandemic.

Coronavirus disease 2019 reactivation

Wölfel et al., described, in a hospital in Munich, a comprehensive virologic analysis on viral replication and infectivity within different body sites. Diagnosis was established via reverse transcription polymerase chain reaction (RT-PCR) using oropharyngeal /nasopharyngeal swab samples.[5] Swabs were taken on day 1 of symptom onset, with an average viral RNA load of 6.76 × 105 copies per whole swab. They were taken until day 5 and day 28 after symptom onset. Seroconversion was detected by immunoglobulin G (IgG) and immunoglobulin M (IgM) immunofluorescence, observed in 50% of patients by day 7 and in all patients by day 14.IgM antibodies signify initial antibodies produced, and seroconversion to IgG indicates past infection or immunization. All patients had detectable antibodies that did not correlate with clinical courses. Similar to SARS, IgM was not detected significantly earlier than IgG, partially due to technical errors.[5] Xiang et al., concluded that antibodies against SARS-CoV-2 can be found in the middle-late stage of the illness. They also reported the sensitivity (70.8% [17/24]), specificity (96.6%), positive predictive value (85.0%), negative predictive value (89.1%), and consistency rate (88.1%) of IgG from serological testing.[6] Establishment of false diagnosis is potentially feasible because of technical inaccuracies. Moreover, RT-PCR has an increased chance of producing false-negative test results, which may influence the diagnosis of COVID-19 reactivation, where viral shedding would still be observed.[5]

Wölfel et al., suggested that active replication occurs concurrently with upper respiratory tract symptoms. This study described the viral shedding of SARS-CoV-2 and asserted that shedding reached maximum values in the first week of symptom onset, peaking roughly on the fourth day of infection. They further added that viral RNA shedding from patient sputum had outlasted the resolution of symptoms, where viral load did not rapidly decline as would have been expected. The prolonged shedding can guide discharge management to discharge patients after 10 days of symptom onset, with less than 100,000 viral RNA copies per ml of sputum.[5] One variable that may dominate this trend is false-negative test result, which should not be excluded in patients whose symptoms have subsided, as this could represent a substantial number of tests producing positive results. The prolonged shedding of SARS-CoV2 observed in several recorded patients may explain why certain patients have positive test results during retest.[5] Furthermore, although some patients with a previous history of SARS-CoV2 infection may present with similar earlier symptoms, they may be incorrectly diagnosed with COVID-19 reactivation. These late symptoms can be a manifestation of a cytokine storm rather than a viral reactivation.[7]

Such findings have prompted the World Health Organization to begin systematic investigations on the nature of long-term viral dynamics, including the half-life of SARS-CoV-2.[3] Ye et al., noted that 5 out of the 55 patients discharged experience COVID-19 reactivation. Throat swabs obtained from all 5 patients tested positive, with one patient presenting with progressive lymphopenia and neutrophilia. Although the study notes that its small patient population limits its conclusion, instrumentation error and false-negative result are possible as shown by Xie et al., where 5 patients with negative test results using RT-PCR had positive viral pneumonia findings on computed tomography (CT) scan.[8] These patients subsequently had positive RT-PCR test results 2–8 days later. Xie et al., argued that although RT-PCR with a swab test has been the standard method in diagnosing patients with COVID-19, the test is time-consuming and is prone to false-negative test result. Fang et al., further reaffirmed this in a case series comprising 51 patients, where the sensitivity of RT-PCR for SARS-CoV-2 was lower (71%) than that in CT scan (98%) (p < .001).[9] The presence of COVID-19 reactivation or reinfection in patients who initially had RT-PCR negative test results and subsequently positive test results remains unclear. With viral load use and insufficient viral culture, available information used to formulate a conclusion is considered insufficient.[10]

Conclusion

Although SARS-CoV-2 displays active replication concurrently with upper respiratory tract symptoms, viral shedding is prolonged, outlasting the resolution of symptoms, where viral load did not rapidly decline as would have been expected.[5] Shedding reaches its maximum values in the first week of symptom onset, peaking on day 4. The period where a test result changes from negative to positive ranged from 4 to 17 days, suggesting that recovered patients may need further isolation and viral detection.[4] Furthermore, based on the existing evidence, false-negative test results may also be observed with RT-PCR while displaying positive findings on CT scan.[8] Although the evidence regarding the subsequent COVID-19 reactivation seems unlikely, the potential risks are significantly high to cast this differential aside. Although the potential consequences of viral reactivation may warrant further scientific studies, countries with first reports of perceived recurrence of COVID-19 positive test results, namely, South Korea and China, have yet to support these data with valid scientific evidence.