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High-dimensional characterization of post-acute sequelae of COVID-19
Open accessPublished version of a preprint
Abstract
The acute clinical manifestations of COVID-19 have been well characterized 1,2, but the post-acute sequelae of this disease 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 sequelae-including diagnoses, medication use and laboratory abnormalities-in patients with COVID-19 who survived for at least 30 days after diagnosis. We show that beyond the first 30 days of illness, people with COVID-19 exhibit a higher risk of death and use of health resources. Our high-dimensional approach identifies incident sequelae in the respiratory system, as well as several other sequelae that include nervous system and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, malaise, fatigue, musculoskeletal pain and anaemia. We show increased incident use of several therapeutic agents-including pain medications (opioids and non-opioids) as well as antidepressant, anxiolytic, antihypertensive and oral hypoglycaemic agents-as well as evidence of laboratory abnormalities in several organ systems. Our analysis of an array of prespecified outcomes reveals a risk gradient that increases according to the severity of the acute COVID-19 infection (that is, whether patients were not hospitalized, hospitalized or admitted to intensive care). Our findings show that a substantial burden of health loss that spans pulmonary and several extrapulmonary organ systems is experienced by patients who survive after the acute phase of COVID-19. These results will help to inform health system planning and the development of multidisciplinary care strategies to reduce chronic health loss among individuals with COVID-19.
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“This is typically referred to as a post-covid syndrome, characterized by several symptoms affecting quality of life (1–5).”
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“COVID-19 or a positive SARS-CoV-2 PCR test, as well as increased risk of myocardial infarction and stroke in the months after infection; these findings may not be generalizable to other populations.(50,51) .”
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Zhang, Y., Hu, H. Z., Fokaidis, V., Lewis, C., V, Xu, J., Zang, C., Xu, Z., Wang, F., Koropsak, M., Bian, J., et al. (2022) · medRxiv · doi:10.1101/2022.10.13.22281010 · Cited by 3
“Studies have 29 identified PASC symptoms and conditions that affect multiple organ systems, including shortness of 30 breath (Al-Aly et al., 2021; Bell et al., 2021; Taquet et al., 2021; Wang et al., 2022), fatigue (Al-Aly et 31 al.”
BackgroundDepression and its associated factors among COVID-19 survivors in a middle income countryPreprint
Moy, F. M., Lim, E. R. J., Hairi, N. N., & Bulgiba, A. M. (2022) · medRxiv · doi:10.1101/2022.12.15.22283550 · Cited by 3
A data set of symptoms and needs of individuals affected by COVID-19
Stanley, H. B., & Bensafi, M. (2024) · Scientific Data · doi:10.1038/s41597-024-02961-6 · Cited by 3
Neuromuscular Signals Shape Fatigue and Effort-Based Decision-Making in HumansPreprint
Casamento-Moran, A., Kim, A., Lee, J. L., & Chib, V. S. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.06.692763 · Cited by 3
“…the different components of fatigue is especially important in clinical settings, where fatigue is among the most debilitating and least understood symptoms across many disorders 2,3 , including multiple sclerosis 34–36 , stroke 37 , cancer 38,39 , depression 16,40 , and Long COVID 41–43 .”
Swann, O. V., Lone, N., Harrison, E. M., Tomlinson, L. A., Walker, A. J., Seaborne, M., Pollock, L., Farrell, J. J., Hall, P. S., Seth, S., et al. (2022) · BMJ Open · doi:10.1136/bmjopen-2022-063271 · Cited by 2
Immunology of post-COVID syndrome
Sсherbak, S. G., Sarana, А. М., Vologzhanin, D. A., Kamilova, Т. A., Голота, А. С., & Макаренко, С. В. (2023) · Russian Medicine · doi:10.17816/medjrf133829 · Cited by 2
Banchelli, F., Gagliotti, C., Paoli, A. D., Buttazzi, R., Narne, E., Ricchizzi, E., Pierobon, S., Fedeli, U., Pitter, G., Fabbri, E., et al. (2025) · BMC Infectious Diseases · doi:10.1186/s12879-025-10526-0 · Cited by 2
Thiol esters as chemical warheads of SARS-CoV-2 main protease (3CLpro) peptide-like inhibitors
Qiao, X., Cui, M., Yu, Z., Ma, L., Liu, H., Yang, X., Chen, Y., Li, D., Che, J., Zhao, L., et al. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117709 · Cited by 2
Carr, C. R., Gentile, N. L., Bertolli, J., Szewczyk, W., Lin, J.-M. S., Unger, E. R., Quan, V. M., Sotoodehnia, N., & Fitzpatrick, A. L. (2025) · PLoS ONE · doi:10.1371/journal.pone.0323104 · Cited by 2
Lim, J. T., Wee, L. E., Tan, W. Z., Chiew, C. J., Kurupatham, L., Poh, C., Suhaimi, N.-A. M., Chua, H. Z., Ng, L. C., Chia, P. Y., et al. (2025) · Open Forum Infectious Diseases · doi:10.1093/ofid/ofaf401 · Cited by 2
“For population-based controls, we generated a comparator group that had a similar distribution of length of follow-up [12] using exact matching without replacement to match each dengue case with ∼ 60 population-based Singapore citizens/permanent residents who had no evidence of recorded dengue…”
A Review: Can Cytokines Induce Vascular Inflammation as a Sequela of Viral Infections?
