Research on gamma globulin unresponsive Kawasaki disease: A review

Abstract

Kawasaki disease (KD) is an acute, self-limited systemic vasculitis that primarily affects children. Treating nonresponding KD with intravenous immunoglobulin (IVIG) presents numerous challenges. This article comprehensively reviews the basic theory, clinical manifestations and diagnosis, treatment strategies, disputes and challenges, historical evolution and current situation, and future research directions of immunoglobulin unresponsive KD. In terms of basic theory, the epidemiological characteristics of KD, the mechanism of IVIG action, and the pathophysiological mechanism of the nonresponsive type are elaborated. In the clinical manifestation and diagnosis section, symptoms, diagnostic criteria, and imaging applications are analyzed. The treatment strategy encompasses drug, nondrug and individualized therapy. Controversies and challenges focus on diagnostic difficulties, treatment disputes, and long-term prognosis research. The historical evolution and current situation review the changes in treatment strategies and the current state of affairs. Future research directions anticipate the role of new therapeutic drug research and development, breakthroughs in basic research, and international cooperation, aiming to provide a comprehensive reference for research and clinical practice in this field.

Key Words: Kawasaki disease; Intravenous immunoglobulin resistance; Biomarkers; Immunomodulation; Coronary artery lesions

Core Tip: Gamma globulin-unresponsive Kawasaki disease (KD) poses significant clinical challenges due to its complex pathophysiology and variable treatment outcomes. This review synthesizes current knowledge on epidemiology, intravenous immunoglobulin resistance mechanisms, diagnostic criteria, and evolving therapeutic strategies (e.g., corticosteroids, biologics). Key controversies include optimal second-line therapies and long-term cardiovascular monitoring. Future directions emphasize targeted drug development and international collaboration to improve management of refractory KD.

INTRODUCTION

Kawasaki disease (KD), an acute systemic vasculitis predominantly affecting children under five, represents the leading cause of acquired pediatric heart disease in developed nations. While intravenous immunoglobulin (IVIG) remains the cornerstone of therapy, 10%-20% of patients exhibit IVIG resistance, associated with higher risks of coronary artery lesions (CALs) and long-term cardiovascular morbidity.

The pathogenesis of IVIG-resistant KD remains incompletely understood, though genetic predisposition (e.g., polymorphisms in ITPKC and FCGR2A), hyperinflammation, and delayed treatment contribute. Epidemiologically, IVIG resistance shows marked ethnic disparities, with higher rates in East Asian populations, particularly infants < 1 year and those with elevated C-reactive protein (CRP) (≥ 10 mg/dL) or hypoalbuminemia.

This review synthesizes current knowledge on IVIG-resistant KD, encompassing: Epidemiology: Ethnic and seasonal trends, high-risk subgroups. Pathophysiology: Immune dysregulation and biomarker profiles. Clinical Management: Second-line therapies [corticosteroids, tumor necrosis factor (TNF)-α inhibitors] and risk stratification. Unresolved challenges: Diagnostic delays, optimal treatment algorithms, and long-term outcomes. By addressing these aspects, we aim to guide clinical decision-making and highlight avenues for future research, including personalized immunotherapy and multinational cohorts.

FUNDAMENTAL THEORY OF KAWASAKI DISEASE NON-RESPONSIVE TO IMMUNOGLOBULINE

Epidemiological characteristics of KD

Overview: The occurrence of KD exhibits a degree of seasonality. The Asian population is at a higher risk of incidence. The incidence rate among males is greater than that among females. Coronary artery disease is the most prevalent complication associated with KD.

KD is prevalent globally, with a particularly high incidence among Asian populations. Research indicates that Japan has the highest incidence rate, followed by South Korea. Asians residing in low-incidence countries maintain the same incidence as those in high-incidence areas[1]. A Malaysian population-based study from 2006 to 2019 included 661 patients with KD. The male-to-female ratio was 2:1, the median age at diagnosis was 1.4 years, and the incidence among children under 5 years was 14.8 per 100000 [95% confidence interval (CI): 13.6–16.0]. The incidence for males was 19 per 100000, and for Chinese individuals, it was 22 per 100000. The prevalence of KD in Chinese children was higher than in other ethnic groups, with the incidence steadily increasing from 5.7 per 100000 in 2006 to 19.6 per 100000 in 2019 (P < 0.001)[2]. A Spanish study revealed that 63% of 625 patients were male, 79% were under 5 years, and 16.8% were under 12 months of age. Coronary artery disease (CAD) was the most commonly detected condition by echocardiography, at 23%, with a coronary artery aneurysm diagnostic rate of 9.6%, and up to 20% of infants under 12 months of age (P < 0.001)[3]. KD has emerged as one of the leading causes of acquired heart disease in childhood in high-income countries[4]. KD exhibits characteristics similar to viral infections and displays a degree of seasonality. In Japan and South Korea, the incidence peaks in January and July, while in the United States, it is higher during winter and spring. Europe experiences its highest incidence in winter, although some tropical regions do not show a significant seasonal variation[5], and the incident season can vary among different age groups[6]. The varying incidence of KD across different ethnic groups and regions suggests that genetic and environmental factors collectively influence its prevalence. Studies have shown that patients with incomplete KD and atypical symptoms face a higher risk of coronary aneurysm, posing challenges for early diagnosis and treatment. Understanding the epidemiological characteristics of KD is beneficial for identifying high-risk groups early and provides a foundation for disease prevention, control, and clinical management.

