Orthostatic and Exercise Effects in Children Years After Kawasaki Disease.

The long-term orthostatic and/or exercise hemodynamic effects in children years after Kawasaki disease (KD) were studied using clinical data from the treadmill exercise test (TMET). Heart rate (HR) and blood pressures (BPs) recorded in TMET were compared between two age, gender, and body scale-matched groups of patients with and without a history of KD. The KD group included 60 patients (9.8 ± 2.7 years old) 6.6 ± 2.6 years after KD without coronary arterial aneurysm. The non-KD group included 60 children (10.2 ± 2.7 years old) with other diagnoses. The exercise tolerance in TMET was not statistically different between the two groups. The KD group had a faster HR on standing than the non-KD group by 8.6% (101.5 ± 12.2 vs. 93.5 ± 15.9 bpm, respectively; P < 0.01), suggesting weaker and/or retarded orthostatic vasoconstriction. The pulse pressure was largely augmented above the 4th stage beyond 160 mmHg in 10.6 versus 0% (5 vs. 0) of the KD and non-KD groups (P < 0.05), respectively, while HR and BPs were not significantly different through exercise stages between the two groups. The KD group also showed a faster HR recovery five minutes after exercise than the non-KD group, by 5.7% (108.0 ± 11.6 vs. 102.2 ± 14.2 bpm, respectively; P < 0.05). Our results might indicate long-term subclinical impacts on the vascular tonus of children years after the disease that have not been recognized in previous studies.

Entire FGF12 duplication by complex chromosomal rearrangements associated with West syndrome.

Complex rearrangements of chromosomes 3 and 9 were found in a patient presenting with severe epilepsy, developmental delay, dysmorphic facial features, and skeletal abnormalities. Molecular cytogenetic analysis revealed 46,XX.ish der(9)(3qter→3q28::9p21.1→9p22.3::9p22.3→9qter)(RP11-368G14+,RP11-299O8-,RP11-905L2++,RP11-775E6++). Her dysmorphic features are consistent with 3q29 microduplication syndrome and inv dup del(9p). Trio-based WES of the patient revealed no pathogenic single nucleotide variants causing epilepsy, but confirmed a 3q28q29 duplication involving FGF12, which encodes fibroblast growth factor 12. FGF12 positively regulates the activity of voltage-gated sodium channels. Recently, only one recurrent gain-of-function variant [NM_021032.4:c.341G>A:p.(Arg114His)] in FGF12 was found in a total of 10 patients with severe early-onset epilepsy. We propose that the patient's entire FGF12 duplication may be analogous to the gain-of-function variant in FGF12 in the epileptic phenotype of this patient.

Effect of i.v. immunoglobulin in the first 4 days of illness in Kawasaki disease.

BACKGROUND: Although early treatment of Kawasaki disease (KD) with i.v. immunoglobulin (IVIG) is expected to prevent coronary artery abnormalities, the effectiveness of IVIG by day 4 of illness remains to be determined. METHODS: This was a multi-institutional, retrospective cohort study. Patients diagnosed with KD at ≤4 days of illness were divided into two groups: those who received initial IVIG before and on day 5 of illness. Baseline characteristics were adjusted using propensity scores. The primary endpoint was the need for additional treatment. RESULTS: Of 339 patients diagnosed with KD by day 4, 181 and 158 received IVIG before and on day 5 of illness, respectively. Patients in the early treatment group had more adverse prognostic factors: infancy, early onset of the principal symptoms, and abnormal laboratory data. We thus adjusted baseline characteristics before treatment decisions using propensity scores. Propensity score matching of the two groups yielded 100 observations. More patients required additional treatment in the matched early treatment group: 37% vs 24% (adjusted OR, 1.7; 95%CI: 1.06-2.8; P = 0.047). The difference was more pronounced for risk of relapse after initial resolution of fever: 14% vs 5.0% (adjusted OR, 3.2; 95%CI: 1.3-7.7; P = 0.02). The risk of coronary artery lesion did not differ significantly. CONCLUSIONS: IVIG treatment by day 4 of illness is associated with the requirement for additional treatment even after adjustment of baseline characteristics. Increased resistance to IVIG when given by day 4 should be considered in order to improve the treatment regimen for early-diagnosed KD.

Fever pattern and C-reactive protein predict response to rescue therapy in Kawasaki disease.

