Recurrence to persistence: Inflammatory markers in pediatric rheumatic heart disease

ABSTRACT

Background:

Studies in adults with chronic rheumatic heart disease (RHD) suggest persistence of elevated inflammatory markers, indicating a potential role of ongoing inflammation in disease chronicity. However, similar data in the pediatric population are lacking.

Methods:

A cross-sectional observational study was conducted in the Division of Pediatric Cardiology at a tertiary care hospital in North India from August 2022 to February 2024. Forty-three patients with RHD <18 years were enrolled. Comprehensive history taking and clinical examinations were conducted. Blood samples were collected to evaluate C-reactive protein (CRP), neutrophil-to-lymphocyte ratio, interleukin-6 (IL-6), IL-17, and tumor necrosis factor alpha (TNF-α) levels. Inflammatory marker levels were compared with American College of Cardiology (ACC) valvular heart disease (VHD) stage.

Results:

Mean age of participants was 13.14 ± 3.17 years. Mean duration of disease was 3.23 ± 1.98 years. The CRP was elevated in 37.2% (n = 16) patients. IL-6, IL-17, and TNF-α were elevated in all patients. IL-6 (P = 0.036) and IL-17 (P = 0.008) showed significant association with ACC VHD stage.

Conclusions:

Pediatric RHD patients exhibit elevated blood inflammatory markers in the absence of acute rheumatic fever. Targeting this chronic inflammation could potentially slow progression of RHD.

INTRODUCTION

Acute rheumatic fever (ARF) is an autoimmune condition that arises from an exaggerated immune response to group A beta-hemolytic streptococcal infections, particularly pharyngitis. Although the incidence of ARF has declined in developed countries due to improved socioeconomic conditions and healthcare access, it remains a significant cause of rheumatic heart disease (RHD) in developing regions, driven by factors such as overcrowding, poor hygiene, and genetic predisposition.[1,2]

The pathophysiology of ARF involves molecular mimicry, where antibodies against streptococcal antigens cross-react with human tissue proteins, resulting in inflammation and damage to the heart, joints, brain, and skin. Notably, recurrent ARF episodes have been implicated toward cumulative valvular injury and chronic inflammation.[2]

Emerging evidences suggest that chronic subclinical inflammation may also contribute to RHD progression, with studies revealing valvular damage in patients who have never experienced ARF recurrences.[3,4] This highlights the importance of understanding the inflammatory processes involved in RHD, particularly in children, where the disease burden is highest. Given the potential for anti-inflammatory therapies to alter disease outcomes, further investigation into inflammatory markers in pediatric RHD is warranted so as to reduce the later morbidity and mortality in adulthood.

Elucidating the continuity of subclinical valvar inflammation as a key pathogenesis pathway toward the development of chronic valvar disease in children is critical. Toward addressing this gap in the literature, we designed this study to explore the inflammatory marker profile in children with RHD as well as its association with severity of valvar lesion.

METHODS

This cross-sectional observational study was conducted between August 2022 and February 2024 in the Division of Pediatric Cardiology at a tertiary care hospital in North India. Ethical approval was obtained from the Institutional Ethics Committee. Sample size was estimated based on a study by Singal et al. in adult RHD patients, wherein the proportion of subjects with deranged inflammatory markers was reported as 79%.[3] With a precision of 12.5%, an alpha error of 0.05, and a 95% confidence interval, the sample size was estimated to be 41 subjects.

Consecutive pediatric patients with RHD under the age group of 18 years were included in the study. Children with active ARF or ARF recurrence within the preceding 3 months were excluded to avoid confounding by acute inflammation. Patients with prior ARF recurrences occurring more than 3 months before enrollment were not excluded. Patients with other comorbidities such as tuberculosis, malignancy, rheumatological diseases, steroid therapy, fever, acute infections, inflammatory diseases, and trauma were also excluded from the study. After obtaining written informed consent/assent, a pre-designed pro forma was filled for each study participant. Comprehensive history and clinical examination were performed. Type of valvar involvement (regurgitant/mixed/stenotic) was labeled based upon echocardiogram. Severity of valvular heart disease (VHD) was designated as per the American College of Cardiology/American Heart Association (ACC/AHA) 2020 classification for VHD based on echocardiogram and patient symptoms.

Blood samples were taken for the evaluation of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), interleukin-6 (IL-6), IL-17, and tumor necrosis factor alpha (TNF-α) levels. The enzyme-linked immunosorbent assay kit was used to test the levels of IL-6, IL-17, and TNF-α, based on the principle of double antibody sandwich technology.

