Tocilizumab for the Treatment of Intravenous Immunoglobulin-Resistant Kawasaki Disease in Children: Two Case Reports and Literature Review

Abstract

Purpose

The treatment of intravenous immunoglobulin-resistant Kawasaki disease remains challenging. We report the clinical course and extended follow-up of two cases of intravenous immunoglobulin-resistant Kawasaki disease successfully treated with tocilizumab. This report includes a summary of the global literature on the use of tocilizumab for the treatment of Kawasaki disease.

Case Presentation

Two children with intravenous immunoglobulin-resistant Kawasaki disease treated with tocilizumab at our institution since 2022 were retrospectively analyzed. Case 1 presented with complete Kawasaki disease manifestations. Despite intravenous immunoglobulin and glucocorticoid treatment, the condition remained uncontrolled. Cyclosporine did not result in improvements, and interleukin-6 levels increased. The fever subsided within 24 h after tocilizumab administration. The coronary artery dilation had returned to normal at day 77; however, an urticarial rash was observed following the third tocilizumab dose. Case 2 exhibited complete Kawasaki disease manifestations, complicated by a giant coronary artery aneurysm. The fever persisted despite treatment with aspirin, intravenous immunoglobulin, and glucocorticoids, and interleukin-6 levels increased markedly. The fever resolved within 24 h following tocilizumab administration. During a 3-year follow-up, no adverse drug reactions were observed and the dilated coronary artery decreased in size. Among the 14 patients reviewed in the literature, 10 had significantly elevated interleukin-6 levels. All patients achieved rapid fever resolution (within 48 h) following tocilizumab administration and favorable coronary outcomes: most (12/14) showed regression of dilation or no dilation during follow-up. Only one patient developed anaphylaxis after a one-time administration.

Conclusion

Tocilizumab could be considered a potential therapeutic option for intravenous immunoglobulin-resistant Kawasaki disease. It is advisable to closely monitor interleukin-6 levels and coronary artery parameters throughout the clinical course, while maintaining a heightened awareness of the possible adverse events related to tocilizumab treatment.

Introduction

Kawasaki disease (KD) is an acute, self-limiting systemic vasculitis of unknown etiology that predominantly affects children younger than 5 years of age. Its diagnosis is based mainly on clinical features, including persistent fever, non-suppurative cervical lymphadenopathy, rash, bilateral nonexudative conjunctival injection, changes in the lips and oral cavity, and erythema or swelling of the hands and feet.¹ If standard and effective treatment is not administered within 10 days of disease onset, approximately 15–20% of affected children may develop coronary artery lesions. Severe cases can lead to subsequent thrombosis, myocardial ischemia, and heart failure. Cardiovascular complications such as myocarditis² and valvular damage may also occur. In addition to coronary involvement, KD may also affect other organs and systems, including the nervous, digestive, and urinary systems, thereby further increasing disease burden and potentially affecting prognosis.³

Intravenous immunoglobulin (IVIG) combined with aspirin remains the standard initial treatment for KD, and most patients respond well to this regimen. However, approximately 10–20% of children continue to have persistent or recurrent fever at least 36 h after completion of the initial IVIG infusion, a condition commonly defined as IVIG-resistant KD. This subgroup is clinically important because IVIG resistance is associated with more intense systemic inflammation and a substantially increased risk of severe complications, including macrophage activation syndrome (MAS), KD shock syndrome (KDSS), and coronary artery aneurysm (CAA).^4–7 Therefore, the management of IVIG-resistant KD remains a major therapeutic challenge in pediatric practice.

Increasing evidence suggests that dysregulated cytokine responses, particularly elevated interleukin-6 (IL-6) levels, may play an important role in the pathophysiology of IVIG-resistant KD,^8,9 which provides a theoretical basis for the application of IL-6 receptor antagonists (IL-6ra), such as tocilizumab (TCZ), in the treatment of IVIG-resistant KD. Although international case reports have documented the successful use of TCZ in IVIG-resistant KD, the available data remain scarce. The prolonged impact of TCZ on cardiovascular outcomes and long-term efficacy, safety, and optimal dosage of TCZ in children with IVIG-resistant KD has yet to be clarified because of limited observation and follow-up periods.

