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Age, Sex and Previous Comorbidities as Risk Factors Not Associated with SARS-CoV-2 Infection for Long COVID-19: A Systematic Review and Meta-Analysis
Open accessAbstract
Identification of predictors of long COVID-19 is essential for managing healthcare plans of patients. This systematic literature review and meta-analysis aimed to identify risk factors not associated with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, but rather potentially predictive of the development of long COVID-19. MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as medRxiv and bioRxiv preprint servers were screened through 15 September 2022. Peer-reviewed studies or preprints evaluating potential pre-SARS-CoV-2 infection risk factors for the development of long-lasting symptoms were included. The methodological quality was assessed using the Quality in Prognosis Studies (QUIPSs) tool. Random-effects meta-analyses with calculation of odds ratio (OR) were performed in those risk factors where a homogenous long COVID-19 definition was used. From 1978 studies identified, 37 peer-reviewed studies and one preprint were included. Eighteen articles evaluated age, sixteen articles evaluated sex, and twelve evaluated medical comorbidities as risk factors of long COVID-19. Overall, single studies reported that old age seems to be associated with long COVID-19 symptoms (n = 18); however, the meta-analysis did not reveal an association between old age and long COVID-19 (n = 3; OR 0.86, 95% CI 0.73 to 1.03, p = 0.17). Similarly, single studies revealed that female sex was associated with long COVID-19 symptoms (n = 16); which was confirmed in the meta-analysis (n = 7; OR 1.48, 95% CI 1.17 to 1.86, p = 0.01). Finally, medical comorbidities such as pulmonary disease (n = 4), diabetes (n = 1), obesity (n = 6), and organ transplantation (n = 1) were also identified as potential risk factors for long COVID-19. The risk of bias of most studies (71%, n = 27/38) was moderate or high. In conclusion, pooled evidence did not support an association between advancing age and long COVID-19 but supported that female sex is a risk factor for long COVID-19. Long COVID-19 was also associated with some previous medical comorbidities.
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![Figure 2 Pooled analysis of odds ratio (OR) for the association between age older than 60 years and the presence of long COVID-19 symptoms [32,42,44].](/paper-figures/86f8f7fd95014f479cd0d94ad3768f63/age-sex-and-previous-comorbidities-as-risk-factors-not-associated-with-sars-cov-figure-2.jpg)
![Figure 3 Pooled weighted mean difference (WMD) for the association between age as continuous variable and the presence of long COVID-19 symptoms [43,45,46].](/paper-figures/f31a83dd623c46a9a29da65a1825c5d4/age-sex-and-previous-comorbidities-as-risk-factors-not-associated-with-sars-cov-figure-3.jpg)
![Figure 4 Pooled analysis of odds ratio (OR) for the association between sex and the presence of long COVID-19 [32,42,43,44,45,46,50].](/paper-figures/a80ed628e4804b85ae07af20a31949d4/age-sex-and-previous-comorbidities-as-risk-factors-not-associated-with-sars-cov-figure-4.jpg)
![Figure 5 Plot of the risk of bias of those studies investigating age as a risk factor of long COVID-19 [10,26,27,28,29,30,31,32,33,35,36,37,38,39,40,41,42,43].](/paper-figures/ca01d351815b4fa59b688b976c1a910a/age-sex-and-previous-comorbidities-as-risk-factors-not-associated-with-sars-cov-figure-5.jpg)
![Figure 6 Plot of the risk of bias of those studies investigating sex as a risk factor of long COVID-19 [1,32,42,43,44,45,46,47,48,49,50,51,52,54,55,56].](/paper-figures/d659e9b9a223430185bf519c95dc692e/age-sex-and-previous-comorbidities-as-risk-factors-not-associated-with-sars-cov-figure-6.jpg)
![Figure 7 Plot of the risk of bias of those studies investigating medical comorbidities as a risk factor of long COVID-19 [4,29,39,44,52,53,56,58,60,61,62,63].](/paper-figures/9dc897af95c94d368a40d80d3718b731/age-sex-and-previous-comorbidities-as-risk-factors-not-associated-with-sars-cov-figure-7.jpg)
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“Since pre-existing comorbidities, such as asthma, diabetes, obesity, and immunosuppressive conditions, can also be associated with higher risks of long COVID [3,7,8]”
From Protective effect of COVID-19 vaccination against long COVID syndrome: A systematic review and meta-analysis (2023) · cites this paper as [7]
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RETRACTED: 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study
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Longitudinal Changes in Physical Function and Their Impact on Health Outcomes in COVID-19 Patients
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Identification of inflammatory clusters in long-COVID through analysis of plasma biomarker levels
Dhingra, S., Fu, J., Cloherty, G., Mallon, P. W. G., Wasse, H., Moy, J. N., LANDAY, A. L., & Kenny, G. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1385858 · Cited by 9
Respiratory training effects in Long COVID-19 patients: a systematic review and meta-analysis