Data were coded and recorded in an MS Excel spreadsheet program (Microsoft Corporation, Washington, USA) SPSS v.23.0 (IBM manufacturer, Chicago, USA) was used for data analysis. Descriptive statistics were analyzed for continuous variables (means and medians) and categorical variables (frequencies and percentages). Normality was assessed via the Shapiro–Wilk test. Chi-squared test was used for categorical associations; Fisher’s exact test was used if conditions were not met. T-tests and one-way analysis of variance were used for comparisons between groups; Tukey’s Honestly Significant Difference for post hoc analysis. Nonparametric tests were used (Mann–Whitney U and Kruskal–Wallis) for non-normally distributed data. Correlation was assessed using Pearson’s (normal) and Spearman’s (non-normal) methods.

RESULTS

During the study period, 55 chronic RHD patients attended pediatric cardiology outpatient department (OPD)/pediatrics OPD/inpatient department. Of these, 12 patients had ARF within the last 3 months (updated Jones criteria 2015) and, hence, were excluded. The baseline characteristics of the 43 patients who met the inclusion and exclusion criteria are shown in Table 1. Mean age at diagnosis was 10.02 ± 3.03 years, with a mean duration of disease of 3.23 ± 1.98 years and time since last episode of ARF being 25.51 ± 21.53 months.

Table 1.

Baseline characteristics of study population

Basic details	Mean±SD Median (IQR) Minimum–Maximum
Age (years)	13.14±3.17
	14.00 (10.00–15.50)
	6.00–17.00
Age (years), n (%)
6–12	17 (39.5)
13–17	26 (60.5)
Gender, n (%)
Male	24 (55.8)
Female	19 (44.2)
Age at diagnosis (years)	10.02±3.03
	10.00 (8.00–12.00)
	4.50–16.50
Duration of disease (years)	3.23±1.98
	3.00 (1.50–4.25)
	0.33–8.00
Time since last ARF episode (months)	25.51±21.53
	24.00 (7.50–36.00)
	4.00–96.00

ARF: Acute rheumatic fever, SD: Standard deviation, IQR: Interquartile range

Regurgitant lesions dominated, with 83.7% cases (n = 36) having regurgitant lesions, whereas 11.6% (n = 5) and 4.7% (n = 2) had mixed and stenotic lesions, respectively [Table 2]. Mitral regurgitation (93.0%, n = 40) was the predominant valvular lesion. According to ACC Valvar Heart Disease Staging, 27.9% (n = 12), 32.6% (n = 14), and 39.5% (n = 17) patients had Stage B, C, and D, respectively. Table 3 depicts the values of basic investigations and inflammatory markers, and Table 4 shows their association with ACC VHD stages. CRP was elevated (>3 mg/dl) in 37.2% (n = 16) patients. IL-6, IL-17, and TNF-α were elevated in 100%, 97.6%, and 100% of patients, respectively.

Table 2.

Details of valvular involvement in study population

RHD details	n (%)
Type of valvar lesion
Regurgitant	36 (83.7)
Mixed lesion	5 (11.6)
Stenotic	2 (4.7)
Number of valves involved
Single valve	21 (48.8)
Multivalvular	22 (51.2)
Echocardiogram findings
Mitral regurgitation	40 (93.0)
Tricuspid regurgitation	13 (30.2)
Aortic regurgitation	12 (27.9)
Mitral stenosis	7 (16.3)
Pulmonary regurgitation	1 (2.3)
Broad diagnosis
Isolated mitral regurgitation	18 (41.9)
Others	25 (58.1)
ACC VHD stage
B	12 (27.9)
C	14 (32.6)
D	17 (39.5)
Symptomatic RHD	17 (39.5)

RHD: Rheumatic heart disease, ACC VHD: American College of Cardiology Valvular Heart Disease

Table 3.

