People with breakthrough COVID-19 – the risks of death and post-acute sequelae are lower than COVID-19 without prior vaccination

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The post-acute sequelae in people with COVID-19 have been characterized1. Increasingly, vaccinated individuals are being diagnosed with COVID-19 as a result of breakthrough SARS-CoV-2 infection – we will refer to it here as breakthrough COVID-192-4. Whether people with breakthrough COVID-19 experience post-acute sequelae is not clear.

Addressing this knowledge gap is important to guide public health policy and post-acute COVID-19 care strategies.

Here we leverage the breadth and depth of the electronic health care databases of the US Department of Veterans Affairs to address the question of whether people with breakthrough COVID-19 develop post- acute sequelae. We characterize the risks and 6-month burdens of a panel of pre-specifled outcomes in a cohort of people who experienced breakthrough SARS-CoV-2 infection after completion of vaccination vs a control group and by care setting of the acute phase of breakthrough COVID-19 (that is whether people were not hospitalized or hospitalized during the flrst 30 days after diagnosis). We then undertake a

comparative evaluation of the magnitude of risk in people with breakthrough COVID-19 vs those with COVID-19 and no prior vaccination and separately hospitalized people with breakthrough COVID-19 vs those hospitalized with seasonal influenza.

Discussion

In this study of 16,035, people with breakthrough COVID-19 and 3,569,525 controls, we show that people who survive the flrst 30 days of breakthrough COVID-19 exhibit increased risk of death and post-acute sequelae in the pulmonary and several extrapulmonary organ systems.

The risks of death and post-acute sequelae were small but evident (and not trivial) among people whose disease did not necessitate

hospitalization during the acute phase of breakthrough COVID-19 (this group represents most people with breakthrough COVID-19). Our results show clear and consistent risk gradient in that the risks and burdens of all outcomes examined (death and post-acute sequelae) increased in a graded fashion according to the care setting of the acute infection and were consistently higher in those who were hospitalized during the acute phase of the disease.

Our comparative approach shows that in people with breakthrough COVID-19, the risks of death and post-acute sequalae are lower than COVID-19 without prior vaccination; in comparative analyses among people who were hospitalized during the acute phase of the disease, those with breakthrough COVID-19 exhibited higher risks of death and post-acute sequelae than those with seasonal influenza.

The constellation of flndings show that the burden of death and disease experienced by people with breakthrough disease is not trivial. Our comparative analyses provide a framework to better evaluate and understand risks of the post viral condition in people with breakthrough COVID-19. The flndings emphasize the need for continued optimization of prevention strategies of breakthrough SARS-CoV-2 infections and will inform care approaches for people with breakthrough COVID-19.

Our flndings show that long covid with its myriad sequelae also manifests in vaccinated individuals who experience a breakthrough SARS-CoV-2 infection; the risk of post-acute sequelae was higher in people with breakthrough COVID-19 vs those with no COVID-19, and lower in people with breakthrough COVID-19 vs those with COVID-19 who had not been previously vaccinated for it. This suggests risk reduction conferred by vaccination for COVID-19.

It also emphasizes that in order to lessen the risk and burden of post-acute sequelae (death and disease), prevention of breakthrough SARS-CoV-2 should be a goal of public health policy. Strategies aimed at reducing risk of breakthrough SARS-CoV-2 infection by maintaining vaccine effectiveness through optimization of vaccine schedules and boosters which may be augmented (or otherwise complemented) by employment of non-pharmaceutical interventions (e.g., masking) may yield less breakthrough infections and subsequently less risk of post-acute sequelae.

Here we provide evidence of increased risk of death and post-acute sequelae following breakthrough COVID-19. Although the absolute rates are smaller than those post-COVID-19 without prior vaccination, given the scale of the pandemic and the potential for breakthrough cases to continue to accumulate, the overall burden of death and disease following breakthrough COVID-19 will likely be substantial, will further add to the toll of this pandemic and will represent an additional strain on already overwhelmed health systems. In planning and development of health resources, governments and health systems should take into account the care needs of people with post-acute sequelae after breakthrough COVID- 195.

The mechanism or mechanisms underlying the reduced risk of post-acute sequelae in people with breakthrough COVID-19 vs those with COVID-19 without prior vaccination is not clear. It is possible that some sequelae are mediated by mechanistic pathways in the immune system that are influenced by vaccination.

We also show that the risk of post-acute sequelae is higher in people with breakthrough COVID-19 than in people with seasonal influenza — a well characterized respiratory viral illness. This extends prior evidence showing that the risk of post-acute sequelae in people with COVID-19 was higher than those with seasonal influenza and again emphasizes the importance of prevention of both COVID-19 and breakthrough COVID-191.

This study has several strengths. To our knowledge, this is the flrst large study to characterize the risks of post-acute sequelae of breakthrough COVID-19 at 6 months. We leveraged the vast national healthcare databases of the US Department of Veterans Affairs (the largest nationally integrated healthcare delivery system in the US) to characterize the risk and 6-month burden of a comprehensive set of pre-specifled incident health outcomes in patients who survived the flrst 30 days of breakthrough COVID-19.

In addition to evaluating risk of breakthrough COVID-19 vs those with no evidence of COVID-19 in the overall cohort and by care setting of the acute phase of the disease (non-hospitalized and hospitalized), we also undertook a comparative evaluation of breakthrough COVID-19 vs COVID-19 in people who had not been previously vaccinated and separately vs seasonal influenza.

We employed advanced statistical methodologies and adjusted through weighting for a battery of predeflned covariates selected based on prior knowledge and algorithmically selected covariates from high dimensional data domains including diagnoses, prescription records, and laboratory test results. 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 has several limitations. The breakthrough COVID-19 and COVID-19 groups only included those that had a positive test for COVID-19 and did not include those who may have had an infection with SARS-CoV-2 but were not tested; however, if present, this will bias the estimates toward the null. Although we balanced our cohorts by vintage to account for temporal variation in characteristics of the SARS-CoV- 2 infection (e.g., variants), our analyses did not directly include data on the different variants of SARS- CoV-2.

Although the VA population is comprised of mostly males, it includes 8-10% females which across the groups in our study included 347,589 female participants. Although we adjusted through overlap weighting approach for a large battery of predeflned and algorithmically selected covariates, and while our approach demonstrated good balance for more than 734 covariates (including all those which were available in the data but not included in the weighting process) from several data domains including diagnoses, prescription medications, and laboratory test results, and resulted in successful testing of positive outcome controls and negative outcome controls, we cannot completely rule out residual confounding.

Finally, the COVID-19 global pandemic is highly dynamic, as vaccine uptake continues to increase, as vaccine schedules continue to be optimized, as treatment strategies of the acute phase of COVID-19 continue to improve, and as new variants of the virus emerge, it is likely that the epidemiology of breakthrough COVID-19 and its downstream sequelae may also change over time.

In sum the flndings provide evidence of increased risk of death and post-acute sequelae in people with breakthrough COVID-19 at 6 months. The risks are manifest even among people whose acute disease did not necessitate hospitalization. Our comparative approach establishes that the risks of death and post-

acute sequelae in people with breakthrough COVID-19 are lower than those with COVID-19 without prior vaccination, but higher than those with seasonal influenza. The constellation of flndings emphasizes the need for continued optimization of strategies to prevent breakthrough SARS-CoV-2 infections in the flrst place and will guide care approaches of people with breakthrough COVID-19.

reference link :https:/ doi.org/10.21203/rs.3.rs-1062160/v1

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