Recurrence of COVID-19 with SARS-CoV-2 RNA reversion to positive and late antibody response: a case report from Brazil

In general, replication of the SARS-CoV-2 in the host reaches its peak in the rst week of infection, decreasing rapidly afterwards, while some level of immunity is build up. Yet, the infection seems to follow a distinctive course in some individuals, reactivating after the apparent resolution of symptoms. We report here the rst case of a more vigorous COVID-19 recurrence with SARS-CoV-2 RNA reversion to positive and late antibody response, and also the rst to address COVID-19 recurrence in Brazil.


Introduction
Since the rst reports on December 2019 up to mid-June 2020, the COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), was responsible for hundreds of thousands of deaths [1] and put the world on hold. As the pandemic progresses, the pattern of the infection becomes more predictable, allowing a more concrete decision making in the prevention and control of the disease. However, a still restricted but growing body of publications indicates that certain patients might reactivate a sub-clinical infection or be re-infected [2], showing that much of the viral pathogenesis remains unclear. reported headache without respiratory symptoms. Two days later, he had respiratory material collected (oropharynx and nasopharynx swabs) for SARS-CoV-2 detection by RT-qPCR using Allplex™2019-nCoV Assay (Seegene Inc., Seoul, Korea), which targets the RNA-dependent RNA polymerase (RdRP), N genes speci c for SARS-CoV-2, and E genes for all Sarbecovirus, including SARS-CoV-2. The cycle threshold (Ct) values from the qRT-PCR were measured; Ct values <40 were reported as positive. The sample tested positive for SARS-CoV-2 RNA (E Ct: 31.5; RdRp Ct: 34.1; N Ct: 31.5).

Case Presentation
Being a mild infection, the patient remained in isolation for 14 days at home, recovering after 7 days of symptoms onset. On 5 May, after a new respiratory swab collection, the viral RNA was no longer detected.
IgM/IgA and IgG antibodies were negative by COVID-19 ELISA test (Vircell, Spain). However, one month later, on 6 June, the symptoms returned more acutely and included fever, cough, headache, myalgia,

Discussion
Different reports indicate that reactivation or re-infection by SARS-CoV-2 are possible, although the event appears to be unusual [3]. Such "reversal to positivity" after negative molecular tests may be due to methodological issues such as sample storage problems, poorly performed sample collection, etc., pointing towards false-negative results [4]. However, such reactivation also has a biological basis [3].
In this case, the virus could still replicate in undetectable levels in nasopharynx and maybe in the lower respiratory tract [5] during convalescence, regaining full replication after some time, probably driven by the host's immune status [6]. On the other hand, a re-infection with a new or maybe the same circulating strain is not unfeasible [3], given the different pro les of immune response to the virus [7]. In fact, the detection of SARS-Cov-2 RNA with the absence of anti-SARS-CoV-2 antibody response has been previously observed [8].
Although cases vary in terms of serological data, timing of reactivation and clinics, patients who retested positive to SARS-CoV-2 generally have a mild or asymptomatic course [9][10][11][12][13], which is perhaps the result of some level of immunity, while symptomatic reactivation is rare but may happen [14]. Our patient, on the other hand, presented a more potent form of COVID-19 after more than 40 days from the rst mild infection, and with a detectable antibody response only after the second infectious episode. Our hypothesis is that the rst mild infection was not su cient to build up a detectable humoral response [8], which occurred only after 14 days of a second more severe episode. In addition, the absence of detectable antibodies in the rst episode may have allowed for a new infection, rather than a recurrence.
However, as we did not investigate viral genetics at different times, such a statement is hypothetical.
A limitation of this study is due to the absence of cell culture assays during the period, which could indicate the presence of infectious particles. Also, a false-positive result in the rst RT-qPCR test cannot be ruled out as well, so that the patient only became infected with SARS-CoV-2 afterwards, instead of its "reactivation". However, given the 1) high speci city of RT-qPCR test; 2) presentation of symptoms coinciding with the positive RT-qPCR; and 3) viral detection in close family members living in the same residence during COVID-19 symptoms (data not shown); such false result is unlikely.
In this paper, we describe a COVID-19 recurrence from a mild to a moderate form after convalescence, with RT-qPCR turning positive and antibody detection after more severe symptoms. These ndings, although summarized in a case report, raise questions about the in uence of the severity of the infection on the immune response and the host's susceptibility, which can have important epidemiological consequences, and should be better understood.

Declarations
Funding This paper was supported by Laboratório Contraprova Análises, Ensino e Pesquisas LTDA. Varella RB. was partially supported by National Council for Scienti c and Technological Development -CNPq.  Chest CT images of the patient showing multiple patchy ground glass opacities.