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.