BACKGROUND: Evidence to guide rescue therapy in refractory Kawasaki disease (KD) is lacking. The aim of this study was to determine the most important variables in predicting non-response to rescue therapy in refractory KD. METHODS: We retrospectively analyzed 171 patients diagnosed with refractory KD resistant to initial i.v. immunoglobulin (IVIG). Participants received rescue therapy consisting of IVIG monotherapy or IVIG plus prednisolone. Characteristics and laboratory variables were compared between rescue therapy non-responders and responders. Multivariate logistic regression analysis was performed to determine the independent predictors of non-response to rescue therapy. RESULTS: Among the 171 participants, 54 (31.6%) were non-responders to rescue therapy. On univariate analysis, fever pattern after initial IVIG, day of illness at rescue therapy, rescue therapy regimen and six laboratory variables (pre-IVIG sodium, C-reactive protein [CRP]; post-IVIG white blood cell count, platelet count, sodium, CRP) were useful in discriminating between non-responders and responders. These nine variables were included in multivariate logistic regression analysis. Persistent fever after initial IVIG (aOR, 2.39; 95%CI: 1.07-5.37) and post-IVIG CRP (aOR, 1.09; 95%CI: 1.02-1.17, per 1 mg/dL increase) were identified as independent predictors of non-response to rescue therapy. IVIG rescue monotherapy (aOR, 3.05; 95%CI: 1.05-8.84) also predicted non-response after adjusting for fever pattern and post-IVIG CRP. CONCLUSIONS: Persistent fever and elevated CRP after initial IVIG are predictive of non-response to rescue therapy for refractory KD. For patients at high risk of non-response, IVIG plus prednisolone, or even further intensified rescue therapy regimens may be preferable.

Two Cases of Cardiovascular Adverse Events Following Subcutaneous Vosoritide Injection in Early Infancy.

Achondroplasia, characterized by short stature and skeletal abnormalities, is caused by a gain-of-function variant in the fibroblast growth factor receptor 3 gene. Vosoritide, a C-type natriuretic peptide analog, is an emerging treatment for achondroplasia that functions by promoting endochondral ossification. Vosoritide was approved for the treatment of achondroplasia in Europe and the United States in 2021, and in Japan, the following year. However, vosoritide is associated with a risk of hypotension and vomiting after subcutaneous injection due to its vasodilating effect. Herein, we present two cases of cardiovascular adverse events in infants following vosoritide injection. Case 1 involved a one-month-old female infant with achondroplasia who received the first subcutaneous injection of vosoritide 30 minutes after her last formula intake. Following injection, she developed transient symptomatic hypotension accompanied by vomiting. Although established guidelines recommend that injections be administered after approximately 30 minutes (Europe/Japan) or within one hour (USA) following the last feeding, an extended interval of 1.5 to two hours was required to prevent hypotension-associated vomiting. Case 2 involved a three-month-old female infant with achondroplasia. The first subcutaneous vosoritide injection was administered four hours after the last formula intake, and she subsequently developed prolonged compensated shock with marked tachycardia requiring intervention, including repetitive bolus saline injection. These cases indicate the need to monitor patients for cardiovascular adverse events following subcutaneous injection of vosoritide in early infancy.

Maculopapular rash in the convalescent phase of Kawasaki disease: case series and literature review.

UNLABELLED: Intravenous immunoglobulin (IVIG) is currently the standard treatment for Kawasaki disease (KD). Although IVIG therapy is generally well tolerated, several minor adverse reactions have been reported. We report a patient with KD treated with IVIG, who developed a cutaneous reaction in the convalescent phase (approximately 10 days after therapy). We identified seven additional KD cases with a similar presentation, accounting for 9.3 % of KD patients at our hospital. We performed a literature review and found that a maculopapular rash could be observed approximately 10 days after IVIG treatment, in patients with and those without KD. CONCLUSION: Maculopapular rash can occur in nearly 10 % of IVIG-treated children with KD in our cohort, approximately 10 days after treatment. A delayed-onset adverse event of IVIG could be a causative etiology of this unrecognized eruption.

Intussusception secondary to anaphylactic reaction to salmon roe (ikura).

Anaphylactic food reaction often involves gastrointestinal symptoms, such as vomiting and abdominal pain, but to date, there have been no publications documenting the association between food hypersensitivity and intussusception. Herein is reported the case of a 2-year-old boy with intussusception accompanied by anaphylactic food reaction. The patient without known allergies complained of severe abdominal pain following ingestion of salmon roe for the first time. Dyspnea, wheezing and generalized urticaria also developed. Subsequently, he had stools containing jelly-like blood with mucus. At hospital arrival, physical examination identified an abdominal mass in the right lower quadrant; imaging confirmed the diagnosis of colo-colic intussusception. This patient was successfully treated with enema and no pathological findings were identified via radiology. Laboratory results supported the presence of IgE-mediated allergy to salmon roe in the present patient. To our knowledge, this is the first report to describe the possible association between intussusception and a hypersensitive food reaction.

