# **RESEARCH Open Access** ![](https://assets.reachrx.ai/images/10.1186%E2%98%8Ds12969-025-01178-0/_page_0_Picture_3.jpeg) # Clinical outcomes of giant coronary aneurysms in South Asian children with Kawasaki disease Kumar Abhinav1\*, Nisanth Selvam2 , Raman Krishna Kumar2 , Aishee Bhattacharya3 , Manu Pradeep1 and Suma Balan1 ## **Abstract** **Background** Kawasaki disease (KD) is the leading cause of acquired childhood heart disease, with untreated cases progressing to giant coronary artery aneurysms (GCAAs) in 2-3% of patients. While outcomes are well-documented in high-income settings, data from low- and middle-income countries (LMICs) remain limited. This study examines clinical profiles, treatment responses, and outcomes of children with GCAAs managed at a tertiary care center in South India. **Methods** We conducted a retrospective review of 18 children with KD-associated GCAAs (z-score >10 or diameter >8mm) treated between 2019-2024 at a tertiary care center in Kerala, India. All patients were referred from external centers with documented IVIg resistance. Treatment intensification included infliximab, corticosteroids, cyclosporine, and anakinra. Primary outcome was GCAA dimension change at last follow-up; secondary outcomes included thrombotic events, mortality, and anticoagulation cessation. **Results** The cohort comprised predominantly of males (*n* = 14, 77.8%) with median symptom onset at 1.1 (IQR 0.3 – 2.7) years; 50% were under one year old. While ten children (55%) experienced delayed diagnosis (>10 days after symptom onset) with median diagnosis at 11 (IQR 7 – 13.5) days; all faced delays in treatment intensification. Excluding two children lost-to-follow-up, during the median follow-up of 8.6 (5.2 – 19.4) months, complete GCAA resolution occurred in three (18.8%), reduction to small/medium aneurysms in six (37.6%), while five (31.3%) remained static. One mortality (6.3%) from myocardial infarction and a patient requiring coronary artery bypass grafting were observed. Anticoagulation was discontinued in 56.25% of children whose aneurysms resolved or reduced significantly. **Conclusion** Delayed diagnosis and treatment intensification may have contributed to mixed outcomes in this GCAA cohort. Early recognition, appropriate risk stratification, and timely immunosuppression intensification are essential to improve prognosis and reduce severe coronary complications in resource-limited settings. **Keywords** Mucocutaneous lymph node syndrome, Coronary aneurysm, Vasculitis, Child, Retrospective studies, Intravenous immunoglobulins, Treatment outcome ![](https://assets.reachrx.ai/images/10.1186%E2%98%8Ds12969-025-01178-0/_page_0_Picture_16.jpeg) © The Author(s) 2025. **Open Access** This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creativecommons.org/licenses/by-nc-nd/4.0/) [vecommons.org/licenses/by-nc-nd/4.0/.](http://creativecommons.org/licenses/by-nc-nd/4.0/) ^\*Correspondence: Kumar Abhinav kabhinav@medical.aims.amrita.edu Department of Rheumatology and Clinical Immunology, Amrita School of Medicine (Amrita Institute of Medical Sciences), Amrita Vishwa Vidyapeetham, Kochi, Kerala, India Department of Pediatric Cardiology, Amrita School of Medicine (Amrita Institute of Medical Sciences), Amrita Vishwa Vidyapeetham, Kochi, Kerala, India Department of Community Medicine, Medical College and Hospital, Kolkata, India Abhinav *et al. Pediatric Rheumatology* (2025) 23:127 Page 2 of 8 ## **Introduction** Kawasaki disease (KD), first described in 1967 by Japanese pediatrician Tomisaku Kawasaki, is an acute febrile illness with vasculitis, primarily affecting children under five. Its etiology remains unclear, though evidence points to infectious triggers interacting with genetic susceptibility. As the leading cause of acquired childhood heart disease in high-income countries, KD surpasses rheumatic fever in prevalence, with 25% of untreated children progressing to coronary artery aneurysms (CAA) – with a further 2–3% developing life-threatening giant aneurysms (>8 mm diameter or Z score>10) linked to thrombosis and myocardial ischemia [[1,](#page-7-0) [7](#page-7-1), [8,](#page-7-2) [11,](#page-7-3) [17](#page-7-4), [18,](#page-7-5) [21](#page-7-6)]. Hemodynamic factors like wall shear stress and computational fluid dynamics modeling reveal significant turbulence in giant aneurysms, correlating with slower vascular recovery and higher complication risks [[6](#page-7-7), [20](#page-7-8)]. While research in high-income settings informs current management [\[9](#page-7-9)], low- and middle-income countries (LMICs) face unique challenges. Delayed diagnosis of KD, scarcity of IVIg availability, a lack of awareness about early identification and risk stratification of intravenous immunoglobulin (IVIg) resistance, may contribute to higher rates of severe complications like giant coronary artery aneurysms (GCAAs) in resource-constrained regions. However, clinical outcomes of GCAAs in KD are seldom reported from LMICs [\[16\]](#page-7-10). This study examines clinical profiles, treatment responses, and outcomes of children developing GCAA, managed at a tertiary care center in Kerala, India. By estimating LMIC-specific barriers—including healthcare access delays and treatment intensification protocols we aim to improve risk stratification and evidence-based management for this high-risk population. **Table 1** Risk factors used for stratifying children diagnosed with KD at our centre, who are at high risk at developing coronary