Here, we report two cases of clinical efficacy and the long-term follow-up outcomes of TCZ-treated children with IVIG-resistant KD, accompanied by a review of the existing literature. This report supplements current evidence on the long-term safety and efficacy of TCZ, thereby accumulating more valuable clinical findings for optimizing this therapeutic regimen.

Case Presentation

Methods

The data of two children with IVIG-resistant KD who were hospitalized in the Maternal and Child Health Care Hospital of Guangxi Zhuang Autonomous Region from January 2022 to August 2025 (including long-term follow-up data) were retrospectively analyzed. The patients were diagnosed with KD according to the 2024 American Heart Association diagnostic criteria.¹ IVIG-resistant KD is defined as persistent or recurrent fever occurring at least 36 h after completion of the first IVIG infusion.¹ This report used the 2016 MAS-systemic juvenile idiopathic arthritis criteria for diagnosis of KD-MAS.¹⁰ Dosage recommendation for TCZ followed the guidelines for juvenile idiopathic arthritis from China: for a body weight <30 kg, administer 12 mg/kg per dose every 2 weeks; for a body weight ≥30 kg, 8 mg/kg per dose every 2 weeks, with gradual extension to once every 4 weeks as the condition stabilizes.^11,12

Literature Review

A literature review was performed to identify published cases of pediatric IVIG-resistant KD treated with TCZ. Databases including PubMed, Web of Science, the Cochrane Library, China National Knowledge Infrastructure, Wanfang Data, and the VIP Medical Database were searched for studies published up to August 2025, using the keywords “Kawasaki disease”, “mucocutaneous lymph node syndrome”, “KD”, “tocilizumab”, and “TCZ”. Only English and Chinese articles were screened. Case reports, case series, and original articles involving pediatric patients with IVIG-resistant KD treated with TCZ were included in the descriptive analysis. Review articles and commentaries were used for background information but not included in the case summary. Inclusion criteria: Children with a confirmed diagnosis of IVIG-resistant KD who were treated with TCZ. Exclusion criteria: Patients with other concurrent autoimmune or inflammatory disorders besides KD, such as juvenile idiopathic arthritis and systemic lupus erythematosus.

Results

Cases Presentation and Treatments

Case 1

A 3-year-old male child was admitted to the hospital because of “fever for 7 days and abdominal pain for 2 days”. The initial presentation involved atypical symptoms. Echocardiography on day 5 of the illness revealed mild left ventricular enlargement. Upon admission (day 7 of illness), inflammatory markers were significantly elevated: white blood cell 19.6 × 10⁹/L, platelets 422 × 10⁹/L, and high-sensitivity C-reactive protein (hs-CRP) >200 mg/L. From day 8 to 12 of the illness, enlarged cervical lymph nodes, a polymorphic rash, and dry red lips subsequently appeared. Echocardiography on day 11 confirmed right coronary artery dilation (RCA: 2.8 mm, Z-score 2.25), leading to a clinical diagnosis of KD. Given co-infection with influenza B virus, high-dose aspirin was contraindicated, and clopidogrel was initiated for antiplatelet therapy. The patient was subjected to two sequential doses of IVIG (day 11, day 14: 2 g/kg/dose) and intravenous methylprednisolone (IVMP) [4 mg/kg/day], but a persistent fever remained. Laboratory tests on day 20 indicated markedly elevated ferritin (129,735 ng/mL) and decreased fibrinogen (1.52 g/L). Combined with other abnormal laboratory findings, These results led to a diagnosis of MAS. Subsequent treatment with methylprednisolone (MP) pulse therapy (day 20–22, day 30–32: 20 mg/kg/day) and cyclosporine A was initiated; however, the response was suboptimal. On day 34 of the illness, IL-6 was specifically noted to be elevated to 48.1 pg/mL. Within 24 h after the first administration of TCZ (12 mg/kg), the patient’s body temperature normalized, and laboratory parameters improved significantly. During follow-up, due to persistent thrombocytosis and coronary artery dilation, two additional doses of TCZ were administered on days 51 and 64, respectively. Urticaria occurred during the third dose, which was considered a drug allergy and resolved after anti-allergy treatment. During 1 year of follow-up, the coronary artery dilation had completely normalized by day 77, with no other cardiac complications observed (Figure 1A–C).

