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.

Interleukin-33 and Soluble ST2 Levels in Infants with Hypoxic-Ischemic Encephalopathy.

INTRODUCTION: Interleukin (IL)-33 and its receptor ST2L play key roles in the IL-33/ST2 signaling pathway. Soluble ST2 (sST2) inhibits the proper function of IL-33. sST2 levels are increased in patients with several neurological diseases, but in infants with hypoxic-ischemic encephalopathy (HIE), IL-33 and sST2 levels have not been studied. This study aimed to investigate whether serum levels of IL-33 and sST2 are useful as biomarkers of HIE severity and prognostic factors for infants with HIE. METHODS: Twenty-three infants with HIE and 16 controls (gestational age ≥36 weeks and ≥1,800 g birth weight) were enrolled in this study. Serum levels of IL-33 and sST2 were measured at <6 h, 1-2, 3, and 7 days of age. Hydrogen-1 magnetic resonance spectroscopy was performed, and ratios of peak integrals of lactate/N-acetylaspartate (Lac/NAA) were calculated as objective indicators of brain damage. RESULTS: In the moderate and severe HIE, serum sST2 concentrations were increased and there was a good correlation between serum sST2 and HIE severity on days 1-2, whereas no variation was observed in serum IL-33. Serum sST2 levels were positively correlated with Lac/NAA ratios (Kendall's rank correlation coefficient = 0.527, p = 0.024), and both sST2 and Lac/NAA ratios were significantly higher in HIE infants with neurological impairment (p = 0.020 and <0.001, respectively). CONCLUSIONS: sST2 may be a useful predictor of severity and later neurological outcomes in infants with HIE. Further investigation is required to elucidate the relationship between the IL-33/ST2 axis and HIE.

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.

Utility of Soluble CD163 in the Clinical Management of Patients With Kawasaki Disease.

Objective: Intravenous immunoglobulin (IVIG) therapy is a useful first-line treatment for Kawasaki disease (KD); however, 10-20% of patients fail to respond and require additional IVIG. Soluble CD163 (sCD163) is considered a biomarker for macrophage activation. There are no reports measuring serum sCD163 in KD patients. This study aimed to explore its possible utility in the clinical management of patients with KD. Methods: Eighty-seven patients with well-defined KD were retrospectively enrolled together with 19 healthy individuals with comparable ages. KD patients were classified into three groups, Group A (initial IVIG responders), Group B (additional IVIG responders), and Group C (additional IVIG non-responders). Serum sCD163 together with complete blood counts, C-reactive protein, d-dimer, albumin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured before the initial IVIG treatment in all cases, and afterward in a fraction of cases. Results: Serum sCD163 in KD patients before initial IVIG was generally much higher than the control group. The median (interquartile range) of sCD163 was as follows: Control 446 (385-521) ng/mL; Group A, 699 (478-1,072); Group B, 1,349 (1,116-1,390); and Group C, 665 (544-1,094). In general, sCD163 showed close positive correlation with ALT and AST, but none with other markers. Among the KD groups, Group B showed the highest sCD163: Group B vs. A: p = 0.0003; B vs. C: p = 0.035). Serum sCD163 was significantly increased after IVIG in Group A, while no change occurred in others. Conclusion: The serum sCD163 levels could be a useful biomarker in the clinical management of KD, especially for predicting responsiveness to IVIG.

Circulating endothelial glycocalyx components as a predictive marker of coronary artery lesions in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is acute and self-limited vasculitis caused by unknown origin, and the critical complication in KD patients is coronary artery lesions (CALs). The endothelial glycocalyx is a network of membranes luminally covering the endothelium. This study aimed to evaluate the clinical utility of serum glycocalyx components as biomarkers of predicting the onset CALs in KD. METHODS: Seventy subjects with complete type KD, 18 subjects as febrile control (FC), and 15 subjects as afebrile controls (AC) were enrolled. Medical, demographic, echocardiography, and laboratory data from the medical records were retrospectively analyzed. Serum syndecan-1 and hyaluronan levels prior to intravenous immunoglobulin (IVIG) therapy were measured at the acute phase, immediately after IVIG, the subacute phase, and the time of discharge at the convalescent phase. RESULTS: Serum syndecan-1 and hyaluronan levels were higher in the KD group than in the AC and FC groups at all three phases. Further, these levels were compared between KD patients with and without the development of CALs. Serum syndecan-1 and hyaluronan levels at the acute phase were significantly elevated in KD patients with the CALs than in those without CALs. Serum hyaluronan, not syndecan-1, was determined as the most contributory parameter to predict CALs by a multiple logistic analysis. CONCLUSIONS: Circulating syndecan-1 and hyaluronan can be useful biomarkers to predict the development of CALs in 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.