artery aneurysm #### **Risk factors for Coronary Artery aneurysms\*** - 1. Age less than one year - 2. Male sex - 3. Prolonged duration of fever>10 days - 4. Persistently elevated inflammatory markers - 5. Coronary artery aneurysm (z score≥2.5) at baseline - 6. IVIg resistance - 7. Macrophage Activation Syndrome (MAS) - 8. Kawasaki disease shock syndrome / Myocarditis \*High risk children (one or more risk factors) were started on intensified primary immunosuppressive therapy using a single dose of infliximab (7–12 mg/ kg), glucocorticoids, and IVIg (2 g/kg). Low risk children were started on high dose aspirin (30 mg/kg/day) and IVIg (2 g/kg). Cyclosporine and anakinra were reserved as second and third line interventions for severe disease Risk factors adapted from a proposed algorithm for primary treatment intensification by Barman et al. (2024) [[2](#page-7-13)] and requires validation in further studies IVIg – Intravenous Immunoglobulin G ## **Methods** ## **Study design, settings and participants** With institutional ethics committee approval, we conducted a retrospective chart review of children with GCAA, attending a pediatric rheumatology clinic or pediatric cardiology clinic within a tertiary care center in Kochi, India. We analyzed electronic health records of children with KD, treated between 2019 and 2024, and abstracted pertinent, routinely collected clinical data from first visit to last follow-up. We included all consecutive children diagnosed with KD according to the clinical criteria set forth by American Heart Association [[14\]](#page-7-11) and confirmed via echocardiography to have giant coronary artery aneurysms (z-score>10 or luminal diameter>8 mm) [\[13\]](#page-7-12). Two researchers systematically extracted clinical variables — including demographics, treatment regimens, laboratory markers, and echocardiographic measurements from electronic health records using standardized case report forms. Search terms such as "Kawasaki disease," "coronary artery aneurysm," and "GCAA" guided data retrieval. ## **Disease management** Our institutional protocol for initial management of KD focuses on risk stratification and timely intensification of immunosuppression. At the point of diagnosis of KD in our institution, children underwent risk stratification for developing coronary artery aneurysm (Table [1\)](#page-1-0). Highrisk children with one or more risk factors (as described in Table [1\)](#page-1-0), received a combination primary intensified immunosuppressive therapy. However, the children included in the present study were diagnosed elsewhere, partially treated with some medications and referred for further management to our center after a coronary artery aneurysm was detected for expert pediatric rheumatology and pediatric cardiology care. Thus, for such children, further treatment was tailored case-by-case basis based on the clinical context. IVIg resistance was diagnosed after the first dose, if any of the following criteria of a proposed expanded definition were met – - 1. Persistence or recrudescence of fever within 36 h, or. - 2. Static or progressive increase in coronary artery diameter observed on serial echocardiograms at 48-hour intervals, or. - 3. Persistently elevated inflammatory markers. If the children were referred in the inflammatory phase of the illness, usually with signs of IVIg resistance, the pediatric rheumatology team intensified immunosuppression with a single dose of infliximab (7–12 mg/kg), three days of intravenous methylprednisolone (IVMP) pulse doses Abhinav *et al. Pediatric Rheumatology* (2025) 23:127 Page 3 of 8 (13–15 mg/kg/day) (if inflammatory markers were markedly elevated, suggestive of impending KD shock, macrophage activation syndrome or myocarditis) and then switched to oral prednisolone (2 mg/kg/day). If there was no clinical response within 48 h (progressive increase in GCAA diameter, persistence of fever, elevated inflammatory markers), cyclosporine (3–5 mg/kg/day in divided doses) and anakinra (4–5 mg/kg/day) were added to the regimen. All included children referred with a coronary artery aneurysm underwent an echocardiogram evaluation by a senior pediatric cardiologist, who confirmed the presence of GCAAs at baseline. Coronary measurements were obtained using high-frequency probes in the precordial short-axis view, with efforts made to capture dimensions at the end of the T wave in most cases. In infants and uncooperative children requiring sedation, where ECG lead attachment was not feasible, the maximal coronary dimension—corresponding to the phase when the aortic valve was closed, i.e., diastole—was recorded. Although every effort was made to replicate the pre-treatment echocardiographic imaging parameters, minor interoperator variability was inevitable, as the measurements were performed at different time intervals. All children with GCAAs were commenced on anticoagulation using low-molecular-weight heparin (LMWH) and anti-platelet therapy using low dose aspirin (3–5 mg/kg/day). Ongoing care of children after the acute inflammatory phase (and children presenting in the "burnt out" phase i.e., ≥ 90 days after symptom onset) was handed over to pediatric cardiology team for surveillance imaging and long-term management. Anticoagulation and antiplatelet therapy were stopped in children whose GCAA resolved completely and were no longer followed up. The rest underwent monthly follow-up for the first six months, with serial echocardiograms – to monitor for resolution