Background overview of IVIG-resistant KD. Characteristics of high-risk children: (1) Age and gender: Commonly seen in children < 1 year or < 5 years old, with more boys than girls; (2) Laboratory indicators: Initial high levels of inflammatory markers (CRP ≥ 10 mg/dL, hyponatremia, hypoalbuminemia and anemia), thrombocytopenia or abnormal elevation. Clinical features: Persistent fever for ≥ 48 hours after IVIG, coronary artery abnormalities (such as Z ≥ 2.5), and multisystem inflammation (such as myocarditis and shock syndrome); (3) Epidemiological data: The global incidence is highest in East Asia (Japan: Approximately 330/100000 children under 5 years old), lower in Europe and America (10–25/100000). The IVIG resistance rate is 10%–20% (approximately 15% in Japan and approximately 10% in Europe and America), related to genetic background (such as ITPKC and CD40 gene polymorphism); and (4) Current challenges: Mechanism unclear: The interaction between immune dysregulation (such as overactivation of the IL-1β/IL-6 pathway), genetic susceptibility, and environmental triggers (such as infection) still needs to be studied. Treatment gap: Second-line therapies (hormones and biologics) have significant differences in efficacy and lack unified standards.

Mechanism of action of immunoglobulin in the treatment of KD

Overview: IVIG in KD: Modulates innate and adaptive immunity (suppresses cytokines, FcγR signaling), reducing the risk of coronary aneurysm from approximately 25% to less than 5% (with 10%-20% of patients being non-responders).

IVIG is the primary therapeutic agent for KD, capable of reducing the risk of coronary artery aneurysm from 25%–30% to < 5%. However, its immunoregulatory mechanism remains incompletely understood[7,8]. Various studies have suggested that IVIG functions through multiple pathways. In terms of regulating the innate immune system, IVIG affects the Toll-like receptor signaling pathway, autophagy, apoptosis within the mononuclear phagocyte system, neutrophil extracellular traps, and the regulation of dendritic cells. IVIG may contribute to the treatment of KD by downregulating the inflammatory response, maintaining the proportion, number, and molecular expression of dendritic cells, and inhibiting the expression of immunoglobulin mucin-3 on T lymphocytes, thereby protecting the vascular system from immune-mediated damage[9]. IVIG can induce neutrophil apoptosis[10] and rapidly alleviate clinical symptoms such as fever, rash, and bulbar conjunctival congestion in most children. IVIG also suppresses the activation of nuclear factor (NF)-κB mediated by TNF-α in monocytes and macrophages, decreases the secretion of cytokines interleukin (IL)-1 and IL-6, and inhibits neutrophil activation. Single-cell sequencing technology applied to peripheral blood has revealed that monocytes express high levels of inflammatory factors during the acute phase of KD, and the proportion of these factors, including IL-10 and IL-17A, decreases following IVIG treatment[11].

IVIG affects T-cell differentiation, cytokine release, and the function of regulatory T cells, thereby regulating the adaptive immune system. IVIG may also contribute by providing specific neutralizing antibodies, anti-idiotypic antibodies, and anticytokine antibodies, inhibiting activated Fcγ receptors, and stimulating inhibitory Fcγ rIIb receptors. However, 10%–20% of patients do not respond to IVIG treatment, and these individuals are at a higher risk of developing coronary aneurysms. Research has indicated that the ineffectiveness of IVIG treatment could be associated with lower sialylation levels of endogenous IgG and reduced transcript and protein levels of β-galactoside α 2-6 sialyltransferase-I, offering a new perspective for further understanding of the mechanism of action of IVIG and the management of nonresponsive KD[12].

Pathophysiological mechanism of unresponsive KD

Overview: Non-response in KD (affecting 10%-20% of cases) is driven by genetic variants (e.g., ITPKC, FCGR2A), hyperactivated neutrophils/macrophages (persistent IL-6/TNF-α), and impaired IVIG FcγRIIB signaling, which increases the risk of coronary aneurysms.

The pathophysiological mechanism of unresponsive KD is complex, involving immune activation, an imbalance of inflammatory response, and genetic susceptibility (Table 1). Studies have shown that the overactivation of the immune system plays a key role in its pathogenesis, with increased expression of a variety of cytokines such as TNF-α and IL-6, leading to vascular endothelial cell damage and continuation of the inflammatory response[13]. In a study of 70 Chinese children with KD, plasma TNF-α increased significantly in the acute phase, and was positively correlated with CRP and procalcitonin. In patients with IVIG nonresponse and coronary arteritis, the level of TNF-α was significantly higher, and was positively correlated with coronary artery diameter, suggesting that TNF-α is superior to traditional inflammatory mediators in predicting IVIG nonresponse and coronary arteritis[13]. Additionally, the imbalance of gut microbiota may participate in the pathogenesis of KD by affecting the immune response. Some studies have proposed that some microbial-related molecular patterns are associated with specific molecules in the serum of patients with KD, and then activate the immune system to trigger inflammatory responses[14]. At the same time, genetic factors cannot be ignored, such as the single nucleotide polymorphism rs17860041 a/c of the PPIA gene, which is associated with the susceptibility of KD in Chinese children, and individuals carrying specific genotypes may have a higher risk[15]. In recent years, with breakthroughs in multiomics techniques and single-cell research, the mechanism study of nonresponsive KD has shifted from a single immune abnormality to a multichannel interactive network model. In 2025, science translational medicine found that carriers of human coronavirus HKU1 in the nasopharynx had a 2.4-fold increased risk of IVIG resistance (activated by molecular simulation of anti-HSP60 autoantibodies).

Table 1 Core pathological features and key mechanisms of Kawasaki disease.

Pathological features/mechanisms	Description
Core pathological features
Systemic vasculitis	Inflammation of blood vessels throughout the body
Specific involvement of coronary arteries	High risk of coronary artery aneurysms and other complications
Key mechanisms
Abnormal immune system activation	Overproduction of inflammatory cytokines leading to vascular damage
Infection trigger hypothesis	Possible role of viral or bacterial infections in initiating the immune response
Genetic susceptibility	Specific genetic variants increasing the risk of developing Kawasaki disease
Endothelial cell dysfunction	Damage to endothelial cells causing increased vascular permeability and blood clot formation

CLINICAL MANIFESTATIONS AND DIAGNOSIS OF IMMUNOGLOBULIN-UNRESPONSIVE KAWASAKI DISEASE

Analysis of clinical symptoms of unresponsive KD

Overview: IVIG-resistant KD is characterized by prolonged fever (lasting more than 5 days in 80% of cases), higher rates of atypical symptoms (such as gastrointestinal and cardiac symptoms), and a greater risk of CAL compared to typical KD. Classic symptoms like rash, conjunctivitis, and oral changes persist but may resolve more slowly. Recurrent fever following IVIG treatment is indicative of poor outcomes.