Mateo, A. C., Reychler, G., Ciuró, A. H., Núñez, J. M., Ortíz‐Rubio, A., Navas‐Otero, A., & Valenza, M. C. (2024) · Expert Review of Respiratory Medicine · doi:10.1080/17476348.2024.2358933 · Cited by 8
Long COVID: cognitive, balance, and retina manifestations
Carmona-Cervelló, M., León-Gómez, B. B., Dacosta‐Aguayo, R., Lamonja-Vicente, N., Montero-Alía, P., Molist, G., Ayet, A., Chacón, C., Costa-Garrido, A., López-Lifante, V. M., et al. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1399145 · Cited by 12
Petracek, L. S., Broussard, C. A., Swope, R. L., & Rowe, P. C. (2023) · Healthcare · doi:10.3390/healthcare11060865 · Cited by 9
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Lee, S.-S., Kisiel, M. A., Lindberg, P., Wheelock, Å. M., Olofsson, A., Eriksson, J. A., Bruchfeld, J., Runold, M., Wahlström, L., Malinovschi, A., et al. (2025) · BMC Medicine · doi:10.1186/s12916-025-04050-w · Cited by 7
Ronca, D. B., Mesquita, L. O., Oliveira, D. B., Figueiredo, A. C. M. G., Wen, J., Song, M., & de Carvalho, K. M. B. (2025) · PLoS ONE · doi:10.1371/journal.pone.0314892 · Cited by 8
Headache as a COVID-19 onset symptom or Post-COVID symptom according to the SARS-CoV-2 Variant
Fernández‐de‐las‐Peñas, C., Cuadrado, M. L., Gómez‐Mayordomo, V., García‐Azorín, D., & Arendt‐Nielsen, L. (2023) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2023.2185138 · Cited by 7
Self-citationCharacteristics of Chemosensory Perception in Long COVID and COVID Reinfection
Jaramillo, M., Thyvalikakath, T. P., Eckert, G. J., & Srinivasan, M. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12103598 · Cited by 6
Bullock, A., Dalton, A. F., Stockwell, M. S., McLaren, S. H., Sano, E. D., Nguyen, H. Q., Rao, S., Asturias, E. J., Lutrick, K., Ellingson, K., et al. (2025) · Clinical Infectious Diseases · doi:10.1093/cid/ciaf026 · Cited by 6
Long COVID-19 and primary care: Challenges, management and recommendations
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Aging mitochondria in the context of SARS-CoV-2: exploring interactions and implications
Delpino, M. V., & Quarleri, J. F. (2024) · Frontiers in Aging · doi:10.3389/fragi.2024.1442323 · Cited by 5
Comorbid Asthma Increased the Risk for COVID-19 Mortality in Asia: A Meta-Analysis
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Traumatic Brain Injury in the Long-COVID Era
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Delgado, I. G., López‐Pastor, A. R., González‐Jiménez, A., Ramos‐Acosta, C., Hernández‐Garate, Y. A. K., Martínez-Micaelo, N., Amigó, N., Espino‐Paisán, L., Anguita, E., & Urcelay, E. (2025) · Cell Biology and Toxicology · doi:10.1007/s10565-024-09976-0 · Cited by 4
Visual analysis of hotspots and trends in long COVID research based on bibliometric
Lai, Z., Pu, T., Li, J., Bai, F., Wu, L., & Tang, Y. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e24053 · Cited by 5
Kiatratdasakul, S., Noisumdaeng, P., & Niyomdecha, N. (2024) · PeerJ · doi:10.7717/peerj.17898 · Cited by 4
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Weathering the Storm: How Age and Biologics Influence the COVID-19 Cytokine Surge
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Barnekow, T., Peters, C., Dulon, M., & Nienhaus, A. (2024) · Journal of Occupational Medicine and Toxicology · doi:10.1186/s12995-024-00431-8 · Cited by 3
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Schizophrenia, Bipolar, or Major Depressive Disorder and Postacute Sequelae of COVID-19
Vekaria, V., Thiruvalluru, R. K., Verzani, Z., Abedian, S., Olfson, M., Patra, B. G., Xiao, Y.-Y., Salamon, K. S., Hoth, K., Blanceró, F., et al. (2025) · JAMA Network Open · doi:10.1001/jamanetworkopen.2025.40242 · Cited by 3
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Metadata
- Authors
- Notarte, K. I., de Oliveira, M. H. S., Peligro, P. J., Velasco, J. V., Macaranas, I., Ver, A. T., Pangilinan, F. C., Pastrana, A., Goldrich, N., Kavteladze, D., Gellaco, M. M. L., Liu, J., Lippi, G., Henry, B. M., & Fernández-de-las-Peñas, C.
- Affiliations
- Johns Hopkins University (US)
- Universidade Estadual de Maringá (BR)
- University of Santo Tomas (PH)
- New York Medical College (US)
- University of Verona (IT)
- Cincinnati Children's Hospital Medical Center (US)
- Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Universidad Rey Juan Carlos, 28933 Madrid, Spain
- ORCID
- Venue
- Journal of Clinical Medicine
- Publisher
- MDPI AG
- Published
- 2022-12-09
- Volume
- 11
- Issue
- 24
- Pages
- 7314
- ISSN
- 2077-0383 (ISSN-L)
- PMC
- PMC9787827
- OpenAlex
- W4311974713
- Cited by
- 209
- References
- 71
- Citations by year
- 2026: 19 · 2025: 55 · 2024: 78 · 2023: 56 · 2022: 1
- FWCI
- 6.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Clinical Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Fondo Europeo De Desarrollo Regional—Recursos REACT-UE del Programa Operativo de Madrid 2014–2020
- 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
- long COVID, risk factors, age, sex differences, female sex as risk factor, comorbidities, obesity, diabetes mellitus, lung disease, organ transplantation, COVID-19 pandemic, prognostic factors, risk of bias
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