SARS-CoV-2 reinfection contributes additional risks of all-cause mortality

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A new study by researchers from Washington University School of Medicine-USA and VA Saint Louis Health Care System-USA has found confirmed that repeated infections or reinfections with SARS-CoV-2 will lead to increased risk of disease severity, mortality and worse PASC (Post-Acute Sequelae of SARS CoV-2 infection) or Long COVID outcomes.

The study findings were published on a preprint server:

Research Square and is current being peer reviewed for publication in the Nature Portfolio journal. https://www.researchsquare.com/article/rs-1749502/v1

In this study of 5,693,208 million people including 257,427 people with first infection, 38,926 people with reinfection, and 5,396,855 non-infected controls, we show that compared to people with first infection, people with reinfection exhibited increased risks of all-cause mortality, hospitalization, and several pre-specified outcomes.

The risks were evident in subgroups including those who were unvaccinated, had 1 shot, or 2 or more shots prior to the second infection. The risks were most pronounced in the acute phase, but persisted in the post-acute phase of reinfection, and risks for most sequelae were still evident at 6 months.

Compared to non-infected controls, assessment of the cumulative risks of repeated infection showed that the risk and burden of all-cause mortality and the prespecified health outcomes increased in a graded fashion according to the number of infections (that is risks were lowest in people with 1 infection, increased in people with 2 infections, and highest in people with 3 or more infections).

Altogether, the findings show that reinfection adds non-trivial risks of all-cause mortality and adverse health outcomes in the acute and post-acute phase of the reinfection. The findings highlight the consequences of reinfection and emphasize the importance of preventing re-infection SARS-CoV-2. Surveillance systems should be de

Estimates suggest that more than half a billion people around the globe have been infected with SARS-CoV-2 at least once10. For the large and growing number of people who encountered a first infection, the question of whether a second infection carries additional risk is important.

In this work, we show that reinfection adds risk of all-cause mortality and adverse health outcomes in both the acute phase and the post-acute phase of reinfection – suggesting that for people who already infected once, continued vigilance to reduce risk of reinfection may be important to reduce overall risk to one’s health.

Given the likelihood that SARS-CoV-2 will remain a threat for years if not decades, we urgently need to develop public health measures that would be embraced by the public and could be sustainably implemented in the long-term to protect people from re-infection. Pharmaceutical interventions to lessen both the risk of reinfection and its adverse health consequences are also urgently needed.

Questions have been raised whether reinfection increases the risk of Long Covid – the umbrella term encompassing the post-acute sequelae of SARS-CoV-2 infection.

Our results show that beyond the acute phase, reinfection with SARS-CoV-2 contributes substantial additional risks of all-cause mortality, hospitalization, and post-acute sequelae in the pulmonary and broad array of pulmonary organ systems.

The mechanisms underpinning the increased risks of death and adverse health outcomes in reinfection are not completely clear. Prior exposure to the virus may be expected to hypothetically reduce risk of reinfection and its severity; however, SARS-CoV-2 is mutating rapidly, and new variants are replacing older ones every few months. Evidence suggests that the reinfection risk is especially higher with the Omicron variant which was shown to have a marked ability to evade immunity from prior infection11.

And any protection from infection also wanes over time11; protection from reinfection declined as the time increased since the last immunity-conferring event in people who had previously been infected with SARS-CoV-2 (regardless of vaccination status)12.

Furthermore, impaired health as a consequence of the first infection might result in increased risk of adverse health consequences upon reinfection. Our results expand this evidence base and show that reinfection adds risk in both the acute and post-acute phase and that this was evident even among fully vaccinated people – suggesting that even combined natural immunity (from prior infection) and vaccine-induced immunity does not abrogate risk of adverse health effects following reinfection. The totality of evidence suggests that prevention strategies of reinfection might benefit people regardless of prior history of infection and vaccination status.

This study has several strengths. To our knowledge, this is the first study to characterize the health risks of reinfection. We used the national healthcare databases of the US Department of Veterans Affairs (the largest nationally integrated healthcare delivery system in the US) to undertake the analyses. We used advanced statistical methodologies and adjusted through weighting for a battery of predefined covariates selected based on prior knowledge and algorithmically selected covariates from high dimensional data domains including diagnoses, prescription records, and laboratory test results.

Because the virus is mutating over time, and because different variants may have different effects on outcomes, we further adjusted our analyses for measures of space and time, and additionally for proportion of variant by region at time of infection. We evaluated both acute and post-acute outcomes of reinfection and examined risks according to vaccination status prior to reinfection.

