Refractory Kawasaki Disease in Infants Complicated with Giant Coronary Artery Aneurysms and Takayasu Arteritis: A Rare Case Report and Literature Review

Abstract

Kawasaki disease (KD) is a common acute systemic vasculitis in children.10% to 20% of children present with refractory KD, and a few critically ill children may develop Kawasaki disease shock syndrome (KDSS) or macrophage activation syndrome (MAS). Coronary artery aneurysm (CAA) is the most serious complication of KD, and giant coronary artery aneurysm (GCAA) has an extremely poor prognosis. Takayasu arteritis (TAK) is a chronic granulomatous vasculitis mainly involving the aorta and its branches. It is extremely rare in infants, with no specific early symptoms and prone to delayed diagnosis. The combination of infant KD and TAK is extremely rare, as there is overlap in vascular involvement, making it difficult to differentiate clinically. This article reports the case of a 45-day-old male infant diagnosed with refractory KD, accompanied by KDSS and MAS. After conventional treatment, the condition relapsed and progressed to a GCAA, and subsequently TAK occurred. The complete clinical diagnosis and treatment process of the case will be elaborated in detail here. At the same time, based on the literature review, the diagnosis and treatment of this disease are analyzed to guide clinical practice.

Background

Kawasaki disease (KD) is a febrile syndrome causing systemic inflammation. It has now replaced rheumatic fever as the most common cause of acquired heart disease in children in developed countries.¹ The KD lesion mainly affects medium-sized arteries throughout the body, especially the coronary arteries, and can also involve large vessels such as the subclavian artery. The formation of coronary artery aneurysms (CAA) is the most serious complication of KD. Giant coronary artery aneurysms (GCAA) can be accompanied by thrombosis, leading to myocardial ischemia, myocardial infarction, and even sudden death, which is the main cause of death in KD patients. Currently, the most effective treatment for preventing coronary artery lesions (CALs) is intravenous immunoglobulin (IVIG), which can reduce the incidence of CAA from 25% to 4%. However, 10% to 20% of children with KD do not respond to IVIG and are diagnosed with refractory Kawasaki disease. Studies have shown that the risk of CAA in such children is significantly increased.² Kawasaki disease shock syndrome (KDSS) is a severe type of manifestation of KD. It occurs on the basis of the symptoms of KD, with changes in hemodynamic parameters, including a sustained systolic blood pressure that is below 20% of the normal value for children of the same age group, or combine the clinical manifestations of tissue hypoperfusion. Fluid resuscitation or vasoactive drugs are required to maintain normal blood pressure levels. Compared with KD, it is associated with more severe inflammatory reactions and has a higher probability of IVIG non-response, CAA, and multi-system damage. Therefore, more aggressive treatment is needed.³ Macrophage activation syndrome (MAS) is a state of high inflammation and a “cytokine storm”, characterized by a slow onset, rapid progression, and high mortality rate. It can occur as a complication of various rheumatic immune disorders. MAS is most commonly observed during the acute phase of KD.⁴ The typical clinical manifestations include persistent fever, hepatosplenomegaly, lymphadenopathy, coagulation dysfunction or central nervous system disorders, and in severe cases, multiple organ dysfunction may occur. The typical laboratory findings include decreased blood cell counts and fibrinogen levels, elevated ferritin, transaminase, triglyceride and lactate dehydrogenase levels. The presence of hemophagocytic cells in the bone marrow is a typical pathological feature, and these hemophagocytic cells can also infiltrate other organs such as the liver, spleen and lymph nodes.⁵ With increasing understanding of this disease, an increasing number of cases of Kawasaki disease-related macrophage activation syndrome (KD-MAS) have been reported. Compared with the incidence of coronary artery lesions in KD, the incidence of coronary artery lesions in KD-MAS is 1.1% to 1.9%, which is relatively low and thus easily overlooked.⁶ Therefore, early diagnosis and timely treatment are particularly important for improving the prognosis of children. Takayasu arteritis (TAK) and KD are two primary childhood vasculitides. TAK mainly involving the aorta and its branches, and it is extremely rare in infants. Currently, the literature mainly consists of case reports.^7–9 According to statistics, the prevalence of TAK in children aged 0–4 years in South Korea is only 0.04/1,000,000, and the clinical symptoms are atypical.¹⁰ Early symptoms often present as non-specific systemic symptoms, making early diagnosis very difficult. When typical symptoms such as hypertension or organ ischemia causing abnormal limb movement occur, it indicates that the blood vessels have been significantly affected.¹¹ Neither TAK nor KD is known to be common in infancy, and the coexistence of the two is even rarer.¹² A single-center retrospective cohort study showed that 67.4% of TAK children were detected with coronary artery involvement.¹³ Therefore, it is easy to be missed in clinical practice and lead to delayed treatment, affecting the prognosis. This article reports a case of a 45-day-old male infant with refractory KD who also had KDSS and MAS. After receiving standard treatment, the condition relapsed and progressed to GCAA, accompanied by TAK. Next, we have formulated an individualized treatment plan for the patient, including anti-inflammatory, anti-platelet aggregation and improvement of cardiac function. As a result, child’s clinical symptoms improved, inflammatory indicators gradually returned to normal, and the GCAA was effectively controlled.

