A systematic review and meta‐analysis of tumor necrosis factor α‐308 polymorphism and Kawasaki disease

Background: There have been genetic studies assessing the association between tumor necrosis factor (TNF)‐α‐308 and Kawasaki disease (KD) but the results have been conflicting due to lack of power. Therefore, a systematic review and meta‐analysis was conducted to increase the power for identifying the association between the TNF‐α‐308 polymorphism and KD. Method: Studies were identified from MEDLINE and EMBASE databases and were included if the subjects were children and the frequencies between TNF‐α‐308 and KD were reported. Data were pooled using a random effect model if heterogeneity between studies was present. Results: Thirteen studies were identified however only six studies were included. The pooled prevalence of minor A allele was 5.2% (95% confidence interval [CI]: 0.1%–9.5%). Gene effect was assessed using per‐allele and per‐genotype approaches. The pooled odds ratio of G versus A with the random effect model was 1.13 (95%CI: 0.34–3.27). The genotype effects for GG versus GA+AA was estimated and the pooled odds ratio was 1.08 (95%CI: 0.42–2.92). Conclusion: This review suggests a trend of association between the TNF‐α‐308 G‐allele and KD. However, the gene effects are heterogeneous and assessing sources of heterogeneity are limited. An updated meta‐analysis is needed if more studies are published.     

Successful treatment of a patient with tumor necrosis factor receptor‐associated periodic syndrome using a half‐dose of etanercept

TNF receptor‐associated periodic syndrome (TRAPS) is caused by mutations of TNFRSF1A gene and characterized by recurrent febrile episodes of prolonged duration and initial good response to steroids. Etanercept, a TNF blocker, has been used as a putative molecular‐targeted agent for TRAPS, with some patients showing limited efficacy. Here, we report a patient with TRAPS who recovered from steroid dependency by etanercept and kept remission with a reduced dose of etanercept. The pathophysiology of TRAPS still remains to be elucidated and several hypotheses have been proposed. In the most recent hypothesis, the concerted action of wild‐type and mutant TNF receptors plays an important role in provoking enhanced inflammation in TRAPS. The excellent response to etanercept in our patient suggested that there is heterogeneity in TRAPS patients in terms of the contribution of normal TNF signaling to autoinflammation.     

The role of TNF‐α in eosinophilic inflammation associated with RSV bronchiolitis

Choi J, Callaway Z, Kim HB, Fujisawa T, Kim CK. The role of TNF‐α in eosinophilic inflammation associated with RSV bronchiolitis.
Pediatr Allergy Immunol 2010: 21: 474–479.
© 2009 John Wiley & Sons A/S The purpose of our study was to investigate whether tumor necrosis factor (TNF)‐α correlates with eosinophilic inflammation that occurs during a lower respiratory tract infection with the respiratory syncytial virus (RSV) in children. Sixty children with RSV bronchiolitis (RSV group) and 20 healthy children with no respiratory symptoms (Control group) were enrolled. We measured the nasal lavage fluid (NLF) Th2 cytokine (IL‐5), proinflammatory cytokine (TNF‐α, IL‐8), eosinophil‐active cytokine [granulocyte‐macrophage colony stimulating factor (GM‐CSF), IFN‐γ], and eosinophil‐active chemokine (eotaxin, regulated on activation normal T cell excreted and secreted) levels for both groups. We also measured serum eosinophil‐degranulation product (eosinophil‐derived neurotoxin; EDN, eosinophil cationic protein; ECP) levels from RSV group. TNF‐α, IL‐8, GM‐CSF, IFN‐γ, and eotaxin levels were significantly higher in the RSV group compared with the Control group. TNF‐α correlated with GM‐CSF (r = 0.87, p < 0.0001), IFN‐γ (r = 0.92, p < 0.0001), eotaxin (r = 0.64, p < 0.0001), and IL‐8 (r = 0.84, p < 0.0001). TNF‐α may have an important role in eosinophilic inflammation of airways in children with RSV bronchiolitis.     

