Clustering of long-term post-covid syndrome phenotypes and determining some pathophysiological mechanisms of their development
Abstract. Long-term post-COVID syndrome (LPS) has a wide prevalence (from 30 to 80%) and is represented by more than 200 symptoms. At the same time, the structure of risk factors and pathogenetic mechanisms of LPS have not been sufficiently studied. The study of these aspects is a promising direction in therapy, which can help in preventing the occurrence of long-term LPS and ensuring its effective treatment.Masalkina O.V., Koziolova N.A., Merk E.I.
The aim: to determine the phenotypes (clusters) of LPS and some pathophysiological mechanisms of their development basing on cluster analysis.
Material and methods. Clinical cross-sectional screening study included 802 patients with LPS symptoms who consecutively visited outpatient clinic from April 2020 to April 2024. LPS was established in the presence of typical signs and symptoms (including in combination with symptoms of comorbid conditions) that developed during or after COVID-19 and lasted more than 12 weeks.
Results. The average duration of the period after COVID-19 in the study participants was 8.5 [3.4; 14.1] months. 802 patients were clustered into 6 LPS phenotypes: 1) polysymptomatic with chronic comorbid pathology; 2) chronic respiratory; 3) cardiovascular; 4) thromboembolic; 5) acute respiratory; 6) acute ischemic.
Conclusion. Performing cluster analysis allowed us to identify the following differences in the frequency of development of LPS phenotypes in 802 outpatients who visited the clinic during 4 years of observation: polysymptomatic with chronic comorbid pathology – 66.6%, chronic respiratory – 14.5%, cardiovascular – 5.2%, thromboembolic – 2%, acute respiratory – 8.0%, acute ischemic – 3.7%. For each LPS phenotype, specific predictors of its formation were determined. It has been proven that the pathogenetic mechanisms of LPS development differ depending on the cluster.
Keywords
cluster analysis
phenotypes of long-term post-COVID syndrome
pathophysiological mechanisms of long-term post-COVID syndrome
References
1. Pretorius E, Venter C, Laubscher GJ, Kotze MJ, Oladejo SO, Watson LR et al. Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with long COVID / post-acute sequelae of COVID-19 (PASC). Cardiovasc Diabetol. 2022;21(1):148.
PMID: 35933347. PMCID: PMC9356426. https://doi: 10.1186/s12933-022-01579-5
2. Cabrera Martimbianco AL, Pacheco RL, Bagattini ÂM, Riera R. Frequency, signs and symptoms, and criteria adopted for long COVID- 19: A systematic review. Int J Clin Pract. 2021;75(10):e14357.
PMID: 33977626. PMCID: PMC8236920. https://doi.org/10.1111/ijcp.14357
3. Tsampasian V, Elghazaly H, Chattopadhyay R, Debski M, Naing TKP, Garg P et al Risk factors associated with post-COVID-19 condition: A systematic review and meta-analysis. JAMA Intern Med. 2023;183(6):566–80.
PMID: 36951832. PMCID: PMC10037203. https://doi.org/10.1001/jamainternmed.2023.0750
4. Ioannou GN, Baraff A, Fox A, Shahoumian T, Hickok A, O’Hare AM et al. Rates and factors associated with documentation of diagnostic codes for long COVID in the National Veterans Affairs Health Care System. JAMA Netw Open. 2022;5(7):e2224359.
PMID: 35904783. PMCID: PMC9338411. https://doi.org/10.1001/jamanetworkopen.2022.24359
5. Vlaming-van Eijk LE, Tang G, Bourgonje AR, den Dunnen WFA, Hillebrands JL, van Goor H. Post-COVID-19 condition: Clinical phenotypes, pathophysiological mechanisms, pathology, and management strategies. J Pathol. 2025;266(4–5):369–89.
PMID: 40492581. PMCID: PMC12256391. https://doi.org/10.1002/path.6443
6. Stavem K, Ghanima W, Olsen MK, Gilboe HM, Einvik G. Persistent symptoms 1.5–6 months after COVID-19 in non-hospitalised subjects: A population-based cohort study. Thorax. 2021;76(4):405–7.
PMID: 33273028. PMCID: PMC7716295. https://doi.org/10.1136/thoraxjnl-2020-216377
7. Al-Aly Z, Xie Y, Bowe B. High-dimensional characterization of post-acute sequelae of COVID-19. Nature. 2021;594(7862):259–64.
PMID: 33887749. https://doi.org/10.1038/s41586-021-03553-9
8. Boaventura P, Macedo S, Ribeiro F, Jaconiano S, Soares P. Post-COVID-19 condition: Where are we now? Life (Basel). 2022;12(4):517.
PMID: 35455008. PMCID: PMC9029703. https://doi.org/10.3390/life12040517
9. National Institute for Health and Care Excellence (NICE). COVID-19 rapid guideline: Managing the long-term effects of COVID-19. Published: 18 December 2020. Last updated: 25 January 2024. URL: https://www.nice.org.uk/guidance/ng188/resources/covid19-rapid-guideline-managing-the-longterm-effects-of-covid19-pdf-66142028400325 (date of access – 11.04.2025).