Case Presentation

A 45-day-old male infant. The mother of this child is 33 years old. She was previously in good health and received regular prenatal check-ups during pregnancy. Cervical posterior amniotic membrane scans, non-invasive DNA test, four-dimensional ultrasound, and fetal ultrasound revealed no abnormalities. At 25 weeks of pregnancy, the glucose tolerance test was completed and it indicated the presence of gestational diabetes, and insulin injected under the skin was used to control blood sugar effectively. Due to the prenatal ultrasound indicating an abnormally large fetal buttock circumference and foot presentation, the delivery was performed via cesarean section at 38+2 weeks of gestation. The Apgar scores at 1, 5, and 10 minutes were 7/9/9 respectively. The birth weight was 2960g. The infant was breastfed after birth and had a good weight gain. At 45 days after birth, the child developed fever (39.4°C) and was sent to the pediatric department. The initial physical examination revealed congestion in the pharynx and coarse breath sounds in both lungs, but no increased tension of the fontanelle, rash, swollen superficial lymph nodes, strawberry tongue, chapped lips, red and swollen scars, hard swelling of hands and feet, or pathological signs. Laboratory tests indicated CRP 26.15mg/L, PCT 1.26ng/mL, and IL-6 294pg/mL. The initial diagnosis was bacterial infection, and ceftriaxone was used for anti-infection treatment. Moreover, the child experienced a decrease in blood pressure, insufficient perfusion, heart failure and a hypercoagulable state (BNP >35000pg/mL, HR >170times/min, BP 61/29mmHg, D-D 5.26mg/L). After fluid resuscitation and the use of vasoactive drugs, the blood pressure was corrected. Given that infants are at high risk group for purulent meningitis, we performed a lumbar puncture. The cerebrospinal fluid was normal, but the child continued to have a high fever. Oral medications and physical cooling failed to return the temperature back to normal. We upgraded the antibiotic treatment to meropenem combined with vancomycin. One day after the illness onset, the child gradually developed chapped lips, non-exudative conjunctival congestion on both sides of the eyes, and maculopapular rashes on the trunk and limbs (Figure 1A and B). Although no superficial lymph nodes were palpably enlarged, ultrasound of the cervical lymph nodes revealed that the left lymph nodes were slightly enlarged (the largest being 1.37cm×0.81cm), raising suspicion of KD combined with KDSS. Therefore, thirds day of illness onset, we completed a cardiac ultrasound examination, which showed a left main coronary artery (LMCA) of 0.17cm (z-score 1.21) and a right coronary artery (RCA) of 0.18cm (z-score 2.46), confirming our conclusion (Figure 2). Based on the diagnostic criteria of the KD guidelines released by ACR in 2021 and AHA in 2017, combined with fever, four out of five specific symptoms, and RCA dilation, we diagnosed the patient with complete KD.^14,15 Four days of illness onset, we administered IVIG at a dosage of 2g/kg/once, and orally administered aspirin (ASA) at a dosage of 30mg/kg/day. During the injection process, the child’s body temperature returned to normal. However, 12 hours after the IVIG infusion, the child again developed persistent high fever, and the CRP 128.48mg/L, PCT 4.35ng/mL, IL-6 791pg/mL, and Hb 75g/L. Meets the diagnostic criteria for refractory KD. We conducted a second course of IVIG and used GC at a dose of 10mg/kg/day for three consecutive days. The child’s clinical symptoms significantly improved, with the body temperature