Analysis of Cytokine Profiles in Pediatric Myocarditis Multicenter Study.

Acute myocarditis (AM) is an inflammatory disease of the heart muscle that can progress to fulminant myocarditis (FM), a severe and life-threatening condition. The cytokine profile of myocarditis in children, especially in relation to fulminant myocarditis, is not well understood. This study aims to evaluate the cytokine profiles of acute and fulminant myocarditis in children. Pediatric patients diagnosed with myocarditis were included in the study. Cytokine levels were measured using a multiplexed fluorescent bead-based immunoassay. Statistical analysis was performed to compare patient characteristics and cytokine levels between FM, AM, and healthy control (HC) groups. Principal component analysis (PCA) was applied to cytokine groups that were independent among the FM, AM, and HC groups. The study included 22 patients with FM and 14 with AM patients. We identified four cytokines that were significantly higher in the FM group compared to the AM group: IL1-RA (p = 0.002), IL-8 (p = 0.005), IL-10 (p = 0.011), and IL-15 (p = 0.005). IL-4 was significantly higher in the AM group compared to FM and HC groups (p = 0.006 and 0.0015). PDGF-AA, and VEGF-A were significantly lower in the FM group than in the AM group (p = 0.013 and <0.001). Similar results were obtained in PCA. Cytokine profiles might be used to differentiate pediatric FM from AM, stratify severity, and predict prognosis. The targeted therapy that works individual cytokines might provide a potential treatment for reducing the onset of the FM and calming the condition, and further studies are needed.

The electrophysiological index can effectively predict subsequent coronary artery aneurysm in children with Kawasaki disease.

Objectives: The Gunma score is used to predict the severity of Kawasaki disease (KD), including coronary artery aneurysm (CAA) as a cardiac complication, in Japan. Additionally, the characteristic ratio of ventricular repolarization (T-peak to T-end interval to QT interval [Tp-e/QT]) on a surface electrocardiogram reflects myocardial inflammation. This study aimed to determine whether the Tp-e/QT can be used to predict CAA in children with KD. Methods: We analyzed chest surface electrocardiograms of 112 children with KD before receiving intravenous immunoglobulin therapy using available software (QTD; Fukuda Denshi, Tokyo, Japan). Results: The Tp-e/QT (lead V5) was positively correlated with the Gunma score (r=0.352, p<0.001). The Tp-e/QT was larger in patients with CAA (residual CAA at 1 month after onset) than in those without CAA (0.314±0.026 versus 0.253±0.044, p=0.003). A receiver operating characteristic curve analysis was performed to assess whether the Gunma score and Tp-e/QT could predict subsequent CAA. The area under the curve of the Gunma score was 0.719 with the cutoff set at 5 points. The area under the curve of the Tp-e/QT was 0.892 with a cutoff value of 0.299. The fit of the prediction models to the observed probability was tested by the Hosmer-Lemeshow test with calibration plots using Locally weighted scatterplot smoothing (LOESS) fit. The Gunma score (p=0.95) and Tp-e/QT (p=0.95) showed a good fit. Conclusions: The Tp-e/QT is a useful biomarker in predicting coronary aneurysm complications in KD.

Case report: A case of severe retropharyngeal edema after COVID-19 successfully treated with intravenous immunoglobulin.

Multisystem inflammatory syndrome in children (MIS-C) has been widely reported, mainly in Western countries. The clinical features of MIS-C and Kawasaki disease are similar. The latter is common in Asian countries, including Japan. Meanwhile, the incidence of MIS-C seems to be low in Japan. Retropharyngeal edema is relatively common in older patients with Kawasaki disease and has been reported in a few patients with MIS-C. We describe a case of severe retropharyngeal edema after coronavirus disease 2019 (COVID-19) that improved quickly with high-dose of intravenous immunoglobulin treatment. Onset of retropharyngeal edema was 3 weeks after COVID-19. The patient received appropriate intravenous antibiotics for 5 days, but his symptoms worsened. Therefore, we suspected that his retropharyngeal edema was caused by suspected MIS-C even though he did not have the typical clinical symptoms of suspected MIS-C such as gastrointestinal symptoms and shock. Retropharyngeal edema was refractory to antibiotic therapy but lessened quickly with high-dose immunoglobulin therapy, without other typical clinical manifestations of MIS-C, suggesting that early immunoglobulin therapy might prevent the progression of MIS-C.

Dexmedetomidine versus fentanyl for sedation in extremely preterm infants.

