Infliximab as a second-line therapy for children with refractory Kawasaki disease: A systematic review and meta-analysis of randomized controlled trials.

AIMS: Infliximab is a tumour necrosis factor-alpha inhibitor that is used to treat children with refractory Kawasaki disease (KD). Our purpose was to evaluate the safety and impact of infliximab versus intravenous immunoglobulins on the incidence of coronary artery aneurysms (CAAs) and treatment resistance in children with refractory KD. METHODS: The Medline/PubMed, Embase, CINAHL, Cochrane Central Register of Controlled Trials and clinical trials registries were searched to December 2021. Randomized controlled trials (RCTs) comparing infliximab as second-line therapy to a second dose of intravenous immunoglobulin (IVIG) in children with refractory KD, reported in abstract or full text, were included. Studies were selected and assessed for risk of bias by two reviewers. Data were extracted and pooled using conventional random-effects meta-analysis. The certainty of evidence was assessed using the GRADE system. RESULTS: A total of 199 participants from four RCTs were included. The pooled risk ratio (RR) for the incidence of treatment resistance in patients treated with infliximab was 0.40 (95% confidence interval [CI] 0.25-0.64). For incidence of CAAs RR was 1.20 (95% CI 0.54-2.63), the incidence of adverse effect "infusion reactions" RR was 0.48, (95% CI 0.12-1.92) and for "infections" RR was 0.55 (95% CI 0.27-1.12). Overall, the GRADE strength of evidence for the primary outcomes was low. Evidence on the duration of fever and inflammatory biomarkers was sparse, heterogeneous and inconclusive. CONCLUSION: Moderate-certainty evidence indicates that infliximab may reduce the incidence of treatment resistance in children with refractory KD. However, the limited strength of evidence warrants further research.

Decreased levels of histidine-rich glycoprotein and increased levels of high-mobility group box 1 are risk factors for refractory Kawasaki disease.

OBJECTIVES: Histidine-rich glycoprotein (HRG) and high-mobility group box 1 (HMGB1) regulate the activation of neutrophils and vascular endothelium. The aim of this study was to quantify HRG and HMGB1 levels in patients with Kawasaki disease (KD) and evaluate their use in the clinical management of KD. METHODS: This study was prospectively performed. Patients were divided into two groups and analysed depending on whether KD symptoms improved by Day 10 of illness. HRG, HMGB1, and other laboratory variables were measured before the first treatment in all cases and, in most cases, afterwards for assessing trends. RESULTS: In this prospective study, we enrolled 60 patients with KD and 48 healthy controls. The HRG level in the KD group was significantly lower than that in the healthy control group; HMGB1 levels showed no obvious differences. In the KD group, HRG levels were negatively correlated with white blood cell and neutrophil counts. In the poor responders and responders groups, a tendency for a decrease in HRG and HMGB1 levels, respectively, was observed from pretreatment to post-treatment. CONCLUSIONS: HRG and HMGB1 are related to the pathogenesis of KD; low HRG and high HMGB1 levels cause resistance against KD treatment.

Plasma exchange and infliximab as a third-line therapy for refractory infantile Kawasaki disease.

BACKGROUND: The treatment for Kawasaki disease (KD) patients refractory to intravenous immunoglobulin (IVIG) therapy is still controversial, and the efficacy of plasma exchange (PE) and infliximab (IFX) therapy for infantile KD is unknown. METHODS: A total of 22 infantile KD patients refractory to initial and additional IVIG, who received either PE or IFX as third-line therapy from October 2008 to February 2020 were examined retrospectively. The patients' sex, age, days of first IVIG, days of PE or IFX therapy, laboratory data preceding PE or IFX therapy, coronary artery lesions (CALs), and adverse effects were investigated. RESULTS: Thirteen patients received PE and nine patients received IFX as the third-line therapy. For the median age at onset, the median days of first IVIG and PE or IFX, and pre-PE or IFX therapy blood test results, there were no significant between-group differences. At admission, and before and after the third-line therapy, there were also no significant differences in occurrence of CALs. The frequency of serious adverse events was significantly higher in the PE group than in the IFX group. CONCLUSIONS: Although there were no significant differences in patient background, blood test results, or frequency of CALs, the frequency of adverse events was significantly higher in the PE group. With the trend of expansion of IFX therapy for KD patients refractory to IVIG, the role of PE as the additional therapy may become more limited.

