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.

Childhood primary angiitis of the central nervous system following COVID-19 vaccination (BNT162b2/Pfizer-BioNtech): A case report.

Childhood primary angiitis of the central nervous system (cPACNS) is a vasculitis of unknown etiology that is confined to the central nervous system (CNS) and can lead to repeated cerebral infarctions if left untreated. Several cases of cPACNS after COVID-19 have been reported. Herein, we present a case of post-vaccination cPACNS. A 9-year-old healthy boy presented with persistent headache and fever after receiving the second COVID-19 vaccine (BNT162b2/Pfizer-BioNtech) dose. Brain magnetic resonance angiography (MRA) performed on the sixth day of symptom onset after vaccination revealed stenosis of the left middle cerebral artery; the patient was referred to our department on the 12th day of symptom onset. Blood tests indicated only minimal evidence of inflammation, whereas cerebrospinal fluid examination indicated pleocytosis. Brain magnetic resonance imaging (MRI) revealed vascular wall thickening and contrast enhancement of the artery with worsened stenosis. We diagnosed the patient as having cPACNS and treated him with three courses of methylprednisolone pulse therapy. The headaches and fever disappeared with improvement of vascular stenosis. The patient has been in remission for more than 1 year since cPACNS onset. This is the first report of a case of cPACNS after mRNA vaccination for COVID-19. Most previous cases of COVID-19-associated cPACNS presented with ischemic stroke. However, the present case could be treated for vasculitis prior to stroke and thus had a favorable prognosis. The mRNA vaccine for COVID-19 differs from other existing vaccines, and further accumulation of data of cases is required to determine adverse CNS reactions.

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.

A novel mutation in early-onset sarcoidosis/Blau syndrome: an association with Propionibacterium acnes.

BACKGROUND: Early-onset sarcoidosis (EOS) and Blau syndrome (BS) are systemic inflammatory granulomatous diseases without visible pulmonary involvement, and are distinguishable from their sporadic and familial forms. The diseases are characterized by a triad of skin rashes, symmetrical polyarthritis, and recurrent uveitis. The most common morbidity is ocular involvement, which is usually refractory to conventional treatment. A gain-of-function mutation in the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene has been demonstrated in this disease; however, little is known about the relationship between the activation of NOD2 and the pathophysiology of EOS/BS. Here we describe EOS/BS with a novel mutation in the NOD2 gene, as well as detection of Propionibacterium acnes (P. acnes) in the granulomatous inflammation. CASE PRESENTATION: An 8-year-old Japanese girl presented with refractory bilateral granulomatous panuveitis. Although no joint involvement was evident, she exhibited skin lesions on her legs; a skin biopsy revealed granulomatous dermatitis, and P. acnes was detected within the sarcoid granulomas by immunohistochemistry with P. acnes-specific monoclonal (PAB) antibody. Genetic analyses revealed that the patient had a NOD2 heterozygous D512V mutation that was novel and not present in either of her parents. The mutant NOD2 showed a similar activation pattern to EOS/BS, thus confirming her diagnosis. After starting oral prednisolone treatment, she experienced an anterior vitreous opacity relapse despite gradual prednisolone tapering; oral methotrexate was subsequently administered, and the patient responded positively. CONCLUSIONS: We presented a case of EOS/BS with a novel D512V mutation in the NOD2 gene. In refractory granulomatous panuveitis cases without any joint involvement, EOS/BS should be considered as a differential diagnosis; genetic analyses would lead to a definite diagnosis. Moreover, this is the first report of P. acnes demonstrated in granulomas of EOS/BS. Since intracellular P. acnes activates nuclear factor-kappa B in a NOD2-dependent manner, we hypothesized that the mechanism of granuloma formation in EOS/BS may be the result of NOD2 activity in the presence of the ligand muramyl dipeptide, which is a component of P. acnes. These results indicate that recognition of P. acnes through mutant NOD2 is the etiology in this patient with EOS/BS.

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.

Time-Course Evaluation of Body Mass Index in Japanese Children With Obstructive Sleep Apnea Syndrome After Adenotonsillectomy: A Three-Years Follow-Up Study.