Deena, S. A., Tonima, S. A., Khan, S. A., Biswas, M. S., & Dewan, S. M. R. (2025) · Health Science Reports · doi:10.1002/hsr2.71105 · Cited by 2
“However, there is a lack of comprehensive understanding of the natural progression of the condition, including its impact on symptoms, organ damage, and overall functioning [25].”
Kisiel, M. A., Lee, S.-S., Hasselström, J., Hagströmer, M., Nyberg, F., Hajiebrahimi, M., & Carlsson, A. C. (2025) · Scientific Reports · doi:10.1038/s41598-025-21712-0 · Cited by 2
“Furthermore, COVID-19 itself may result in long-term health effects, including hypertension, other cardiovascular disorders 56 and post-COVID-19 condition 57 .”
Shitaye, G., Yizengaw, M. G., Mekonnen, Z., D’Abrosca, G., Fattorusso, R., Isernia, C., Amuamuta, A., & Malgieri, G. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1737894 · Cited by 4
“In addition to metabolic abnormalities such as hyperlipidemia and cardiovascular, gastrointestinal, and neurologic conditions, growing evidence indicates the incidence of diabetes as a post-acute sequela following COVID-19 pandemic (5, 13 – 16).”
InfluentialManoukian, G., Kundukulam, S. S., Asatorian, G., Johnson, D. M., Masood, M. H., Venugopal, A., Manoukian, M. V., & Aswathappa, S. (2026) · Cureus · doi:10.7759/cureus.102117 · Cited by 2
“Acute SARS-CoV-2 infection may amplify these existing dysfunctions and result in a destabilization of blood pressure and glycemic control in vulnerable subjects [5].”
Links between COVID-19, long COVID, and neurodegeneration: The role of glycosphingolipids
Spedding, M., Aerts, J. M. F. G., Alexander, S. P. H., Woestelandt, A.-G. B., Chiricozzi, E., Henriques, A., Lledo, P., Loeffler, J., Perera, R. M., Platt, F. M., et al. (2026) · Pharmacological Reviews · doi:10.1016/j.pharmr.2026.100113 · Cited by 2
Anagnostakis, F., & Kokkorakis, M. (2026) · Endocrine Practice · doi:10.1016/j.eprac.2026.02.003 · Cited by 2
Symptom Patterns, Recovery, and Impact of Long COVID: Findings From a Longitudinal Survey
Ziauddeen, N., Pantelic, M., O’Hara, M. E., Hastie, C., & Alwan, N. A. (2026) · Open Forum Infectious Diseases · doi:10.1093/ofid/ofag040 · Cited by 2
“The risk of developing Long COVID is higher in those requiring hospitalization or intensive care during the acute phase [7, 9], but the majority of cases are in people with acute infections initially classified as mild due to the higher prevalence of these cases [10].”