or aneurysmal rupture. If uneventful, the follow-up intervals were extended to every three to six months. Children who GCAAs regressed to small aneurysms (z score≥2.5 to <5) were switched to a single antiplatelet therapy (low dose aspirin) and children whose GCAA regressed to medium aneurysms (z score≥5 to <10, and absolute dimension<8 mm) were switched to a dual antiplatelet therapy (low dose aspirin+clopidogrel). Children with persistent GCAAs continued on LMWH and dual antiplatelet therapy. Hypertensive patients were managed with either beta-blockers or angiotensin-converting enzyme inhibitors, as appropriate. Children who suffered a myocardial infarction were referred for computed tomography (CT) angiography to assess for distal vessels (aneurysms/stenosis). For those with persistent GCAAs, functional and ischemic cardiac status was further evaluated using meta-iodobenzylguanidine (MIBG) scintigraphy. #### **Outcomes** As the primary outcome, we assessed the change in GCAA dimensions at last follow-up, categorized them as: resolved, a reduction to small or medium aneurysm, or remained static as a GCAA. As secondary outcomes, we reported the rates of anticoagulation cessation, serious adverse events or infections, thrombotic events and mortality. We also estimated the delay in diagnosis and delay in treatment intensification. A delay in diagnosis defined as diagnosis made>10 days after symptom onset. A delay in treatment intensification was defined as failure to initiate appropriate intensified immunosuppression at diagnosis of KD in children at high risk for coronary artery aneurysm or after a diagnosis of IVIg resistance in low-risk children. #### **Statistical analysis** We performed descriptive analysis to express the summary estimates for cohort characteristics, stratified by the coronary artery outcomes as defined. For continuous variables, we reported medians with interquartile ranges, while for categorical variables we summarized the estimates as frequencies and percentages, unless specified otherwise. We did not attempt to perform any inferential analysis due to the small sample size of the cohort. ## **Results** ## **Cohort characteristics** Between 2019 and 2024, 59 children were diagnosed and/ or treated for KD or KD-related complications at our center. Among them, we included 18 consecutive children (30%) with GCAAs for this analysis. All 18 children in the cohort were referred from other hospitals with a diagnosis of KD, already having received some treatment. Nine children with evolving coronary artery aneurysms (with one child developing an anterior wall myocardial infarction), were referred for an expert paediatric cardiology evaluation at our centre - where GCAA was confirmed. The other nine children (50%) were referrals with confirmed GCAAs, with three such children (16.7%) referred during "burnt-out" phase (>90 days after KD diagnosis) for long-term management. This GCAA cohort (*n*=18) showed a male predominance (*n*=14, 77.8%). The median age of symptom onset was 1.1 years (0.3–2.7). Nine children (50%) were under one year of age; of whom seven children (38.9%) were below six months of age at symptom onset. All children were of South Asian ethnicity, hailing from Kerala (72.2%), and Tamil Nadu (16.7%), the two southern-most states in India while two children were citizens of the Republic of Maldives (11.1%). Abhinav *et al. Pediatric Rheumatology* (2025) 23:127 Page 4 of 8 #### **Clinical and laboratory features** Classical clinical features at diagnosis were: fever (100%), rashes (17/18, 94.4%), conjunctival congestion (14/18, 77.8%) and lymphadenopathy (12/18, 66.6%), while atypical presentations included generalized tonic-clonic seizures and facial nerve palsy in one child (1.6%), while another developed cardiogenic shock (1.6%). Incomplete KD was diagnosed in four children (22.2%). Macrophage Activation Syndrome was diagnosed in one patient on presentation (5.5%). The median duration from symptom onset to KD diagnosis was 11 days (IQR 7–13.5). Delay in diagnosis (>10 days) was present in 10/18 children (55.5%). Ten children (55.5%) were referred with persistent/ recurrent fever despite an initial dose IVIg from external centres. The cohort were admitted to our centre after a median of 21.5 (17–33) days after symptom onset. As depicted in Table [2](#page-3-0), at admission, total leucocyte count, C-reactive protein (CRP) and N -terminal pro B-type natriuretic peptide were elevated. However, ferritin and serum sodium levels showed wide variability with liver enzymes within normal ranges. At the last followup, CRP levels returned to within normal limits in all children. ## **Interventions** All children received the first dose of IVIg, at a median 12 days (7–18) after symptom onset. Only six children (33.3%) received their first dose of IVIg within 10 days of symptom onset, while the remaining 12 children received their first dose after the recommended 10-day window. All children referred in the inflammatory phase (*n*=15), provided a history suggestive of IVIg resistance, necessitating intensification therapies. External centers administered a second dose of IVIg in six children (33.3%) and intensified immunosuppression with a low dose of infliximab (5 mg/kg) in two children (11.1%) before referring **Table 2** Cohort blood parameters at admission (*N*=18) | Parameter | Median (IQR) | | |-----------------------------------|------------------|--| | Haemoglobin (g/dL) | 9.4 (8.1–9.9) | | | Total leucocyte