We evaluated the rigor of our approach by testing positive and negative outcome controls to determine whether our approach would produce results consistent with pre-test expectations.

The study also has several limitations. The cohorts of people with 1, 2, 3 or more infections included those that had a positive test for SARS-CoV-2 and did not include those who may have had an infection with SARS-CoV-2 but were not tested, if present in large numbers this may have resulted in misclassification of exposure.

Although the VA population is comprised of mostly men, it includes 10% women which across the groups in our study included 566,020 female participants. Although we balanced the exposure groups (through weighting using a battery of predefined and algorithmically selected covariates), we cannot completely rule out residual confounding.

The COVID-19 pandemic is a highly dynamic global event that is still unfolding in real time; as various epidemiologic drivers of this pandemic change over time (including emergence of new variants, increase in vaccine uptake, and waning vaccine immunity), it is likely that the epidemiology of reinfection and its health consequences may also change over time.

In sum, in this study of 5,693,208 we provide evidence that reinfection contributes additional health risks beyond those incurred in the first infection including all-cause mortality, hospitalization, and sequelae in the pulmonary and broad array of extrapulmonary organ systems.

The risks were evident in the acute and post-acute phase of reinfection. The evidence suggests that for people who already had a first infection, prevention of a second infection may protect from additional health risks. Prevention of infection and reinfection with SARS-CoV-2 should continue to be the goal of public health policy.

DEEPENING …..

Since the beginning of the COVID-19 pandemic, the problem of potential reinfection has always existed. The number of reinfections globally has probably been greatly underestimated, in part because confirmation of reinfection necessitates viral genome sequencing to identify different SARS-CoV-2 strains in a primary and secondary infection [10]. While viral sequencing is the gold standard for minimizing false positives in identifying cases of reinfection, it is technically challenging and cannot identify cases of reinfection with the same viral strain [10]. The Centers for Disease Control and Prevention (CDC) recently released a guideline protocol for supporting public health laboratories to investigate suspected SARS-CoV-2 reinfections [11]. Specifically, the search criteria include a positive RT-PCR test at least 90 days after the initial test or a positive RT-PCR test at least 45 days after the initial test accompanied by the presence of symptoms and epidemiological exposure [11].

COVID-19 infection history may be as effective as SARS-CoV-2 vaccines in preventing reinfection [12, 13]. However, the duration and extent of SARS-CoV-2-induced immunity’s protective effect have not been adequately investigated. Immunity can last at least 5–6 months after infection, according to two studies conducted in the UK [14, 15]. Data from these studies showed that reinfection with SARS-CoV-2 is rare, occurring in less than 1% of people who had previously tested positive for SARS-CoV-2 [14, 15]. Protection against SARS-CoV-2 reinfection was observed for up to 10 months after initial infection in a systematic review [16].

A study that screened 43,000 people from Qatar with PCR suggested that 95% of individuals who caught COVID-19 had protection against recurrent infection lasting at least 7 months [17]. Another study of 12,541 healthcare workers in the UK reported 89% protection lasting at least 6 months [15].

In a study conducted in Italy, a reinfection rate of 0.31% was found in Lombardy, which was one of the most severely affected regions at the beginning of the pandemic, with an average follow-up interval of 230 days [18]. Perez et al. [19] reported that a total of 149,735 individuals had positive PCR tests between March 2020 and January 2021 in Israel. Of these, 154 people have reported two PCR tests as positive at least 100 days apart, and they included them in their study.

They reported the reinfection rate as approximately 0.1%. In our study, the mean reinfection day of 755 reinfection cases was 336.4 ± 120.5. Of the reinfection cases in the current study, 125 (16.5%) were caught COVID-19 for the second time 3–6 months after the first COVID-19 infection, 277 (36.7%) after 6–12 months, and 353 (46.8%) after more than 12 months. A significant difference was found between these periods in reinfection cases.

Most reinfections occurred more than 12 months apart (p = 0.001). Of the 27,487 COVID-19 patients included in our study, 755 (2.7%) were defined as reinfection. Since the patients included in our study consisted of only Alpha, Delta, and Omicron variants, the reinfection rate may be higher than in previous studies.

Available data from published reinfection cases, data from immune response studies after initial SARS-CoV-2 infection, and emerging new variants raise the possibility that reinfection may be widespread. In a UK study, of 36,509 people who had a positive PCR test before October 1, 2020, 249 people who reported two positive tests at least 90 days apart, and 7 symptom-free days between the two positive results were considered reinfections.