BACKGROUND: Few studies have compared the efficacy and complications of dexmedetomidine (DEX) and fentanyl (FEN) in extremely preterm infants. METHODS: We conducted a single-institution, retrospective controlled before and after study of preterm infants before 28 weeks of gestation admitted between April 2010 and December 2018 to compare the complications and efficacy of DEX and FEN for preterm infants. Patients were administered FEN prior to 2015 and DEX after 2015 as the first-line sedative. A composite outcome of death during hospitalization and developmental quotient (DQ) < 70 at a corrected age of 3 years was compared as the primary outcome. Secondary outcomes including postmenstrual weeks at extubation, days of age when full enteral feeding was achieved and additional sedation by phenobarbital (PB) were compared. RESULTS: Sixty-six infants were enrolled into the study. The only perinatal factor that differed between the FEN (n = 33) and DEX (n = 33) groups was weeks of gestation. The composite outcome of death and DQ < 70 at a corrected age of 3 years were not significantly different. Postmenstrual weeks at extubation did not significantly differ between groups after adjustment for weeks of gestation and being small for gestational age. On the other hand, full feeding was significantly prolonged by DEX (p = 0.031). Additional sedation was less common in the DEX group (p = 0.044). CONCLUSION: The composite outcome of death and DQ < 70 at a corrected age of 3 years were not significantly different by DEX or FEN for primary sedation. Prospective randomized controlled trials should examine the long-term effects on development.

QT Variability Index is Correlated with Autonomic Nerve Activity in Healthy Children.

The QT variability index (QTVI), which measures the instability of myocardial repolarization, is usually calculated from a single electrocardiogram (ECG) recording and can be easily applied in children. It is well known that frequency analysis of heart rate variability (HRV) can detect autonomic balance, but it is not clear whether QTVI is correlated with autonomic tone. Therefore, we evaluated the association between QTVI and HRV to elucidate whether QTVI is correlated with autonomic nerve activity. Apparently, healthy 320 children aged 0-7 years who visited Fujita Health University Hospital for heart checkup examinations were included. The RR and QT intervals of 60 continuous heart beats were measured, and the QTVI was calculated using the formula of Berger et al. Frequency analysis of HRV, including the QTVI analysis region, was conducted for 2 min and the ratio of low-frequency (LF) components to high-frequency (HF) components (LF/HF) and HF/(LF + HF) ratio was calculated as indicators of autonomic nerve activity. Then, the correlations between QTVI and these parameters were assessed. QTVI showed a significant positive correlation with LF/HF ratio (r = 0.45, p < 0.001) and negative correlation with HF/(LF + HF) ratio (r = -0.429, p < 0.001). These correlations remained after adjustment for sex and age. QTVI, which is calculated from non-invasive ECG and can detect abnormal myocardial repolarization, is significantly correlated with frequency analysis of HRV parameters. QTVI reflects autonomic nerve balance in children.

Maturation of the QT Variability Index is Impaired in Preterm Infants.

Reduced heart rate (HR) variability in preterm infants compared with full-term infants suggests that autonomic cardiac control is developmentally delayed. However, the association between developmental changes in myocardial repolarization and gestational age remains unknown. This study investigated the association between the myocardial repolarization lability index, namely the QT variability index (QTVI) = log10 [(QTv/QTm2)/(HRv/HRm2)], and the perinatal profile of healthy 1-month-old infants. We included 209 infants (143 boys and 87 girls; mean gestational weeks at birth, 38.6 ± 1.7) who were born in university hospitals between 2014 and 2015 without apparent cardiac disease. We compared the ECG variability indices in 28 infants born before 37 gestational weeks (mean gestational weeks at birth, 35.6 ± 1.1 as preterm) and 181 infants born at the average number of gestational weeks (mean gestational weeks at birth, 38.8 ± 1.1 as controls). There was a negative correlation between the QTVI and gestational weeks (r = - 0.460, p = 0.035). QTVI values in preterm infants were larger than those in the controls (0.01 ± 0.50 vs. -0.26 ± 0.48, p = 0.023). In conclusion, the QTVI is negatively correlated with gestational age. The QTVI can serve as an index of the maturity of the cardiac autonomic nervous system and myocardial depolarization.

Case report of severe myocarditis in an immunocompromised child with Respiratory Syncytial Virus infection.