The clinical symptoms of unresponsive and typical KD share many similarities, but there are also distinct characteristics. Fever is a common clinical symptom, although unresponsive KD may persist longer. In some clinical studies, patients have continued to experience fever even after IVIG treatment. For instance, a retrospective study of 195 patients with KD was conducted, where patients were categorized based on their fever patterns following IVIG treatment into a nonresponse, early recurrent fever (within 72 hours), late recurrent fever (after 72 hours), and good response groups. Nearly one-third of the patients exhibited recurrent fever. Although some fevers resolved spontaneously, two patients with late recurrent fever still developed CAD[16]. Additionally, patients may present with skin rash, bulbar conjunctival congestion, oral mucosal changes, and cervical lymph node enlargement. In a study of 25 patients with KD, the incidence of fever (lasting > 5 days) was 80%, oral mucosal changes accounted for 75.8%, bilateral bulbar conjunctival congestion for 73.7%, pleomorphic rash for 73.2%, limb end changes for 63.7%, and cervical lymphadenopathy for 60.0%[17]. Compared to typical KD, patients with unresponsive disease may be more susceptible to atypical clinical manifestations, such as gastrointestinal symptoms and cardiac complications. Patients with gastrointestinal manifestations of KD are more likely to exhibit IVIG resistance and have a higher risk of coronary aneurysm[18]. The diversity and atypical nature of these clinical symptoms complicate early diagnosis, necessitating careful identification by clinicians.

Diagnostic criteria of immunoglobulin-unresponsive KD

Overview: Criteria for IVIG-unresponsive KD: Persistent or recurrent fever ≥ 38 °C following IVIG (2 g/kg) administration, along with KD symptoms. Predictive factors include low FT3/TSH ratio, elevated levels of CRP/IL-6/IL-17A, decreased Na⁺ and NK cells, and increased PTX3/IL-41. Combined models incorporating WBC/Na⁺/CRP measurements enhance diagnostic accuracy but require further refinement.

The diagnostic criteria for KD are outlined by the Expert Consensus on Diagnosis and Acute Treatment, encompassing both complete and incomplete forms of the disease. Children have fever lasting ≥ 5 days, accompanied by at least four of the following five primary clinical features: (1) Lip redness, cracking, a strawberry tongue, and/or oral or pharyngeal redness; (2) Conjunctival congestion without discharge; (3) Polymorphous erythema, which includes a spotted rash, diffuse skin redness; (4) Hand and foot changes, such as acute stage hand and foot swelling with red spots on the fingers and toes, or during the recovery period, membranous peeling of the toe segments; and (5) Unilateral nonsuppurative cervical lymph node enlargement (≥ 1.5 cm), typically on one side. Complete KD is diagnosed when the above criteria are met. Incomplete KD is diagnosed when there is a fever lasting ≥ 5 days, or in infants, ≥ 7 days, accompanied by two or three of the main clinical features, after excluding other diseases, and with laboratory tests showing CRP ≥ 30 mg/L or an erythrocyte sedimentation rate ≥ 40 mm/hour, and meeting ≥ 3 of the following laboratory indicators: (1) Anemia; (2) After 7 days of fever, a platelet count ≥ 450 G/L; (3) Albumin level ≤ 30 g/L; (4) Elevated alanine aminotransferase levels; and (5) White blood cell count ≥ 15 G/L. Additionally, when the number of white blood cells in urine is ≥ 10/HP, or < 3, but with any of the following echocardiogram results, a diagnosis can also be made: (1) Coronary artery aneurysm; (2) The A value of the left anterior descending artery (LAD) or right coronary artery (RCA) is ≥ 2.5; and (3) ≥ 3 diagnostic features: Pericardial effusion, mitral regurgitation, reduced left ventricular systolic function, and Z 2.0–2.5 for LAD or RCA. The diagnosis is incomplete KD.

Currently, there is no universally accepted and clear diagnostic criteria for immunoglobulin-unresponsive KD. It is generally accepted that, following the diagnosis of KD, if body temperature remains ≥ 38 C, or if they experience a recurrence of fever within 2 weeks after receiving the standard IVIG dose (2 g/kg) for 36–48 hours, and this occurs alongside at least one of the main clinical features of KD, excluding other potential causes of fever, the condition can be considered as IVIG-unresponsive KD[19]. Some studies have aimed to predict the responsiveness to IVIG treatment through clinical characteristics and laboratory indicators. Recent literature has reported[20] that the levels of free triiodothyronine, free thyroxine and thyroid-stimulating hormone were significantly lower in the IVIG nonresponsive group, which can predict the treatment response of IVIG. CD56^-CD16⁺ natural killer cells were also significantly reduced in the IVIG nonresponsive group. The number of neutrophils, CRP, and serum sodium levels were significantly higher in children with IVIG nonresponse compared to those with IVIG response. IVIG nonresponse in children with KD varies with the duration of fever before IVIG treatment. In children with KD whose fever duration before treatment exceeds 4 days, there is a correlation between decreased blood sodium levels and IVIG nonresponse[21]. The combined cytokine IL-6 and neutrophil ratio can predict IVIG nonresponse[22]. It has also been reported that serum IL-17A levels are elevated in children with nonresponsive KD, and when IL-17A is ≥ 44.06 pg/mL, it has a good predictive value[23]. Serum IL-41 Levels are significantly elevated in children with IVIG nonresponse and CAD, with a sensitivity of 54.55% and specificity of 81.71% for predicting IVIG nonresponse[24]. Serum pentraxin-3 is an independent risk factor for IVIG nonresponse in children with KD, potentially causing IVIG nonresponse by activating the NF-κB pathway. The accuracy of predicting IVIG nonresponse is higher when combined with commonly used blood indicators such as white blood cell count, creatinine, serum sodium and CRP[25]. However, the predictive accuracy of these indicators still requires improvement, and more reliable diagnostic markers and criteria need to be further explored to achieve early and precise diagnosis and treatment.