Depicting the values of investigations in the study population

Investigations	Mean±SD Median (IQR) Range
Hemoglobin (g/dL)	10.40±1.49
	10.50 (9.35–11.35)
	7.20–13.40
TLC (/mm2)	7445.58±2771.65
	7600.00 (4950.00–9150.00)
	3600.00–13,500.00
Platelet count (lacs/mm3)	2.99±1.21
	3.00 (2.00–3.60)
	1.20–6.80
ESR (mm in first h)	15.93±12.41
	12.00 (6.00–23.00)
	2.00–50.00
≤30 n (%)	37 (86.0)
>30 n (%)	6 (14.0)
CRP (mg/dL)	2.90±3.28
	1.20 (0.50–4.10)
	0.00–11.60
≤3 n (%)	27 (62.8)
>3 n (%)	16 (37.2)
ASO (U/L)	60.05±82.04
	5.00 (5.00–100.00)
	5.00–280.00
PR interval(s)	0.13±0.03
	0.12 (0.10–0.16)
	0.08–0.20
NLR	1.52±1.13
	1.50 (0.61–2.15)
	0.00–3.70
IL-6 (pg/mL)	154.56±14.18
	152.71 (145.40–162.71)
	126.69–189.57
IL-17 (pg/mL)	122.98±23.69
	127.57 (120.75–134.21)
	0.00–155.14
TNF alpha (pg/mL)	636.26±247.80
	656.8 (465.15–788.45)
	80.1–996.8

SD: Standard deviation, IQR: Interquartile range, TNF: Tumor necrosis factor, NLR: Neutrophil-to-lymphocyte ratio, IL-6: Interleukin-6, ESR: Erythrocyte sedimentation rate, CRP: C-reactive protein, TLC: Total leukocyte count, IL-17: Interleukin-17, ASO: Anti streptolysion O

Table 4.

Association of American College of Cardiology valvular heart disease stage with demographic and inflammatory parameters

Parameters	ACC VHD stage			P
	B (n=12), n (%)	C (n=14), n (%)	D (n=17), n (%)
Age (years)	14.58±2.39	12.29±3.38	12.82±3.28	0.234a
Age***
6–12	1 (8.3)	8 (57.1)	8 (47.1)	0.029b
13–17	11 (91.7)	6 (42.9)	9 (52.9)
Gender
Male	7 (58.3)	8 (57.1)	9 (52.9)	0.952b
Female	5 (41.7)	6 (42.9)	8 (47.1)
Age at diagnosis (years)	11.25±2.76	9.71±2.81	9.41±3.28	0.157a
Duration of disease (years)	3.49±1.94	2.71±2.02	3.47±2.02	0.368a
Time since last ARF episode (months)	36.33±22.48	23.86±23.89	19.24±16.55	0.077a
ESR (mm in first h)	13.58±16.17	16.79±12.77	16.88±9.30	0.227a
ESR (mm in first h)
≤30	9 (75.0)	12 (85.7)	16 (94.1)	0.342c
>30	3 (25.0)	2 (14.3)	1 (5.9)
CRP (mg/dL)	1.25±1.77	3.59±4.07	3.49±3.14	0.081a
CRP (mg/dL)
≤3	10 (83.3)	7 (50.0)	10 (58.8)	0.196b
>3	2 (16.7)	7 (50.0)	7 (41.2)
ASO (U/L)	21.67±40.36	71.31±104.27	77.88±78.48	0.135a
NLR	1.08±0.86	1.79±1.29	1.60±1.12	0.286a
IL-6 (pg/mL)***	147.64±16.05	155.60±13.63	158.58±12.09	0.036a
IL-17 (pg/mL)***	108.14±36.09	125.31±15.72	131.53±11.37	0.008a
TNF alpha (pg/mL)	662.10±188.15	531.35±281.66	704.42±239.41	0.164a

***Significant at P<0.05, ^aKruskal–Wallis test, ^bChi-squared test, ^cFisher’s exact test. ACC VHD: American College of Cardiology Valvular Heart Disease, CRP: C-reactive protein, TLC: Total leukocyte count, ARF: Acute rheumatic fever, ESR: Erythrocyte sedimentation rate, IL-6: Interleukin-6, TNF: Tumor necrosis factor, IL-17: Interleukin-17, NLR: Neutrophil-to-lymphocyte ratio, ASO: Anti streptolysion O

There were no association between patient age, age category (6–12 years and 13–17 years), gender, age at diagnosis, disease duration, or time since the last ARF in relation to ACC VHD stage [Table 4]. No significant associations were observed between the type of valvular lesion (regurgitant, mixed, and stenotic) and the level of inflammatory markers (ESR, CRP, NLR, IL-6, IL-17, and TNF-α). There were no notable correlations between ESR, CRP, NLR, or TNF-α and ACC VHD stage.

However, both IL-6 (P = 0.036) and IL-17 (P = 0.008) showed significant associations with ACC VHD stage. IL-17 was significantly associated with younger age (P = 0.007), younger age at diagnosis (P = 0.002), and time since the last ARF episode (P = 0.004), highlighting its potential role in the disease’s progression and patient demographics.