count (x 10³/mm³) | 18.3 (14.2–24.7) | | | Platelet Count (x 10³/mm³) | 705 (344–994) | | | NT-proBNP (pg/mL) | 125 (0–527) | | | Ferritin (ng/mL) | 41 (0–330) | | | LDH (IU/L) | 0 (0- 284) | | | ALT (IU/L) | 21 (12–32) | | | AST (IU/L) | 24 (12–34) | | | Sodium (mmol/L) | 134 (130–136) | | | CRP at admission (mg/L) | 60 (4–132) | | | CRP at final follow-up (mg/L) | 0.5 (0.1–4) | | NT-proBNP - N-terminal pro B-type natriuretic peptide, LDH – Lactate dehydrogenase, ALT – Alanine aminotransferase, AST - Aspartate aminotransferase, CRP – C-reactive protein, SD – Standardn Deviation, IQR – Inter Quartile Range to our center. We intensified immunosuppression in children presenting in acute KD with steroids (IVMP in 8/18, 44.4% and oral prednisolone in 15/18, 83.3%), infliximab (14/18, 77.7%), cyclosporine (5/18, 27.7%), and anakinra (2/18, 11.1%). All children could be categorized as high risk for developing coronary artery aneurysm at diagnosis (either male sex or age<1 year) as per our protocol. Thus, these children were eligible for intensified immunosuppression at the time of diagnosis at external centers. Although IVIg resistance was evident after the first dose at external centers, appropriate intensified immunosuppression was initiated only after admission to our center, at a median of 11 (5–22) days from disease onset. Functional assessments in children with persistent GCAA revealed reversible ischemia in one child and an admixture of viable and (mostly) non-viable myocardium in two children via MIBG imaging. However, CT angiography did not identify any distal peripheral aneurysms in the one child who survived the myocardial infarction and underwent a CABG. ## **Coronary aneurysm characteristics** Multiple (proximal, middle and distal) segments of the left anterior descending (LAD) artery were affected in 13 children (72.2%) with the largest noted to have a z score of +19.16. The right circumflex artery (RCA) was affected in seven children (38.9%) with the largest aneurysm demonstrating a z score of +22.55. The LMCA was involved in five children (27.8%), with the largest aneurysm having a Z score of +35.37. Pan-coronary GCAA (LAD, LMCA, RCA) were detected in four children (22.2%), while double vessel GCAAs (LAD+RCA/LMCA) detected in in five children (27.7%). #### **Outcomes** Two children were lost-to-follow-up. A child who presented to us on the 29th day of illness (referred eight days after diagnosis) had a GCAA that reduced to a moderate-sized aneurysm after 22 days under our care but was subsequently lost to follow-up. Another child, who presented to us on the 15th day of undifferentiated fever and was diagnosed at our centre, was lost to follow-up after 18.5 months, during which the GCAA remained static with no complications. Sixteen children completed a median follow-up of 8.6 months (IQR 5.2–19.4). Three children (18.8%) achieved a complete resolution of their GCAA. Three children's (18.8%) GCAA had reduced to small aneurysms, while yet another three children's (18.8%) GCAA's had reduced to medium aneurysms. However, five children's (31.3%) GCAA's dimensions remained static or worsened during the follow-up period. Abhinav *et al. Pediatric Rheumatology* (2025) 23:127 Page 5 of 8 **Table 3** Cohort characteristics stratified by coronary artery outcomes, excluding two children lost to follow-up (*N*=16) | Clinical Parameters | Resolved
(n=3) | Reduction to small | Reduction to moder
ate aneurysm
(n=3) | Table 3 Cohort characteristics stratified by coronary artery outcomes, excluding two children lost to follow-up (N=16)
Static GCAA
(n=7)* | |---------------------------------------------------|--------------------|--------------------|---------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------| | | | aneurysm | | | | | | (n=3) | | | | Age at diagnosis, in months | 4 (4–36) | 3.9 (2.33–16) | 31.5 (21–44) | 18 (5–74) | | Male sex | 2 (66.7%) | 2 (66.7%) | 2 (66.7%) | 7 (100%) | | Atypical KD | 1 (33.3%) | 1 (33.3%) | 2 (66.7%) | 4 (57.1%) | | Incomplete KD | 1 (33.3%) | 1 (33.3%) | 0 | 2 (28.6%) | | Day of diagnosis | 7 (4–10) | 10 (6–12) | 14 (13–27) | 12 (4–20) | | Diagnosis made>10 days | 0 | 1 (33.3%) | 3 (100%) | 5 (71.4%) | | Initial treatment | | | | | | IVIg – first dose | 3 (100%) | 3 (100%) | 3 (100%) | 7 (100%) | | IVIg – second dose | 2 (66.7%) | 1 (33.3%) | 1 (33.3%) | 2 (28.6%) | | Infliximab (5 mg/kg) | 1 (33.3%) | 0 | 0 | 1 (14.3%) | | Anticoagulation | 1 (33.3%) | 1 (33.3%) | 2 (66.7%) | 4 (57.1%) | | Dual Antiplatelet therapy | 3 (100%) | 3 (100%) | 3 (100%) | 7 (100%) | | Referral to our center on day of illness | 23 (22–28) | 17 (12–34) | 20 (14–33) | 22 (17–730) | | Admission blood parameters | | | | | | Haemoglobin (g/dL) | 11 (8.4–13.6) | 7.6 (7.4–7.7) | 9.7 (8.2–9.7) | 9.5 (8–10.9) | | Total leucocyte count (x 10³/mm³) | 23.8 (13.8–33.8) | 23 (19.6–32.8) | 17.5 (14.3–18.2) | 18.4 (8.6–26.8) | | Platelet Count (x 10³/mm³) | 527 (331–723) | 991 (796–1051) | 803 (501–1274) | 349 (130–819) | | NT-proBNP (pg/mL) | 107 (15–214) | 294 (20–1292) | 126 (123–157) | 522 (0–5490) | | Ferritin (ng/mL) | 118.4 (57–236.8) | 814 (53–910) | 165 (76–217) | 367 (101–649) | | LDH (IU/L) | 125 (103–206) | 154 (105–324) | 156 (110–258) | 140 (125–310) | | ALT (IU/L) | 62.5 (12–113) | 23 (9.7–26) | 26 (15.3–30) | 19.5 (0–67.9) | | AST (IU/L) | 20.3 (6.6–34) | 24 (13–51) | 30.4 (10–33) | 24 (0–85) | | Sodium (mmol/L) | 137 (136.6- 137.8) | 136 (129–140) | 131.9 (130–133) | 134 (130–138) | | CRP (mg/L) | 11.6 (5–18.1) | 