Application of imaging techniques in unresponsive KD

Overview: Imaging in IVIG-resistant KD: Echocardiography (the first-line method with limited distal views) detects aneurysms but misses 53.3% of lesions. Computed tomography coronary angiography (CTCA)/digital subtraction angiography (DSA) (considered the gold standard) exposes children to risks associated with radiation and contrast agents. Emerging non-contrast-enhanced cardiac magnetic resonance angiography offers noninvasive, radiation-free 3D coronary mapping and myocardial assessment (including T1/T2 mapping), enabling lifelong monitoring of CAL progression.

Imaging techniques play a significant role in the diagnosis and disease assessment of unresponsive KD. Once the coronary artery is damaged, it is necessary to monitor the development of CALs for life. Continuous, noninvasive, nonradiation coronary angiography and accurate assessment of CALs caused by KD are the focus of early diagnosis, early intervention and long-term follow-up management[26]. At present, the main imaging methods used to evaluate CALs in children with KD include ultrasound, DSA, CTCA, intravascular ultrasound, and non-contrast-enhanced coronary magnetic resonance angiography (NCE-CMRA), among others. Ultrasound is the most commonly used examination for the diagnosis and follow-up of CALs in patients with KD. It can observe the morphology, structure, and blood flow of coronary arteries in real time, and detect coronary aneurysms, coronary artery dilatation, and other lesions. In a study of patients with KD, echocardiography revealed that some nonresponsive patients had CALs, such as coronary artery aneurysm, which varied in different studies. This was essential for evaluating the severity of the disease and prognosis. Ultrasound, as the preferred screening method, is simple and noninvasive, but it is often insufficient to show the middle and distal segments and small branches of the coronary artery, which can lead to missed diagnoses of CALs. Borhanuddin et al[27] reported that the diagnostic coincidence rate of ultrasound for CALs in children with KD was only 46.7%. DSA and CTCA are usually considered the gold standard for evaluating CAD. In a study of 52 patients with KD, CTCA clearly showed the anatomical structure of the coronary arteries, which can effectively evaluate CALs. However, there is a significant radiation risk for infants and children, and the use of contrast agents is necessary, which can cause renal damage in children. CTCA assessment of CALs is also vulnerable to calcified plaques[28]. Intravascular ultrasound is an invasive examination with a complex operation, which carries the risk of complications such as acute coronary artery obstruction, spasm, or coronary artery dissection. With the advantages of being noninvasive, radiation-free, and having high tissue resolution, NCE-CMRA can be used to evaluate coronary arteries in children, and it has clear advantages in displaying the main coronary artery and its branches. At the same time, when combined with cardiac film, myocardial perfusion, myocardial deformation, and quantitative analysis (T1 mapping, T2 mapping), and other one-stop comprehensive examinations, it can comprehensively and accurately evaluate the degree of myocardial and coronary artery lesions in children with KD. This has important clinical significance for the diagnosis, treatment, follow-up, and pre-evaluation of children with KD. The comprehensive application of imaging technology is helpful in fully understanding the cardiovascular lesions of unresponsive KD and provides an important basis for the formulation of treatment plans.

THERAPEUTIC STRATEGIES FOR IMMNOGLOBULIN-UNRESPONSIVE KAWASAKI DISEASE

Progress in drug treatment of immunoglobulin-unresponsive KD

Overview: Treatment options for IVIG-resistant Kawasaki Disease: IVIG retreatment (common but debated); Glucocorticoids combined with IVIG (reduces the risk of CALs); Biologics [e.g., infliximab (anti-TNF-α), IL-6/IL-1 blockers – limited evidence]; Cyclosporine/ulinastatin (anti-inflammatory, endothelial protection). The optimal timing and regimens require further study.

For patients with immunoglobulin-resistant KD, there are currently several drug treatment options available. In terms of traditional therapeutic drugs, the re-administration of IVIG is a common strategy, while other drug treatment options remain controversial[29]. Although glucocorticoids alone are not recommended for the treatment of KD, their combination with immunoglobulin can reduce the incidence of CALs and delay their progression[30]. Additionally, some new drugs are also under research and application. Infliximab, a monoclonal antibody against TNF-α, exerts anti-inflammatory effects by inhibiting TNF-α or soluble TNF-α receptors, thereby reducing IL-6 or CRP levels to mitigate the severity of vasculitis and, consequently, the incidence of CALs. However, its clinical effectiveness requires further verification[31,32]. Other second-line drugs, such as cyclosporine, IL-6 receptor antagonists, and IL-1 receptor antagonists, have less clinical experience. Moreover, ulinastatin has been utilized in the treatment of KD because it can inhibit inflammatory factors (TNF-α, IL-6, etc.), protect vascular endothelium, and improve microcirculation[33,34], which can alleviate patients' symptoms, shorten the duration of fever, and reduce CALs. These drugs offer more options for the treatment of resistant KD, but further research is necessary to determine the optimal treatment plan and the appropriate timing for drug administration.

Application of non-drug therapy in unresponsive KD

Overview: Non-drug therapies for IVIG-resistant KD: Plasma exchange (PE) rapidly removes inflammatory cytokines, thereby reducing coronary risks. Immunoadsorption selectively filters out pathogens. When combined with drug and nutritional support, these methods show promise, but larger trials are needed to confirm their efficacy and safety.

