Clinical utility of gastric fluid cytokine levels in preterm infants for predicting histological chorioamnionitis.

BACKGROUND: The risk of various complications, such as neonatal death, early onset sepsis, and chronic lung disease, is increased in infants born to mothers with chorioamnionitis (CAM). However, predicting the diagnosis of histological CAM (hCAM) in the early postnatal period is challenging for clinicians due to pathological considerations. Therefore, an early diagnostic tool for hCAM is needed. Gastric fluid at birth is considered a suitable biomarker for predicting the intrauterine environment because most of its components are from amniotic fluid, and the sampling technique is less invasive. This study aimed to evaluate the clinical utility of cytokines in the gastric fluid of preterm infants at birth as predictors of hCAM. METHODS: We retrieved gastric fluid and serum from 21 preterm infants with a gestational age of ≤ 32 weeks within 1 h after birth and used cytometric bead array to measure the concentrations of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-alpha, and interferon-gamma. We compared the cytokine concentrations in the gastric fluid and serum of the preterm infants born to mothers with or without hCAM. RESULTS: The gastric fluid, serum IL-6, and serum IL-10 concentrations were significantly higher in the hCAM group than that in the non-hCAM group. The best cutoff values for predicting hCAM was > 2,855 pg/mL and > 315 pg/mL for IL-6 in the gastric fluid and serum, respectively. Receiver operating characteristic curves showed that gastric fluid IL-6 concentrations correlated more strongly with the presence of hCAM than serum IL-6 concentrations. CONCLUSION: IL-6 in the gastric fluid at birth may be a more promising biomarker for predicting the presence of hCAM than that in serum. IL-6 concentration analysis in the gastric fluid at birth might help to diagnose hCAM immediately after birth and improve the prognosis of preterm infants.

Congenital Pulmonary Lymphangiectasia Masked by Postoperative Pulmonary Venous Obstruction in an Infant with Total Anomalous Pulmonary Venous Connection.

Congenital pulmonary lymphangiectasia (CPL) is associated with fetal pulmonary venous obstructive physiology. The precise morbidity of CPL is unknown as CPL is generally fatal in neonates. Here, we report an infant with secondary CPL in total anomalous pulmonary venous connection (TAPVC). He developed severe pulmonary hypertension (PH) after corrective surgery for TAPVC. However, cardiac catheterization showed mild left pulmonary venous obstruction (PVO), which was deemed unnecessary for re-intervention. He died at 11 months-old due to an exacerbation of PH. Autopsy revealed medial hypertrophy of the pulmonary arteries, mild left PVO, and marked dilatation and proliferation of the pulmonary lymphatics which might have been involved in the PH, although CPL was not conclusively identified based on the previous biopsy findings. We should be aware of the possibility of CPL in addition to postoperative PVO when encountering patients with fetal pulmonary venous obstructive physiology. Furthermore, a cautious approach to the interpretation of lung biopsy results is warranted.

Use of the index of pulmonary vascular disease for predicting long-term outcome of pulmonary arterial hypertension associated with congenital heart disease.

Aims: Limited data exist on risk factors for the long-term outcome of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD-PAH). We focused on the index of pulmonary vascular disease (IPVD), an assessment system for pulmonary artery pathology specimens. The IPVD classifies pulmonary vascular lesions into four categories based on severity: (1) no intimal thickening, (2) cellular thickening of the intima, (3) fibrous thickening of the intima, and (4) destruction of the tunica media, with the overall grade expressed as an additive mean of these scores. This study aimed to investigate the relationship between IPVD and the long-term outcome of CHD-PAH. Methods: This retrospective study examined lung pathology images of 764 patients with CHD-PAH aged <20 years whose lung specimens were submitted to the Japanese Research Institute of Pulmonary Vasculature for pulmonary pathological review between 2001 and 2020. Clinical information was collected retrospectively by each attending physician. The primary endpoint was cardiovascular death. Results: The 5-year, 10-year, 15-year, and 20-year cardiovascular death-free survival rates for all patients were 92.0%, 90.4%, 87.3%, and 86.1%, respectively. The group with an IPVD of ≥2.0 had significantly poorer survival than the group with an IPVD <2.0 (P = .037). The Cox proportional hazards model adjusted for the presence of congenital anomaly syndromes associated with pulmonary hypertension, and age at lung biopsy showed similar results (hazard ratio 4.46; 95% confidence interval: 1.45-13.73; P = .009). Conclusions: The IPVD scoring system is useful for predicting the long-term outcome of CHD-PAH. For patients with an IPVD of ≥2.0, treatment strategies, including choosing palliative procedures such as pulmonary artery banding to restrict pulmonary blood flow and postponement of intracardiac repair, should be more carefully considered.

