Hyperinflammation syndromes represent one of the most challenging clinical entities in pediatric practice, requiring rapid diagnosis and careful differentiation between conditions with overlapping clinical features. Among these, Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C), associated with SARS-CoV-2 infection occupy a central position, having attracted considerable attention in recent years due to their potentially severe course and high risk of cardiovascular complications (1–3).

KD is an acute systemic vasculitis of medium-sized vessels, with a predilection for the coronary arteries, most commonly affecting children under five years of age. Coronary artery involvement, particularly the development of aneurysms, constitutes the leading cause of long-term cardiovascular morbidity in affected patients (3). In the absence of a specific laboratory biomarker, the diagnosis of KD relies on a combination of clinical presentation and supportive laboratory findings.

Despite substantial advances in understanding KD, its etiology remains incompletely elucidated. Current evidence suggests a multifactorial pathogenesis involving immune dysregulation, infectious triggers, and genetic susceptibility (3–5). Both conventional antigens, which activate a limited fraction of T lymphocytes, and superantigens, capable of stimulating up to 20%–30% of T cells in an MHC-independent manner, have been implicated; these mechanisms may act concurrently and converge on similar pathways of immune activation and vascular inflammation. Support for the role of infectious triggers comes from autopsy studies demonstrating IgA-producing plasma cells within coronary arteries that recognize cytoplasmic inclusion bodies of probable viral origin, as well as increased expression of interferon-response genes in the bronchial epithelium, consistent with responses to respiratory viral infections (4).

During the COVID-19 pandemic, a subset of children developed a hyperinflammatory condition involving multiple organ systems, frequently resembling KD (5, 6). The first reported case of what would later be recognized as MIS-C was described in 2020 in a 9-year-old boy who presented with fever, shock, and multiorgan involvement following SARS-CoV-2 infection (7). By late April 2020, MIS-C was formally defined as a distinct clinical entity based on clusters of similar cases reported in Europe and the United States, characterized by multisystem involvement, cardiovascular dysfunction, markedly elevated inflammatory markers, and temporal association with SARS-CoV-2 infection (8, 9).

MIS-C is currently regarded as a post-infectious inflammatory condition that typically develops 2–6 weeks after SARS-CoV-2 exposure. It is characterized by involvement of two or more organ systems, including cardiovascular, gastrointestinal, hematologic, and mucocutaneous systems along with pronounced elevation of inflammatory markers such as C-reactive protein, D-dimer, ferritin, interleukin-6, and procalcitonin, and a high prevalence of shock and myocardial dysfunction (1, 9, 10).

Despite distinct etiopathogenetic mechanisms, KD and MIS-C share substantial clinical and laboratory overlap, including persistent fever, rash, conjunctivitis, mucosal changes, cardiac involvement, and systemic inflammation (11, 12). This overlap poses significant diagnostic challenges, particularly in cases with incomplete or atypical presentations.

The aim of this report is to present and analyze a clinically challenging case of a 7-year-old boy with overlapping features of Kawasaki disease and MIS-C, illustrating the diagnostic uncertainty that may arise in such presentations. Through a detailed analysis of clinical, laboratory, and cardiologic findings, we compare key characteristics of these two syndromes and discuss the diagnostic and therapeutic challenges encountered in real-world clinical practice. Of particular interest, the disease course was complicated by the development of coronary artery aneurysms in the setting of a congenital coronary artery anomaly.

A 7-year-old boy was admitted to the pediatric cardiology and rheumatology unit with fever up to 38.5 °C, limping, and severe bilateral hip pain.

The illness began 14 days prior to admission with an acute onset of cervical lymphadenopathy and left-sided neck pain, followed by low-grade fever that progressively increased. Due to parental concern, particularly in light of a previous episode two years earlier characterized by marked lymphadenopathy, fever, and rapid clinical deterioration requiring intensive care, the patient was initially hospitalized in the oncohematology department. The mother also reported recurrent cervical lymph node enlargement during most episodes of acute respiratory viral infections.

At initial admission, physical examination revealed pharyngeal hyperemia and tender posterior cervical lymphadenopathy (up to 3 × 1 cm on the left and 2 × 1 cm on the right), with mobile nodes and intact overlying skin. No other significant abnormalities were identified.

On day 2, body temperature rose to 38.0 °C with mild rhinorrhea. Laboratory evaluation demonstrated leukocytosis (14.76 × 10⁹/L) with neutrophilia (88%), normal platelet count, and elevated C-reactive protein (CRP, 47.2 mg/L) (Supplementary Table S1). A diagnosis of cervical lymphadenitis was made, and antibacterial therapy with adjunctive dexamethasone (0.15 mg/kg) was initiated.