returning to normal, the color of the rash becoming lighter, and there was membrane-like desquamation. The inflammatory indicators decreased (CRP 86.39mg/L), coronary artery dilation reversed, LMCA 0.15cm (z-score 0.35), left anterior descending branch (LAD) 0.15cm (z-score 1.6), left circumflex artery (LCX) 0.13cm (z-score 1.22), RCA 0.15cm (z-score 1.6). The GC was changed to oral administration of 6mg/day, and ASA was changed to 3mg/kg/day. Three days after the fever subsided, the child experienced a recurrence of fever, persistent irritability with inconsolable crying. Moreover, rechecking the inflammatory markers revealed that the C-reactive protein level had further increased (CRP 99.49mg/L), moderate anemia, the hemoglobin reduction (Hb 64g/L), mild reduction in platelets (PLT 91×10^9/L), decreased fibrinogen (FIB 1.16g/L), elevated ferritin (SF 790ng/mL), increased triglycerides (TG 1.98mmol/L), and elevated soluble interleukin-2 receptor (sCD25 3451.77U/mL). KD-MAS is a rare condition in clinical practice and there is currently no unified diagnostic standard. The diagnosis is based on the 2022 MAS/sJIA (MS) scoring tool, the 2016 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR)/International Pediatric Rheumatology Trial Organization (PRINTO) sJIA-MAS diagnostic criteria, and the International Society of Cellular Therapy HLH-2004 diagnostic criteria.^16–18 The child had persistent high fever, elevated SF (>684ng/mL), decreased PLT (<181×10^9/L), decreased FIB (<3600mg/L), increased TG (>1560mg/L), and increased sCD25 (>2400U/mL). No hemophagocytic cells were observed in the bone marrow puncture, and the whole exome sequencing test was negative. The primary HLH and HLH-related pathogenic gene mutations were excluded. The MS value was 2.047 (≥-2.1), and the final diagnosis was KD-MAS. Infliximab (IFX) 5mg/kg was used. The rash significantly subsided, but the child still had a high fever and the level of inflammatory markers did not decrease. We used GC pulse therapy for the second time, 15mg/kg/day, for three consecutive days, which was then changed to oral administration (the same oral dosage as before). ASA was changed to 30mg/kg/day, and Cyclosporine A (CsA) was orally administered 5mg/kg/day, twice a day. The child’s body temperature returned to normal, and within a few days after the treatment, the inflammatory markers gradually decreased (IL-6 107pg/mL, CRP 35.50mg/L). However, ferritin continued to increase further (SF 840ng/mL), and the levels of cytokines (IL-2 33.12pg/mL, IL-4 75.01pg/mL, IL-6151.64pg/mL, IL-10,123.76pg/mL, IL-17A 62.15pg/mL, IL-1β 56.49pg/mL, IL-5 6.63pg/mL, IL-12P70 86.02pg/mL, IL-β 141.37pg/mL, TNF-α 39.19pg/mL, IFN-γ 46.38pg/mL, IFN-α 24.79pg/mL) were relatively high. The clinical symptoms gradually improved. Therefore, the child continued to receive oral treatment with aspirin, GC, and CsA. During this period, the inflammatory factors gradually decreased (Figure 3A–C). However, twenty-eight days of illness onset, CALs progressed to GCAA (LMCA 0.2cm (z-score 2.39), RCA 0.52cm (z-score 10.51)) (Figures 3D and 4). According to the AHA 2017 guidelines,¹⁵ the cardiovascular risk stratification of the child was extremely high. On the basis of ASA, clopidogrel 1mg/kg was added to enhance antiplatelet aggregation, and captopril 3mg/once and metoprolol 3mg/once, twice a day were given orally to synergistically reduce the incidence of intraneuronal thrombus, delay the progressive enlargement of CAA, reduce the risk of rupture, delay ventricular remodeling, and prevent coronary artery stenosis and ischemic cardiovascular