Influence of smoking on human milk tumor necrosis factor‐α, interleukin‐1β, and soluble vascular cell adhesion molecule‐1 levels at postpartum seventh day

Background: The aim of this study was to investigate the effect of maternal smoking during pregnancy on human milk interleukin‐1β, tumor necrosis factor‐α (TNF‐α) and soluble vascular cell adhesion molecule‐1 levels at the postpartum seventh day. Methods: Forty‐four mothers (age range: 21–34 years) were enrolled in the study. Mothers were interviewed and classified according to their smoking status into one of two groups: the smoking mothers (n= 21) and the nonsmoking mothers (n= 23). Results: There were no significant differences between study groups with respect to human milk interleukin‐1β (P= 0.12) and soluble vascular cell adhesion molecule‐1 levels (P= 0.83). However, TNF‐α levels were found to be significantly lower in the smoking mothers compared with the controls (P= 0.002). Conclusion: This study shows that maternal smoking during pregnancy affects the levels of TNF‐α in milk. The protective effect of human milk against infections seems to be impaired in smoking mothers.     

Sputum TWEAK expression correlates with severity and degree of control in non‐eosinophilic childhood asthma

Background

Tumor necrosis factor‐like weak inducer of apoptosis (TWEAK) is known to play a role in the pathogenesis of various inflammatory diseases. However, no study has been performed on childhood asthma.

Methods

Ninety‐five children with asthma and 78 controls aged 5‐18 years were included. Sputum induction, pulmonary function test (PFT), and methacholine challenge test were performed. The subjects were divided into the eosinophilic airway (EA) and non‐EA (NEA) groups based on sputum analysis and into the high and low TWEAK groups according to the TWEAK cutoff level (263.0 pg/mL). TWEAK in induced sputum supernatant was measured through enzyme‐linked immunosorbent assay.

Results

Children with asthma had higher TWEAK levels than healthy controls (493.0 [157.1‐904.3] vs 118.2 (67.5‐345.5) pg/mL, P < .001). Sputum TWEAK levels were significantly correlated with PFT parameters reflecting airway obstruction. This association was particularly prominent in subjects with NEA inflammation. Significant differences in FEF_25‐75 (maximum mid‐expiratory flow, % predicted; P = .017), AX (reactance area; P < .001), R5‐R20 (difference between resistance at 5 and 20 Hz; P = .025), and X5 (reactance at 5 Hz, % predicted; P < .001) were noted between the high and low TWEAK groups within the NEA group. Sputum TWEAK level also showed significant positive correlations with asthma severity (r = .358, P = .001) and control status (r = .470, P < .001), distinctively in subjects with NEA inflammation.

Conclusions

Airway TWEAK may play a role in small airway inflammation especially in children with non‐eosinophilic asthma.     

Soluble tumor necrosis factor receptor‐1 in preterm infants with chronic lung disease

Background: It is clear that inflammation plays an important role in developing chronic lung disease in preterm infants. The purpose of the present study is to investigate changes of serum soluble tumor necrosis factor receptor‐1 levels over time in infants with chronic lung disease. Methods: The serum levels of soluble tumor necrosis factor receptor‐1 were measured after delivery, and at 7, 14, 21 and 28 days of age in 10 infants with chronic lung disease and in 18 infants without chronic lung disease. Results: The serum level of soluble tumor necrosis factor receptor‐1 was significantly higher in infants with chronic lung disease than in infants without chronic lung disease after delivery. The differences between these two groups remained up to 28 days of age. Conclusion: Prenatal inflammation with persistence into postnatal inflammation may be involved in the onset of chronic lung disease.     

重症肺炎血清可溶性肿瘤坏死因子受体检测的临床意义

目的　研究重症肺炎患儿血清可溶性肿瘤坏死因子受体（ Ｓ Ｔ Ｎ Ｆ Ｒ） 浓度变化。方法　采用 Ｅ Ｌ Ｉ Ｓ Ａ 方法测定２７ 例肺炎（１５ 例重症肺炎） 患儿极期与恢复期血清 Ｓ Ｔ Ｎ Ｆ Ｒ 浓度,并进行危重评分。结果　肺炎时血清 Ｓ Ｔ Ｎ Ｆ Ｒ 升高,极期重症肺炎明显高于普通肺炎,随病情改善血清浓度下降; Ｔ Ｎ Ｆ 改变不明显,随着病情好转无显著下降。 Ｓ Ｔ Ｎ Ｆ Ｒ 水平与肺炎疾病危重评分呈负相关。结论　小儿肺炎时血清 Ｓ Ｔ Ｎ Ｆ Ｒ 明显升高,且与疾病危重程度密切相关; Ｓ Ｔ Ｎ Ｆ Ｒ 有助于临床指导肺炎的治疗与观察预后。     