Usefulness and safety of anakinra in refractory Kawasaki disease complicated by coronary artery aneurysm.

Kawasaki disease is an acute self-limited vasculitis of unknown aetiology. The prognosis depends mainly on coronary damage. There is no consensus regarding optimal adjunctive therapeutics for refractory forms to treatment by intravenous immunoglobulins and corticosteroids. We report the case of an 18-month-old infant with refractory Kawasaki disease complicated by diffuse aneurysms of coronary arteries and successfully treated by anakinra with partial regression of coronary aneurysms.

Utility of ferritin as a predictor of the patients with Kawasaki disease refractory to intravenous immunoglobulin therapy.

OBJECTIVES: The aim of this study is to investigate whether ferritin can be a useful marker for the prediction of the patients with Kawasaki disease (KD) refractory to initial intravenous immunoglobulin (IVIG) therapy. METHODS: This retrospective study enrolled 85 patients with KD hospitalized at Kitakyushu General Hospital during 2010-2014. These patients were divided into IVIG responders (n = 57) and non-responders (n = 28). Serum ferritin levels and the scoring systems for the prediction of non-responsiveness to initial IVIG therapy were compared between these two groups. RESULTS: Serum ferritin level was significantly elevated in non-responders (p = 0.010). The area under the receiver-operating characteristics curve was 0.674, and the sensitivity and specificity in more than 165 ng/ml of serum ferritin level were 70.4% and 63.2%, respectively. In two of the three prediction scoring systems, non-responders also showed significantly higher scores than responders, but many non-responders had low scores of these scoring systems. More than half of the patients with a low score of these scoring systems had high serum ferritin level (≥ 165 ng/ml). CONCLUSIONS: Serum ferritin level might be a useful marker for the prediction of non-responsiveness to initial IVIG therapy and could be an important complementary marker to the prediction scoring systems.

Hibiscus score: Developing and validating a predictive tool for intravenous immunoglobulin treatment resistance in Malaysian children with Kawasaki disease.

BACKGROUND: Children with intravenous immunoglobulin (IVIG) resistant Kawasaki disease (KD) are at higher risk of developing coronary artery (CA) aneurysm. Early identification of high-risk patients using a predictive tool would allow for earlier interventions to prevent cardiac complications. METHODS: Children with KD who were admitted to five selected hospitals in Malaysia between 2008 and 2018 and received 2 g/kg of IVIG within 10 days from the onset of illness were included. Predictors of IVIG resistance in KD were determined using multiple logistic regression analysis. An optimal cut-off point was set using receiver operative characteristic curve and a final multiple logistic regression analysis was performed entering these cut-off points. A new scoring system was constructed. RESULTS: A total of 276 patients were included. IVIG resistance occurred in 9.1 % of them. Total bilirubin [OR 7.37; 95 % CI (2.18, 24.83)], male sex [OR 0.34; 95 % CI (0.10, 1.19)], C-reactive protein (CRP) [OR 0.17; 95 % CI (0.02, 1.38)] and neutrophils [OR 0.25; 95 % CI (0.05, 1.21)] were found to be significant predictors for IVIG resistance. The findings led to the development of a new predictive tool called the Hibiscus score, which scored 1 point each for neutrophils ≥60 %, CRP ≥80 mg/L, and male sex, while total bilirubin ≥9.4 µmol/L scored 2 points. A cut-off point of ≥4 with this prediction score yielded a sensitivity of 78.9 % and specificity of 80.5 %, with area under the curve of 0.835 [95 % CI (0.752, 0.919)]. CA aneurysms occurred in 6.7 % of IVIG responders and 32 % of IVIG-resistant children (p < 0.001). CONCLUSION: The findings suggest that the Hibiscus score has a higher predictive power than the existing scoring systems for IVIG resistance in children with KD in Malaysia. However, external validation is required to enable its use to guide treatment decisions.

An Interesting Case of Refractory Kawasaki Disease With Co-infection.

Kawasaki disease (KD), formerly called mucocutaneous lymph node syndrome, is one of the common vasculitides of childhood. KD most commonly occurs in children over six months up to five years of age, although it can occur in young infants, older children, and adults. Early diagnosis is critical to achieving optimal treatment. We present a case of a three-year-old female child who was admitted with a fever for five days and fulfilled the diagnostic clinical criteria for KD. She was given intravenous immunoglobulin (IVIG) and aspirin. However, the fever persisted, and a urine culture showed the growth of Klebsiella pneumoniae. We started an antibiotic based on her sensitivity. Since fever spikes were not subsiding, she was given a repeat dose of IVIG along with an oral corticosteroid for refractory KD, after which she showed clinical improvement. This case highlighted that refractory KD can coexist with infection.