adverse events. Considering that the infant’s coagulation system is extremely immature and it is difficult to maintain a stable therapeutic window, the harm of adverse bleeding events is much greater than the risk of thrombosis, and the child had subcutaneous bleeding when using clopidogrel for the first time. Therefore, we did not adopt the triple antithrombotic regimen (two antiplatelet drugs + one anticoagulant drug) recommended by the guidelines. The most severe stage of CALs was observed at forty days of illness onset (LMCA 0.47cm (z-score 9.73), LAD 0.41cm (z-score 6.99), LCX 0.41cm (z-score 6.33), RCA 0.56cm (z-score 11.16)). Fifty-two days of illness onset, the level of IL-6 in the child was detected to have risen again. Tocilizumab was administered at 12mg/kg, following which the abnormal inflammatory markers gradually returned to normal ranges. Coronary Computed Tomography Angiography (CTA) performed on sixty-one days of illness onset demonstrated variable-degree dilatation and stenosis of multiple arteries, involving the coronary arteries, ascending aorta, descending aorta and abdominal aorta (Figure 5A–F). Given that infantile TAK often presents atypically, irreversible vascular complications such as hypertension or organ ischaemia may emerge years after disease onset, rendering early-stage differentiation from KD challenging. The vascular lesions in this patient extended far beyond the coronary arteries, aortic root and ascending aorta, which are the typical sites involved in KD. Furthermore, inflammatory markers rebounded after IVIG therapy and vascular lesions continued to progress, which could not be fully explained by isolated KD. The patient fulfilled the 2010 EULAR/PRINTO/PRES classification criteria for childhood-onset TAK.¹⁹ As the disease progressed, the patient developed mitral valve prolapse, rupture of the mitral chordae tendineae, severe mitral regurgitation, tricuspid regurgitation, mild pulmonary hypertension and heart failure (Figure 6A and B). Digoxin 10ug/kg/day was given for cardiac strengthening, hydrochlorothiazide 1mg/kg/once, twice a day, spironolactone 1mg/kg/once, twice a day for diuresis, sacubitril/valsartan for heart failure treatment, atorvastatin 2mg/day for lipid reduction and improvement of endothelial function, and to prevent thrombosis formation. Seventy-six days of illness onset, heart failure was corrected. But the coronary arteries showed a trend of further dilation compared to the previous examination (71 days: LMCA 0.41cm (z-score 8.42), LAD 0.42cm (z-score 7.12), LCX 0.40cm (z-score 6.23), RCA 0.52cm (z-score 10.51); 76 days: LMCA 0.42cm (z-score 8.66), LAD 0.41cm (z-score 7), LCX 0.41cm (z-score 6.33), RCA 0.56cm (z-score 11.17)). Considering that the local inflammatory injury of the blood vessels may have worsened, IFX 5mg/kg was used again. At eighty-four days of illness onset, the diameter of CAA did not undergo progressive expansion during the re-examination but slightly decreased (LMCA 0.42cm (z-score 8.61), LAD 0.26cm (z-score 6.64), LCX 0.39cm (z-score 6.11), RCA 0.52cm (z-score 10.5)). We believe that the child’s condition has been effectively controlled, and the child was discharged from the hospital on the eighty-six days of the illness onset. The child undergoes monthly echocardiographic follow-up. At six months of age, measure the LMCA 0.42cm (z-score 7.84), LAD 0.28cm (z-score 4.48), LCX 0.22cm (z-score 3.22), and RCA 0.45 cm (z-score 8.51). Cardiac function and pulmonary artery pressure are normal, with no evidence of thrombus formation. Waiting for the timing for the surgical procedure.