10. Rahmati M, Udeh R, Yon DK, Lee SW, Dolja-Gore X, McEVoy M et al. A systematic review and meta-analysis of long-term sequelae of COVID-19 2-year after SARS-CoV-2 infection: A call to action for neurological, physical, and psychological sciences. J Med Virol 2023;95(6):e28852.
PMID: 37288652. https://doi.org/10.1002/jmv.28852
11. Fernandez-de-Las-Penas C, Notarte KI, Macasaet R, Velasco JV, Catahay JA, Ver AT et al. Persistence of post-COVID symptoms in the general population two years after SARS-CoV-2 infection: A systematic review and meta-analysis. J Infect. 2024;88(2):77–88.
PMID: 38101521. https://doi.org/10.1016/j.jinf.2023.12.004
12. Thaweethai T, Jolley SE, Karlson EW, Levitan EB, Levy B, McComsey GA et al.; RECOVER Consortium. Development of a definition of postacute sequelae of SARS-CoV-2 infection. JAMA. 2023;329(22):1934–46.
PMID: 37278994. PMCID: PMC10214179. https://doi.org/10.1001/jama.2023.8823
13. Kenny G, McCann K, O’Brien C, Savinelli S, Tinago W, Yousif O et al.; All-Ireland Infectious Diseases (AIID) Cohort Study Group. Identification of distinct long COVID clinical phenotypes through cluster analysis of self-reported symptoms. Open Forum Infect Dis. 2022;9(4):ofac060.
PMID: 35265728. PMCID: PMC8900926. https://doi.org/10.1093/ofid/ofac060
14. Epsi NJ, Chenoweth JG, Blair PW, Lindholm DA, Ganesan A, Lalani T et al. Precision symptom phenotyping identifies early clinical and proteomic predictors of distinct COVID-19 sequelae. J Infect Dis. 2025;232(1):39–49.
PMID: 38916431. PMCID: PMC12308661. https://doi.org/10.1093/infdis/jiae318
15. Canas LS, Molteni E, Deng J, Sudre CH, Murray B, Kerfoot E et al. Profiling post-COVID-19 condition across different variants of SARS-CoV-2: A prospective longitudinal study in unvaccinated wild-type, unvaccinated alpha-variant, and vaccinated delta-variant populations. Lancet Digit Health. 2023;5(7):e421–e434.
PMID: 37202336. PMCID: PMC10187990. https://doi.org/10.1016/S2589-7500(23)00056-0
16. Gentilotti E, Gorska A, Tami A, Gusinow R, Mirandola M, Rodriguez Bano J et al. Clinical phenotypes and quality of life to define post-COVID-19 syndrome: A cluster analysis of the multinational, prospective ORCHESTRA cohort. EClinicalMedicine. 2023;62:102107.
PMID: 37654668. PMCID: PMC10466236. https://doi.org/10.1016/j.eclinm.2023.102107
17. Reese JT, Blau H, Casiraghi E, Bergquist T, Loomba JJ, Callahan TJ et al.; N3C Consortium; RECOVER Consortium. Generalisable long COVID subtypes: Findings from the NIH N3C and RECOVER programmes. EBioMedicine. 2023;87:104413.
PMID: 36563487. PMCID: PMC9769411. https://doi.org/10.1016/j.ebiom.2022.104413
18. Bowe B, Xie Y, Al-Aly Z. Postacute sequelae of COVID-19 at 2 years. Nat Med. 2023;29(9):2347–57.
PMID: 37605079. PMCID: PMC10504070. https://doi.org/10.1038/s41591-023-02521-2
19. Aggarwal G, Cheruiyot I, Aggarwal S, Wong J, Lippi G, Lavie CJ et al. Association of cardiovascular disease with coronavirus disease 2019 (COVID-19) severity: A meta-analysis. Curr Probl Cardiol. 2020;45(8):100617.
PMID: 32402515. PMCID: PMC7187816. https://doi.org/10.1016/j.cpcardiol.2020.100617
20. Huang HP, Wang HW, Cheng CH, Chang YS, Yeh TK, Huang WH et al. Post-COVID-19 condition and pulmonary embolism. J Multidiscip Healthc. 2024;17:6153–59.
PMID: 39741525. PMCID: PMC11687424. https://doi.org/10.2147/JMDH.S492159
21. Canale MP, Menghini R, Martelli E, Federici M. COVID-19-associated endothelial dysfunction and microvascular injury: From pathophysiology to clinical manifestations. Card Electrophysiol Clin. 2022;14(1):21–28.