The reinfection rate in the study was found to be 0.7%. In the study, this ratio was seen as a positive sign that vaccination against pre-existing variants or innate immunity may also be effective against the Alpha variant [20]. In a study that considered cases with laboratory-confirmed SARS-CoV-2 infection by positive nucleic acid amplification test (NAAT) and a positive NAAT result documented at least 90 days after the first positive test as reinfection, the median time to reinfection was found as 39.2 weeks.

In the study, they reported that the percentage of SARS-CoV-2 reinfections among all NAAT-positive COVID-19 cases increased from 0.5% in the pre-Delta surge period to 1.8% during the fluctuation [21]. In another study that used genome sequencing to identify VOCs, 6 (1.2%) and 9 (1.8%) patients with Delta and Alpha variants were reported to have had previous natural exposure to SARS-CoV-2. In the study, the median (minimum–maximum) reinfection times were found to be 207 (115–529) days and 127 (9–453) days, respectively [22].

In our study, 5554 (20.2%) of 27,487 COVID-19 patients had Alpha variant, 17,941 (65.3%) Delta, and 3992 (14.5%) Omicron variant. We defined 26 (0.46%) of 5554 Alpha variants, 209 (1.16%) of 17,941 Delta variants, and 520 (13.0%) of 3992 Omicron variants as reinfections. The mean reinfection days were 204.4 ± 51.1 days in the Alpha variant, 291.2 ± 58.2 days in the Delta variant, and 361.2 ± 131.6 days in the Omicron variant.

The median reinfection days of the variants were found as 192 in the Alpha variant, 291 in the Delta variant, and 418 in the Omicron variant. In a recent study conducted in Qatar by Altarawneh et al. [23], the median interval between previous infection and PCR testing among cases and controls were reported as 279, 254, and 314 days for analyzing the Alpha, Delta, and Omicron variants, respectively.

When the reinfection rates of the variants and the mean of reinfection days were compared, a statistically significant difference was found (p = 0.000). As can be seen, the variant with the highest reinfection rate in our study is the currently dominant Omicron variant (13.0%). Of those with a reinfection period of 3–6 months, 11 (8.8%) had Alpha variant, 9 (7.2%) Delta variant, and 105 (84.0%) Omicron variant.

Of those with a reinfection period of 6–12 months, 15 (5.4%) had Alpha variant, 188 (67.9%) Delta variant, and 74 (26.7%) Omicron variant. Alpha variant was detected in 0 (0%) of those with reinfection duration > 12 months, Delta variant in 12 (3.4%), and Omicron variant in 341 (96.6%). When the reinfection times were compared between the variants, a statistically significant difference was found (p = 0.000).

As can be seen, in our study, approximately half of the reinfection cases (46.8%) were reinfected with an interval of more than 12 months, and almost all (96.6%) of the reinfected patients in this period were infected with the Omicron variant. In addition, it is noteworthy that most of the patients (84.0%) with a reinfection period of 3–6 months were infected with the Omicron variant in our study.

Available data indicate that the Omicron variant is highly transmissible and spreads several times faster than previous variants [5]. The Omicron variant may evade vaccines or innate immunity that occurred from previous infections and may blunt the potency of neutralizing antibodies, causing existing vaccines to be less effective against Omicron than other variants [24].

Recent research showed that the B.1.1.7 (Alpha), B.1.351 (Beta), and B.1.617.2 (Delta) variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confer strong protection against reinfection [25,26,27]. Multiple mutations in the B.1.1.529 (Omicron) variant, on the other hand, can mediate immune evasion [23]. The reinfection risk profile of the Omicron variant is much higher than other variants [28]. The findings of our study also support these data.

Our study had some limitations. First, the analysis of variants in our study was done only by RT-PCR and was not confirmed by sequence analysis. Secondly, since our study was retrospective and we did not perform sequence analysis, we may have missed some reinfection cases since the valid time interval for the diagnosis of reinfection is considered to be at least 90 days.

Third, there is a large number of patients with asymptomatic and undetected primary infection, which may have affected reinfection rates. Fourth, since the Omicron variant has been detectable in our laboratory for approximately 1 month, the follow-up period and the number of patients in terms of reinfection was relatively shorter compared to the Alpha and Delta variants.

reference link : https://link.springer.com/article/10.1007/s11845-022-03060-4

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