Figure 1.

The patient’s skin rash. (A) One day after the fever, the child developed maculopapular rashes on the trunk. (B) One day after the fever, the child developed maculopapular rashes on the limbs.

Figure 2.

Cardiac ultrasound examination was conducted on three days of illness onset, the result showed that the right coronary artery was widened (arrow), with a diameter of 1.8mm and a Z value of 2.46.

Figure 3.

Clinical treatment (A) inflammatory parameters (B) cytokines (C) coronary artery (D) according to the day of illness.

Abbreviations: PLT, blood platelet (×10^9/L); CRP, C-reactive protein (mg/L); IL-6, Interleukin 6 (pg/mL); IL-17A, Interleukin 17A (pg/mL); IL-10, Interleukin 10 (pg/mL); IL-4, Interleukin 4 (pg/mL); IFN-γ, interferon-γ (pg/mL); TNF-ɑ, tumor necrosis factor-α (pg/mL); IL-2, Interleukin 2 (pg/mL); LMCA, left main coronary artery; RCA, right coronary artery; LAD, left anterior descending; LCX, left circumflex artery.

Figure 4.

Eighty-five days of illness onset, the cardiac ultrasound showed that there was an aneurysm in the right coronary artery (arrow), with a diameter of 5.2mm and a Z value of 10.5.

Figure 5.

Coronary artery CTA performed on day 62 of illness, showed that the left main coronary artery (arrow) (A) the anterior descending branch (arrow) (B) and the right coronary artery (arrow) (C) were all moderately widened, the thoracic aorta was widened (arrow) (D) the ascending aorta was significantly widened (upward arrow), and the descending aorta stenosis (downward arrow) (E). The abdominal aorta has uneven thickness (arrow) (F).

Figure 6.

Mitral valve elongation (arrow) (A). Severe mitral valve regurgitation (arrow) (B).

Discussion

KD and TAK are both common vasculitides in childhood, with significant clinical overlap in symptoms, inflammatory markers, and vascular involvement, making them difficult to distinguish.²⁰ KD is an acute self-limiting medium-sized vessel vasculitis characterized primarily by coronary artery damage. During the acute phase, inflammation affecting all layers of the vessel wall can lead to persistent coronary artery dilation or even giant coronary aneurysms.¹⁵ TAK is a chronic granulomatous vasculitis affecting the aorta and its major branches, characterized by persistent thickening of the vessel walls and progressive luminal narrowing. Isolated CAA is extremely rare and lacks distinctive clinical features or specific biomarkers, making diagnosis highly challenging and often resulting in delayed diagnosis and poor prognosis.¹¹ Infantile KD complicated by TAK is extremely rare. The article presents a detailed clinical analysis of the case.

Stepwise Anti-Inflammatory Treatment for Refractory Kawasaki Disease

This case was a 45-day-old infant with KD, and KDSS was present in the early stage. After standard IVIG combined with aspirin treatment for 12 hours, the fever recurred. The second course of IVIG combined with GC was given, and the condition temporarily improved; however, the disease relapsed and CAA occurred. IFX was then added, but the effect was poor. A second GC pulse therapy was subsequently administered.

GC was once believed to potentially aggravate CALs. However, they have now become a crucial life-saving treatments for children with IVIG-resistant conditions. GC can bind to the NF-κB pathway, promote the release of IL-10, inhibit excessive activation of T cells, B cells and macrophages, and protect the vascular endothelium.²¹ Multiple studies have shown that the multi-dose GC regimen is superior to the pulse regimen in reducing the risk of CAA and the rate of treatment failure. The domestic consensus recommends that when IVIG has no response and KDSS/MAS occurs, GC should be administered at a dose of 10–30mg/kg/d for three consecutive days, followed by oral tapering.^22–24 In this case, this treatment plan was adopted, supplemented by the use of gastric mucosa and bone metabolism protectants, and no adverse reactions occurred.

Tumor Necrosis Factor-α (TNF-α) is the key pro-inflammatory factor in KD and directly damages the endothelium and participates in the formation of CAA. When IVIG fails to respond, IFX can effectively shorten the fever duration and reduce the incidence of CALs. Several studies in China recommend IFX as the preferred rescue drug for KD that does not respond to IVIG.^25–28 In this case, the rash and fever improved after using IFX, but there was no significant reversal of CALs. The above clinical outcomes may be attributed to the inherent therapeutic limitations of the drugs, individual differences in body sensitivity, and related confounding factors that affect the binding of the drugs to their targets and the distribution of the drugs in tissues. Pharmacokinetic studies have shown that when IFX is administered after IVIG, a high dose of IVIG can cause saturation of the newly formed Fc receptor (FcRn), resulting in a nearly 50% decrease in the peripheral distribution volume of IFX, and the rate of decrease in blood drug concentration monitored 4 weeks after administration also significantly increases.²⁹ However, Burns et al²⁹ confirmed that in children treated with IFX alone, IFX anti-drug antibodies (ATI) were detected in their bodies, although the inflammatory response was controlled, it could not prevent the progression of CALs. This indicates that without the immunosuppressive protection of IVIG, the body is more likely to produce ATI, so it can only be used as a remedial treatment for IVIG resistance. Logistic regression analysis suggested that for every 1 ng/mL increase in IL-6 level, the risk of drug insensitivity to IFX increased by 1.141 times.³⁰ Soluble tumor necrosis factor receptor 1 (sTNFR-1) mainly neutralizes the pro-inflammatory factor TNF-α. When inflammation occurs, sTNFR-1 is not bound by IFX, so it can better reflect the degree of damage to the coronary arteries by inflammatory factors. The higher the level of sTNFR-1 in the circulation of CALs children, the more it suggests that the amount of TNF-α generated in the body of these children has exceeded the binding and neutralization capacity of IFX at a dose of 5mg/kg. This often indicates the need for a larger drug dose.³¹ sTNFR-1 is expected to serve as a reference marker for determining the individualized dosage of IFX in clinical practice.