107 (76–205) | 107 (40–205) | 90 (0.2–288) | | Intensified treatment at our center | | | | | | IV Methyl Prednisolone (13–15 mg/kg/day x 3 days) | 1 (33.3%) | 1 (33.3%) | 3 (100%) | 4 (57.1%) | | Oral prednisolone (2 mg/kg/day) | 3 (100%) | 3 (100%) | 3 (100%) | 4 (57.1%) | | Infliximab (7–12 mg/kg) | 2 (66.7%) | 3 (100%) | 3 (100%) | 4 (57.1%) | | Cyclosporine (3–5 mg/kg/day in divided doses) | 0 | 1 (33.3%) | 1 (33.3%) | 3 (42.9%) | | Anakinra (4–5 mg/kg/day) | 1 (33.3%) | 0 | 1 (33.3%) | 0 | **^\***Includes one child who underwent a coronary artery bypass graft procedure and another child who died.Continuous and categorical variables are summarized as median (range), and n (%) respectively There were two incidences (11.1%) of myocardial infarction and one mortality (6.3%) in the cohort. A child suffered a fatal myocardial infarction 10.75 months after diagnosis. Another child with a recent history of anterior myocardial infarction (LAD occlusion) three weeks post-diagnosis; suffered another myocardial infarction with complete occlusion across the RCA and proximal LAD, 4.75 months after diagnosis. The child underwent a CABG and since has been asymptomatic at 67 months of follow-up. There were no other incidences of thrombotic events. Anticoagulation was stopped in nine children (56.25%) whose GCAA's either resolved completely or reduced to a small/medium aneurysm; and with single or dual antiplatelet therapy continued in children with small or medium aneurysms, respectively. There were no incidences of any serious adverse events attributable to the intensified immunosuppression such as infusion reactions with infliximab, hypertensive episodes with steroids or cyclosporine or injection site reactions for anakinra or any serious infections. Table [3](#page-4-0) describes the clinical presentation, day of diagnosis of each outcome group, along with the initial and subsequent intensified treatments the children received. This exploratory analysis revealed trends that suggested that poorer outcomes were linked to delayed diagnoses and higher inflammatory markers at admission. However, these inferences must not be interpreted as causal, since we did not perform any hypothesis testing, as the study was underpowered for such comparisons. ## **Discussion** This retrospective study describes the outcomes of a cohort of children with GCAAs referred to a tertiary center for multidisciplinary specialist management. The observed male predominance and early disease onset (<1 year of age) are consistent with global trends. Our Abhinav *et al. Pediatric Rheumatology* (2025) 23:127 Page 6 of 8 results highlight the heightened vulnerability of infants, who often experience delayed diagnosis due to atypical presentations. During the relatively short follow-up, outcomes in the cohort were mixed. Nine children (50%) achieved either complete GCAA resolution or a significant reduction to a small/medium aneurysm, allowing discontinuation of anticoagulation. However, there were five children who had persistent GCAAs, two incidences of myocardial infarction, one child who required CABG, and one mortality with two children lost to follow-up. Most children were referred to our center between two to four weeks after symptom onset, thereby missing the optimal window for immunosuppression intensification during the acute phase. Ideally, all children should have received intensified immunosuppression at the time of diagnosis, given their high risk for developing GCAAs. If not initiated at diagnosis, intensified immunosuppression could have been considered upon detection of IVIg resistance in these children. These delays in diagnosis and treatment intensification may have been partly due to incomplete and atypical presentations of KD, which in turn contributed to the poorer outcomes observed in our cohort. Our cohort's outcomes align with several international studies GCAAs in KD, while also highlighting unique challenges in resource-limited settings. A retrospective study from southwest China (2002–2018) documented 5.3% mortality and 21.1% myocardial infarction rates among 38 children with GCAA over a median followup of 30.5 months [[22\]](#page-7-14). Albeit with a shorter follow-up, the complete resolution rates in our cohort are lower than those reported in a large Japanese multicenter study (Z-Score 2nd Project) (*N*=1006), which reported a 28.8% ten year regression rate of GCAAs [[10](#page-7-15)]. Of the five children in our cohort with persistent GCAAs and the one child who underwent CABG, three of them had presented in the chronic phase (120–730 days after symptom onset) with little chance for regression. Our findings of delayed diagnosis and treatment intensification are in stark contrast with high-income settings like South Korea where early diagnosis, risk stratification is prioritized, and standardized step-wise treatment protocols are implemented. A retrospective nationwide review of 11,340 South Korean children developing KD between 2015 and 2017, reported a giant aneurysm rate in only 19 children (0.17%) [[12](#page-7-16)]. In India, the absence of nationally validated risk stratification criteria is further exacerbated by the limited availability of essential drugs such as IVIg and anakinra, which contributes to a lack of clinician familiarity with standardized treatment protocols. Nevertheless, in the absence of robust national-level epidemiological data, the true proportion of children with KD who require intensified immunosuppressive therapy