Utility of Color Doppler Ultrasonography in Monitoring of a Free Jejunal Flap.

OBJECTIVES: External color Doppler ultrasonography is reported to be a useful monitoring technique that is simple and noninvasive; however, details of imaging of the transferred free jejunal flap have not been reported. We reviewed our experience using external color Doppler ultrasonography to monitor a transferred free jejunal flap and examined its utility. STUDY DESIGN: Retrospective study. METHODS: Subjects were 43 patients who underwent total pharyngolaryngectomy, reconstruction with a free jejunal flap, and color Doppler ultrasonography before, during, and after surgery between September 2017 and December 2021. RESULTS: During surgery, arterial thrombosis was detected up to 100% with the loss of continuous color signals in the entire circumference. After surgery, the positive predictive value was 100% for each of wiggling movement, dynamic intestinal movement, and continuous color signals in the entire circumference on color Doppler ultrasonography for detecting flap viability. Their negative predictive value was 100%, 7.1%, and 50%, respectively. CONCLUSIONS: During surgery, the continuous color signals in the entire circumference sign were useful with 100% negative predictive value for detecting the arterial thrombosis. After surgery, the wiggling movement sign very was useful with 100% positive and negative predictive values, enabling salvage surgery to be performed soon after detection of flap failure. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:3361-3369, 2023.

Genotyping of Mycoplasma pneumoniae strains isolated in Japan during 2019 and 2020: spread of p1 gene type 2c and 2j variant strains.

We characterized 118 Mycoplasma pneumoniae strains isolated from three areas of Japan (Saitama, Kanagawa, and Osaka) during the period of 2019 and 2020. Genotyping of the p1 gene in these strains revealed that 29 of them were type 1 lineage (29/118, 24.6%), while 89 were type 2 lineage (89/118, 75.4%), thereby indicating that type 2 lineage was dominant in this period. The most prevalent variant of type 2 lineage was type 2c (57/89, 64%), while the second-most was type 2j, a novel variant identified in this study (30/89, 33.7%). Type 2j p1 is similar to type 2 g p1, but cannot be distinguished from reference type 2 (classical type 2) using the standard polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP) with HaeIII digestion. Thus, we used MboI digestion in the PCR-RFLP analysis and re-examined the data from previous genotyping studies as well. This revealed that most strains reported as classical type 2 after 2010 in our studies were actually type 2j. The revised genotyping data showed that the type 2c and 2j strains have been spreading in recent years and were the most prevalent variants in Japan during the time-period of 2019 and 2020. We also analyzed the macrolide-resistance (MR) mutations in the 118 strains. MR mutations in the 23S rRNA gene were detected in 29 of these strains (29/118, 24.6%). The MR rate of type 1 lineage (14/29, 48.3%) was still higher than that of type 2 lineage (15/89, 16.9%); however, the MR rate of type 1 lineage was lower than that found in previous reports published in the 2010s, while that of type 2 lineage strains was slightly higher. Thus, there is a need for continuous surveillance of the p1 genotype and MR rate of M. pneumoniae clinical strains, to better understand the epidemiology and variant evolution of this pathogen, although M. pneumoniae pneumonia cases have decreased significantly since the COVID-19 pandemic.

Severe pallid breath-holding spells treated with low-dose theophylline.

BACKGROUND: The medical treatment for severe pallid breath-holding spells accompanied with severe bradycardia or transient cardiac arrest is controversial. Although various medications have been reported to be effective, patients treated with pacemaker insertion are not always evaluated for pharmacological therapy beforehand. CASE REPORT: A 9-month-old boy developed pallid breath-holding spells. At 15 months of age, a Holter electrocardiogram revealed 12 s of asystole during a breath-holding spell. Treatment with low-dose theophylline sustained-release dry syrup (5.3 mg/kg/day) led to complete control of the spells. The peak concentration of theophylline was 4.4 µg/mL which was below the therapeutic range for bronchial asthma. When he turned 3 years and 5 months of age, theophylline treatment was discontinued without recurrence of pallid breath-holding spells. DISCUSSION: Theophylline is now infrequently used to treat pediatric bronchial asthma due to its limited effect coupled with its side effects, which include headache, digestive symptoms, and theophylline-associated convulsions. The effectiveness of theophylline as a treatment for pallid breath-holding spells has been reported in several reports. In our case, the theophylline dosage was approximately half the amount described in previous reports. CONCLUSIONS: In this case, low-dose theophylline was adequate in controlling the pallid breath-holding spells. Because theophylline-associated seizures are a major concern, we suggest an evaluation of low-dose theophylline for treating patients with severe pallid breath-holding spells without febrile convulsions or epilepsy before proceeding with permanent pacemaker insertion. Further development of preventive strategies for theophylline-associated seizures and characterization of patients who respond well to theophylline treatment is required.