Kawasaki Disease-Related Macrophage Activation Syndrome

MAS is a rare and severe complication of KD. Its clinical manifestations lack specificity and is prone to being missed. It progresses rapidly during the acute phase and can cause multi-organ damage or even failure. The key to successful treatment lies in early detection and timely intervention. Previous studies have found that the incidence of IVIG non-response in KD-MAS is significantly increased.³² Currently, there is no unified diagnostic standard. The main criteria are based on the 2016 HLH/MAS and 2004 HLH diagnostic standards. When a KD patient shows abnormal elevation of ferritin, hepatosplenomegaly, no response to intravenous injection, ESR does not increase but decreases, as well as a decrease in hemoglobin, platelets, albumin and fibrinogen, accompanied by elevated transaminases, lactate dehydrogenase and triglycerides, and MAS should be suspected. GC are the preferred treatment for KD-MAS. The key is to use high doses early on. Some children can relieve symptoms by using hormones alone.^33,34 For those who do not respond to GC, CsA can be used in combination to increase the remission rate.³⁵ Excessive activation of the calcium ion (Ca²⁺⁾/ Nuclear Factor of Activated T Cells (NFAT) pathway is an important molecular mechanism of KD. Mutations in the Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) and Caspase-3 (CASP3) genes can upregulate this pathway, increasing the risk of IVIG resistance and CAA. CsA, as an inhibitor of this pathway, can inhibit T cell activation, block the infiltration of CD8+ T cells, and reduce coronary artery damage.³⁶ A Japanese study revealed that early combined use of CsA in high-risk children can reduce the incidence of CALs.³⁷ In 2022, the domestic consensus listed CsA as an important option when multiple treatments are ineffective.³⁸ In this case, in accordance with the 2024 AHA guidelines, CsA was administered at a dose of 5mg/kg/d in two divided doses orally. After the medication was given, the body temperature was quickly controlled, and the ratio of cytokines to CD8+ T cells significantly decreased.³⁹

Risk Factors and Clinical Characteristics of GCAA

CAA is the most serious complication of KD, and it usually occurs in the second week of the disease course.¹⁵ IVIG reduced the incidence of CAA from 25% to 4%, but still 0.13–0.7% of the children developed GCAA.⁴⁰ The areas of RCA and LAD are the most frequently affected, and the prognosis is poor.⁴¹ Age less than 6 months, with fever lasting for more than 10 days, anemia, elevated CRP, low albumin, elevated BNP, no response to IVIG, and KDSS are all high-risk factors for CAA.⁴² In this case, the child was treated with IVIG, ASA, GC and immunosuppressants, and the body temperature and inflammatory indicators were gradually controlled. However, the child still progressed to GCAA. GCAA has a high risk of thrombosis during both acute and chronic phases. Endothelial injury and platelet aggregation are the main causes. According to the AHA 2017 guidelines,¹⁵ the cardiovascular risk stratification is extremely high. On the basis of ASA, add clopidogrel to enhance antiplatelet aggregation. At the same time, administer captopril and metoprolol to synergistically reduce the incidence of thrombus formation within the aneurysm, slow down the progressive enlargement of CAA, lower the risk of rupture, delay ventricular remodeling, and prevent coronary artery stenosis and ischemic cardiovascular adverse events. Regular monitoring of thrombus and tumor changes was conducted. No thrombus formation was observed, and the aneurysm did not undergo progressive dilation.