Delayed physical growth is a common complication of pediatric obstructive sleep apnea syndrome (OSAS). Adenotonsillectomy (AT) is the first-line treatment for pediatric OSAS. Only a few studies have performed time-course BMI evaluation in pediatric OSAS patients post-operatively. Thus, we aimed to evaluate the time-course changes in pediatric OSAS patients after AT. Thirty-three children with OSAS who underwent AT were included and divided into two groups on the basis of their BMI z-scores (delayed physical growth group, n = 15; non-delayed physical growth group, n = 18). Clinical records of height and weight were collected before AT and at 6, 12, 24, and 36 months after AT. Changes in the mean BMI z-scores of the two groups were assessed up to 36 months. The mean BMI z-score was significantly increased in the delayed physical growth group at 6 months after AT. In contrast, the increase in mean BMI z-score was not observed in the non-delayed physical growth group. Growth improvement was noted in pediatric OSAS patients with delayed physical growth after AT. Our results suggest that AT is a promising therapy for improving the physical growth of pediatric OSAS patients with such problems.

Survival and ocular preservation in a long-term cohort of Japanese patients with retinoblastoma.

BACKGROUND: Retinoblastoma is an ocular tumor in infants with cancer predisposition. Treatment of the rare tumor needs to be optimized for ocular preserved survival without second primary malignancy (SPM). METHODS: We studied the outcomes of all patients with retinoblastoma at a tertiary center in 1984-2016, when preservation method changed from radiotherapy (1984-2001) to systemic chemotherapy (2002-2016). RESULTS: One-hundred sixteen infants developed unilateral- (n = 77), bilateral- (n = 38), or trilateral-onset (n = 1) tumor. Ten (8.6%) had a positive family history, despite a few studies on RB1 gene. Contralateral disease occurred in one unilateral-onset case. One-hundred eight of 155 eyes (70%) were enucleated. Nine binocular survivors were from 5 bilateral- and 4 unilateral-onset cases. Two survivors received bilateral enucleation. Six deaths occurred; brain involvement (including 3 trilateral diseases) in 4 bilateral-onset, systemic invasion in a unilateral-onset, and SPM (osteosarcoma) in a bilateral-onset case(s). Two others survived SPM of osteosarcoma or lymphoma. The 10-year overall survival (OS: 98.5% vs. 91.3%, p = 0.068) and binocular survivors (13.2% vs. 5.2%, p = 0.154) between bilateral- and unilateral-onsets did not differ statistically. The 10-year OS and cancer (retinoblastoma/SPM)-free survival (CFS) rates of all patients were 94.9 and 88.5%, respectively. The proportion of preserved eyes did not differ between radiotherapy and chemotherapy eras. The CFS rate of bilateral-onset cases in systemic chemotherapy era was higher than that in radiotherapy era (p = 0.042). The CFS rates of bilateral-onset patients with neoadjuvant chemotherapy (upfront systemic therapy for preservation) was higher than those without it (p = 0.030). CONCLUSIONS: Systemic chemotherapy and local therapy raised OS and binocular survival rates of bilateral-onset patients similarly to those of unilateral-onset patients. All but one death was associated with a probable germline defect of the RB1 gene. Neoadjuvant stratified chemotherapy may support the long-term binocular life with minimized risk of SPM.

Purpuric drug eruption without leukocytoclastic vasculitis associated with vancomycin.

Vancomycin (VCM) has been reported to elicit adverse cutaneous drug reactions. However, VCM-associated purpuric drug eruption has not been reported yet, except leukocytoclastic vasculitis. A 16-year-old Japanese girl was admitted with a respiratory infection. We initiated intravenous administration of VCM. After the start of treatment, impalpable purpuric eruption appeared on her trunk. The eruption gradually extended to her neck, legs, and arms. Skin biopsy showed vasculitis with lymphocyte infiltration in the superficial dermis. A drug lymphocyte stimulation test yielded positive results for VCM. Her cutaneous symptoms rapidly reversed after the withdrawal of VCM. To the best of our knowledge, this is the first reported case of VCM-associated purpuric drug eruption, which differs from leukocytoclastic vasculitis. We recommend that VCM-associated purpuric drug eruption should be considered in the differential diagnosis during the administration of VCM, and a drug lymphocyte stimulation test may be useful for assessment of pathogenesis.

Serum soluble ST2 as a marker of renal scar in pediatric upper urinary tract infection.