Figure 1.

Mapping of coronary artery lesions, clinical diagnosis, and treatment in a child with KD (Case 1).

Note: (A) Trend chart of body temperature. (B) Treatment course. (C) Trend chart of coronary artery and IL-6.

Abbreviations: IVIG, intravenous immunoglobulin; IVMP, intravenous methylprednisolone; CSA, cyclosporin A; TCZ, tocilizumab; PSL, Prednisolone; LMCA, left main coronary artery; LAD, left anterior descending; LCX, left circumflex; RCA, right coronary artery; IL-6, interleukin 6.

Case 2

A 1-year-old male child was admitted because of a “persistent fever for 6 days”, presenting with symptoms of typical complete KD. Echocardiography performed at an external hospital indicated left main coronary artery dilation (3.1 mm, Z-score 2.864). The patient had received IVIG (day 5, 2 g/kg) and IVMP with inadequate response and was subsequently transferred to our hospital. Despite a second dose of IVIG (day 7, 2 g/kg) as intensified therapy, the child remained febrile, and on day 8, the level of IL-6 was significantly elevated to 71.97 pg/mL. MP pulse therapy (15 mg/kg/day) was administered from day 11 to 13 of the illness. Echocardiography on day 14 showed significant coronary artery dilation (left anterior descending artery [LAD]: 4.6 mm, Z-score 9.776). Within 24 h after the first administration of TCZ (12 mg/kg), the body temperature normalized, and clinical symptoms improved markedly. However, the coronary artery lesions continued to progress, and a giant CAA formed in the LAD by day 29 (7.5 mm, Z-score 19.872). Due to persistently abnormal IL-6 levels (reaching 943.26 pg/mL on day 60), five additional doses of TCZ were subsequently administered (day 27, day 42, day 59, day 93, day 123). After 3 years of follow-up, all dilated coronary arteries showed significant regression, with the LAD diameter measuring 3 mm (Z-score 3.55). No coronary artery calcification or stenosis was detected, and no adverse drug reactions were reported during the treatment period (Figure 2D–F).

Figure 2.

Mapping of coronary artery lesions, clinical diagnosis, and treatment in a child with KD (Case 2).

Note: (D) Trend chart of body temperature. (E) Treatment course. (F) Trend chart of coronary artery and IL-6. Aspirin was continued beyond Day 22 and remained ongoing at the end of data collection.

Abbreviations: IIVIG, intravenous immunoglobulin; IVMP, intravenous methylprednisolone; CSA, cyclosporin A; TCZ, tocilizumab; PSL, Prednisolone; LMCA, left main coronary artery; LAD, left anterior descending; LCX, left circumflex; RCA, right coronary artery; IL-6, interleukin 6.

Patient and Family Perspectives

Following the CARE guidelines, initially, when arriving at the hospital, the parents of the patients were anxious, fearing that their child’s condition was severe. However, through effective communication between the medical team and the family, coupled with active treatment, the families developed high levels of trust in the medical care provided during the hospitalization. The families were fully informed about all treatment measures and associated risks and cooperated closely with the treatment plan. After discharge, the family expressed deep gratitude to the medical staff and regularly returned to the hospital for follow-up, in compliance with the medical advice.

Global Case Reports of IVIG-Resistant KD Treated with TCZ

A literature search, including literature published up to and including August 2025, identified 12 reported cases of IVIG-resistant KD successfully treated with TCZ, originating from three studies (one Japanese study reporting four cases, and two Chinese studies reporting a total of eight cases) (Table 1).^13–15 Including the two cases presented in this study, a total of 14 pediatric patients were included in the analysis.

Table 1.