Mahajan, S., Mahajan, S., & Kaushik, N. (2026) · Viruses · doi:10.3390/v18040458 · Cited by 2
Cardiovascular sequelae of Long COVID: immune dysregulation inflammation as central drivers
Liu, A., Chen, H., Liu, Q. Y., Al-Azab, M., Shaher, F., Li, J., Liu, T., & Yang, M. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1815269 · Cited by 3
Ayala-León, M., Aceves-Velázquez, E. D., Barrera-Oranday, E. A., Cano-Zárate, R., Escobedo-Mercado, D., Gaxiola-Macías, M., Ilazarra-Lomelí, H., Ixcamparij-Rosales, C. H., Vargas-Estrada, J. L., Meave‐González, A., et al. (2022) · Archivos de cardiología de México · doi:10.24875/acm.21000287 · Cited by 2
Symptoms in the Long Period after the Coronavirus Infection: Results of Long-Term Follow-Up
Всеволодович, М. А., Agaeva, A. I., & Nikitin, I. G. (2022) · The Russian Archives of Internal Medicine · doi:10.20514/2226-6704-2022-12-4-302-309 · Cited by 2
Prescription Opioid Resiliency and Vulnerability: A Mixed-Methods Comparative Case Study
Hochstetler, A., Peters, D. J., & Monnat, S. M. (2022) · American Journal of Criminal Justice · doi:10.1007/s12103-022-09701-9 · Cited by 2
“…opioid overdose crisis, but to our knowledge there is no research examining why communities that appear similar across multiple economic and demographic measures have disparate outcomes in opioid deaths (Ciccarone, 2018;Dasgupta et al., 2018; Monnat, 2020; Peters et al., 2020; Ziyad & Xie, 2021).”
BackgroundAtahan, E., Öztürk, B. Ç., Akçin, R., Sarıbaş, S., & Kocazeybek, B. S. (2022) · Balkan Medical Journal · doi:10.4274/balkanmedj.galenos.2022.2022-8-64 · Cited by 2
Chapin, N., & Sen, R. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-91794-0.00014-7 · Cited by 2
COVID-19 as a polymorphic inflammatory spectrum of diseases: a review with focus on the brain
Tang, S. W., Helmeste, D. M., & Leonard, B. E. (2023) · Acta Neuropsychiatrica · doi:10.1017/neu.2023.17 · Cited by 3
Incident New Onset Diabetes after COVID-19 Infection: Results from a National Multicenter Cohort
Zisis, S. N. (2023) · Journal of Diabetes and Treatment · doi:10.29011/2574-7568.010114 · Cited by 2
Márquez, N. G., Jamal, A., Johnston, R., Richter, E., Gorbach, P. M., Vannorsdall, T. D., Rubin, L. H., Jennings, C., LANDAY, A. L., Peluso, M. J., et al. (2023) · JMIR Research Protocols · doi:10.2196/47079 · Cited by 4
Ali, M., & Mehjabin, T. (2023) · Annals of Medicine and Surgery · doi:10.1097/ms9.0000000000000851 · Cited by 2
“The widespread and heterogeneous manifestation of COVID-19 undermines the respiratory, gastrointestinal, cardiovascular, andmusculoskeletal systems.([13]) Myalgia and arthralgia are among the most prevalent symptoms of the COVID-19 acute phase.”
Background
Metadata
- Authors
- Al-Aly, Z., Xie, Y., & Bowe, B.
- Affiliations
- VA St. Louis Health Care System (US)
- Venue
- Nature
- Published
- 2021-04-22
- Volume
- 594
- Issue
- 7862
- Pages
- 259-264
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W3153493739
- Cited by
- 1,518
- References
- 46
- Citations by year
- 2026: 95 · 2025: 170 · 2024: 268 · 2023: 365 · 2022: 391 · 2021: 228
- FWCI
- 149.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs
- American Society of Nephrology
- McDonnell Center for Systems Neuroscience
- Topics
- Health Sciences › Medicine › Clinical Neurology › Long-Term Effects of COVID-19
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Keywords
- post-COVID-19 sequelae, long COVID, COVID-19 mortality, health resource utilization, pulmonary sequelae, neurocognitive disorders, mental illness, metabolic disorders, cardiovascular disease, gastrointestinal diseases, fatigue, musculoskeletal pain, anemia, medication use, laboratory abnormalities, disease severity, intensive care unit admission, veterans
- MeSH terms
- COVID-19, SARS-CoV-2, COVID-19 Drug Treatment, Post-Acute COVID-19 Syndrome, Female, Hospitalization, Humans, Influenza, Human, Male, Outpatients, Risk, Time Factors, United States, United States Department of Veterans Affairs, Cohort Studies, Databases, Factual, Electronic Health Records, Datasets as Topic
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