Relationship between post-IVIG IgG levels and clinical outcomes in Kawasaki disease patients: new insight into the mechanism of action of IVIG.

INTRODUCTION/OBJECTIVES: The dosing of intravenous immunoglobulin (IVIG) therapy for Kawasaki disease (KD) has been a matter of debate for decades, with recent studies implicating that larger doses lead to better outcomes. Despite this, few have investigated post-IVIG infusion immunoglobulin G (IgG) levels in relation to outcomes of KD such as response to IVIG and development of coronary artery abnormalities (CAAs). The present study investigated how varying levels of post-infusion IgG affected these outcomes. METHOD: We collected demographic and laboratory data, including post-infusion IgG, from children with KD who were admitted to six hospitals in Japan between 2006 and 2012. We conducted multivariate analyses to examine the relationship between independent variables and non-response to IVIG and development of CAAs. We used random forest, a decision tree-based machine learning tool, to investigate the marginal effect of varying post-infusion IgG levels on non-response to IVIG and development of CAAs. RESULTS: Of 456 patients included in the study, 130 (28.5%) were non-responders and 38 (8.3%) developed CAAs. Sodium, post-infusion IgG, and AST were significantly associated with non-response. Post-infusion IgG and sodium were significantly associated with CAA development. The random forest plots revealed a decrease in non-response and CAA rates with increasing post-infusion IgG until post-infusion IgG was near the median (2821 mg/dL), after which the non-response and CAA rates leveled off. CONCLUSIONS: Greater post-infusion IgG is associated with better response to IVIG and decreased CAA development in KD patients, but this effect levels off at post-infusion IgG levels greater than the median. Key points • Though previous studies have shown that post-intravenous immunoglobulin (IVIG) infusion immunoglobulin G (IgG) is associated with non-response to IVIG therapy and coronary artery abnormality (CAA) development in Kawasaki disease (KD) patients, no study has investigated the relationship between varying levels of post-infusion IgG and these clinical outcomes. • Our study showed that non-response to IVIG therapy and CAA development in Kawasaki disease patients follow a decreasing trend with increasing post-infusion IgG at post-infusion IgG levels below the median. • At values of post-infusion IgG greater than the median, non-response and CAA development rates remain relatively constant with increasing post-infusion IgG. • Our study suggests that when post-infusion IgG is greater than the median, IgG may have fully bound to the therapeutic targets of KD, and in these patients, there may be limited benefit in administering additional IVIG.

Periodic Genotype Shifts in Clinically Prevalent Mycoplasma pneumoniae Strains in Japan.

Nationwide increases in Mycoplasma pneumoniae pneumonia cases in Japan were reported in 2011, 2012, 2015, and 2016. In this study, we isolated 554 M. pneumoniae strains in 4 areas in Japan (Kanagawa, Okayama, Osaka, and Saitama) between 2006 and 2019, and performed genotyping analysis. More than 80% of the strains isolated in 2011 and 2012 harbored type 1 p1 adhesin gene; however, strains harboring type 2 or its variant p1 gene increased in 2015 and 2016 and dominated after 2017. These findings suggested that a shift in the prevalent genotype of M. pneumoniae clinical strains occurred recently in Japan. More than 90% of the type 1 strains isolated after 2010 harbored macrolide-resistance mutations in their 23S rRNA gene, whereas most type 2 lineage strains had no such mutations. Consequently, the increase in type 2 lineage strains in Japan has reduced the macrolide resistance rate of clinical M. pneumoniae strains. During this analysis, we also identified M. pneumoniae strains carrying a novel variant type 1 p1 gene, and we classified it as type 1b. We then sequenced the genomes of 81 selected M. pneumoniae strains that we collected between 1976 and 2017 in Japan, and compared them with 156 M. pneumoniae genomes deposited in public databases to provide insights into the interpretation of M. pneumoniae genotyping methods, including p1 typing, multiple-locus variable-number tandem repeat analysis (MLVA), multi-locus sequence typing (MLST), and typing by 8 single-nucleotide polymorphism markers (SNP-8). As expected, p1 typing, MLST, and SNP-8 results exhibited good correlation with whole-genome SNP analysis results in terms of phylogenetic relationships; however, MLVA typing results were less comparable to those of the other methods. MLVA may be useful for the discrimination of strains derived from a single outbreak within a limited area; however, is not reliable for classification of strains collected from distantly separated areas at different time points. This study showed the usefulness of genome-based comparison of M. pneumoniae for molecular epidemiology. Genome sequencing of more strains will improve our understanding of global propagation routes of this pathogen and evolutionary aspects of M. pneumoniae strains.