DISCUSSION

ARF is a delayed autoimmune complication of Group A streptococcal (GAS) tonsillopharyngitis. It results from molecular mimicry between the M protein epitopes of GAS and cardiac proteins in genetically susceptible individuals. This mimicry triggers the production of autoreactive antibodies, which activate complement proteins and induce inflammation, ultimately leading to valvular injury.[1,2,4]

The mechanisms underlying the progression of acute valvular inflammation to chronic rheumatic valve disease, including calcification, remain poorly understood. Revisiting the pathogenesis pathway is essential for devising effective intervention strategies. Key aspects include the initial antigenic mimicry-driven autoimmune valvular damage, subsequent hemodynamic injury, and the perpetuation of a chronic, subclinical inflammatory response.

The prevailing hypothesis suggests that recurrent ARF episodes during the early postinfection years result in cumulative valve damage, neovascularization, and progressive fibrosis. Evidence indicates that if carditis does not occur during the first ARF episode, the risk of cardiac involvement in subsequent episodes decreases. Conversely, initial carditis significantly increases the likelihood of developing severe chronic valvular disease following recurrent episodes. Prospective studies by Majid et al.,[5] and Meira et al.,[6] have corroborated this, highlighting the role of early recurrence in disease progression. Furthermore, Vincent et al.[7] reported that the incidence of ARF recurrence and the progression to chronic RHD is highest in the 1^st year after an initial ARF episode. Thus, recurrence of an ARF episode is central to progression to chronic valvular disease and has formed the basis for recommending secondary prophylaxis with penicillin.

Historical studies comparing penicillin prophylaxis with no treatment have demonstrated its efficacy in reducing ARF recurrence rates.[8] Notably, a study by Yousef et al. reported a 55% reduction in recurrences with penicillin prophylaxis, while two others indicated a nonsignificant trend favoring penicillin.[9]

Understanding disease progression in pediatric RHD is particularly crucial in regions such as Africa and Asia, where rates are significantly higher than in North America and Europe.[10] Severe RHD tends to manifest in late childhood or adolescence in these regions, unlike the later onset typically observed in European populations. The resultant valvular damage remains a leading cause of mortality, underscoring the need to elucidate its pathogenesis and identify reliable markers to track disease severity.

Inflammatory mechanisms have been implicated in the pathogenesis of various cardiovascular diseases, including coronary artery disease, atheroma formation, and degenerative aortic stenosis.[11,12] In these conditions, inflammatory cells and lipid deposits drive early lesion formation and active calcification. Furthermore, recent studies in adult RHD patients have highlighted the role of chronic inflammation in progressive valvular injury. Pediatric studies addressing its role in disease progression and valve calcification remain lacking.

Our study, conducted exclusively in pediatric patients (mean age: 13.14 ± 3.17 years; median: 14.00 years; range: 6–17 years), demonstrated elevated inflammatory markers – CRP, IL-6, IL-17, and TNF-α in RHD patients, none of whom had a recent episode of ARF. The mean age at first diagnosis of ARF/RHD was 10.02 ± 3.03 years, with an average disease duration of 3.23 ± 1.98 years. The mean time since the last ARF episode was 25.51 ± 21.53 months, and most patients (72%) had advanced valvular disease (AHA VHD stages C and D) despite no recent recurrences.[5]

We found no significant association between valvular disease severity (ACC VHD stage) and patient age, age at diagnosis, disease duration, or time since the last ARF episode. The early onset of advanced valvular disease in the absence of recurrent ARF episodes suggests that the initial disease episode (s) cause the most substantial valvular injury. These findings may indicate that the severity of chronic RHD may be determined by the extent of initial inflammatory damage and subsequent maladaptive repair, rather than by the frequency of recurrent ARF episodes.[13] However, longitudinal studies are required to establish this relationship. Among the evaluated biomarkers, IL-17 demonstrated the strongest association with valvular disease severity, followed by IL-6. The study was not designed or powered to derive clinically meaningful cutoff values. Larger prospective studies incorporating receiver operating characteristic analyses are required before thresholds can be proposed.