Global Case Reports of IVIG- Resistance KD Treated with TCZ

Case	Sex	Age Years	Kobay-ashi Score	Complication	IVIGg/kg	Glucoc-orticoid	MP Pulse	Aspirin	TCZ	IL-6 (pg/mL)		Coronary Follow-Up
										Before TCZ	After TCZ
1	M	3.75	6	MAS	4	Y	Y	N	Day 36	48.1	2.48	Coronary arteries normalized at day 77
2	M	1.42	5	Giant CAA	4	Y	Y	Y	Day 14	71.97	943.26→17.09	Coronary aneurysm regressed after 3 years
314	M	0.42	5	Cardiac failure, giant CAA	2	N	Y	Y	Day 13	82.69	4355.03	Coronary artery dilatation at 12 months
414	F	3	5	Aseptic meningitis	4	N	Y	Y	Day 8	253.41	144.82	No dilation
514	F	4.08	5	KDSS	4	N	Y	Y	Day 7	696.12	66.21	No dilation
615	M	3.16	6	Giant CAA	4	Y	N	Y	Day 8	Median: 461.05	Median: 26.35	Coronary artery dilatation reduced than before after 37 weeks
715	F	3.17	2	Thrombocytopenia Hyperferriinemia	2	Y	Y	Y	Day 10			Three children had coronary artery dilation before using TCZ, than returned to normal during follow-up. Another child had no coronary artery dilation.
815	F	2.83	6	NA	2	Y	N	Y	Day 7
915	M	6.83	5	Hyperferriinemia	2	Y	N	Y	Day 7
1015	M	2.33	2	MAS	4	Y	Y	Y	Day 9
1113	F	1	NA	Giant CAA	2	NA	NA	NA	Day 7	NA	NA	Coronary aneurysm regressed after 6 months
1213	M	8	NA	Giant CAA	3	NA	NA	NA	Day 7	NA	NA	Percutaneous coronary intervention for coronary artery stenosis 2 years later
1313	M	4	NA	NA	2	NA	NA	NA	Day 8	NA	NA	No dilation
1413	F	1	NA	NA	2	NA	NA	NA	Day 7	NA	NA	No dilation

Note: Cases 1 and 2 were children enrolled in this study.

Abbreviations: NA, No relevant information available; N, No; Y, Yes; F, Female; M, Male; CAA, Coronary artery aneurysm; TCZ, Tocilizumab; KDSS, Kawasaki disease shock syndrome; MAS, Macrophage activation syndrome; MP, Methylprednisolone.

The mean age of the patients was 3.21 ± 2.14 years, with 13 cases classified as complete KD. Among them, five cases (35.7%) were severe KD, with complications including MAS (two cases), KDSS (one case), cardiac failure (one case), and aseptic meningitis (one case). Eight patients had a Kobayashi score ≥5. None of the patients were responsive to initial therapy (four cases to IVIG alone, one to IVIG + glucocorticoid, and nine to IVIG + glucocorticoid + aspirin).

Following the first dose of TCZ, the fever and other clinical symptoms were resolved in all patients. Among a total of 21 TCZ administrations, one case of an allergic reaction was reported. IL-6 levels measured in 10 patients before treatment were significantly elevated in all patients; after treatment, these levels decreased in eight cases and increased in two (Cases 2 and 3). One patient (Case 3) with increased IL-6 levels did not receive further TCZ, and a giant CAA was revealed at the patient’s 12-month follow-up. The other patient (Case 2) received five additional TCZ doses, and the coronary aneurysm gradually regressed over a 3-year follow-up period.

Coronary artery abnormalities developed in nine patients, including five with giant aneurysms. Long-term follow-up showed coronary artery regression in seven cases. One patient (Case 12) underwent percutaneous coronary intervention for stenosis at the 2-year follow-up mark. Details are provided in Table 1.

Discussion

IVIG-resistant KD remains a major clinical challenge because it is associated with persistent systemic inflammation, an increased risk of severe complications, and a higher likelihood of coronary artery involvement. Although several second-line treatment strategies—including repeat IVIG, corticosteroids, and biologic agents—have been used in refractory cases, the optimal management approach has not yet been clearly established. In the two cases presented in this paper, recurrent fever persisted and clinical symptoms were not alleviated after two doses of IVIG combined with glucocorticoid therapy. Before TCZ administration, both children exhibited coronary artery dilation, with one case complicated by a giant coronary aneurysm, and the other developing MAS during treatment. Following TCZ treatment, the fever subsided in the two cases and coronary artery dilation gradually recovered. In Case 1, the patient experienced an allergic reaction during the third dose of TCZ. Long-term follow-up of these two children revealed no adverse reactions.