remains uncertain. It is also possible that our cohort overestimates the burden of complications due to referral bias inherent to tertiary care settings. A retrospective Japanese study (1999–2013) analyzing outcomes in 16 children with GCAAs reported a strikingly high myocardial infarction rate of 43.7% over a median follow-up of 5.8 years [\[19](#page-7-17)]. The authors linked this elevated risk to their institutional protocol of discontinuing anticoagulation after 2–3 years in children with persistent GCAAs who remained asymptomatic. Lifelong anticoagulation combined with dual antiplatelet therapy may represent an unavoidable yet challenging strategy for long term management in children with GCAAs. While critical for thromboprophylaxis, this approach carries significant long-term risks - including bleeding complications, medication adherence challenges, and substantial financial burdens - particularly in resource-limited settings. Thus, the prevention of GCAAs in children hinges on timely diagnosis, accurate risk stratification, and appropriate immunosuppression—all of which present significant challenges in resource-limited settings. In our cohort, we observed a concerning delay in the administration of the first dose of IVIg, with the majority of children receiving treatment more than ten days after disease onset, thereby missing the optimal therapeutic window for preventing coronary aneurysms [[3\]](#page-7-18). Additionally, 15 children who presented during the acute phase had a documented history of IVIg resistance, necessitating intensive immunosuppression. These trends suggest that clinicians may be experiencing delays in diagnosing KD, potentially due to incomplete or atypical presentations compounded by limited access to specialist care in rural settings. Furthermore, even after a diagnosis of KD is established, clinicians may lack awareness of appropriate risk stratification, leading to further delays and inaccuracies in the administration of immunosuppressive regimens for high-risk children. We also noted that clinicians were often unaware of occult vasculitis in IVIg-resistant children and did not perform serial echocardiograms to detect developing coronary artery aneurysms, likely due to resource constraints. As a result, GCAAs were frequently detected late in the disease course, typically during screening echocardiograms performed prior to discharge. Our proposed expanded definition of IVIg resistance, we speculate, more accurately detects the occult vasculitis that persists despite the first dose of IVIg, likely leading to the development of coronary artery aneurysm, that will be missed without serial echocardiographic surveillance. Once a child at high risk for GCAA or with IVIg resistance has been identified, intensive immunosuppression becomes necessary. However, clinicians in India are often hesitant to escalate immunosuppressive Abhinav *et al. Pediatric Rheumatology* (2025) 23:127 Page 7 of 8 therapy with higher doses of steroids or infliximab during the acute phase. This reluctance appears to stem from limited experience with combined immunosuppression regimens and concerns regarding adverse events, such as serious infections and the potential reactivation of tuberculosis. Based on our clinical experience, we believe that such concerns may be overstated. Among children with IVIg resistance included in this study, our intensified regimen — comprising dual immunosuppressants (steroids and infliximab), followed by anakinra and cyclosporine as second- and third-line interventions — may have contributed to the regression of GCAAs. Given the risk of developing GCAAs, as well as the potential for subsequent aneurysmal rupture and thrombotic events within the first six months, short-term but intensive immunosuppression should be considered a life-saving intervention for high-risk or IVIg-resistant children. International treatment guidelines from highincome countries recommend initiating dual therapy in high risk children — either corticosteroids or infliximab in combination with IVIg, with additional immunomodulators used as step-up therapy [\[4,](#page-7-19) [5](#page-7-20), [9](#page-7-9), [14,](#page-7-11) [15\]](#page-7-21). However, it remains unclear whether these recommendations are generalizable to all populations, as the definitions of high-risk factors and IVIg resistance have not been validated in South Asian children. Our triple therapy regimen (IVIg+steroids+infliximab) closely resembles the protocol employed at another referral center in North India [\[2](#page-7-13)] which has shown promise in selected high-risk children. Nonetheless, both protocols require further validation through robust clinical studies. In the interim, there is an urgent need to increase awareness among clinicians in India regarding the diagnostic criteria for both classical and incomplete/atypical KD, appropriate risk stratification, IVIg resistance, and coronary artery surveillance. Currently, pediatric rheumatology services are limited to a few tertiary care centers in India, with only one or two specialists available in each state. Nevertheless, we believe that clinicians could greatly benefit from timely telephonic or virtual crossconsultations with pediatric rheumatologists, who can provide their expertise in the differential diagnosis of acutely ill, febrile young children. Furthermore, expert guidance on accurate risk stratification and the timely initiation of appropriate immunomodulatory therapies could prevent the