Interleukin-33/ST2 Axis as Potential Biomarker and Therapeutic Target in Kawasaki Disease.

Kawasaki disease (KD) is an acute, self-limiting, febrile systemic vasculitis of unknown cause associated with the development of coronary artery lesions (CALs) during childhood. Damage-associated molecular patterns (DAMPs) from cell death and oxidative stress have been shown to be involved in the development of KD vasculitis. Interleukin (IL)-33 is released from damaged endothelial cells and acts as a DAMP. We studied whether IL-33 and its receptor (ST2) might be involved in KD pathogenesis. Serum levels of soluble ST2 (sST2) in KD patients were measured before their first therapy. Furthermore, we investigated the impact of IL-33 on human coronary artery endothelial cells (HCAECs). Serum levels of sST2 were significantly higher in KD patients with CALs than in those with normal coronary arteries. In vitro, IL-33 upregulated the expression of ST2L and increased production of sST2, IL-6, IL-8, and monocyte chemoattractant protein-1 in HCAECs in a time- and concentration-dependent manner. Moreover, IL-33 induced significantly greater production of IL-6 and IL-8 in HCAECs compared to the condition stimulated with isoconcentration of tumor necrosis factor-α. The results of the present study suggest that the IL-33/ST2 axis might be involved in the development of KD vasculitis. The IL-33/ST2 axis may be a therapeutic target for the treatment of KD.

Fetal cardiac capillary hemangioma resulting in tachyarrhythmia.

We present the case of a fetus with cardiac capillary hemangioma in the right atrial cavity. The tumor showed dramatic growth between the 28th and 32nd week of gestation and resulted in tachyarrhythmia. The patient was born at the 33 weeks of gestation weighing 2430 g via urgent cesarean section because the rapidly growing cardiac tumor caused incessant tachyarrhythmia, pericardial effusion, and fetal circulatory incompetence. Coronary angiography revealed that the right coronary artery drained into the tumor. Due to hemodynamic deterioration, the patient underwent subtotal resection of the tumor on the 2nd day after birth. Histopathological examination revealed an undifferentiated capillary hemangioma. The patient was discharged at the age of 86 days, as the tachyarrhythmia and hemodynamic incompetence had subsided; however, bradycardia and intermittent atrioventricular conduction disturbance gradually developed. Capillary hemangioma, a rare primary cardiac space-occupying tumor in children, can invade the conduction system.

Safety and Feasibility of Infliximab Therapy in Children With Kawasaki Disease Who Received Live Vaccinations.

BACKGROUND: Kawasaki disease (KD) is an acute and febrile systemic vasculitis that occurs during childhood. Infliximab (IFX) is a chimeric monoclonal antibody that binds to tumor necrosis factor-α. Although IFX therapy is a useful option for refractory KD, vaccine-associated infections may develop after therapy. In Japan, IFX therapy is recommended after a duration of at least 3 months after live vaccinations or at least 6 months after Bacillus Calmette-Guérin (BCG) in children with KD. However, the appropriate duration between live vaccinations and IFX therapy is unclear. METHODS: We investigated children who developed KD within 3 months after live vaccinations or within 6 months after BCG. Clinical characteristics, side effects of therapies and efficacy of live vaccinations were retrospectively investigated. RESULTS: Forty-eight patients developed KD within 3 months of live vaccinations or within 6 months after BCG. Eight patients underwent IFX therapy. There were no apparent vaccine-associated infections. The patients who underwent IFX acquired protective IgG antibody titers in the 5 of 6 live vaccines. CONCLUSIONS: Safe and appropriate duration between live vaccinations and IFX therapy for KD patients could be shorter in the future, although more studies are warranted to establish the safe duration.

