The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has profoundly impacted global health since its emergence in late 2019. While most patients recover from the acute phase of infection, a significant proportion continue to experience lingering symptoms affecting multiple organ systems—a condition now termed post-COVID syndrome or long COVID (1,2). This syndrome encompasses a spectrum of clinical manifestations such as fatigue, dyspnea, myalgia, neurocognitive impairment, and cardiovascular dysfunction, persisting for weeks or even months after initial recovery (3,4).

Emerging evidence suggests that post-COVID syndrome is largely driven by a persistent inflammatory response triggered during the acute infection (5). Studies have identified elevated levels of inflammatory markers such as C-reactive protein (CRP), interleukin-6 (IL-6), D-dimer, ferritin, and erythrocyte sedimentation rate (ESR) in patients with long COVID, implicating them in the pathophysiology of prolonged symptoms (6,7). These biomarkers, which are readily measurable in routine clinical practice, may offer valuable insight into predicting disease progression and multisystem involvement in affected individuals.

Multisystem involvement, including respiratory, cardiovascular, neurological, and renal manifestations, has been frequently observed in post-COVID patients and often correlates with disease severity during the acute phase (8,9). However, the clinical utility of inflammatory biomarkers in forecasting the extent of post-acute sequelae remains under-explored. Identifying reliable predictors for organ involvement could help clinicians prioritize monitoring and rehabilitation efforts in high-risk groups.

Therefore, this study was undertaken to assess the relationship between inflammatory biomarkers and multisystem involvement in patients with post-COVID syndrome. By evaluating commonly used laboratory indicators, the study aims to facilitate early detection and intervention strategies in individuals vulnerable to persistent organ dysfunction following COVID-19.

Study Design and Setting

This prospective observational study was conducted over a six-month period in the Department of Internal Medicine at a tertiary care hospital in India. Written informed consent was collected from all participants.

Study Population

The study included adult patients (aged 18 years and above) who had a confirmed history of COVID-19 (via RT-PCR or rapid antigen test) and continued to exhibit symptoms beyond four weeks of recovery. Exclusion criteria comprised patients with pre-existing autoimmune diseases, active infections, malignancies, or those on immunosuppressive therapy.

Sampling Technique

Purposive sampling was employed to recruit a total of 120 participants who met the eligibility criteria and presented to the outpatient post-COVID clinic or were admitted for further evaluation.

Clinical Assessment

A comprehensive evaluation was performed for all participants, which included detailed medical history, physical examination, and symptom documentation. A structured clinical checklist was used to record the involvement of various organ systems including respiratory (e.g., dyspnea, cough), cardiovascular (e.g., palpitations, chest pain), neurological (e.g., headache, brain fog), renal (e.g., altered urine output), and musculoskeletal (e.g., myalgia, fatigue) systems.

Laboratory Investigations

Venous blood samples were collected from each participant for evaluation of inflammatory biomarkers. The parameters measured included C-reactive protein (CRP), interleukin-6 (IL-6), ferritin, D-dimer, and erythrocyte sedimentation rate (ESR). All investigations were carried out in the hospital’s central diagnostic laboratory using standardized protocols and commercially available assay kits.

Definition of Multisystem Involvement

Multisystem involvement was defined as the clinical or radiological involvement of two or more organ systems persisting beyond four weeks after recovery from the acute phase of COVID-19.

Statistical Analysis

Descriptive statistics were used to summarize demographic and clinical data. Continuous variables were expressed as means ± standard deviation, and categorical variables as frequencies and percentages. The chi-square test was applied to assess associations between elevated biomarkers and multisystem involvement. Pearson’s correlation coefficient was used to explore the relationship between biomarker levels and the number of systems affected. A p-value of less than 0.05 was considered statistically significant. Statistical analysis was performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA).

A total of 120 patients with post-COVID symptoms persisting beyond four weeks were included in the study. The mean age of participants was 45.2 ± 12.6 years, with a nearly equal gender distribution (62 males, 58 females). The most commonly reported persistent symptoms were fatigue (76%), dyspnea (65%), myalgia (53%), and cognitive disturbances (41%).

Multisystem Involvement

Out of 120 patients, 82 (68.3%) exhibited involvement of two or more organ systems. Respiratory symptoms were present in 78 patients (65%), followed by neurological symptoms in 56 (47%), cardiovascular in 49 (41%), musculoskeletal in 63 (52.5%), and renal manifestations in 18 patients (15%).

Inflammatory Biomarker Levels

Table 1 summarizes the distribution of inflammatory biomarkers among patients with and without multisystem involvement. CRP levels above 10 mg/L were noted in 59 patients (72%) with multisystem involvement, compared to 9 patients (23%) without it (p<0.001). Similarly, elevated IL-6 (>7 pg/mL) was present in 52 patients (63.4%) with multisystem symptoms, in contrast to 8 patients (20.5%) without (p<0.001).