Protective effect of breastfeeding on Kawasaki disease: A systemic review and meta-analysis.

BACKGROUND: Previous research has indicated a negative correlation between exclusive breastfeeding and the incidence of Kawasaki disease (KD). However, the validation of this discovery through meta-analytical studies has been lacking. Furthermore, uncertainties persist regarding whether breastfeeding reduces the risk of coronary artery lesions (CAL) or resistance to intravenous immunoglobulin (IVIG). METHODS: A systematic exploration of the MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, and ClinicalTrials.gov databases was conducted to identify longitudinal or randomized controlled trials investigating the efficacy of breastfeeding in preventing KD. The primary focus was on the incidence of KD, with secondary emphasis placed on the incidence of CAL and IVIG resistance. Data were pooled using a frequentist-restricted maximum-likelihood random-effects model. RESULTS: Of the 179 potentially eligible studies identified, five (n = 1,982,634) were included. The analysis revealed a significantly lower risk of KD (expressed as odds ratio, with 95% confidence intervals and p-values) in comparisons between exclusive breastfeeding and formula feeding (0.62, 0.43-0.91, p = 0.014), exclusive breastfeeding/partial breastfeeding and formula feeding (0.66, 0.46- 0.96, p = 0.03), and exclusive breastfeeding and partial breastfeeding/formula feeding (0.81, 0.74- 0.90, p < 0.01). However, no significant difference was observed in the risk of developing KD when comparing partial breastfeeding to formula feeding exclusively. Regarding secondary outcomes, no statistically significant difference was found in the risk of CAL or IVIG resistance across any comparison formats. CONCLUSIONS: Our study suggests that breastfeeding correlated with a reduced risk of KD but not with a reduced risk of CAL or IVIG resistance. These findings advocate for the implementation of breastfeeding policies in clinical practice.

Under-Recognized Macrophage Activation Syndrome in Refractory Kawasaki Disease: A Wolf in Sheep's Clothing.

Recognition of macrophage activation syndrome (MAS) in patients with refractory Kawasaki disease (KD) can be challenging. This study aimed to investigate the incidence of MAS in patients with refractory KD and to compare the characteristics of refractory KD and MAS. Medical records of 468 patients diagnosed with KD from January 2010 to December 2019 were retrospectively reviewed. Of the 468 KD patients, 63 were enrolled in the study as a refractory KD group (n = 59) and an MAS group (n = 4). The incidence of MAS was 0.8% (4/468) in patients with KD and 6.3% (4/63) in patients with refractory KD. Compared to the refractory KD group, the MAS group had higher frequencies of incomplete KD, hepatosplenomegaly, third-line treatment, and MAS screening, and showed lower levels of albumin. No significant differences were found in other clinical and laboratory findings. In addition to four patients with MAS, five patients with refractory KD who received third-line treatment showed severe systemic inflammation and organ dysfunction, but only one in five patients underwent MAS screening, including ferritin levels. In conclusion, given the relatively high incidence of MAS in children with refractory KD and the similar phenotype between refractory KD and MAS, we propose that MAS screening should be included in routine laboratory tests for refractory KD.

Combined Single Nucleotide Variants of ORAI1 and BLK in a Child with Refractory Kawasaki Disease.

Kawasaki disease (KD) is a systemic vasculitis with an unknown etiology affecting young children. Although intravenous immunoglobulin (IVIG) plus acetylsalicylic acid is effective in most cases, approximately 10-20% of patients do not respond to this therapy. An 8-month-old boy was admitted to a local hospital with the presumptive diagnosis of KD. He received IVIG twice and four series of methylprednisolone pulse therapy from the third to the tenth day of illness. Despite these treatments, his fever persisted with the development of moderate dilatations of the coronary arteries. A diagnosis of refractory KD was made, and infliximab with oral prednisolone was administered without success. Defervescence was finally achieved by cyclosporine A, an inhibitor of the signaling pathway of the calcineurin/nuclear factor of activated T cells (NFAT). Whole-genome sequencing of his deoxyribonucleic acid samples disclosed two single nucleotide variants (SNVs) in disease-susceptibility genes in Japanese KD patients, ORAI1 (rs3741596) and BLK (rs2254546). In summary, the refractory nature of the present case could be explained by the presence of combined SNVs in susceptibility genes associated with upregulation of the calcineurin/NFAT signaling pathway. It may provide insights for stratifying KD patients based on the SNVs in their susceptibility genes.