Responses to Treatment According to the Cytokine Profiles of Pericardial Effusion in Two Children with Idiopathic Pericarditis.

Acute pericarditis is inflammation of the pericardium with or without pericardial effusion. In the pediatric population, most patients with acute pericarditis are diagnosed with idiopathic pericarditis. Herein, we present two children with idiopathic pericarditis who underwent immunological assessment of pericardial effusion for the first time. Both patients showed equally high levels of interleukin-6 in the pericardial effusion. However, they had different treatment responses, in accordance with the pericardial effusion and serum interleukin-10 concentrations. Our present cases suggest that interleukin-10 may be associated with the response to anti-inflammatory therapy in idiopathic acute pericarditis.

Pulmonary Hypertension Following Increased Dosing of Diazoxide in an Infant.

Diazoxide, a drug used to treat hyperinsulinemic hypoglycemia (HH), is associated with pulmonary hypertension (PH), as reported by the US Food and Drug Administration. However, no report has detailed the association between diazoxide dose and PH development. We report a case of an infant with HH, subsequently complicated by diazoxide-induced PH. When diazoxide was introduced, PH did not appear initially, but it developed during increased dosing. We monitored PH via regular echocardiography examinations. PH gradually improved with tapering of the diazoxide dose and disappeared after drug discontinuation. Our case suggests a diazoxide dose threshold might induce PH. Therefore, close echocardiography examinations should accompany diazoxide treatment.

Cerebral Insufficiency Caused by Diazoxide in a Premature Neonate with Congenital Hyperinsulinism.

Diazoxide is a peripheral vasodilator that has been used for intravenous treatment of hypertensive emergencies. However, it is currently used mainly for hyperinsulinemic hypoglycemia in lower dose orally, and its major side effects are edema and pulmonary hypertension. Herein, we report the first association between periventricular leukomalacia (PVL) and intractable hypotension due to diazoxide. A Japanese female premature infant showed hypoglycemia concomitant with hyperinsulinemia. She was diagnosed with congenital hyperinsulinism, and oral diazoxide was started. Six days after starting diazoxide, she suddenly showed peripheral coldness, oliguria, and severe hypotension. The hypotension was refractory to general vasopressor therapies and persisted even after the discontinuation of diazoxide. Cranial echography showed periventricular echodensities followed by cystic PVL. Low-dose vasopressin effectively treated the hypotension. This single case reminds us the serious adverse events of diazoxide that have been forgotten, especially in premature neonates.

Relationship Between Pulmonary Arterial Resistance and Compliance in Patients with Down Syndrome.

This study aimed to clarify the characteristics of pulmonary arterial resistance (Rp)-compliance (Cp) coupling in individuals with Down syndrome (DS), who have increased risks of pulmonary arterial hypertension (PAH). We performed cardiac catheterization before and after corrective surgery in 85 DS infants and 85 controls with congenital heart disease and PAH. We retrospectively collected hemodynamic data and compared Rp and Cp between the groups. Age at surgery was 3.5 (2.6-4.6) months. The first and second catheterizations were performed 1 month before and after corrective surgery in both groups. Preoperative Cp in DS patients was significantly lower than that in controls [2.27 (1.62-3.0) vs. 2.50 (1.86-3.31) mL/mmHg/m2, p = 0.039], although there was no significant difference in mean pulmonary arterial pressure and Rp between the groups. Analysis of covariance revealed that the slopes of the preoperative regression lines for the logarithmic transformations of Rp and Cp were identical in DS patients and controls (p = 0.299). However, the postoperative regression line was shifted downward in DS patients after corrective surgery. Postoperative home oxygen therapy (HOT) was performed in 39 patients (36 DS patients) and multivariate logistic regression analysis revealed that postoperative HOT was significantly related to low preoperative Cp (p = 0.039) and DS (p = 0.0001). Individuals with DS have the unique pulmonary vasculature characterized with low Cp that is related to postoperative HOT.