PMID: 35221082. PMCID: PMC8556628. https://doi.org/10.1016/j.ccep.2021.10.003
22. Suh YJ, Hong H, Ohana M, Bompard F, Revel MP, Valle C et al. Pulmonary embolism and deep vein thrombosis in COVID-19: A systematic review and meta-analysis. Radiology. 2021;298(2):E70–E80.
PMID: 33320063. PMCID: PMC7745997. https://doi.org/10.1148/radiol.2020203557
23. Tomczyk P, Tomczyk D. Pulmonary embolism in patients in acute COVID-19, long-COVID and post-COVID syndrome. Przegl Epidemiol. 2023;77(2):172–84.
PMID: 37846660. https://doi.org/10.32394/pe.77.17
24. Shah B, Ahmad MN, Khalid M, Minhas A, Ali R, Sarfraz Z, Sarfraz A. Long COVID and wavering incidence of pulmonary embolism: A systematic review. J Community Hosp Intern Med Perspect. 2023;13(5):23–31.
PMID: 37868668. PMCID: PMC10589046. https://doi.org/10.55729/2000-9666.1233
25. Jakubec P, Fiserova K, Genzor S, Kolař M. Pulmonary complications after COVID-19. Life (Basel). 2022;12(3):357.
PMID: 35330108. PMCID: PMC8955291. https://doi.org/10.3390/life12030357
26. Clark JR, Batra A, Shlobin NA, Hoffman SC, Orban ZS, Koralnik IJ, Liotta EM. Acute-care hospital reencounters in COVID-19 patients. Geroscience. 2021;43(4):2041–53.
PMID: 34019232. PMCID: PMC8138514. https://doi.org/10.1007/s11357-021-00378-2
27. Oronsky B, Larson C, Hammond TC, Oronsky A, Kesari S, Lybeck M, Reid TR. A review of persistent post-COVID syndrome (PPCS). Clin Rev Allergy Immunol. 2023;64(1):66–74.
PMID: 33609255. PMCID: PMC7896544. https://doi.org/10.1007/s12016-021-08848-3
28. Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med. 2022;28(3):583–90.
PMID: 35132265. PMCID: PMC8938267. https://doi.org/10.1038/s41591-022-01689-3
29. Katsoularis I, Fonseca-Rodriguez O, Farrington P, Lindmark K, Fors Connolly AM. Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden: A self-controlled case series and matched cohort study. Lancet. 2021;398(10300):599–607.
PMID: 34332652. PMCID: PMC8321431. https://doi.org/10.1016/S0140-6736(21)00896-5
30. Alsaidan AA, Al-Kuraishy HM, Al-Gareeb AI, Alexiou A, Papadakis M, Alsayed KA et al. The potential role of SARS-CoV-2 infection in acute coronary syndrome and type 2 myocardial infarction (T2MI): Intertwining spread. Immun Inflamm Dis. 2023;11(3):e798.
PMID: 36988260. PMCID: PMC10022425. https://doi.org/10.1002/iid3.798
31. Kamal M, Abo Omirah M, Hussein A, Saeed H. Assessment and characterisation of post-COVID-19 manifestations. Int J Clin Pract. 2021;75(3): e13746.
PMID: 32991035. PMCID: PMC7536922. https://doi.org/10.1111/ijcp.13746
32. Taquet M, Geddes JR, Husain M, Luciano S, Harrison PJ. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: A retrospective cohort study using electronic health records. Lancet Psychiatry. 2021;8(5):416–27.
PMID: 33836148. PMCID: PMC8023694. https://doi.org/10.1016/S2215-0366(21)00084-5
33. Greenhalgh T, Sivan M, Perlowski A, Nikolich JŽ. Long COVID: A clinical update. Lancet. 2024;404(10453):707–24.
PMID: 39096925. https://doi.org/10.1016/S0140-6736(24)01136-X
34. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: Major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(3):133–46.
PMID: 36639608. PMCID: PMC9839201. https://doi.org/10.1038/s41579-022-00846-2
About the Authors
Olga V. Masalkina, MD, PhD (Medicine), associate professor of the Department of internal medicine and cardiology, Academician E.A. Wagner Perm State Medical University of the Ministry of Healthcare of Russia. Address: 614000, Perm, 26 Petropavlovskaya St.E-mail: omasalkina@mail.ru
ORCID: https://orcid.org/0009-0006-3364-0591. SPIN: 4394-5330
Natalia A. Koziolova, MD, Dr. Sci. (Medicine), professor, head of the Department of internal medicine and cardiology, Academician E.A. Wagner Perm State Medical University of the Ministry of Healthcare of Russia. Address: 614000, Perm, 26 Petropavlovskaya St.
E-mail: nakoziolova@mail.ru
ORCID: https://orcid.org/0000-0001-7003-5186. SPIN: 1044-0503
Elizaveta I. Merk, senior architect of artificial intelligence solutions, Fraport JSC, Germany, Frankfurt am Main.
E-mail: elisaweta.merk@gmail.com
ORCID: https://orcid.org/0009-0005-7425-9968
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