At present, the optimal treatment window for IVIG therapy in children with KD is within 7 days of onset, which can effectively reduce the risk of coronary artery lesions and cardiac sequelae.¹⁶ However, early IVIG treatment within 4 days of illness onset is associated with a high resistance rate.^16–18 In both cases, children in this article were diagnosed with IVIG-resistant KD, with one child receiving IVIG on day 11 of disease beyond the optimal therapeutic window and the other using IVIG within the optimal therapeutic window; however, they still developed coronary artery dilation. It has been shown that leukocytosis, thrombocytopenia, hypoalbuminemia, hyponatremia, hyperbilirubinemia, elevated hs-CRP, and age <1 year are predictive risk factors for IVIG resistance.^3,19 In this study, the patient in Case 1 had leukocytosis with a left shift, thrombocytopenia, hypoalbuminemia, and elevated hs-CRP, while the patient in Case 2 exhibited leukocytosis with a left shift and elevated hs-CRP, suggesting that both children had risk factors for IVIG resistance.

The pathogenesis of IVIG-resistant KD involves abnormalities in both innate and adaptive immunity, which are closely related to the suppression of regulatory T cells during the acute phase, accompanied by a significant cytokine storm. The decrease in regulatory T cell numbers and impairment of their function may be associated with the immune dysfunction observed in KD.²⁰ Treatment targeting IVIG resistance is referred to as salvage therapy, with the preferred recommendation of adding glucocorticoids or infliximab.^3,21,22 However, children treated with IVMP tend to relapse later in terms of body temperature and glucocorticoid-related adverse effects.²³ Infliximab is a human-mouse chimeric anti-tumor necrosis factor (TNF)-α monoclonal antibody, which downregulates KD vasculitis-associated transcript levels and IVIG resistance.²⁴ A randomized controlled trial demonstrated that, in the treatment of patients with first-time IVIG-resistance KD, infliximab shortened the fever duration and caused fewer adverse reactions than a second IVIG treatment.²⁵ A further meta-analysis indicated that infliximab was the optimal choice for treating children with KD resistant to the first dose of IVIG. However, the effectiveness did not differ significantly among IVMP, infliximab, and a second IVIG treatment in preventing CAA in patients with IVIG-resistant KD.²⁶ Additionally, anakinra^27,28 and cyclophosphamide²⁹ have achieved positive results in treating refractory KD, but their safety needs to be supported by further clinical data.

In our two cases, the patients failed to achieve defervescence with IVMP. Infliximab was not administered owing to the absence of significantly elevated TNF levels. Our decision to employ TCZ, an IL-6ra, was guided by the Chinese expert consensus on KD³⁰ and, more critically, by specific biomarker evidence. Both patients exhibited markedly elevated IL-6 levels in their T-helper (Th)1/Th2 cytokine profiles (9- and 13-fold above normal, respectively), providing a compelling rationale for IL-6 pathway blockade. Although the guidelines for KD from Italy,²² the United States,²¹ and Japan,³ do not include any recommendation regarding the use of TCZ, this rationale is supported by a growing body of evidence. Clinical studies have consistently shown that IL-6 levels are significantly elevated in KD, particularly in IVIG-resistant cases, and are associated with more severe disease phenotypes, including incomplete KD and KDSS.^8,9,31–33 This suggests that IL-6 levels may serve as a biomarker for the severity of the systemic inflammatory response. In this article, among the 14 summarized cases of children with IVIG-resistant KD, body temperature returned to normal within 24 to 48 h after administration of the first dose of TCZ, accompanied by a subsequent gradual decrease in IL-6 levels, supporting the drug’s potent anti-inflammatory effect and establishing it as the optimal personalized therapy. We further observed that the most significant IL-6 increase occurred in patients with severe complications, such as CAA and concomitant MAS. Moreover, the peak IL-6 level appeared to correlate with the degree of coronary artery dilation. This supports the hypothesis that a significant increase in IL-6 may be associated not only with IVIG resistance but also with overall disease severity and the development of CAA, though further validation in larger prospective cohorts is warranted.