BACKGROUND AND OBJECTIVES: Upper urinary tract infection is the most common serious bacterial infection in childhood. Patients with upper urinary tract infection have a risk for renal scarring with subsequent complications including hypertension, proteinuria, and progressive renal failure. However, the predictive biomarkers of renal scarring in children with upper urinary tract infection are still unknown. In this study, we evaluated whether soluble ST2 levels can be biomarkers of subsequent renal scarring in patients with upper urinary tract infection. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: We retrospectively studied pediatric patients with upper urinary tract infection at a tertiary center. Twenty-eight children had an upper urinary tract infection with (n = 14) and without (n = 14) renal scarring and underwent 99mtechnetium dimercaptosuccinic acid imaging. In addition, 13 control subjects were enrolled. The clinical data and serum cytokine levels, including soluble ST2 levels, were compared between those with and without renal scars. RESULTS: Serum soluble ST2 levels were significantly higher in the scar group than in the non-scar group, whereas there was no difference in the levels of serum interferon-γ, interleukin-6, interleukin-10, soluble tumor necrosis factor receptor 1, and transforming growth factor-ß between the scar and non-scar groups. The area under the curve for differentiating between the non-scar and scar groups on the basis of measurements of serum soluble ST2 was 0.79, with a sensitivity and specificity of 92.9% and 64.3%, respectively. CONCLUSION: These results suggest that serum soluble ST2 levels on admission could be a useful biomarker of subsequent renal scarring in pediatric patients with upper urinary tract infection.

Early canakinumab therapy for the sensorineural deafness in a family with Muckle-Wells syndrome due to a novel mutation of NLRP3 gene.

Cryopyrin-associated periodic syndrome (CAPS) is one of the autoinflammatory disorders caused by mutations in NLRP3 gene. The over-production of interleukin (IL)-1ß induced by NLRP3 gene mutations plays an important role in the pathophysiology of CAPS. We diagnosed 3 patients with CAPS, who were lineal family members having a novel mutation of NLRP3 gene. The objective of this report is to compare the characteristics of symptoms and differences in the therapeutic responses of them, who had the same mutation. In addition, we aimed to examine the usefulness of cytokine measurement for diagnosis or determination of treatment effect of CAPS. A 5-year-old Japanese boy (proband) came to our hospital because of short stature, reached the diagnosis of Muckle-Wells syndrome (MWS) due to a mutation in NLRP3 gene, which had not been reported so far (p.G328E, c.G983A). His mother and grandmother harbored the same mutation of NLRP3. We measured serum concentrations of cytokines in the proband assessed by flow-cytometric bead array. All of them had episodic skin eruptions with conjunctivitis, hearing loss, and arthralgia, but not periodic fever, cold-triggered episodes, and chronic aseptic meningitis. Only the proband had short stature. Canakinumab therapy led to a prompt relief of symptoms and normalized laboratory data in all patients. Audiograms demonstrated an improved hearing level in the proband, but not two others despite of the same mutation. All cytokines did not show any characteristic findings. Sensorineural hearing loss and itchless rash but not serum cytokine profile deserved attention to the diagnosis and treatment start of CAPS. The early intervention of IL-1ß blockade may reduce the chance of complete deafness in patients with CAPS.

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.

[Refractory primary immune thrombocytopenia in pregnancy requiring splenectomy and repeated intravenous immunoglobulin therapy].

A 30-year-old primigravid woman without a history of thrombocytopenia was referred to our hospital because of severe thrombocytopenia (<1,000 thrombocytes/µl) at 16 weeks of gestation and diagnosed with idiopathic thrombocytopenic purpura (ITP). There was no improvement in the platelet count after treatment with 0.5-1.0 mg/kg/day prednisolone, and the 400 mg/day intravenous immunoglobulin (IVIg) administered for 5 days gradually became ineffective; therefore, a laparoscopic splenectomy was performed at 25 weeks of gestation. The increase in the platelet count after the splenectomy was temporary, but the effects of IVIg therapy improved, and the patient received IVIg therapy seven times in total during her pregnancy. Her platelet count ranged between 10,000 and 70,000/µl after the splenectomy, compared with <5,000/µl before the surgery. The patient underwent an elective cesarean section at 34 weeks of gestation without any significant bleeding. The baby was diagnosed with thrombocytopenia at birth (34,000 thrombocytes/µl) and was administered only one dose of IVIg, which increased the baby's platelet count to a normal level after 14 days. The patient's platelet count also increased after delivery. Splenectomy and repeated IVIg therapy can be considered for refractory severe ITP during pregnancy.