BACKGROUND: Respiratory syncytial virus (RSV) infection is common and may be severe among patients with preexisting cardiac anomalies, but direct involvement of myocardial damage is not common in those patients. Additionally, myocardial involvement has been rarely described among immune compromised children. CASE PRESENTATION: A 4-year-old girl with acute lymphoblastic leukemia who received maintenance chemotherapy in an outpatient clinic developed systemic inflammatory response syndrome. RSV infection was confirmed by a positive rapid antigen test and serological assay. Subsequently, she was diagnosed with severe myocarditis caused by RSV infection, which was diagnosed by abnormal findings of cardiac echography and ECG and elevated biomarkers for myocardial damage. Then, she was treated in the intensive care unit for 13 days. High amounts of RSV type B RNA was detected in tracheal aspirates and serum sample. CONCLUSION: This case report emphasizes that RSV infection may be associated with myocarditis in immunocompromised children receiving maintenance chemotherapy.

Relationship between QT and JT peak interval variability in prepubertal children.

BACKGROUND: The QT variability index (QTVI) is a noninvasive index of repolarization lability that has been applied to subjects with cardiovascular disease. QTVI provides a ratio of normalized QT variability to normalized heart rate variability, and therefore includes an assessment of autonomic nervous activity. However, measurement of QT time is particularly difficult in children, who exhibit physiologically high heart rates compared with adults. In this study, we developed a set of standard values of J-point to Tpeak interval (JTp) for infants by age, and assessed the correlation of QTVI with the JTp variability index (JTpVI). METHODS: Subjects included 623 infants and children (0-7 years of age) without heart disease and 57 healthy university students. All subjects were divided into three groups by age. QTVI and JTpVI were calculated based on an electrocardiogram, and age-specific standard values, a gender-specific classification, and a standard growth curve were constructed. RESULTS: JTpVI markedly decreased in infancy and slowly decreased thereafter, reaching adult values by school age. There was also a strong correlation of JTpVI with QTVI (r = .856). CONCLUSIONS: JTp can be used to evaluate the variability of the repolarization time in healthy infants, and may be useful for detection of early repolarization abnormalities.

Electrocardiographic RR and QT Interval Variability in Patients with Atrial Septal Defect and Healthy Children.

Atrial septal defect is a common congenital heart disease. In patients with atrial septal defect, left-to-right shunting increases the right atrial and right ventricular preload. This pathological change affects sinus node automaticity and myocardial depolarization and repolarization, and has the potential to evoke arrhythmogenic substrates. We examined the effect of atrial septal defect on sinus node automaticity and myocardial repolarization by investigating the variability in the repolarization interval, namely the QT variability index (QTVI) and variability ratio (VR). This retrospective study included 38 patients (mean age, 2.2 ± 1.9 years; mean left-to-right shunt ratio, 2.1 ± 0.70) and 40 age-matched healthy control subjects evaluated from 2008 to 2015. QTVI was calculated using the ratio of the repolarization parameter variance to heart rate variance, and VR was calculated as the ratio of the standard deviation (SD) of QT intervals to the SD of RR intervals on electrocardiography. There was a significant difference in the SD of all normal RR intervals, heart rate variance, VR, and QTVI of control subjects or patients with low shunt ratio compared with patients with high shunt ratio (all P < 0.05). Linear regression analysis revealed strong positive correlations between the left-to-right shunt ratio and VR (r = 0.662, P < 0.0001) or QTVI (r = 0.808, P < 0.0001). These repolarization indices provide information on alteration of sinus node autonomic control and the pathophysiology of myocardial repolarization, and could be used as a noninvasive indicator of the shunt ratio in children with atrial septal defect.

A case of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis with severe cardiac complications.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life threatening hematological disorder associated with severe systemic inflammation caused by an uncontrolled and ineffective immune response resulting in cytokine storm. Epstein-Barr virus (EBV) is the most common infectious agent in patients with the viral-associated HLH. Limited numbers of cases with cardiac complication have been demonstrated in other viral-associated HLH patients. Herein, we report a pediatric case of severe EBV-associated HLH with cardiac complications. CASE PRESENTATION: A previously healthy 4-year-old Japanese female was admitted to a local hospital with a four day history of fever. Despite antibiotic treatment, her fever persisted to day 7 of the illness. Finally, the diagnosis of HLH was confirmed by fulfilling diagnostic criteria for HLH and pathological analysis of bone marrow aspiration. Real-time PCR detected a high copy number of EBV DNA in the peripheral blood mononuclear cells (PBMCs) at the time of hospital admission. During treatment according to HLH-2004 protocol, sudden cardiopulmonary arrest (CPA) occurred on day 30 of the illness and immediate resuscitation was successful. Acute myocarditis was considered the cause of the CPA. Although the treatment regimen was completed on day 88 of the illness, a remarkably high copy number of EBV DNA was still detected in her PBMCs. Based on our flow cytometric in situ hybridization analysis that revealed EBV infection of only B lymphocytes, we decided to administer rituximab to control the abnormal EBV infection. Afterwards the amount of EBV DNA decreased gradually to undetectable level on day 130 of the illness. Unfortunately, a coronary artery aneurysm was discovered at the left main coronary artery on day 180 of the illness. Finally, the patient was discharged from the hospital on day 203 of the illness without sequelae except for a coronary aneurysm. CONCLUSIONS: In this case report, EBV-HLH was complicated with cardiac symptoms such as myocarditis and coronary artery aneurysm. Although remarkably high copy number of EBV DNA was detected in PBMCs after completion of the HLH-2004 protocol, rituximab treatment resulted in a dramatic decrease of EBV DNA to undetectable levels. Rituximab treatment might have been beneficial for the patient's survival.

