Long COVID after breakthrough SARS-CoV-2 infection

The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection—also referred to as Long COVID—have been described, but whether breakthrough SARS-CoV-2 infection (BTI) in vaccinated people results in post-acute sequelae is not clear. In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 33,940 individuals with BTI and several controls of people without evidence of SARS-CoV-2 infection, including contemporary (n = 4,983,491), historical (n = 5,785,273) and vaccinated (n = 2,566,369) controls. At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with BTI exhibited a higher risk of death (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR = 1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders. The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI.


Supplementary Information
Long COVID after breakthrough SARS-CoV-2 infection  Figure 1: Standardized mean differences between those with breakthrough SARS-CoV-2 infection and the contemporary control group before and after weighting by organ system. 4 Supplementary Figure 2: Standardized mean differences between those with breakthrough SARS-CoV-2 infection that were non-hospitalized, hospitalized, and admitted to the intensive care unit during the acute phase of the disease and the contemporary control group before and after weighting by organ system.  Table 1: Demographic and health characteristics of those with breakthrough SARS-CoV-2 infection, SARS-COV-2 infection without prior vaccination, the contemporary control group, the historical control group, and the vaccinated control group before weighting.  Table 4: Characteristics and standardized mean differences of those with breakthrough SARS-CoV-2 infection, SARS-COV-2 infection without prior vaccination, and the contemporary control group after weighting.

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Supplementary Table 5: Risk and 6-month burden of death, at least one post-acute sequela, and post-acute sequelae by organ system in breakthrough SARS-CoV-2 infection compared to the contemporary control group.  Table 7: Risk and 6-month burden of death, at least one post-acute sequela, and post-acute sequelae by organ system in breakthrough SARS-CoV-2 infection compared to the historical control group.

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Supplementary Table 8: Risk and 6-month burden of death, at least one post-acute sequela, and post-acute sequelae by organ system in breakthrough SARS-CoV-2 infection compared to the vaccinated control group.
Excel sheet Supplementary Table 9: Risk and burden of death, at least one post-acute sequela, and post-acute sequelae by organ system in breakthrough SARS-CoV-2 infection compared to the contemporary control group in the first 30-90, and 91-180, days of follow-up.

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Supplementary Table 10: Risk and 6-month burden of death, at least one post-acute sequela, and post-acute sequelae by organ system in those with breakthrough SARS-CoV-2 infection by immunocompromised status.

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Supplementary Table 11: Risk and 6-month burden of death, at least one post-acute sequela, and post-acute sequelae by organ system in breakthrough SARS-CoV-2 infection by vaccination type.    Table 20: Risk and 6-month burden of death, at least one post-acute sequela, and post-acute sequelae by organ system in those with breakthrough SARS-CoV-2 infection compared to those with SARS-COV-2 infection without prior vaccination by immunocompromised status.

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Supplementary Table 21: Risk and 6-month burden of death, at least one post-acute sequela, and post-acute sequelae by organ system in those with breakthrough SARS-CoV-2 infection compared to those with SARS-COV-2 infection without prior vaccination by care setting of the acute phase of the disease.  Table 24: Risk and 6-month burden of death, at least one post-acute sequela, and post-acute sequelae by organ system in breakthrough SARS-CoV-2 infection hospitalized during the acute phase compared to those hospitalized with seasonal influenza.  Figure 4: Standardized mean differences between those with breakthrough SARS-CoV-2 infection and those with SARS-COV-2 infection without prior vaccination that were non-hospitalized, hospitalized, and admitted to the ICU during the acute phase of the disease by organ system. Figure 6: Risk of post-acute sequelae in people who were hospitalized during the acute phase of breakthrough SARS-CoV-2 infection compared to those hospitalized with seasonal influenza. Incident outcomes were assessed from 30 days after the positive SARS-COV-2 infection test to end of followup. Results are in comparison of those hospitalized with breakthrough SARS-CoV-2 infection (n=3,667) to those hospitalized with seasonal influenza (n=14,337). Adjusted hazard ratios (dots) and 95% confidence intervals (error bars) are presented. Outcomes that occurred in less than 10 participants in a group were excluded.