By day 3, fever resolved and lymphadenopathy regressed; however, lip dryness developed (Figure 1). On day 7 from symptom onset, conjunctival hyperemia appeared, accompanied by persistent cheilitis and mucosal changes. Laboratory tests showed persistent leukocytosis (15.23 × 10⁹/L), elevated ESR (22 mm/h), and CRP of 50.25 mg/L.

Subsequently, fever recurred with worsening conjunctivitis (Figure 2). These findings were initially interpreted as adenoviral infection, and the patient was discharged under outpatient supervision. However, clinical deterioration ensued, and on day 12, he developed hip pain and limping, prompting re-admission to the cardiology and rheumatology department.

The presented clinical case is distinguished by three key aspects. First, it highlights a common and clinically relevant diagnostic dilemma—differentiation between MIS-C and KD, particularly in the context of ongoing SARS-CoV-2 circulation. Second, it reflects the complexity of therapeutic decision-making in patients diagnosed beyond the early phase of illness, when standard treatment strategies, including intravenous immunoglobulin (IVIG), may require individualization based on clinical course and inflammatory activity. Third, it addresses the potential role of a congenital coronary artery anomaly (CAA) in the pathogenesis and accelerated development of coronary artery aneurysms.

Table 1 summarizes the principal differences between KD and MIS-C associated with SARS-CoV-2. In our patient, several features were consistent with incomplete KD, including unilateral cervical lymphadenopathy, characteristic non-purulent conjunctivitis, absence of prominent gastrointestinal symptoms, development of thrombocytosis from day 13, lack of marked elevation in CRP, absence of severe coagulopathy, and only mild cardiac involvement (borderline NT-proBNP levels with normal CK-MB). Collectively, these findings favored a diagnosis of KD. Conversely, the patient's age, pronounced arthritis, elevated D-dimer and procalcitonin levels, and high titers of anti–SARS-CoV-2 IgG antibodies supported the diagnosis of MIS-C (10, 15). Thus, the clinical presentation represented a mixed or transitional phenotype, complicating diagnostic decision-making.

Previous studies have similarly demonstrated substantial overlap between MIS-C and KD, underscoring the challenges of differential diagnosis based on clinical, laboratory, and cardiovascular features. In a cohort of 277 patients with MIS-C, 45.1% exhibited clinical features overlapping with KD, with incomplete KD accounting for 66.7% of these cases (16).

Age distribution represents an important distinguishing factor. The median age of patients with MIS-C is significantly higher than that of patients with KD (96 vs. 30 months, respectively) (17). In another study comparing 71 KD and 73 MIS-C patients, the mean age was 2.5 vs. 5.7 years (18). The age of our patient (7 years, 92 months) lies within the upper range described for MIS-C and outside the typical age group for classic KD. In addition, MIS-C has been associated with a significantly higher rate of intensive care unit admission compared with KD (34.2% vs. 2.8%) (18).

Fever is a central diagnostic criterion for both conditions. MIS-C is defined by fever ≥38 °C lasting at least 24 h in combination with systemic inflammation (19), whereas KD requires persistent fever for ≥5 days as a cornerstone diagnostic criterion according to American Heart Association guidelines (3).

Regarding other clinical manifestations, gastrointestinal symptoms (nausea, vomiting, abdominal pain) and respiratory involvement (dyspnea) have been reported significantly more frequently in MIS-C (p = 0.007, p = 0.000, and p = 0.002, respectively) (2). Our patient did not exhibit prominent gastrointestinal, a profile more consistent with KD. Furthermore, conjunctivitis (77.5% vs. 68.5%), lymphadenopathy (73.2% vs. 41.1%), and mucosal changes (83.1% vs. 57.5%) have been reported more frequently in KD than in MIS-C (18), further supporting a KD-like phenotype in this case.

Cardiovascular involvement also differs between the two conditions. Coronary artery abnormalities are significantly more common in KD (17), with reported rates of 26.7% in KD vs. 10.9% in MIS-C (18). In contrast, valvular involvement, left ventricular systolic dysfunction, and pericardial effusion occur more frequently in MIS-C (p = 0.000, p = 0.001, and p = 0.023, respectively) (17). Acute cardiac decompensation is a hallmark complication of MIS-C, with approximately one-third of patients demonstrating severely reduced left ventricular ejection fraction (<30%) (9). In our case, no evidence of acute myocardial dysfunction or significant systolic impairment was observed, whereas coronary artery aneurysms developed during follow-up—findings more characteristic of KD.