Non-drug therapy also occupies a certain place in the treatment of immunoglobulin-resistant KD. PE involves the centrifugation of blood, replacing the plasma containing inflammatory cytokines with albumin, thereby achieving a curative effect by rapidly clearing a large number of inflammatory factors in the plasma[35]. PE is suitable for treating children with nonresponsive and refractory KD, and can prevent the occurrence of coronary aneurysms[36]. If the effect of IVIG combined with glucocorticoid treatment remains poor, PE can be considered as an alternative[37,38].

Additionally, immunoadsorption therapy can selectively remove pathogenic substances from the blood. In some cases, the combination of immunoadsorption and drug therapy has yielded good results. Simultaneously, nutritional support and symptomatic treatment are indispensable, as they are crucial for maintaining the patient's physical condition and alleviating symptoms. For instance, for patients with cardiac complications, appropriate cardiovascular support treatment can aid in improving the prognosis. The combination of non-drug therapy and drug therapy offers more approaches for the comprehensive treatment of resistant KD. However, the sample size of relevant studies was small, necessitating further large-scale studies to clarify its efficacy and safety.

Individualized treatment of immunoglobulin-unresponsive KD

Overview: Individualized KD treatment considers factors such as age (with infants requiring aggressive care), genetics (for example, PLA2G7 variants that predict IVIG resistance), and laboratory markers. Customized plans may improve outcomes in refractory cases.

An individualized treatment plan aims to formulate the most appropriate treatment strategy according to the specific situation of each patient. Since different patients respond to treatment differently, multiple factors must be considered comprehensively. For instance, age is a significant factor. Studies have indicated that infants with KD exhibit more severe coronary artery dilatation and a higher incidence of medium and large aneurysms, necessitating closer monitoring and potentially more aggressive treatment for infant patients[39].

Genetic factors can influence treatment response. Some studies have genotyped patients with KD and identified that specific gene polymorphisms are linked to IVIG treatment resistance. For example, the rs1051931 G>A polymorphism of the PLA2G7 gene is associated with resistance to IVIG treatment in patients with KD in Southern China, and the AA homozygous mutation may serve as a protective factor against IVIG resistance. Additionally, clinical characteristics and laboratory indicators can guide individualized treatment, such as tailoring the treatment plan based on the patient's fever pattern and inflammatory markers. By considering these factors comprehensively and formulating an individualized treatment plan, it is anticipated that the treatment efficacy for unresponsive KD will improve and the prognosis for patients will be enhanced.

Appropriate intervention and support strategies are essential for the psychological and social adaptation of children with KD who are resistant to treatment. (1) Psychosocial assessment and early intervention: Psychological assessments, such as those measuring child anxiety and depression, should be included in follow-up care. Cognitive–behavioral therapy can assist children in coping with medical trauma, while mindfulness training can help alleviate anxiety; (2) Family support and education: Offer psychological counseling to parents to alleviate their sense of helplessness and establish mutual aid groups for parents of sick children; and encourage open communication within families and work to optimize family dynamics, balancing the needs of the ill child with those of other family members; (3) Collaboration between schools and communities: Schools should provide academic support and modify the intensity of physical activities for children who have missed classes, and strengthen community awareness and publicity about the disease to reduce discrimination and foster an inclusive environment; and (4) Multidisciplinary team management: Implement joint follow-up by cardiologists, psychologists, and social workers, coordinating medical treatment with psychosocial support; and integrate psychological counseling into cardiac rehabilitation programs and have social workers assist families in applying for medical subsidies or educational resources.

CONTROVERSY AND CHALLENGES OF IMMUNOGLOBULIN-UNRESPONSIVE KAWASAKI DISEASE

Difficulties in the diagnosis of immunoglobulin- unresponsive KD

Overview: Diagnosing IVIG-resistant KD is challenging: Early symptoms mimic common febrile illnesses, often causing delays in recognition. Reliable biomarkers, such as CRP and erythrocyte sedimentation rate (ESR), lack precision, and atypical presentations further complicate detection. There is an urgent need for improved early diagnostic tools.

The diagnosis of immunoglobulin-resistant KD presents numerous challenges. Initially, its clinical manifestations are nonspecific, resembling those of various other pediatric febrile illnesses. Some children require cardiac color Doppler ultrasound examination, and while diagnosis can be confirmed by integrating laboratory tests and clinical symptoms, this approach is prone to misdiagnosis and missed diagnoses[40].

Upon analyzing clinical practice research data, it was discovered that most children with KD initially exhibit fewer clinical characteristics in primary care settings, presenting only with fever or a polymorphic rash. At the initial diagnosis, most physicians do not consider KD, and the more typical syndromic manifestations often do not emerge until the children are hospitalized[41].

Secondly, there is a scarcity of reliable early diagnostic markers. Although certain laboratory indicators, such as ESR, CRP and platelet count, are associated with IVIG resistance, the predictive accuracy of these indicators is limited. For instance, in a study of 48 patients with KD, while CRP and ESR were correlated with IVIG resistance, some predictive models in Japan demonstrated poor accuracy within this study population[42]. Moreover, some patients may exhibit atypical or delayed symptoms, further complicating the diagnostic process. For example, some patients may initially only present with fever, with other typical symptoms manifesting later in the disease course, which can lead to delayed diagnosis. Consequently, there is an urgent need to identify more specific and sensitive diagnostic markers and methods to enhance the accuracy of early diagnosis.

Controversial points of treatment options

Overview: Debate continues regarding the treatment of IVIG-resistant KD: There is no consensus on the optimal timing, dosing, and combinations of second-line drugs such as steroids, infliximab, and cyclosporine. Scoring systems designed to predict resistance require validation, and the long-term risks associated with combined therapies are yet to be fully understood.