Erythema Nodosum Masking Kawasaki Disease with an Initial Manifestation of Skin Lesions.

We report the first case demonstrating an association between Kawasaki disease (KD) and erythema nodosum (EN). A 3-year-old girl presented with EN as an initial manifestation of KD. At the initial visit, she showed high fever of 40°C, injection of the oropharynx, cervical lymphadenopathy, and red-purple cutaneous nodules, particularly on the lower limbs. She complained of severe pain in the neck and cutaneous lesions. Initially, the development of EN was attributed to Salmonella spp infection, which was detected in stool culture. However, the patient did not respond to high-dose ampicillin/sulbactam to which the Salmonella spp is sensitive. Echocardiography performed as screening for fever of unknown origin revealed medium-sized aneurysms of the left anterior descending artery. EN masked the diagnosis of KD, and the patient developed a coronary artery lesion. KD should be considered in the differential diagnosis of refractory EN in pediatric patients.

Pulmonary arterial compliance is a useful predictor of pulmonary vascular disease in congenital heart disease.

Histopathological assessment of the pulmonary arteries is crucial to determine the surgical indications in patients with congenital heart disease (CHD) and intractable pulmonary vascular disease (PVD). We aimed to clarify whether pulmonary hemodynamic parameters can predict PVD in patients with CHD and pulmonary arterial hypertension (PAH) We performed histopathological evaluations of lung specimens and cardiac catheterizations in 27 patients with CHD-PAH. We divided these patients into the patients with and without PVD, and compared pulmonary hemodynamic parameters including pulmonary arterial compliance (Cp) between two groups. Age at lung biopsy was 4 (2-7) months. There were 16 patients with trisomy 21. Cardiac diagnosis included ventricular septal defect in 16, atrial septal defect in 5, atrioventricular septal defect in 4, and others in 2. There were 11 patients with histopathologically proven PVD (Heath-Edwards classification grade ≥ 3 in 5; the index of PVD ≥ 1.1 in 3; extremely thickened media in 6; hypoplasia of the pulmonary arteries in 3). Cp in the patients with PVD was significantly lower than that in patients without PVD (0.99 [0.74-1.42] vs 1.56 [1.45-1.88], p = 0.0047), although there was no significant difference in the ratio of systemic to pulmonary blood flow, pulmonary arterial pressure, and resistance between two groups. A Cp cutoff value of < 1.22 ml/mmHg m2 as a predictor of PVD yielded a sensitivity and a specificity of 93% and 64%, respectively. Pulmonary arterial compliance can be a predictor of PVD among patients with CHD-PAH.

Effective infliximab therapy for the early regression of coronary artery aneurysm in Kawasaki disease.

BACKGROUND: There is limited information available regarding the role of infliximab (IFX) following the acute phase of Kawasaki disease (KD). We aimed to evaluate whether IFX is associated with coronary artery aneurysm (CAA) regression. METHODS: Between 2005 and 2016, we identified 971 consecutive patients with KD from 3 tertiary institutions, and 49 (5%) with CAAs were enrolled in our study. Patients were divided into 2 groups: 27 who received IFX and 22 who did not. The persistence rate of CAAs was compared between the groups. RESULTS: Age, sex, and duration of the febrile period did not significantly differ between the groups. The maximum value of C-reactive protein was higher in the IFX- than in the non-IFX group. The maximum z-score of CAAs did not differ between the groups. The 2-, 4- and 6-year cumulative persistence rate of CAA was 24%, 24% and 24% in IFX-group, whereas 67%, 52% and 33% in non-IFX group, respectively (P = 0.03). The median duration of CAA regression was 1.1 vs. 4.6 years. Among those who developed medium- or large-sized CAAs, the 2-, 4- and 6-year cumulative persistence rate of CAA was 33%, 33% and 33% in IFX group, whereas 77%, 51% and 48% in non-IFX group, respectively (P = 0.047). Multivariate logistic regression analysis indicated that the maximum z-score (hazard ratio 0.72, p < 0.001) and response to IFX (hazard ratio 4.56, p = 0.017) were independently related to regression. CONCLUSION: IFX therapy was observed to be effective for the early improvement of CAAs in patients with intravenous immunoglobulin-resistant KD.