Table 1: Distribution of Inflammatory Biomarkers in Patients With and Without Multisystem Involvement

As shown in Table 1, the levels of all five inflammatory biomarkers were significantly higher among patients with multisystem involvement than those without.

Correlation between Biomarkers and Number of Systems Involved

A positive correlation was observed between the levels of CRP and the number of organ systems affected (r=0.68, p<0.001). IL-6 levels also showed a moderate positive correlation (r=0.54, p=0.002) with the extent of system involvement. The correlation coefficients for ferritin, D-dimer, and ESR were lower but still statistically significant.

Table 2: Correlation between Biomarker Levels and Number of Organ Systems Involved

As evident from Table 2, CRP and IL-6 exhibited the strongest correlations with the number of organ systems involved, suggesting their potential role as predictive markers in post-COVID syndrome.

The findings of this study highlight the significant role of inflammatory biomarkers—particularly C-reactive protein (CRP) and interleukin-6 (IL-6)—in predicting multisystem involvement in patients with post-COVID syndrome. A majority (68.3%) of the participants experienced persistent symptoms affecting more than one organ system, corroborating earlier reports on the high burden of long COVID in the recovering population (1,2).

Elevated levels of CRP and IL-6 were significantly associated with multisystem manifestations. CRP, a well-established acute-phase reactant, has been shown to correlate with disease severity in acute COVID-19 and appears to remain elevated in cases with ongoing inflammation post-recovery (3,4). Our study found that 72% of patients with multisystem involvement had CRP levels >10 mg/L, which is in line with prior reports suggesting sustained systemic inflammation in long COVID (5,6). Similarly, IL-6, a pro-inflammatory cytokine implicated in cytokine storm during acute infection, remained elevated in 63.4% of those with multisystem symptoms. This finding is supported by previous research demonstrating prolonged IL-6 elevation in convalescent patients with persistent fatigue and neurocognitive symptoms (7,8).

Ferritin, D-dimer, and ESR also showed significant associations with multisystem involvement. Ferritin, known to be a marker of both inflammation and oxidative stress, was elevated in 58.5% of such cases, consistent with previous studies linking hyperferritinemia to systemic inflammation in post-viral syndromes (9). Elevated D-dimer levels in 42.6% of patients suggest ongoing endothelial dysfunction or a pro-thrombotic state, which may contribute to lingering cardiovascular or neurological symptoms (10,11). ESR, a general marker of chronic inflammation, also correlated with the number of organ systems affected, echoing similar observations in post-viral fatigue syndromes and autoimmune-like sequelae seen post-COVID (12,13).

The observed correlation between CRP and number of organ systems involved (r=0.68) and between IL-6 and system involvement (r=0.54) points to a dose-response relationship, indicating that higher systemic inflammation may drive wider multisystem impact. This supports prior hypotheses that low-grade chronic inflammation underlies many of the long-term sequelae observed after acute COVID-19 (14). These results underscore the utility of measuring inflammatory biomarkers not only during acute infection but also in follow-up to identify individuals at risk of prolonged morbidity.

Our study adds to the growing body of literature emphasizing the need for post-COVID monitoring protocols that include biomarker-based risk stratification. Integrating such parameters into routine post-COVID care may enable early intervention through immunomodulatory or rehabilitative strategies in high-risk individuals. Moreover, persistent biomarker elevation could inform future research on targeted anti-inflammatory treatments to mitigate long COVID progression (15).

Inflammatory biomarkers, particularly CRP and IL-6, show strong predictive value for multisystem involvement in post-COVID syndrome. However, this study is not without limitations. The sample size was relatively modest and recruited from a single tertiary center, which may limit generalizability. In addition, longitudinal follow-up data beyond the study period was not included, which would have provided insights into the prognostic value of these markers over time. Future studies with larger, multicentric cohorts and extended follow-up will be valuable in validating these findings and guiding therapeutic interventions.