There are numerous controversies surrounding the treatment options for immunoglobulin-unresponsive KD. Initially, the selection of second-line treatment drugs after IVIG nonresponse remains inconclusive. Currently, commonly used second-line drugs include glucocorticoids, infliximab and cyclosporine A[43]. However, there are variations in the efficacy and safety profiles of these different drugs. For instance, while methylprednisolone pulse therapy offers a rapid antipyretic effect, long-term follow-up studies have indicated that the incidence of treatment failure and CALs may be higher than with IVIG treatment[44]. Additionally, the timing and dose of these drugs are also subjects of debate. Presently, there is no consensus on when to initiate second-line drug therapy and what dose would yield the optimal therapeutic effect. Some studies have attempted to predict IVIG resistance using scoring systems to guide the early use of second-line drugs, yet the accuracy and practicality of these scoring systems require validation[45]. The choice of combination therapy is also contentious, with the efficacy and safety of various drug combinations necessitating further research to confirm. For example, the long-term effects and potential risks associated with the combination of IVIG with glucocorticoids or other immunosuppressants remain to be elucidated.

Long term prognosis of immunoglobulin-unresponsive KD

Overview: IVIG-resistant KD carries long-term risks: Coronary aneurysms (with a 30-year cardiac event-free rate of 36%) and systemic vascular dysfunction persist, even in the absence of overt coronary damage. There is a need for improved preventive strategies and long-term monitoring.

The long-term prognosis of patients with immunoglobulin-unresponsive KD is of importance, yet it continues to present challenges. CAD is a critical factor influencing the long-term prognosis. Patients with coronary artery aneurysm, coronary artery stenosis, and other lesions may experience myocardial infarction, heart failure, and other severe cardiovascular events. A survey of 245 patients with KD and giant coronary aneurysms revealed that the 30-year event-free rate for cardiac events was 36% (95%CI: 28%–45%); the survival rate was 90% (95%CI: 84%–94%); the 30-year survival rate for patients with bilateral giant aneurysms was 87% (95%CI: 78%–93%), and that for patients with unilateral giant aneurysm was 96% (95%CI: 85%–96%)[46].

Apart from CAD, patients may also suffer from other long-term complications, such as cardiovascular dysfunction and metabolic abnormalities. Systematic reviews and meta-analyses have indicated that patients with KD may exhibit long-term vascular endothelial dysfunction, even in the absence of coronary artery abnormalities, characterized by reduced flow-mediated diastolic function and increased pulse wave velocity[47]. However, the current understanding of the mechanisms and preventive measures for these long-term complications remains limited. Further long-term follow-up research is essential to elucidate the development patterns and influencing factors, to devise effective intervention strategies, and to enhance the long-term prognosis for patients.

Immunoglobulin-unresponsive KD increases the risk of cardiovascular complications in children and may also profoundly affect their psychological and social adaptability due to long-term health management needs, repeated medical visits, and disease uncertainty. (1) From a mental health perspective, the uncertainty of the disease necessitates long-term monitoring of CALs (such as coronary artery aneurysms), frequent medical examinations (echocardiography, cardiac magnetic resonance imaging), and treatment adjustments, which can lead to ongoing concerns about health deterioration. Additionally, some children may develop medical trauma memories due to repeated hospitalizations and invasive treatments, such as venipuncture. Adolescent children might experience feelings of inferiority due to changes in their body image (such as weight gain from hormone therapy) or limited mobility; (2) In terms of social adaptation and academic challenges, children with this condition may frequently miss classes due to frequent hospitalization, follow-up examinations, or fatigue, which can affect their peer relationships and confidence. Children with CAD should avoid strenuous activities, which can prevent them from participating in sports or extracurricular activities and exacerbate their sense of social isolation. Moreover, excessive restrictions on daily activities by parents due to health concerns may impede the development of their independence and social skills; (3) The impact on the family is significant; the need for multiple uses of IVIG, biologics or surgical interventions in children with unresponsive KD increases the economic burden on families. Additionally, parents of drug-resistant children with KD have a higher incidence of anxiety and depression, which can affect the family atmosphere and parent–child relationship. Parents' focus on children with unresponsive KD may lead to emotional neglect of other children, causing internal conflicts within the family; and (4) There is a long-term decline in the quality of life; CAD may lead to decreased exercise endurance in children, affecting daily activities. Related studies have shown that drug-resistant children with KD have significantly lower scores in vitality, emotional health and social functioning compared to healthy children.

HISTORICAL EVOLUTION AND CURRENT SITUATION OF IMMNUNOGLOBUNLIN-UNRESPONSIVE KAWASAKI DISEASE

Historical evolution of therapeutic strategies for KD

Overview: KD treatment has evolved; IVIG and aspirin have reduced aneurysm rates from 30% to less than 5%. New biologics, such as anti-TNFα and IL-1/6 blockers, along with immunosuppressants like cyclosporine, show promise for cases resistant to IVIG, but further randomized controlled trials are required for validation.

Since KD was recognized, its treatment strategies have undergone significant evolution. Initially, the treatment was mainly supportive. With a deeper understanding of the disease, it gradually developed into a standard treatment based on IVIG and aspirin. Since IVIG was introduced clinically, the incidence of coronary aneurysm in KD patients has significantly decreased, from 25%–30% to < 5%[7].

In recent years, with further research into the pathogenesis of KD, new therapeutic drugs and methods have been emerging. For instance, biological agents targeting the inflammatory factor pathway have begun to be applied clinically, and anti-TNF-α monoclonal antibodies such as infliximab have been tried to treat IVIG-unresponsive KD. A retrospective study by Korean researchers indicated that for IVIG-unresponsive KD, early use of infliximab can reduce the incidence of coronary aneurysms[48]. A Japanese study showed that infliximab can shorten the duration of fever in children[49]. Domestic studies, such as that by Xie et al[48], have shown that inflammatory indicators such as CRP and serum amyloid A in children after infliximab treatment were significantly decreased, which demonstrated better efficacy and safety in KD children with IVIG nonresponse or continuous progression of coronary artery aneurysm.