Refractory Kawasaki Disease-a Challenge for the Pediatrician.

Kawasaki disease (KD) is an acute, self-limiting febrile illness of childhood associated with vasculitis, mainly of the medium-sized arteries. The clinical significance and impact of this condition arise from its predilection for the coronary arteries. The criteria for classic Kawasaki disease are clearly defined, but many children present with atypical forms, and clinicians need to consider this possibility. Although most diagnosed cases respond to intravenous immunoglobulin (IVIG) and aspirin, some have proven resistant to the standard treatment. This article aims to provide a brief overview of Kawasaki disease, focusing on the resistant/refractory cases, and the treatment options available for such cases.

Do cytokines correlate with refractory Kawasaki disease in children?

BACKGROUND: Kawasaki disease (KD) is a type of pediatric vasculitis. Ten to twenty percent of children with KD do not respond to initial intravenous immunoglobulin (IVIG) treatment which called refractory Kawasaki disease. If untreated, approximately 15-25% of KD patients have complications. Therefore, it is important to predict whether KD is resistant to IVIG at an early stage. The aim of this study was to determine whether cytokines are predictors of refractory KD in children. METHODS: We retrospectively reviewed the medical records of 265 children diagnosed with KD who received IVIG within 10 days of fever onset at Beijing Children's Hospital. Refractory Kawasaki disease was defined as persistent or recrudescent fever beyond 36 h after IVIG. Before IVIG and 3 days after temperature normalization following IVIG treatment, the concentrations of cytokines in the serum including interferon gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), interleukin-6 (IL-6), interleukin-4 (IL-4), interleukin-2 (IL-2) and other conventional inflammatory mediators including white blood cells counts (WBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and albumin were detected. The patients were divided into 2 groups: IVIG-sensitive group and refractory group. RESULTS: Of the 265 patients, 47 (17.7%) were refractory. After treatment with IVIG, the serum levels of IFN-γ, TNF-α, IL-10 and IL-6 in both groups were significantly lower than those before treatment (P < 0.05). Before treatment, the serum levels of IFN-γ, TNF-α, IL-10 and IL-6 in refractory group were significantly higher than those in IVIG-sensitive group (P < 0.05). There were no significant differences in IL-4 or IL-2 levels between the 2 groups. The results of logistic regression analysis showed that IFN-γ, IL-6, fever duration and serum albumin were independent risk factors for refractory KD. The area under the receiver operating characteristic curve (ROC curve) for IFN-γ was 0.781, and the cut-off value for refractory was 7.37 pg/ml, while the area under the ROC curve for IL-6 was 0.837, and the cut-off value for refractory was 70.13 pg/ml. CONCLUSIONS: IFN-γ and IL-6 were independent risk factors for refractory Kawasaki disease in children. KD patients with serum levels of IFN-γ above 7.37 pg/ml and IL-6 above 70.13 pg/ml before treatment were prone to refractory.

Comparison of second-line therapy in IVIg-refractory Kawasaki disease: a systematic review.

BACKGROUND: Evidence remains contradictory regarding second-line therapy in patients with Kawasaki disease (KD) refractory to initial intravenous immunoglobulin (IVIg). The objective of this study aims to evaluate the efficacy and safety of three treatments [i.e. a second IVIg infusion, methylprednisolone (IVMP), and infliximab (IFX)] in patients with refractory KD. METHODS: A systematic search of PubMed, Embase, Cochrane, and ClinicalTrials.gov using predefined MeSH terms was performed from 1990 through 2017. Relevance screening was performed by two independent reviewers. Inclusion criteria included English-only, original clinical data. Eight studies met the inclusion criteria. Fever resolution, coronary lesions, and adverse event outcomes were extracted and pooled for analysis. RESULTS: Of the 388 patients included from the 8 studies analyzed, a majority received a second IVIg dose (n = 263, 68%). Fever resolution was comparable between IVIg (72%) and IVMP (73%). IFX (88%) significantly increased fever resolution by approximately 20% compared to IVIg re-dose (RR 1.2; [95% CI: 1.1-1.4]; p = 0.03) and IVMP (RR 1.2; [95% CI: 1.0-1.5]; p = 0.04). Clinical significance of differences in coronary outcomes remains unclear. CONCLUSIONS: This combined analysis was limited due to variability in design and data reporting methods between the studies and risk of bias. In the absence of a clinical trial, IFX monotherapy as second-line treatment should be considered in patients who fail to respond to initial IVIg. This conclusion is based on a systematic review of the literature with pooled outcome data analysis suggesting IFX is more effective in fever resolution compared to a second IVIg dose and IVMP.