Cardiac Function Support and Cardiovascular Protection Strategies

The acute inflammatory shock caused by KD can directly damage the myocardium and valves, inhibit the contraction function, when combined with coronary artery ischemia, increase the likelihood of progression to heart failure. Patients with KDSS are more likely to present with left ventricular function decline, valve regurgitation and coronary artery injury.^43,44 In this case, there were enlarged heart chambers, weakened ventricular wall movement, multiple valve insufficiency and heart failure. Therefore, digoxin, and diuretics were used, after which sacubitril/valsartan was added. This drug is an angiotensin receptor enkephalinase inhibitor, that can dilate blood vessels, reduce load, reduce sodium and water retention, and improve hemodynamics and cardiac function. Its cardioprotective effect is superior to that of traditional Angiotensin-Converting Enzyme Inhibitors (ACEIs).^45,46

The application of statins in children with KD combined with CAA remains controversial. However, the 2020 Japanese JCS/JSCS guidelines recommend the empirical use of statins for children with CAA to exert anti-inflammatory, antioxidant, and endothelial function-improving effects.⁴⁷ A Japanese I/IIa phase study confirmed that 0.5mg/kg/d atorvastatin was safe and tolerable for children with KD and CAA.⁴⁸ In this case, owing to the GCAA, elevated blood lipids and high thrombosis risk, atorvastatin 2mg/day was administered orally and close monitoring was carried out.

Control and Follow-Up of TAK

Both are caused by immune inflammation, and TAK mainly affects the aorta and its branches. It can present in forms such as vascular occlusion, stenosis, dilation, and thickening of the vessel wall. Moreover, it has a high recurrence rate and requires long-term treatment.⁴⁹ The manifestations of TAK in infants and young children are often atypical. Symptoms and signs of irreversible vascular lesions such as hypertension or organ ischemia may not appear until many years after the onset of the disease. Therefore, it is difficult to distinguish TAK from KD in the early stage. Coronary artery involvement can also occur in children with TAK. For children with fever, when antibiotic treatment is ineffective and non-specific systemic symptoms occur, along with increased acute-Phase Inflammatory markers, in addition to KD, TAK should also be considered, especially for atypical KD. When the treatment effect for KD is poor, misdiagnosis or missed diagnosis may occur.¹¹ On the other hand, numerous studies have confirmed that KD not only affects the coronary arteries but can also invade large blood vessels, leading to the formation of systemic aneurysms. This further increases the difficulty in differentiating TAK from KD.^50,51 At this point, the condition of the aorta, the dynamic changes of platelets, the response to IVIG, and the characteristics of the disease course can assist in the differentiation. In this case, the child’s response to IVIG, GC, and immunosuppressants was not satisfactory. Moreover, at two months of the disease course, the main thoracic and abdominal aorta and other major blood vessels showed varying degrees of dilation, thickening, and stenosis. Additionally, the coronary artery wall thickened and the proximal segment of the left anterior descending branch had local stenosis. During the course of the disease, the child’s PLT did not show the typical peak of KD. It fluctuated with repeated inflammation and could not be explained by simple KD. Currently, GC, biological inhibitors and immunosuppressants remain the cornerstones of TAK treatment. Considering the high risk of disease recurrence and the side effects of GC, the 2025 Expert Consensus on Diagnosis and Treatment of Pediatric Polyarteritis Nodosa recommends early induction and remission treatment with GC combined with immunosuppressants.⁵² For refractory and life-threatening TAK, it is recommended to use the GC pulse therapy regimen. Multiple studies have shown that the combination of GC and methotrexate (MTX) is a safe and effective treatment option for pediatric TAK. In addition, TNF inhibitors and IL-6 inhibitors can shorten the disease course and prevent the occurrence of new vascular lesions.^53,54 After early standardized and individualized treatment, the children have now achieved clinical remission. Long-term regular follow-up, prevention and treatment of related complications, and close monitoring of adverse drug reactions are crucial for improving the long-term prognosis of the children. However, there are no standardized treatment guidelines for pediatric TAK, and the treatment decisions still face great challenges. For patients with refractory TAK or those who cannot tolerate TNF and IL-6 inhibitors, new alternative drugs are emerging. A small prospective trial found that secukinumab (an IL-17 inhibitor) was proven to have similar efficacy to TNF inhibitors, and a prospective case study of the Janus Kinase (JAK) inhibitor baricitinib also showed good results. Given the rarity and clinical heterogeneity of pediatric TAK, multi-center, cross-border cooperation will be beneficial for advancing and improving the diagnosis and treatment of TAK.^54–56