A single dose of intravenous immunoglobulin (2 g/kg) combined with oral aspirin (30–50 mg/kg/day) is the standard treatment regimen for acute KD. For children with KD who do not respond to IVIG, salvage treatment plans are necessary, but there is no universally accepted standard recommendation. Different centers adopt various treatment protocols, with common salvage therapies including a second dose of IVIG, corticosteroids, and infliximab. In cases where patients with KD do not respond to IVIG, a second dose of IVIG (2 g/kg) is often administered, although there is a 50% chance that it will not control the inflammatory response[7]. Clinically, high-dose methylprednisolone shock therapy at 10–30 mg/kg/day is used for 1–3 days, or low-dose methylprednisolone therapy at 0.8–2 g/kg/day is gradually tapered off until the systemic inflammatory response is halted. Infliximab can more rapidly terminate inflammation, with the commonly used dose being a single infusion of 5 mg/kg administered slowly over > 2 hours.

In recent years, other nonhormonal immunosuppressive drugs have been used to treat IVIG-unresponsive KD, such as cyclosporine A and the IL-1 receptor antagonist anakinra, which can inhibit the cytokine storm in children with KD. In children with high-risk KD who do not respond to IVIG, cyclosporine A combined with IVIG can reduce the incidence of CAD and quickly bring inflammatory indicators, such as CRP, back to normal levels by inhibiting the nuclear factor pathway of calcium-activated T cells[50]. IL-1 receptor antagonists can be used in KD children with IVIG nonresponse or glucocorticoid resistance[51], and anakinra can improve the body temperature of children, reduce inflammatory markers and the incidence of CAD. Nozawa et al[50] used the IL-6 receptor antagonist tocilizumab to treat four children with IVIG-unresponsive KD, which rapidly improved the clinical manifestations and inflammatory indicators of children, but randomized controlled studies are needed to confirm its effectiveness and safety. The evolution of treatment strategies reflects the continuous exploration and understanding of the pathogenesis of KD, aiming to improve the treatment effectiveness, reduce the occurrence of complications, and improve the prognosis of patients.

Analysis of the current situation of immunoglobulin-unresponsive KD

Overview: IVIG-resistant KD presents significant challenges: 10%-20% of patients do not respond to initial therapy, increasing the risk of coronary complications. Current second-line treatments, such as infliximab and steroids, are inconsistent, and their high costs restrict accessibility. There is an urgent need for improved biomarkers and cost-effective therapies.

Currently, immunoglobulin-resistant KD remains a significant challenge in clinical treatment. While IVIG is the standard treatment for KD, between 10% and 20% of patients do not respond to it, and these individuals face a higher risk of CAD[12]. Regarding diagnosis, although certain clinical characteristics and laboratory indicators can predict IVIG resistance, there is a shortage of diagnostic markers with strong specificity and high sensitivity, leading to challenges in early diagnosis.

As for treatment, there are several second-line drugs available, but their efficacy and safety vary, and there is a lack of unified treatment selection criteria. For instance, the therapeutic effects of infliximab, methylprednisolone and other drugs have shown inconsistent results. Some new drugs and treatment methods are costly, restricting their widespread application in certain areas. Consequently, further research is essential to identify more effective diagnostic methods and more cost-effective treatment strategies to enhance the outcomes for patients with immunoglobulin-resistant KD and to improve their prognosis. For the treatment of children with IVIG-unresponsive KD, salvage treatment plans are necessary, but there is currently no universally accepted standard treatment recommendation. Different centers use various treatment protocols, with the second dose of IVIG, corticosteroids, and infliximab being commonly used as salvage treatment medications. In most treatment centers, if KD patients do not respond to the initial IVIG treatment, a second dose of IVIG (2 g/kg) is often administered. However, there is a 50% chance that this second dose may not control the inflammatory response of KD. Wang et al[42] demonstrated that using different doses of glucocorticoids in combination with standard IVIG treatment can reduce the incidence of coronary artery abnormalities and IVIG nonresponse in children with KD. A retrospective study[46] by Korean researchers indicated that early use of infliximab can decrease the incidence of coronary artery aneurysms in IVIG-unresponsive KD. A real-world study in Japan[47] revealed that infliximab can shorten the duration of fever in children. Compared to the second dose of IVIG, infliximab can save additional treatment costs and decrease the incidence of severe anemia in IVIG-unresponsive children, although there is no significant difference in the outcome of CAD. Studies conducted by Xie et al[48] in China have shown that after treatment with infliximab, inflammatory markers such as CRP and serum amyloid A in children with KD significantly decrease. Infliximab shows good efficacy and safety in children with IVIG-unresponsive KD or who have persistent progression of coronary artery aneurysms.

Limitations and deficiencies of existing studies

Overview: Significant research gaps remain: Small retrospective studies predominantly inform IVIG-resistance prediction (lacking standardized models). Evidence for treatment is fragmented (with various second-line options). There is an urgent need for deeper mechanistic insights and large multicenter trials.

Current research on immunoglobulin-unresponsive KD has its limitations. In terms of diagnosis, most studies have depended on retrospective analysis of past cases, which often had small sample sizes. Additionally, there were inconsistencies in the inclusion criteria and observation indicators across different studies, leading to limited comparability of the research outcomes[52]. At present, in the field of predicting IVIG resistance, various studies have used different clinical characteristics and laboratory indicators, complicating the creation of a unified prediction model[44]. Furthermore, the application of existing models is constrained by the differences in clinical practices among different populations[53].

