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High-dimensional characterization of post-acute sequalae of COVID-19

Abstract

The acute clinical manifestations of COVID-19 are well characterized1,2; however, its post-acute sequalae have not been comprehensively described. Here, we use the national healthcare databases of the US Department of Veterans Affairs to systematically and comprehensively identify 6-month incident sequalae including diagnoses, medication use, and laboratory abnormalities in 30-day survivors of COVID-19. We show that beyond the first 30 days of illness, people with COVID-19 exhibit higher risk of death and health resource utilization. Our high dimensional approach identifies incident sequalae in the respiratory system and several others including nervous system and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, malaise, fatigue, musculoskeletal pain, and anemia. We show increased incident use of several therapeutics including pain medications (opioids and non-opioids), antidepressants, anxiolytics, antihypertensives, and oral hypoglycemics and evidence of laboratory abnormalities in multiple organ systems. Analysis of an array of pre-specified outcomes reveals a risk gradient that increased across severity of the acute COVID-19 infection (non-hospitalized, hospitalized, admitted to intensive care). The findings show that beyond the acute illness, substantial burden of health loss — spanning pulmonary and several extrapulmonary organ systems — is experienced by COVID-19 survivors. The results provide a roadmap to inform health system planning and development of multidisciplinary care strategies to reduce chronic health loss among COVID-19 survivors.

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Correspondence to Ziyad Al-Aly.

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Supplementary Figures

This file contains Supplementary Figures 1-8.

Reporting Summary

Supplementary Table 1

Balance of baseline variables after overlap weighting in COVID-19 vs VHA users.

Supplementary Table 2

Identification of the post-acute incident diagnoses in COVID-19 vs. all VHA users.

Supplementary Table 3

Identification of the post-acute incident medication use in COVID-19 vs. all VHA users.

Supplementary Table 4

Identification of the post-acute incident laboratory abnormalities in COVID-19 vs. all VHA users.

Supplementary Table 5

Burden of post-acute sequalae of COVID-19. Excess burdens were estimated vs. a comparator group of all users of the Veteran Health Administration.

Supplementary Table 6

Balance of baseline variables after overlap weighting in hospitalized COVID-19 vs seasonal influenza.

Supplementary Table 7

Identification of the post-acute incident diagnoses in people who had been hospitalized with COVID-19 vs. those who had been hospitalized with seasonal influenza.

Supplementary Table 8

Identification of the post-acute incident medication use in people who had been hospitalized with COVID-19 vs. those who had been hospitalized with seasonal influenza.

Supplementary Table 9

Identification of the post-acute incident laboratory abnormalities in people who had been hospitalized with COVID-19 vs. those who had been hospitalized with seasonal influenza.

Supplementary Table 10

Burden of post-acute sequalae of COVID-19 which required hospitalization during the acute infection. Excess burdens were estimated vs. a comparator group of people with seasonal influenza which required hospitalization during the acute infection.

Supplementary Table 11

Identification of the post-acute incident diagnoses in people who had been hospitalized with COVID-19 vs. those who had been hospitalized with seasonal influenza after additionally adjusting for severity of the acute infection.

Supplementary Table 12

Identification of the post-acute incident medication use in people who had been hospitalized with COVID-19 vs. those who had been hospitalized with seasonal influenza after additionally adjusting for severity of the acute infection.

Supplementary Table 13

Identification of the post-acute incident laboratory abnormalities in people who had been hospitalized with COVID-19 vs. those who had been hospitalized with seasonal influenza after additionally adjusting for severity of the acute infection.

Supplementary Table 14

Burden of post-acute sequalae of COVID-19 which required hospitalization during the acute infection after additionally adjusting for severity of the acute infection. Excess burdens were estimated vs. a comparator group of people with seasonal influenza which required hospitalization during the acute infection.

Supplementary Table 15

Identification of the post-acute incident diagnoses in people who had been hospitalized with COVID-19 vs. those who had been hospitalized for other causes.

Supplementary Table 16

Identification of the post-acute incident medication use in people who had been hospitalized with COVID-19 vs. those who had been hospitalized for other causes.

Supplementary Table 17

Identification of the post-acute incident laboratory abnormalities in people who had been hospitalized with COVID-19 vs. those who had been hospitalized for other causes.

Supplementary Table 18

Burden of post-acute sequalae of COVID-19 which required hospitalization during the acute infection. Excess burdens were estimated vs. a comparator group of people who required hospitalization for other causes. Estimates are provided per 1000 persons at 6-month.

Supplementary Table 19

Risks of incident pre-specified high resolution post-acute COVID-19 outcomes at 6 months in all users of the Veteran Health Administration healthcare system (referent category), people with COVID-19, people hospitalized for COVID-19, and people admitted to intensive care for COVID-19.

Supplementary Table 20

Pairwise comparison of risks of incident pre-specified high resolution post-acute COVID-19 outcomes at 6 months in all users of the Veteran Health Administration healthcare system, people with COVID-19, people hospitalized for COVID-19, and people admitted to intensive care for COVID-19.

Supplementary Table 21

Risks of incident pre-specified high resolution post-acute COVID-19 outcomes at 6 months in hospitalized people with COVID-19 vs. seasonal influenza (the referent category). Outcomes were ascertained from day 30 after COVID-19 diagnosis until end of follow-up.

Supplementary table 22

Measures of the association between negative exposure control (exposure to influenza vaccine in even vs. odd months) and the risks of incident diagnoses.

Supplementary Table 23

Measures of the association between negative exposure control (exposure to influenza vaccine in even vs. odd months) and the risks of incident medication use.

Supplementary Table 24

Measures of the association between negative exposure control (exposure to influenza vaccine in even vs. odd months) and the risks of incident laboratory abnormalities.

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Al-Aly, Z., Xie, Y. & Bowe, B. High-dimensional characterization of post-acute sequalae of COVID-19. Nature (2021). https://doi.org/10.1038/s41586-021-03553-9

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