Immunological profiling further supports a hybrid inflammatory phenotype. Studies comparing MIS-C and KD have demonstrated distinct cytokine signatures, with MIS-C-associated hyperinflammation differing from both KD and acute severe COVID-19. KD is characterized by a Th17-skewed immune response and elevated IL-17A levels, whereas MIS-C generally exhibits lower IL-8 and IL-7 levels, although elevated IL-17A has also been reported in some MIS-C cohorts (20).

A meta-analysis of 12 studies involving 3,073 participants (969 with MIS-C) demonstrated clear laboratory differences between MIS-C and KD. MIS-C was associated with lower leukocyte, lymphocyte, and platelet counts, while neutrophil counts and hemoglobin levels were comparable (21). In our patient, leukocytosis persisted throughout days 2–24 (14.7–19.7 × 10⁹/L), with fluctuating lymphocyte percentages, reflecting a mixed inflammatory pattern. Notably, marked thrombocytosis developed after day 14 (459–611 × 10⁹/L), a hallmark feature of KD, typically peaking in the third week and normalizing within 4–6 weeks, as described by McCrindle et al. (3).

Inflammatory markers such as CRP, D-dimer, and ferritin are generally higher in MIS-C, whereas procalcitonin and ESR show less discriminatory value (21). In this case, elevated CRP (71.6 mg/L), ferritin (375 ng/mL), and D-dimer (1.31 µg FEU/mL) were observed on day 14, alongside mildly increased procalcitonin and ESR, again suggesting a mixed inflammatory profile. Among cardiac biomarkers, only NT-proBNP was mildly elevated, while CK-MB, AST, ALT remained within normal ranges, diverging from the typical MIS-C biochemical profile.

Despite clinical and laboratory overlap, the post-infectious association with SARS-CoV-2 remains a key distinguishing feature of MIS-C. Large cohort studies have shown that most MIS-C patients exhibit positive SARS-CoV-2 serology or other evidence of prior infection, even when PCR testing at admission is negative (10). In contrast, KD has no established causal link to SARS-CoV-2 or any specific infectious agent (3). In our patient, markedly elevated anti–SARS-CoV-2 IgG levels on day 14 support prior infection and argue in favor of MIS-C.

The optimal timing of IVIG administration beyond day 10 of illness remains controversial. While early IVIG administration within the first 10 days is standard for KD, current guidelines (3, 22) allow for later IVIG use in cases of persistent inflammation, fever, or progressive coronary involvement. In this case, IVIG was not administered due to a rapid and sustained clinical response to systemic glucocorticoids, consistent with current MIS-C treatment recommendations, which endorse corticosteroids as first-line therapy or effective monotherapy in selected patients. Large multicenter studies have demonstrated comparable outcomes between glucocorticoid therapy and IVIG, including rates of coronary aneurysm development and resolution (23).

An additional feature of this case was the presence of a complex congenital coronary artery anomaly—a single coronary artery arising from the left sinus of Valsalva with an interarterial course of the right coronary artery and approximately 40% luminal compression. This anomaly was identified incidentally during the evaluation of coronary involvement.

Congenital coronary artery anomalies are occasionally detected during the acute phase of Kawasaki disease and, as reported in previous studies do not appear to independently increase the risk of coronary aneurysm formation (24, 25), Rather, they represent an anatomical variant that may complicate diagnostic interpretation of coronary findings during inflammatory conditions.

In contrast, delayed administration of IVIG is a well-established risk factor for coronary artery aneurysm development in KD. In the present case, the prolonged febrile illness prior to IVIG treatment (>10 days) likely played a central role in the development of coronary dilatations.

The coexistence of an underlying coronary artery anomaly and systemic hyperinflammation added to the diagnostic complexity but should be interpreted with caution. The coronary changes observed in this patient are most plausibly explained by inflammation-related vascular injury associated with KD/MIS-C rather than by the congenital anomaly itself.

This case underscores the importance of early recognition of inflammatory syndromes, timely initiation of IVIG therapy, and careful longitudinal coronary assessment, particularly in patients with atypical anatomy that may confound imaging interpretation.

This case illustrates the diagnostic complexity of differentiating KD from MIS-C during the COVID-19 pandemic, particularly in patients with incomplete or overlapping clinical presentations. The coexistence of clinical features, laboratory abnormalities, and coronary involvement required an integrated, multidisciplinary approach to interpretation and therapeutic decision-making.

A notable aspect of this case was the incidental identification of a complex congenital coronary artery anomaly during the evaluation of coronary involvement. Such anomalies, although not associated with an increased risk of coronary aneurysm formation, may add to diagnostic complexity and require careful interpretation in the context of inflammatory vascular disease.

Overall, the case the case underscores the importance of early recognition of inflammatory conditions, timely initiation of appropriate therapy, careful longitudinal monitoring of coronary arteries, and individualized clinical management, particularly in children with atypical coronary anatomy.