Introduction

Since the discovery of the highly infectious Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, countries around the globe have been on a red alert (1). By the end of January 2021, more than 100 million SARS-CoV-2 infected cases and more than 2 million and 50 thousand fatal cases have been reported across the world (2). Although the disease resolves in most cases, some experience worse outcomes such as requiring intensive care (e.g., mechanical ventilation) or death (3).
The body’s immune response to an external pathogen (a virus, in this case) consists of two main lines of defense: the innate and the adaptive immune systems. The innate immune system, which mainly consists of neutrophils, macrophages, and natural killer cells, acts non-specifically on viruses and infected cells and is the first to arrive on the infected site. Type I and Type III interferons produced by infected cells also contribute to the immune cascade and the anti-viral response. On the other hand, adaptive immunity can produce an antigen-specific response, but takes more time to become activated. Adaptive immunity, itself, is comprised of two arms: the cellular and humoral arm. Cytotoxic T lymphocytes are the most important cell types involved in cellular immunity and can destroy infected cells using specific cytotoxic substances like granzymes and perforin. In humoral immunity, B-lymphocytes play the main role by producing antibodies that contribute to neutralization and destruction of the virus (either by opsonization or activating the complement system). Both innate and adaptive immune systems can form some kind of memory that facilitates future responses to pathogens.
An immune response against SARS-CoV-2 occurs similarly. The innate immune system produces inflammatory cytokines such as IL-6 and TNF-α, causing the adaptive immune cells to recruit and secrete more cytokines, further strengthening the immune response against the virus. Adaptive immune cells, especially T cells, are the mainstay of the body’s defense mechanism against COVID-19 (4, 5). According to a study, CD8+ cells comprise 80% of the population of infiltrating cells in COVID-19 (6). Humoral response against SARS-CoV-2 acts by the production of antibodies that prevent the attachment of the virus to its target cells (i.e. ACE2+ cells) (4, 7, 8). Though the degree of cellular and humoral responses are usually correlated, in some cases, the antibody response is absent despite T-cell activity (9). This is either due to less severity of the disease, which diminishes the need for a humoral response or due to the persistence of cellular immunity memory at the time when antibodies are no longer detectable.
It has been shown that preliminary immune response to SARS-CoV-2 (such as anti-viral interferon and inflammatory cytokine secretion) is relatively suppressed and delayed, compared to other viral pneumonia (including SARS-CoV, another coronavirus that was the responsible pathogen for SARS disease), which may attribute to the severity of the disease (4, 10, 11). COVID-19’s relatively long incubation period could also be explained by this phenomenon (12). However, in some cases, the immune response leads to oversecretion of pro-inflammatory cytokines (i.e. cytokine storm), which is an important mechanism in acute respiratory distress syndrome (ARDS), lung damage, and mortality of COVID-19 (13).
Currently, it is unclear whether immunity develops after recovery from COVID-19. Although multiple scenarios have been proposed, it is yet to be determined which one turns out to be true (14). Experience from the previous SARS outbreak indicates that while anti-SARS-CoV antibody titers are significantly reduced a year after infection and are detectable in only 50% of the infected population after 4 years (15), SARS-CoV related memory T cells could be detected even at six to eleven years post-infection (16, 17). Also, it has been shown that humoral short-term immunity (IgM and IgA-mediated) appears through the first week from the onset of symptoms; however, long-lasting antibodies (IgG) become apparent after 14 days (4, 18, 19). IgG titers remain detectable at least two weeks after discharge, while high neutralizing antibody levels are only expected to be seen in newly recovered cases (20). According to a study conducted in Singapore, T cells of all patients who have recovered from COVID-19 can express anti-SARS-CoV-2 activity up to 28 days after negative PCR, most notably against nucleocapsid protein-1 (NP-1) and NP-2 of the virus (21). While a high number of anti-NP T cells are observed in newly recovered cases, anti-receptor-binding domain (RBD) T lymphocytes persist for a longer duration, though the number of these T cells is significantly lower than that of the anti-NP population in early recovery (20). Moreover, central memory CD4+/total CD4+ T cell ratio increases in recovered cases (22), although patients with severe disease have been reported to demonstrate lower percentages of memory CD4+ cells (23). On the other hand, declined number of T lymphocytes in peripheral blood of the subjects might cause impaired production of memory cells (24) and consequently a failure in cellular immune memory creation.
Still, we are aware that re-infection of COVID-19 exists and some patients have re-tested positive for SARS-CoV-2 even after full recovery from the disease (i.e., resolution of symptoms and negative PCR). In this systematic review, we have gathered and summarized available literature regarding re-positivity of SARS-CoV-2 tests. Our goal was to determine the epidemiology of recurrent COVID-19 positive PCR and to provide an overview of post-infectious immunity to the disease.