Conclusion

This article reports a case of a male infant with refractory KD who also had KDSS and MAS. Both of these are severe complications of KD, and their simultaneous occurrence is extremely rare, leading to an increase in the rate of IVIG non-response and the incidence of CALs. Although we made an early diagnosis and treated according to the guidelines, the patient still progressed to GCAA, and immune abnormal activation led to TAK. Infants under 6 months of age have a poor response to KD-specific treatment and an increased risk of developing CAA. The specific mechanism behind this deserves in-depth study, in order to provide more effective clinical treatment plans for such patients and improve their prognosis. Infantile TAK deficiency shows no specific clinical manifestations, making it difficult to identify early on. In the later stage, due to irreversible vascular damage, the treatment effect is often poor. We look forward to more clinical and basic research to help us better understand the disease, optimize assessment tools for early identification, and optimize treatment plans and long-term management strategies.

Funding Statement

All phases of this study were supported by the Science and Technology Program of Xinjiang Production and Construction Corps (XPCC), including the Key Research and Development Program of XPCC (Grant No.2023AB018-11), the XPCC Guiding Science and Technology Plan Project (Grant No.2022ZD024), and the Talent Development Fund of XPCC Key Laboratory-Clinical Research Center for Children’s Diseases (GrantNo.CZ001209).

Abbreviations

KD, Kawasaki Disease; CAA, Coronary artery aneurysm; GCAA, Giant coronary artery aneurysm; IVIG Intravenous immunoglobulin; KDSS, Kawasaki disease shock syndrome; MAS, Macrophage activation syndrome; TAK, Takayasu arteritis; GC, Glucocorticoids; IFX, Infliximab; CsA, Cyclosporine A; CRP, C-reactive protein; PCT, Procalcitonin; IL-6, Interleukin-6; BNP, B-type natriuretic peptide; HR, Heart rate; BP, Blood pressure; D, D dimer; LMCA, Left main coronary artery; RCA, Right coronary artery; Hb, Hemoglobin; LAD, Left anterior descending branch; LCX, Left circumflex artery; SF, Ferritin; TNF-α, Tumor necrosis factor-α; NK, cell Natural killer cell; IFN-γ, Interferon-γ; AHA, American Heart Association; CTA, Computed Tomography Angiography; NF-κB, Nuclear Factor kappa-B; ACEIs, Angiotensin converting enzyme inhibitors; JCS/JSCS, Japanese Circulation Society/Japanese Society of Cardiovascular Surgery; MTX, Methotrexate; IL-17, Interleukin-17; Ca²⁺, Calcium ion; NFAT, Nuclear Factor of Activated T Cells; ITPKC, Inositol 1,4,5-trisphosphate 3-kinase C; CASP3, Caspase-3; JAK, Janus Kinase; CALs Coronary artery lesions; KD-MAS, Kawasaki disease complicated with macrophage activation syndrome; PLT, Platelets; FIB, Fibrinogen; sCD25, Soluble interleukin-2 receptor; IFN-α, Interferon-α.

Ethics Declaration

This case report was compiled strictly in accordance with the ethical principles outlined in the Declaration of Helsinki. Formal institutional review board (IRB) review was waived by our hospital’s Ethics Committee, because this manuscript only retrospectively summarizes clinical diagnosis, treatment and follow-up data of a single patient without prospective intervention trials or human biological sample research. Written informed consent for publication of clinical data was obtained from the patient’s legal guardian prior to manuscript submission. All personal identifiable information has been thoroughly de-identified to protect patient privacy.

Ethics and Consent Statement

Written informed consent has been obtained from the patient’s guardian (patient’s mother) to have the case details and any accompanying images published. Institutional approval was not required to publish the case details.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave 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 no competing interests.