development of GCAAs and their complications, as well as reduce the need for long-term anticoagulation in children with KD. Similarly, pediatric cardiology services are invaluable for the early detection of small or progressively worsening coronary artery dilatations, thereby enabling appropriate escalation of therapy. We propose that serial echocardiograms be performed by a trained pediatric echocardiographer at more frequent intervals in high-risk children during inpatient care, while low risk children must receive at least a repeat echocardiogram before discharge. Albeit being resourceintensive, this close-monitoring for developing coronary artery aneurysms maybe the key to preventing the development of GCAAs in children with KD. ## **Strengths, limitations, and future directions** As the first South Asian cohort analyzing the disease course of GCAAs, this study provides actionable insights into KD management in resource-limited settings. The availability of expert pediatric rheumatology and pediatric cardiology services are likely to improve the diagnostic, risk stratification and treatment protocols. However, its single-center design and referral bias may overrepresent severe cases. Small sample size prevented risk factor analysis for regression outcomes. Our institutional risk stratification criteria and IVIg resistance require further validation in longitudinal studies. Future multicenter registries from South Asia could standardize diagnostic pathways and evaluate cost-effective therapies like anakinra and etanercept for refractory KD. ## **Conclusion** Our study highlights the significant burden and complex management of giant coronary artery aneurysms in children with Kawasaki disease. Delayed diagnosis and treatment intensification and late referrals contributed to mixed outcomes, including persistent aneurysms and mortality. Early recognition, risk stratification and appropriate immunosuppression are essential to improve prognosis. Strengthening awareness about of KD symptoms (including incomplete and atypical presentations) and engaging in cross-consultations with paediatric rheumatology and cardiology specialists may help clinicians explore alternate diagnoses as well as initiate timely intensive immunosuppression. These measures may help reduce the incidence of severe coronary complications in South Asian children. #### **Abbreviations** KD Kawasaki Disease CAA Coronary Artery Aneurysm GCAA Giant Coronary Artery Aneurysm IVIg Intravenous Immunoglobulin CABG Coronary Artery Bypass Graft LAD Left Anterior Descending coronary artery RCA Right Circumflex coronary artery LMCA Left Main Coronary Artery MIBG Meta-IodoBenzylguanidine scintigraphy CRP C Reactive Protein #### **Acknowledgements** Not applicable. #### **Author contributions** SB, RKK contributed to the study conception and design. Material preparation, data collection and analysis were performed by KA, NS, MP and AB. The first draft of the manuscript was written by KA, MP, AB and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. #### **Funding** The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. #### **Data availability** The datasets used during the current study are available from the corresponding author on reasonable request. ## **Declarations** #### **Ethics approval and consent to participate** This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Amrita School of Medicine Ethics Committee (ECASM-AIMS-2025-110) with waiver of consent. #### **Consent for publication** Not applicable. #### **Competing interests** The authors declare no competing interests. Received: 20 July 2025 / Accepted: 16 November 2025 #### **References** - 1. Bang JS, Kim GB, Kwon BS, Song MK, An HS, Song YW, Bae EJ, Noh CI. Long-Term prognosis for patients with Kawasaki disease complicated by large coronary aneurysm (diameter≥6 mm). Korean Circulation J. 2017;47:516–22. [https://doi.org/10.4070/kcj.2016.0163.](https://doi.org/10.4070/kcj.2016.0163) - 2. Barman P, Pilania R, Kumar R, Gayathri CV, Thangaraj A, Arora M, et al. Treatment intensification in Kawasaki disease – current perspectives. Expert Rev Clin Immunol. 2024;20:1179–1191. [https://doi.org/10.1080/1744666X.2024.23](https://doi.org/10.1080/1744666X.2024.2378900) [78900](https://doi.org/10.1080/1744666X.2024.2378900). - 3. Broderick C, Kobayashi S, Suto M, Ito S, Kobayashi T. Intravenous Immunoglobulin for the treatment of Kawasaki disease. Cochrane Database Syst Reviews CD014884. 2023. [https://doi.org/10.1002/14651858.CD014884.pub2.](https://doi.org/10.1002/14651858.CD014884.pub2) - 4. Gorelik M, Chung SA, Ardalan K, Binstadt BA, Friedman K, Hayward K, Imundo LF, Lapidus SK, Kim S, Son MB, Sule S, Tremoulet AH, Van Mater H, Yildirim-Toruner C, Langford CA, Maz M, Abril A, Guyatt G, Archer AM, Conn DL, Full KA, Grayson PC, Ibarra MF, Merkel PA, Rhee RL, Seo P, Stone JH, Sundel RP, Vitobaldi OI, Warner A, Byram K, Dua AB, Husainat N, James KE, Kalot M, Lin YC, Springer JM, Turgunbaev M, Villa-Forte A, Turner AS, Mustafa RA. 2021 American college of Rheumatology/Vasculitis foundation guideline for the management of Kawasaki disease. Arthritis Care Res. 2022;74:538–48. [https://](https://doi.org/10.1002/acr.24838) [doi.org/10.1002/acr.24838.](https://doi.org/10.1002/acr.24838) - 5. de Graeff N, Groot N, Ozen S, Eleftheriou D, Avcin T, Bader-Meunier B, Dolezalova P, Feldman BM, Kone-Paut I, Lahdenne P, McCann L, Pilkington C, Ravelli A, van Royen-Kerkhof A, Uziel Y, Vastert B, Wulffraat N, Kamphuis S, Brogan P, Beresford MW. European consensus-based recommendations for the diagnosis and treatment of Kawasaki disease – the SHARE initiative. Rheumatology. 