Variability of Myocardial Repolarization in Pediatric Patients with a Ventricular Septal Defect.

In patients with a ventricular septal defect, left-to-right shunting increases the left ventricular preload. This pathological change affects myocardial depolarization and repolarization and has the potential to evoke arrhythmogenic substrates. We examined the effect of ventricular septal defects on myocardial repolarization by investigating the variability in the repolarization interval. This retrospective study included 19 patients (mean age, 1.8 ± 2.1 years) who underwent surgical closure (mean left-to-right shunt ratio, 2.60 ± 0.55) and 26 age-matched healthy controls from 2008 to 2015. Using preoperative electrocardiograms, we studied two electrocardiographic parameters (heart rate-corrected repolarization and variability of repolarization) and four repolarization intervals (QT, JT, J point to T peak [JTp], and T peak to T end [Tp-e] intervals). The variability index (VI) was calculated from the logarithm of the ratio of the repolarization parameter variance to heart rate variance. The various measures were compared between the patients and controls, and significant differences were found in the corrected QT, JTp, and Tp-e intervals (p < 0.05). The VI of the four intervals also showed significant differences (patients vs. CONTROLS: QTVI, -0.55 ± 0.61 vs. -1.10 ± 0.53; JTVI, -0.33 ± 0.60 vs. -0.86 ± 0.57; JTpVI, -0.15 ± 0.78 vs. -0.73 ± 0.56; Tp-eVI, 0.75 ± 0.70 vs. 0.11 ± 0.73, respectively; p < 0.05). No correlation was found between the QTVI and corrected QT interval using linear regression analysis. These repolarization characteristics provide not only electrophysiological indices but also a new index with which to assess the pathophysiology of congenital heart disease.

A PDE3A mutation in familial hypertension and brachydactyly syndrome.

Hypertension and brachydactyly syndrome (HTNB) with short stature is an autosomal-dominant disorder. Mutations in the PDE3A gene located at 12p12.2-p11.2 were recently identified in HTNB families. We found a novel heterozygous missense mutation c.1336T>C in exon 4 of the PDE3A gene in a Japanese family with multiple HTNB patients. This mutation was found to be completely linked to the family members who inherited this condition. The mutation, resulting in p.Ser446Pro, was located within the cluster region of reported mutations. This mutation may also affect the phosphodiesterase activity of PDE3A to reduce the cyclic AMP level in the cell and thereby influencing the development of limbs and the function of the cardiovascular system.

Inflammation aggravates heterogeneity of ventricular repolarization in children with Kawasaki disease.

Kawasaki disease complicates with myocarditis and vasculitis. Even if myocarditis is asymptomatic, heterogeneity of ventricular repolarization may be increased in the acute phase. We evaluated whether the change in repolarization characteristics can be used as a predictor for myocarditis and coronary lesions. Enrolled 34 children who were treated with intravenous immunoglobulin therapy. There were no sequelae in the recovery phase in any subjects, including those who had transient coronary artery lesion. QT and the interval from the Tpeak to Tend (Tp-e) were determined. The Tp-e/QT ratios were compared between the acute and recovery phases and correlations with CRP level and body temperature were evaluated. A retrospective evaluation of Tp-e/QT as predictors of coronary dilation was also performed. Tp-e/QT in the acute phase correlated positively with body temperature and CRP level. In a comparison of patients with and without transient coronary artery lesion, Tp-e/QT was significantly higher in those with dilation. In conclusion, Tp-e/QT was strongly related to transient coronary dilation, in comparison with inflammatory indicators including fever and CRP level.