Takotsubo cardiomyopathy associated with Paragonimiasis westermani.

An 11-year-old boy collapsed during morning assembly at his junior high school. The automated external defibrillator detected ventricular fibrillation and provided shock delivery. He was successfully resuscitated and reverted to sinus rhythm. Electrocardiography showed ST-T elevation in the precordial leads. Echocardiography and angiography demonstrated akinesia of the apex and mid-wall of the left ventricle with preserved contraction of the basal segments, which suggested Takotsubo cardiomyopathy. The patient and his family had often eaten uncooked crab, and his father had a past history of infection with Paragonimiasis westermani. The patient had had a persistent cough and chest pain for several weeks. Chest radiograph showed cystic cavities in the left upper lung. Microbiological examination of the sputum demonstrated an egg of P. westermani and immunological assay showed a raised antibody titre to P. westermani. On the12th day of admission, he developed seizures, and magnetic resonance imaging demonstrated cerebral involvement. After the administration of praziquantel for 3 days, the clinical manifestations improved immediately, and echocardiography normalised within 3 weeks. The patient was discharged on the 32nd day + and follow-up was normal. Takotsubo cardiomyopathy following a potentially fatal arrhythmia is a rare cardiac complication associated with pulmonary and central nervous system infection by P. westermani.

Intravascular Ultrasound-Guided Cardiac Intervention in a Fontan Patient with Allergy to Contrast Media.

Allergy to contrast media is hazardous in patients who need multiple cardiac catheterizations. We describe the case of a 16-year-old boy who presented with fatigue and cyanosis. He had undergone a Fontan operation 14 years previously, after which he developed an allergy to iodinated contrast media. Contrast echocardiograms by manual injection of microbubbles suggested the presence of a venovenous collateral vessel from the brachiocephalic vein draining into the pulmonary vein. We used intravascular ultrasound as the sole imaging method to identify the target vessel and to guide deployment of an Amplatzer Vascular Plug II. The patient experienced immediate improvement in his systemic saturation. Our experience shows that intravascular ultrasound may be a feasible alternative to standard imaging methods in patients with congenital heart disease who need cardiac interventional procedures and are allergic to contrast media.

Distinct Distribution of Immunocytes in a Retropharyngeal Lymphadenopathy Associated with Kawasaki Disease: A Case Study Compared with Tonsillitis.

OBJECTIVES: Retropharyngeal lesions are often associated with Kawasaki disease (KD). A 4-year-old male first presented a peritonsillar and retropharyngeal abscess-like lesion. Surgical tonsillectomy was performed to avoid a risk of mediastinal abscess, but he fulfilled the diagnostic criteria of KD after the operation. This prompted us to perform a histological study on the KD tonsils. METHODS: The histopathology of the KD tonsil specimens were compared with hypertrophic tonsils obtained from 4 patients with chronic tonsillitis unrelated to KD assessed by the immunostainings. RESULTS: KD tonsils showed small lymphatic follicles and neutrophil infiltration in the peritonsillar muscle layer, with no evidence of vasculitis or abscess formation. The KD tonsils exclusively showed (1) predominant activated CD4+ T cells in the perifollicular interstitium, (2) sparse scattering of CD68+ monocytes/macrophages in the lymphatic follicles, and (3) polyclonal carcinoembryonic antigen-positive cells in the lymphatic follicles and venules with the high endothelial cells. CONCLUSIONS: The uniquely distributed immunocytes suggest the inflammatory process of KD involving the pathogen-associated molecules.