1. Christaki M, Samanidou V, Liontos A, Konstantopoulou R, Milionis H. Post-COVID-19 Multisystem Inflammatory Syndrome in Adults (MIS-A) With Elevated Levels of Soluble Urokinase Plasminogen Activator Receptor (suPAR) Treated With Anakinra: A Case Report. Cureus. 2024 Oct 4;16(10):e70848. doi: 10.7759/cureus.70848. [PMID: 39493146]
2. Louka M, Tatsi EB, Vassiliu S, Theoharis G, Straka K, Filippatos F, et al. The Soluble Urokinase Plasminogen Activator Receptor as a Severity Biomarker in Children With Acute COVID-19 or Multisystem Inflammatory Syndrome. Pediatr Infect Dis J. 2024 May 1;43(5):477-82. doi: 10.1097/INF.0000000000004244. [PMID: 38251905]
3. Kyriazopoulou E, Panagopoulos P, Metallidis S, Dalekos GN, Poulakou G, Gatselis N, et al. An open label trial of anakinra to prevent respiratory failure in COVID-19. Elife. 2021 Mar 8;10:e66125. doi: 10.7554/eLife.66125. [PMID: 33682678]
4. Segala FV, Rando E, Salvati F, Negri M, Catania F, Sanmartin F, et al. Anakinra in hospitalized COVID-19 patients guided by baseline soluble urokinase plasminogen receptor plasma levels: A real world, retrospective cohort study. PLoS One. 2023 Apr 4;18(4):e0273202. doi: 10.1371/journal.pone.0273202. [PMID: 37014833]
5. Aggarwal A, Cohen E, Figueira M, Sabharwal V, Herlihy JM, Bronwen C, et al. Multisystem Inflammatory Syndrome in an Adult With COVID-19-A Trial of Anakinra: A Case Report. Infect Dis Clin Pract (Baltim Md). 2021 Nov;29(6):e420-e423. doi: 10.1097/IPC.0000000000001028. [PMID: 34803350]
6. Helena C, Giulia T, Alessandra C, Roberto G, Caterina S, Sabrina G, et al. Detection of Inflammatory Biomarker suPAR in COVID-19 Disease With CHORUS TRIO Instrument. Biomark Insights. 2023 Nov 29;18:11772719231210407. doi: 10.1177/11772719231210407. [PMID: 38035182]
7. Padelli M, Gueye P, Guilloux D, Banydeen R, Campana V, Cabie A, et al. Soluble urokinase plasminogen activator receptor levels are predictive of COVID-19 severity in Afro-Caribbean patients. Biomark Med. 2022 Feb;16(3):169-77. doi: 10.2217/bmm-2021-0669. [PMID: 35081737]
8. Cattaneo P, Volpe A, Cardellino CS, Riccardi N, Bertoli G, Ursini T, et al. Multisystem Inflammatory Syndrome in an Adult (MIS-A) Successfully Treated with Anakinra and Glucocorticoids. Microorganisms. 2021 Jun 28;9(7):1393. doi: 10.3390/microorganisms9071393. [PMID: 34203277]
9. Akinosoglou K, Kotsaki A, Gounaridi IM, Christaki E, Metallidis S, Adamis G, et al. Efficacy and safety of early soluble urokinase plasminogen receptor plasma-guided anakinra treatment of COVID-19 pneumonia: A subgroup analysis of the SAVE-MORE randomised trial. EClinicalMedicine. 2023 Feb;56:101785. doi: 10.1016/j.eclinm.2022.101785. [PMID: 36590789]
10. Füller D, Liu C, Ko YA, Alkhoder AA, Desai SR, Almuwaqqat Z, et al. Soluble urokinase Plasminogen Activator Receptor (suPAR) mediates the effect of a lower education level on adverse outcomes in patients with coronary artery disease. Eur J Prev Cardiol. 2024 Mar 27;31(5):521-28. doi: 10.1093/eurjpc/zwad311. [PMID: 37788634]
11. Tolunay O, Çelik Ü, Arslan İ, Orgun A, Demir H, Demir O, et al. Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19: A Case Series Experience in a Tertiary Care Hospital of Southern Turkey. J Trop Pediatr. 2021 May 17;67(2):fmab050. doi: 10.1093/tropej/fmab050. [PMID: 34028528]
12. Kostopoulou E, Kalavrizioti D, Davoulou P, Sinopidis X, Papachristou E, Goumenos DS, et al. Soluble urokinase plasminogen activator receptor (suPAR) in children with obesity or type 1 diabetes as a marker of endothelial dysfunction: a cross-sectional study. Eur J Pediatr. 2024 May;183(5):2383-89. doi: 10.1007/s00431-024-05496-5. [PMID: 38448612]
13. Shabil M, Khatib MN, Banda GT, Zahiruddin QS, Ballal S, Bansal P, et al. Effectiveness of early Anakinra on cardiac function in children with multisystem inflammatory syndrome of COVID-19: a systematic review. BMC Infect Dis. 2024 Aug 21;24(1):847. doi: 10.1186/s12879-024-09581-w. [PMID: 39169304]
14. Enocsson H, Wetterö J, Skogh T, Sjöwall C. Soluble urokinase plasminogen activator receptor levels reflect organ damage in systemic lupus erythematosus. Transl Res. 2013 Nov;162(5):287-96. doi: 10.1016/j.trsl.2013.07.003. [PMID: 23916811]
15. Weckman AM, Guagliardo SAJ, Crowley VM, Moro L, Piubelli C, Ursini T, et al. Host Response Markers of Inflammation and Endothelial Activation Associated with COVID-19 Severity and Mortality: A GeoSentinel Prospective Observational Cohort. Viruses. 2024 Oct 15;16(10):1615. doi: 10.3390/v16101615. [PMID: 39459948]