Novel Risk Assessment Tool for Immunoglobulin Resistance in Kawasaki Disease: Application Using a Random Forest Classifier.

BACKGROUND: Resistance to intravenous immunoglobulin (IVIG) therapy is a risk factor for coronary lesions in patients with Kawasaki disease (KD). Risk-adjusted initial therapy may improve coronary outcome in KD, but identification of high risk patients remains a challenge. This study aimed to develop a new risk assessment tool for IVIG resistance using advanced statistical techniques. METHODS: Data were retrospectively collected from KD patients receiving IVIG therapy, including demographic characteristics, signs and symptoms of KD and laboratory results. A random forest (RF) classifier, a tree-based machine learning technique, was applied to these data. The correlation between each variable and risk of IVIG resistance was estimated. RESULTS: Data were obtained from 767 patients with KD, including 170 (22.1%) who were refractory to initial IVIG therapy. The predictive tool based on the RF algorithm had an area under the receiver operating characteristic curve of 0.916, a sensitivity of 79.7% and a specificity of 87.3%. Its misclassification rate in the general patient population was estimated to be 15.5%. RF also identified markers related to IVIG resistance such as abnormal liver markers and percentage neutrophils, displaying relationships between these markers and predicted risk. CONCLUSIONS: The RF classifier reliably identified KD patients at high risk for IVIG resistance, presenting clinical markers relevant to treatment failure. Evaluation in other patient populations is required to determine whether this risk assessment tool relying on RF has clinical value.

A recurrent de novo FAM111A mutation causes Kenny-Caffey syndrome type 2.

Kenny-Caffey syndrome (KCS) is a rare dysmorphologic syndrome characterized by proportionate short stature, cortical thickening and medullary stenosis of tubular bones, delayed closure of anterior fontanelle, eye abnormalities, and hypoparathyroidism. The autosomal dominant form of KCS (KCS type 2 [KCS2]) is distinguished from the autosomal recessive form of KCS (KCS type 1 [KCS1]), which is caused by mutations of the tubulin-folding cofactor E (TBCE) gene, by the absence of mental retardation. In this study, we recruited four unrelated Japanese patients with typical sporadic KCS2, and performed exome sequencing in three patients and their parents to elucidate the molecular basis of KCS2. The possible candidate genes were explored by a de novo mutation detection method. A single gene, FAM111A (NM_001142519.1), was shared among three families. An identical missense mutation, R569H, was heterozygously detected in all three patients but not in the unaffected family members. This mutation was also found in an additional unrelated patient. These findings are in accordance with those of a recent independent report by a Swiss group that KCS2 is caused by a de novo mutation of FAM111A, and R569H is a hot spot mutation for KCS2. Although the function of FAM111A is not known, this study would provide evidence that FAM111A is a key molecule for normal bone development, height gain, and parathyroid hormone development and/or regulation.

Genotype-phenotype correlations in alternating hemiplegia of childhood.

OBJECTIVE: Clinical severity of alternating hemiplegia of childhood (AHC) is extremely variable. To investigate genotype-phenotype correlations in AHC, we analyzed the clinical information and ATP1A3 mutations in patients with AHC. METHODS: Thirty-five Japanese patients who were clinically diagnosed with AHC participated in this study. ATP1A3 mutations were analyzed using Sanger sequencing. Detailed clinical information was collected from family members of patients with AHC and clinicians responsible for their care. RESULTS: Gene analysis revealed 33 patients with de novo heterozygous missense mutations of ATP1A3: Glu815Lys in 12 cases (36%), Asp801Asn in 10 cases (30%), and other missense mutations in 11 cases. Clinical information was compared among the Glu815Lys, Asp801Asn, and other mutation groups. Statistical analysis revealed significant differences in the history of neonatal onset, gross motor level, status epilepticus, and respiratory paralysis in the Glu815Lys group compared with the other groups. In addition, 8 patients who did not receive flunarizine had severe motor deteriorations. CONCLUSIONS: The Glu815Lys genotype appears to be associated with the most severe AHC phenotype. Although AHC is not generally seen as a progressive disorder, it should be considered a disorder that deteriorates abruptly or in a stepwise fashion, particularly in patients with the Glu815Lys mutation.