Intractable Back Pain After Coil Embolization of Giant Veno-Venous Collaterals in a Patient With Fontan Circulation.

Veno-venous collaterals are sometimes seen in patients after the Fontan procedure. A 28-year-old female with tricuspid atresia who underwent the Fontan procedure had oxygen desaturation due to a giant veno-venous collateral. Coil embolization was performed for the collateral. After the procedure, she complained of severe back pain. Anti-inflammatory analgesics and steroids were not effective, although carbamazepine promptly relieved the intractable pain. Treatment-related pain after coil embolization for veno-venous collaterals in patients with Fontan physiology is quite rare, although cardiologists must recognize a critical condition to be differentiated from vascular occlusion.

Cytokine profile of bronchoalveolar lavage fluid from a mouse model of bronchial asthma during seasonal H1N1 infection.

BACKGROUND: Several studies support the role of viral infections in the pathogenesis of asthma exacerbation. However, several pediatricians believe that influenza virus infection does not exacerbate bronchial asthma, except for influenza A H1N1 2009 pandemic [A(H1N1)pdm09] virus infection. We previously reported that A(H1N1)pdm09 infection possibly induces severe pulmonary inflammation or severe asthmatic attack in a mouse model of bronchial asthma and in asthmatic children. However, the ability of seasonal H1N1 influenza (H1N1) infection to exacerbate asthmatic attacks in bronchial asthma patients has not been previously reported, and the differences in the pathogenicity profiles, such as cytokine profiles, remains unclear in bronchial asthma patients after A(H1N1)pdm09 and H1N1 infections. METHODS: The cytokine levels and viral titers in the bronchoalveolar lavage (BAL) fluid from mice with and without asthma after H1N1 infection (A/Yamagata and A/Puerto Rico strains) were compared. RESULTS: The interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, IL-5, interferon (IFN)-α, IFN-ß, and IFN-γ levels were significantly higher in the BAL fluids from the control/H1N1 mice than from the asthmatic/H1N1 mice. The viral titers in the BAL fluid were also significantly higher in the control/H1N1mice than in the asthmatic/H1N1 mice infected with either A/Yamagata or A/Puerto Rico. CONCLUSIONS: A(H1N1)pdm09 infection, but not H1N1 infection, can induce severe pulmonary inflammation through elevated cytokine levels in a mouse model of asthma.

High mobility group box 1 in patients with 2009 pandemic H1N1 influenza-associated encephalopathy.

BACKGROUND: Patients with 2009 pandemic H1N1 influenza-associated encephalopathy (pIE) have been reported in Japan. The most common clinical symptoms of this condition are seizures and progressive coma with high-grade fever. We previously highlighted the cytokine profile of pIE; our results suggest that proinflammatory cytokines play an important role in the pathogenesis. High mobility group box 1 (HMGB1) protein is a late mediator of inflammation or sepsis. However, there are few reports regarding the serum and cerebrospinal fluid (CSF) levels of HMGB1 in pIE patients. METHODS: We measured serum and CSF levels of HMGB1 in the following: pIE patients with poor outcomes, pIE patients without neurological sequelae, influenza patients without pIE, and control subjects. RESULTS: Serum HMGB1 levels were significantly higher in pIE patients with poor outcomes compared to those without neurological sequelae. In contrast, there was no difference in CSF HMGB1 levels among all groups. Regarding pIE patients, we found a significant positive correlation between HMGB1 levels and IL-6 in the serum but not in the CSF. CONCLUSIONS: Our results suggest that HMGB1 protein may be involved in the pathogenesis of pIE and that a high serum, but not CSF, level of inflammatory cytokines plays an important role in the severity of pIE.