In addition, inflammatory marker levels in our pediatric cohort were markedly higher than those reported in adult RHD cases.[14] This aligns with evidence indicating that the risk of severe chronic valvular injury is highest in the early years following the initial ARF episode, with disease progression being most rapid in the 1^st year after diagnosis.[5,6]

Our observations challenge the conventional view that recurrent Group A β-hemolytic Streptococcus (GABHS) infections in the early years following an initial ARF episode are the primary drivers of chronic valvular inflammation. Instead, they suggest a persistent, smoldering immune response after the initial ARF episode as a key contributor to chronic disease progression and escalating valvular damage.[7]

Subclinical inflammation appears to play a critical role in RHD progression, as evidenced by Bland and Jones’ long-term data showing mitral stenosis development in patients without recurrent ARF episodes.[15] Similarly, echocardiographic studies have identified subclinical RHD in school children with no prior ARF history. Kayali et al. reported subclinical carditis in patients without ARF, with some cases worsening despite penicillin prophylaxis, underscoring the potential role of persistent inflammation.[4]

The hypothesis of subclinical persistent inflammation is further supported by the detection of high levels of advanced oxidation protein products and high-sensitivity CRP (hs-CRP) in the plasma of adult patients with RHD. Moreover, hs-CRP levels correlated with the severity of valvular dysfunction.[16,17] Our pediatric cohort showed raised CRP levels in 37.2% of patients, correlating with IL-17 (P < 0.05) but not with lesion type or severity, unlike findings in adult studies. Golbasi et al. reported elevated hs-CRP levels in chronic RHD patients compared to healthy individuals and those with prosthetic valves, suggesting a persistent inflammatory response in the chronic phase of the disease.[17]

The presence of an inflammatory response is also suggested by the observed elevated levels of cytokines such as IL-6, IL-17, TNF-α, and IL-1, in chronic RHD, indicating a strong immune response contributing to long-term immunological disturbances. Soares et al. found correlations between elevated cytokine levels (IL-6, IL-17, and TNF-α) and RHD severity.[18] Similarly, Tripathi et al. reported increased IL-6, IL-10, IL-18, TNF-α, and hs-CRP levels in adults with rheumatic mitral stenosis.[19] In our study, IL-6 was elevated in all patients, with significant correlation to valvular lesion severity (P < 0.05), though not to lesion type, likely due to the limited number of stenotic lesions.

Similarly, IL-17 was elevated in 97.6% of our cohort and significantly associated with younger age, earlier diagnosis, and shorter time since the last ARF episode (P < 0.05). It also correlated with valvular disease severity and symptomatic RHD. Prior studies in adults, including those by Soares et al.,[18] Bilik et al.,[20] and Bas et al.,[21] reported similar findings, though mean IL-17 levels in our younger population were higher, likely due to the predominance of severe, multivalvular, and regurgitant lesions.

TNF-α was elevated in all participants, though no association with lesion type or severity was observed. While previous studies reported a significant association of the NLR with systemic inflammation in RHD, we found no significant correlation between NLR and valvular lesion characteristics in our pediatric cohort.

Our findings highlight a strong inflammatory response in pediatric RHD, with elevated IL-6, IL-17, TNF-α, and CRP levels. Although CRP correlated with IL-17, it showed no association with lesion type or severity, suggesting it reflects systemic rather than localized inflammation. IL-6 emerged as a potential marker for disease progression, given its consistent elevation and significant association with lesion severity. IL-17’s correlation with younger age and recent ARF episodes points to its role in ongoing inflammation and disease activity. These results are consistent with prior adult studies but emphasize the need for further research to clarify the link between serum markers and histological inflammation in pediatric RHD.

The study of inflammatory infiltrates in the mitral valve of end-stage RHD has revealed a predominance of mononuclear cells, such as CD4+ T cells, CD8+ T cells, macrophages, and B cells.[22] CD4+ T cells play a pivotal role in the pathogenesis of RHD. These cells exhibit high cross-reactivity with cardiac myosin epitopes, and upon activation, differentiate into various subpopulations that release a variety of cytokines, driving a complex inflammatory cascade.[23]

Macrophages recognize GAS antigens, including M proteins, peptidoglycans, and nucleic acids, and subsequently release proinflammatory cytokines such as IL-1β, IL-6, IL-8, IFN-γ, and TNF-α. These cytokines promote the differentiation of naive CD4+ T cells into effector T helper cells (Th1, Th2, and Th17).[12] Th1 cells secrete IL-2, IL-6, and IL-8, which contribute to T cell recruitment, autoantibody synthesis, and regulation of T regulatory cells, respectively. Th2 cells release IL-4 and IL-5, stimulating the production of Th1 cells and activating MHC class II, thereby exacerbating the inflammatory cascade. Th17 cells, in turn, secrete IL-17, a key driver of autoimmunity and inflammation.[13,22] In our study, the choice of IL-6, IL-17, and TNF-α as inflammatory markers was based on their established role in Th1/Th17-mediated inflammatory pathways implicated in chronic RHD.[18,20,21,22] CRP and NLR were included as accessible markers of systemic inflammation.