Coronary artery lesions (CALs) represent the most critical complication of KD, typically emerging in the acute phase and reaching peak dilation within 2–3 weeks of disease onset. The incidence of CALs is significantly higher in patients with IVIG-resistant KD than in those responsive to IVIG.³⁴ While monoclonal antibodies and anti-cytokine biologics (such as infliximab, anakinra, and rituximab) are not effective in reducing the incidence of CAA in patients with KD, compared with traditional IVIG monotherapy, these drugs may reduce the occurrence of treatment resistance.³⁵ Clinical data confirm that IL-6 levels in children with KD before IVIG treatment were three times higher with CALs than without CALs;³¹ thus, the IL-6 level may be an effective predictor for CALs in patients with KD.^9,36 Among the 14 children with IVIG-resistant KD summarized in this article, 9 developed coronary artery dilation, including 5 with giant CAA. In our two cases (Case 1, Case 2), TCZ was administered every 2–4 weeks (for a total of three and six doses, respectively) until IL-6 levels significantly decreased or normalized. Follow-up echocardiography demonstrated a progressive reduction in coronary artery dilation. Case 3 showed a significant increase in IL-6 levels after one dose of TCZ treatment, with no subsequent IL-6 monitoring results available (Table 1). This child developed giant CAA at the 12-month follow-up. This suggests that clinicians may consider the number of TCZ administrations based on IL-6 levels, echocardiographic findings, and other serum inflammatory markers. Although CALs in KD can exhibit spontaneous regression, the potential role of TCZ in actively promoting their recovery remains unclear. Our experience suggests that sustained IL-6 suppression through multiple TCZ doses may offer a therapeutic advantage, although this requires further validation. The management of severe KD remains a clinical challenge. In this report, five cases of severe KD (including MAS, KDSS, and cardiac failure) achieved remission following TCZ treatment. This suggests that TCZ may be a valuable therapeutic option for severe KD.

The safety profile of any new therapy is paramount. After TCZ (21 doses) was administered to 14 children with KD reviewed in this study, urticaria (suspected allergic reaction) developed in 1 child (Case 1, third dose) [4.8%]. Therefore, attention is needed regarding adverse reactions to TCZ. The most commonly reported adverse reaction is infection,^37–39 followed by neutropenia, elevated transaminase levels,³⁷ hypofibrinogenemia,⁴⁰ and psoriasis rash.⁴¹ Further meta-analysis showed that the efficacy and safety of IL-6 inhibition in inflammatory diseases were comparable to those of other biological Disease-Modifying Anti-Rheumatic Drugs.⁴² None of the 14 children with KD included in this study experienced exacerbation of infection or secondary infection after TCZ use. Overall, the therapy was safe and effective.

Conclusion

This study suggests that TCZ may have a potential role in controlling inflammation and improving clinical manifestations in some children with IVIG-resistant KD. However, as this study is merely a report of two cases and lacks a control group, it is insufficient to demonstrate TCZ efficacy and cannot rule out the possibility that coronary artery changes were influenced by the natural course of the disease. The existing evidence in the literature also primarily originates from case reports and small-sample studies, which carry a risk of publication bias. Therefore, high-quality research is required to further validate the efficacy, safety, and value of IL-6 inhibitors for TCZ in the treatment of IVIG-resistant KD.

Funding Statement

This research was supported by the Guangxi Science and Technology Program [grant number AD22035121] and Guangxi Medical and Health key discipline project.

Data Sharing Statement

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Ethics Approval and Consent to Participate

All children who were administered TCZ signed an informed consent form from their parents. Additionally, this study complied with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region (Ethical Review Report No. 2024-12-4).

Consent for Publication

Written informed consent was obtained from the parents of all children receiving TCZ treatment.

Author Contributions

Li-E Wu: Data curation, Investigation, Writing – original draft; Chun-Lin Huang: Data curation, Writing – original draft; Jun-Yu Wei: Conceptualization, Writing – review and editing, Supervision; Si-Liang Lu: Conceptualization, Writing – review and editing, Supervision. All authors have given their final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no conflicts of interest.