Kawasaki disease: etiopathogenesis and novel treatment strategies.

INTRODUCTION: Kawasaki disease is an acute febrile systemic vasculitis that predominantly occurs in children below five years of age. Its etiopathogenesis is still not clear, but it is thought to be a complex interplay of genetic factors, infections and immunity. Areas covered: This review article discusses in detail Kawasaki disease, with particular emphasis on the recent updates on its pathogenesis and upcoming alternate treatment options. Though self-limiting in many cases, it can lead to severe complications like coronary artery aneurysms and thrombo-embolic occlusions, and hence requires early diagnosis and urgent attention to avoid them. Intravenous immunoglobulin (IVIG) with or without aspirin has remained the sole treatment option for these cases, but 10-15% cases develop resistance to this treatment. Expert commentary: There is a need to develop additional treatment strategies for children with Kawasaki disease. Targeting different steps of pathogenesis could provide us with alternate therapeutic options.

Adjunctive therapies for Kawasaki disease.

Kawasaki disease (KD) is the most common cause of acquired heart disease in children in developed countries.(1,2) The primary goal of treatment is to prevent coronary artery aneurysms (CAA). Between 10 and 20% of KD patients are resistant to treatment with intravenous immunoglobulin (IVIG) and have an almost nine-fold increased risk of developing CAA.(3) In addition, approximately 80-90% of patients who go on to develop CAA have abnormal coronary artery dimensions on their first echocardiogram and can therefore be identified as high-risk patients. These two subsets of KD patients are candidates for adjunctive therapy, in addition to IVIG. Understanding the mechanism of action of IVIG may provide insight into IVIG resistance and guidance for choosing adjunctive therapies in KD. Therapeutic options in the treatment of refractory KD and patients with early CAA include additional IVIG, glucocorticoids, tumor necrosis factor inhibitors, calcineurin inhibitors and interleukin-1 (IL-1) blockers.(3-10) Animal studies suggest that the anti-inflammatory properties of statins may also be beneficial in blocking CAA progression.(6) It is unlikely that these therapies will be studied in large, randomized controlled trials in the future due to required sample size and funding constraints. Thus, data from the research laboratory may be helpful in guiding selection of the most promising adjunctive therapies.

Demographic and treatment variability of refractory kawasaki disease: a multicenter analysis from 2005 to 2009.

OBJECTIVE: Approximately 10% to 15% of Kawasaki disease (KD) is refractory to treatment with initial intravenous immunoglobulin (IVIG). However, there is no consensus on pharmacologic treatment of refractory KD (rKD). Demographic characteristics of patients with rKD and regional variability in their treatment in the United States have not been reported on a large scale. The goal of this study was to describe the demographic and treatment variability in rKD by using a large multi-institutional database. METHODS: Data were obtained for patients with KD from January 2005 to June 2009 by using the Pediatric Health Information System. Patients who received a single dose of IVIG were labeled as having standard KD (sKD) and those who required additional medications were labeled as having rKD. RESULTS: Of the 5633 patients studied, 4818 (85.5%) received 1 dose of IVIG (sKD) and 815 (14.5%) received >1 medication (rKD). Median age was 30 months (interquartile range: 14-53) and 30 months (interquartile range: 15-54) for rKD and sKD patients, respectively (P= .438). No significant change was noted in the gender or ethnic distribution of patients between rKD and sKD groups. Seasonal distribution of rKD was comparable to sKD. IVIG was the most common (64.5%) initial medication chosen to treat rKD, followed by methylprednisolone (27.1%) and infliximab (8.3%); however, there was significant regional variability. Of patients with rKD, 81% required only 1 additional medication (after the initial IVIG) for treatment. CONCLUSIONS: Patients with rKD have similar age, gender, ethnic, and seasonal distribution as sKD patients. IVIG is the most common initial medication chosen to treat rKD; however, there is regional variation.