The presence of inflammatory cells and the increased expression of multiple cytokines in cases of end-stage RHD reflect a possible subclinical, ongoing insult by an unidentified antigenic stimulus, likely related to Group A beta-hemolytic streptococcal antigens. This process may prime various target tissues, culminating in permanent valve deformities.[23] Earlier studies have shown the prolonged persistence of antibodies against GAS carbohydrates after the initial attack of rheumatic fever (RF), with antibody levels decreasing following surgical valve removal.[24] Moreover, inflammation associated with acute RF may remain active for months after the clinical disease has entered remission, which could similarly explain progressive valvular damage in RHD.[16] Given that the majority of valvular injury in RHD occurs in the pediatric age group, it is likely that the severity of chronic inflammation is higher in this population.

Numerous studies have documented elevated inflammatory markers and cytokines in the serum of adult chronic RHD patients, but few have correlated these with histopathological evidence of subclinical cardiac inflammation. Singal et al.[3] (mean age 34.07 ± 11 years) reported elevated IL-6 levels in 90% of chronic RHD patients, though histopathologically confirmed subclinical cardiac inflammation was observed in only one-third of patients without clinical evidence of rheumatic activity in the recent past. Notably, serum inflammatory markers did not correlate with histologic inflammation. They further noted that regurgitant lesions might be more prone to subclinical inflammation, though this association was not statistically significant, possibly due to the predominance of stenotic lesions and the older mean age of the cohort.[3] In contrast, pediatric studies, including ours, predominantly feature regurgitant valvular lesions, suggesting a higher likelihood of subclinical inflammation in this age group.

Supporting evidence from Raizada et al.,[25] showed histologic inflammation in 25%–33% of RHD cases, while Chopra et al.,[26] reported leukocyte infiltration in 28 of 50 excised LA appendages. Interestingly, the patients in Chopra’s study were about a decade younger than those in Singal et al.[3] (23 vs. 34 years), indicating a potential age-related predilection for subclinical carditis in younger patients.

Current RHD management primarily targets preventing ARF episodes, with benzathine penicillin G as the preventive cornerstone, and is not focused on addressing smouldering chronic valvular damage. Yousef et al. found that long-acting penicillin significantly reduces CRP and IL-6 levels, suggesting its role in mitigating chronic inflammation and supporting indefinite use in RHD patients.[9] Anti-inflammatory drugs, such as corticosteroids and salicylates, have limited impact on long-term outcomes, and the potential benefits of aspirin or statins in chronic RHD warrant further investigation through randomized trials.

Although our study could not establish a direct cause-effect relationship between inflammatory markers and valvular damage, it highlights a significant association between elevated markers and disease severity. Pediatric RHD patients, an understudied group closest to initial ARF episodes, exhibit a more pronounced inflammatory response compared to adults, possibly due to frequent GABHS infections and heightened immune activity during early life. These findings support the hypothesis that following an acute RF episode, there is ongoing chronic inflammation of the cardiac valves. Patients who exhibit a more intense inflammatory response are likely to experience more rapid progression of valvular dysfunction. Furthermore, an abnormal antibody response may trigger an autoimmune process, leading to progressive, smouldering damage to the heart valves. Further research is warranted to better understand the correlation between serum inflammatory markers and histologic inflammation in pediatric RHD.

This study has several limitations. It was a single-center cross-sectional study with a relatively small sample size, which may limit generalizability. In addition, the study design precludes establishing causal relationships between inflammatory markers and disease progression. The present study was also not designed to derive clinically meaningful biomarker cut-off values. Larger multicentric longitudinal studies are required to validate these findings.

CONCLUSION

Pediatric RHD patients exhibit persistent elevation of inflammatory markers despite the absence of recent ARF, supporting the hypothesis of ongoing subclinical inflammation. IL-6 and IL-17 showed significant associations with valvular disease severity and may represent promising biomarkers for future investigation. However, their role in guiding treatment remains uncertain and warrants validation in larger longitudinal studies before therapeutic interventions targeting chronic inflammation can be recommended.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.