Cytokines in human milk and late‐onset breast milk jaundice

Background: Maternal milk plays an important role in the development of late‐onset breast milk jaundice (BMJ), possibly due to the unique characteristics of breast milk. The aim of this study was to investigate whether there is a relation between cytokine concentrations in the milk of nursing mothers and BMJ. Methods: Breast milk samples were collected from breast‐feeding mothers of healthy full‐term neonates, 40 with BMJ and 40 without jaundice. Milk samples were taken between the second and the fourth postpartum week. The concentrations of interleukin (IL)‐1 β, IL‐6, IL‐8, IL‐10, and tumor necrosis factor‐α were measured by flow cytometric bead array. Results: There were significant differences between the study groups in terms of IL‐1 β concentrations (P= 0.013). Not statistically significant but similar trends were also seen for IL‐10 (P= 0.067) and tumor necrosis factor‐α (P= 0.053) concentrations. However, no significant differences were noted in IL‐6 (P= 0.174) and IL‐8 (P= 0.285) concentrations. Conclusions: IL‐1 β concentration seems to be increased in milk of mothers whose infants had BMJ. Although the effect of these cytokines on BMJ is unknown, it may cause prolonged jaundice via hepatic uptake, hepatic excretion, conjugation and intestinal absorption.     

Fatal graft‐versus‐host disease after living‐donor liver transplantation from an HLA‐DR‐mismatched donor

Acute GVHD is a rare complication after liver transplantation that has a high mortality rate. We experienced an infant case complicated with acute GVHD. An 8‐month‐old infant with biliary atresia underwent LDLT with a graft obtained from his mother. Their HLAs showed a donor‐dominant one‐way match, not at HLA‐DR but at HLA‐A, HLA‐B, and HLA‐C (recipient; A 31/33, B 51/54, C 1/14, DR 9/11, donor; A 31/‐, B 51/‐, C 14/‐, DR 8/11). The patient exhibited a high fever, skin rash, and diarrhea, and was diagnosed with acute GVHD based on the blood chimerism test. Despite immunosuppression treatment with prednisolone and tacrolimus, plasma exchange, blood transfusion including cord blood transplantation, and antibiotics, the child died on postoperative day 126. Donor‐dominant one‐way matching at HLA class 1 can be a high‐risk factor for acute GVHD despite HLA class 2 mismatching.     

原发性肾小球疾病患儿外周血肿瘤坏死因子水平变化

研究目的探讨原发性肾小球疾病与外周血肿瘤坏死因子水平变化的关系。研究设计病例对照研究。患者和其他参与者急性肾炎患者7例，肾病综合征9例，对照组30例，均为正常儿童。处理方法所有患者和参与者均于清晨取空腹静脉血，分离血浆-20℃保存待检。检测和主要结果采用L929细胞生物学活性法，经重组人TNF（Sigma）校准（1U＝1．67pg），并经抗TNF血清中和试验证实。对照组，肾炎组、肾病组TNF水平分别为133．33±146．44、468．57±267．05，613．33±387．81U／ml，痊愈好转后复查与治疗前对照，TNF水平分别为271．11±201．52、595．0±341．88U／ml，观察组与对照组及治疗前后相比均有显著性差异。结论肾脏病患儿外周血TNF水平显著高于正常健康儿童，而且TNF水平的增高与肾功能损伤和病情密切相关，提示应用抗TNF血清治疗原发性肾小球疾病可能有效。     

Ex vivo‐expanded donor CD4+ lymphocyte infusion against relapsing neuroblastoma: A transient graft‐versus‐tumor effect

High‐risk neuroblastoma has a poor prognosis despite multimodal treatment including high‐dose chemotherapy. A 7‐year‐old male with neuroblastoma received ex vivo‐expanded donor CD4⁺ T lymphocyte infusion (CD4⁺ DLI) after recurrence in the bone marrow following allogeneic hematopoietic stem cell transplantation from his HLA‐identical mother. The disease transiently responded to CD4⁺ DLI with reduction of tumor cells and a decrease of serum neuron‐specific enolase. The response was associated with development of continued high fever and an increase of cytotoxic T lymphocytes in peripheral blood. This case suggests a possibility of a graft‐versus‐tumor effect against neuroblastoma. Pediatr Blood Cancer 2009;52:895–897. © 2009 Wiley‐Liss, Inc.