2019;58:672–82. . - 6. Gutierrez NG, Mathew M, McCrindle BW, Tran JS, Kahn AM, Burns JC, Marsden AL. Hemodynamic variables in aneurysms are associated with thrombotic risk in children with Kawasaki disease. Int J Cardiol. 2019;281:15–21. [https://doi.or](https://doi.org/10.1016/j.ijcard.2019.01.092) [g/10.1016/j.ijcard.2019.01.092.](https://doi.org/10.1016/j.ijcard.2019.01.092) - 7. Harnden A, Takahashi M, Burgner D. Kawasaki disease. BMJ. 2009;338:b1514. [h](https://doi.org/10.1136/bmj.b1514) [ttps://doi.org/10.1136/bmj.b1514](https://doi.org/10.1136/bmj.b1514). - 8. Jindal AK, Pandiarajan V, Khubchandani R, Kamath N, Sabui T, Mondal R, Pal P, Singh S. The emergence of Kawasaki disease in India and China. Glob Cardiol Sci Pract. 2017. [https://doi.org/10.21542/gcsp.2017.21.](https://doi.org/10.21542/gcsp.2017.21) - 9. Jone P-N, Tremoulet A, Choueiter N, Dominguez SR, Harahsheh AS, Mitani Y, et al. Update on diagnosis and management of Kawasaki disease: a scientific - statement from the American Heart Association. Circulation. 2024;150:e481– 500. . - 10. Kato T, Miura M, Kobayashi T, Kaneko T, Fukushima N, Suda K, Maeda J, Shimoyama S, Shiono J, Hirono K, Ikeda K, Sato S, Numano F, Mitani Y, Waki K, Ayusawa M, Fukazawa R, Fuse S, The Z-Score Project 2nd Stage Study Group. Analysis of coronary arterial aneurysm regression in patients with Kawasaki disease by aneurysm severity: factors associated with regression. J Am Heart Association. 2023;12:e022417. [https://doi.org/10.1161/JAHA.121.022417.](https://doi.org/10.1161/JAHA.121.022417) - 11. Kim DS. Kawasaki disease. Yonsei Med J. 2006;47:759–72. [https://doi.org/10.3](https://doi.org/10.3349/ymj.2006.47.6.759) [349/ymj.2006.47.6.759.](https://doi.org/10.3349/ymj.2006.47.6.759) - 12. Kim GB, Eun LY, Han JW, Kim SH, Yoon KL, Han MY, Yu JJ, Choi J-W, Rhim JW. Epidemiology of Kawasaki disease in South korea: A nationwide survey 2015–2017. Pediatr Infect Dis J. 2020;39:1012. [https://doi.org/10.1097/INF.000](https://doi.org/10.1097/INF.0000000000002793) [0000000002793.](https://doi.org/10.1097/INF.0000000000002793) - 13. McCrindle BW, Li JS, Minich LL, Colan SD, Atz AM, Takahashi M, Vetter VL, Gersony WM, Mitchell PD, Newburger JW, Pediatric Heart Network Investigators. Coronary artery involvement in children with Kawasaki disease: risk factors from analysis of serial normalized measurements. Circulation. 2007;116:174– 9. [https://doi.org/10.1161/CIRCULATIONAHA.107.690875.](https://doi.org/10.1161/CIRCULATIONAHA.107.690875) - 14. McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135:e927–99. [https://doi.org/10.1161/CIR.00000](https://doi.org/10.1161/CIR.0000000000000484) [00000000484.](https://doi.org/10.1161/CIR.0000000000000484) - 15. Miura M, Ayusawa M, Fukazawa R, Hamada H, Ikeda S, Ito S, Kanai T, Kobayashi T, Suzuki H, Yamamura K, Miyata K, Yokoyama U, Ichida F, Mitani Y, Terai M. Guidelines for medical treatment of acute Kawasaki disease (2020 revised Version). J Pediatr Cardiol Cardiac Surg. 2021;5:41–73. [https://doi.org/](https://doi.org/10.24509/jpccs.0501G1) [10.24509/jpccs.0501G1](https://doi.org/10.24509/jpccs.0501G1). - 16. Moreno E, Garcia SD, Bainto E, Salgado AP, Parish A, Rosellini BD, et al. Presentation and outcomes of Kawasaki disease in Latin American infants younger than 6 months of age: a multinational multicenter study of the REKAMLATINA Network. Front Pediatr. 2020;8.. - 17. Newburger JW, Takahashi M, Burns JC. Kawasaki disease. J Am Coll Cardiol. 2016;67:1738–49.. - 18. Pilania RK, Basu S, Dixit J, Kumrah R, Jindal AK, Thangaraj A, et al. Incidence of Kawasaki disease among children in Chandigarh, India during 2015–2019: a trend analysis. Lancet Reg Health Southeast Asia. 2024;29. [https://doi.org/10.](https://doi.org/10.1016/j.lansea.2024.100474) [1016/j.lansea.2024.100474.](https://doi.org/10.1016/j.lansea.2024.100474) - 19. Saito N, Ebata R, Okunushi K, Yasukawa K, Hamada H. Treatment and prognosis of patients with Kawasaki disease and giant coronary artery aneurysm: a retrospective observational study. Cardiovasc Diagnosis Therapy. 2025;15:784–784. [https://doi.org/10.21037/cdt-24-289.](https://doi.org/10.21037/cdt-24-289) - 20. Seo J. Advancing risk stratification of coronary artery aneurysms caused by Kawasaki disease using hemodynamics analysis and computational fluid dynamics. Kawasaki Disease. 2023;1. . - 21. Singh S, Kawasaki T. Kawasaki disease - an Indian perspective. Indian Pediatr. 2009;46:563–71. - 22. Yuan P, Su D, Mandal KD, Qin S, Zhao N, Pang Y. Outcomes of Kawasaki disease with giant coronary aneurysms: a single-centre study in Southwest China. Cardiol Young. 2020;30:834–9. [https://doi.org/10.1017/S104795112000](https://doi.org/10.1017/S1047951120001134) [1134.](https://doi.org/10.1017/S1047951120001134) #### **Publisher's note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. **Dr. Raman Krishna Kumar, MD, DM, FAHA** is a senior Pediatric Cardiologist with 30+ years of experience and currently serves as Clinical Professor and Head of the Department of Pediatric Cardiology at Amrita School of Medicine, Kochi, India. **Dr. Suma Balan, MD, MRCP, CCST** Dr. Suma Balan, MD, MRCP, CCST is a senior Pediatric Rheumatologist with 20+years of experience, currently serving as the Professor and Head of the Department of Rheumatology and Clinical Immunology at Amrita School of Medicine, Kochi, India.