Regarding treatment research, the current prediction of IVIG nonresponse primarily comes from single-center, small-scale retrospective studies. External validation of these results is poor, and there is no established, accurate prediction index or model. Further research is required, incorporating the interaction of multi-ethnic factors, gene polymorphisms and environmental influences, to achieve early identification of IVIG nonresponse. Different scoring systems and prediction models for various indicators are used to forecast IVIG nonresponse. Children with IVIG-unresponsive KD can be treated with a second dose of IVIG, glucocorticoids, or biological agents to suppress the inflammatory response during the acute phase of KD, thereby reducing the incidence of severe CAD and enhancing the therapeutic efficacy and long-term prognosis. Additionally, research into the pathogenesis of KD is not yet sufficiently comprehensive. Although several potential mechanisms have been proposed, the specific molecular pathways and regulatory mechanisms remain to be fully elucidated, which hampers the development of targeted therapeutic drugs. Consequently, there is a need for future high-quality, large-scale studies to bridge these gaps and provide a more solid foundation for clinical treatment.

FUTURE RESEARCH DIRECTIONS IN IMMUNOGLOBULI-UNRESPONSIVE KAWASAKI DISEASE

Research and development prospects of new therapeutic drugs

Overview: Novel therapies for IVIG-resistant KD: Targeted IL-1 inhibitors (such as anakinra) and repurposed drugs [like non-steroidal anti-inflammatory drugs (NSAIDs)] show promise. Emerging biotechnologies, including gene editing and biologics, may yield safer and more effective treatments.

The development of new therapeutic drugs is important for improving the treatment of immunoglobulin-unresponsive KD. It is an important direction to develop targeted drugs for the key links in the pathogenesis. For example, given the key role of IL-1 in the pathogenesis of KD, developing inhibitors targeting the IL-1 pathway has potential therapeutic value. At present, some relevant clinical trials have been carried out, such as anakinra, a recombinant human IL-1 receptor antagonist, which has shown therapeutic effects on IVIG-resistant KD in some studies, reducing fever, inflammatory marker levels and coronary artery dilatation[54].

Drug-repurposing strategies also deserve attention. Through the re-evaluation and research of marketed drugs, new therapeutic indications have been found. For example, some NSAIDs may have potential therapeutic effects on KD by regulating immune responses and inflammatory pathways. Additionally, with the continuous development of gene editing technology and biopharmaceutical technology, it is expected that new therapeutic drugs with greater specificity, efficacy and safety will be developed, which will bring new breakthroughs in the treatment of unresponsive KD.

Breakthrough in basic research of immunoglobulin-unresponsive KD

Overview: Key research priorities include decoding genetic polymorphisms and immune dysregulation, such as cytokine networks and immune cell subsets, in patients with IVIG-resistant KD. Investigating interactions with the gut microbiome may reveal novel therapeutic strategies.

Breakthroughs in basic research are essential for an in-depth understanding of the pathogenesis of immunoglobulin-unresponsive KD and for improving treatment strategies. In the study of genetic factors, it is necessary to further clarify the gene polymorphisms and their mechanisms related to KD susceptibility and IVIG resistance. For instance, while some genes have been identified as being associated with KD, the specific gene–environment interactions and the effects of these genes on immunoregulation and inflammatory response require further exploration[27].

In the study of immune mechanisms, the activation and regulation mechanisms of the immune system in the pathogenesis of KD need to be further elucidated. For example, investigating the functional changes in different immune cell subsets and the imbalance of cytokine networks will aid in identifying new therapeutic targets. Additionally, the relationship between gut microbiota and KD warrants further investigation to clarify its role in the onset and progression of the disease, which may offer new approaches for treatment, such as enhancing the immune response and modifying the disease process by regulating gut microbiota.

Role of international cooperation in the study of unresponsive KD

Overview: Global collaboration is key: Pooling multinational data and expertise (genetics, immunology, clinical) can overcome current limitations in IVIG-resistant KD research, accelerating breakthroughs in diagnosis and treatment.

International cooperation is pivotal in advancing research on immunoglobulin-unresponsive KD. Given that KD is a global phenomenon, with variations in incidence, clinical manifestations and genetic backgrounds across different regions, international collaboration enables the aggregation of large-scale multicenter data. This, in turn, facilitates the conduct of research with larger sample sizes, enhancing the reliability and universality of the findings. For instance, the KD registration systems established by numerous international research teams have amassed extensive clinical data and genetic information, aiding in the understanding of the epidemiological characteristics, genetic susceptibility, and treatment response disparities of the disease[52].

International cooperation fosters the cross-integration of various disciplines, uniting experts in immunology, genetics, clinical medicine, and other fields to collaboratively address challenges. Concurrently, the sharing of research resources and technology platforms can expedite the development of new therapeutic drugs and diagnostic methods. With international cooperation, it is anticipated that significant strides will be made in understanding the pathogenesis, diagnosis and treatment of unresponsive KD, ultimately offering improved treatment and prognosis for children around the world.

CONCLUSION

KD, especially the IVIG-resistant form, continues to pose a significant clinical challenge in pediatric medicine. This comprehensive review highlights key aspects of IVIG-resistant KD, including its epidemiology, pathophysiology, diagnostic criteria and evolving treatment strategies. Despite advances in understanding the disease mechanism, the precise factors contributing to IVIG resistance remain incompletely understood, necessitating further research into genetic, immunological and environmental influences.

Current therapeutic approaches, such as corticosteroids, biologics (e.g., TNF-α inhibitors), and immunomodulatory agents, show promise but require optimization through large-scale clinical trials. The lack of standardized protocols for refractory KD underscores the need for personalized treatment strategies based on risk stratification and biomarker-guided therapy.

Future research should focus on: (1) Novel therapeutics – investigating targeted immunomodulators and small-molecule inhibitors; (2) Biomarker discovery – identifying reliable predictors of IVIG resistance and disease severity; and (3) International collaboration – establishing multicenter registries to enhance data sharing and clinical trial design. By addressing these challenges, the medical community can improve outcomes for children with IVIG-resistant KD and move closer to a precision medicine approach in its management.