原发性免疫缺陷病的诊断与治疗进展

原发性免疫缺陷病(PID)是一类主要以单基因遗传为主的少见免疫缺陷疾病,2007年发表的新版PID分类纳入了一些以免疫失衡和自身炎性反应为主要表现的PID。其诊断除仍应强调临床和免疫功能初步筛查外,部分疾病的分子诊断、快速诊断和功能学诊断也有了较大进展。近半数PID需免疫重建治疗,规范合理的开展造血干细胞移植是挽救患儿生命的关键。现就PID的诊断治疗进展作简要介绍。     

我国原发性免疫缺陷病的诊治现状与发展方向

原发性免疫缺陷病(primary immunodeficiency disease,PID)是免疫细胞或其组成成分量或质的变化,导致机体对多种病原体易感性显著增高的疾病,为儿科少见的免疫遗传性疾病.单基因突变导致的免疫学变化和临床表现对研究人类免疫应答规律很有价值,受到国际免疫学界的高度重视[1].随着我国经济发展,发生于免疫功能正常儿童的各种感染机制和防治手段逐渐明确,但PID患儿感染特点、除感染以外的PID特殊表现、疾病发生发展规律和开展新型防治手段仍存在明显不足.     

原发性免疫缺陷病早期识别

原发性免疫缺陷病(primary immunodeficiency disease,PID)是一类以单基因遗传为主的少见免疫缺陷疾病。国外流行病学研究认为,具有临床表现的PID发病率为1/20000～1/5000活产婴。我国目前仅有极少部分PID患儿得到确诊,早期诊断是提高PID患儿生存率和生活质量的关键。本文首先分析国外PID预警症状在PID诊断中的价值,然后根据笔者单位多年来积累的临床经验,结合我国国情,提出PID早期识别线索,以供儿童免疫专科医师讨论和儿科医生参考。     

儿童原发性免疫缺陷病的临床特点

目的了解儿童原发性免疫缺陷病(PID)的临床特点,以助于早期识别和诊断。方法对本院儿科住院诊断为PID的26例病例进行回顾性分析,记录病史、出生史、家族史、临床表现、实验室检查、诊断、治疗和转归等情况。结果PID中选择性IgA缺乏症6例,普通变异性免疫缺陷病、婴儿暂时性低丙种球蛋白血症各5例,T、B细胞联合免疫缺陷病、湿疹血小板减少伴免疫缺陷综合征各4例,慢性肉芽肿病2例。25例临床表现为反复感染,感染部位主要是呼吸道和消化道;确定有条件致病菌感染6例,自身免疫性疾病5例,有家族病史6例。住院期间死亡、放弃治疗各1例,其他病情好转出院。结论对反复感染、条件致病菌感染或伴自身免疫性疾病患儿,结合家族史,应尽早行免疫学检查,以早期识别和诊断PID。     

单中心174例原发性免疫缺陷病临床预警症状的初步探讨

目的 分析并总结原发性免疫缺陷病（PID）患儿的临床感染特征和预警症状,了解预警症状对PID早期识别的应用价值。方法 参考2011年免疫学会国际联合会(IUIS)PID分类委员会公布的方案、泛美免疫缺陷病组(PAGID)和欧洲免疫缺陷病协会(ESID)提出的PID诊断和分类标准,在首都医科大学附属北京儿童医院2000年10月至2011年11月病例检索系统检索出院诊断中含有上述PID分类疾病的病历,对于诊断低丙种球蛋白血症和联合免疫缺陷的患儿除外继发性免疫缺陷病,逐份查阅病历重新诊断,并做出明确、可以和可能诊断,以明确、可以诊断的病例进行预警症状的分析。结果 ①174例PID患儿进入分析,男女比例为4.4∶1,其中抗体缺陷为主的免疫缺陷101例(58.0%),严重联合免疫缺陷病（SCID）34例(19.5%),吞噬细胞功能缺陷19例(10.9%),定义明确的免疫缺陷综合征10例(5.7%),免疫失调性疾病10例(5.7%)。②75例(43.1%)存在反复呼吸道感染,以抗体缺陷为主的免疫缺陷最为常见,与SCID间差异有统计学意义;卡介苗接种后异常反应在慢性肉芽肿病（CGD）中最多见,与抗体缺陷为主的免疫缺陷和SCID比较差异有统计学意义;腹泻病在定义明确的免疫缺陷综合征中较常见,败血症在SCID和CGD患儿中较常见,但PID各类型间比较差异无统计学意义。③72例(41.4%)患儿存在营养发育落后,PID各类型间差异无统计学意义;淋巴结、肝和脾肿大以CGD和免疫失调性疾病最为常见;鹅口疮在SCID中常见,与抗体缺陷为主的免疫缺陷差异有统计学意义;肛周脓肿以CGD多见,与其他PID类型比较差异有统计学意义。107例(61.5%)有明确微生物学证据。④PID患儿共电话随访到85例(48.8%),其中死亡28例(32.9%)。⑤124例为明确和可以诊断PID,其中106例(85.5%)具备≥2条预警症状。静脉应用抗生素清除病灶(96.0%)、体重不增或生长发育极度迟缓(41.1%)、反复呼吸道感染(41.9%)和PID家族史(22.6%)在不同类型PID中均占有较高的比例。结论 预警症状对PID有着很好的提示作用,需要静脉应用抗生素清除病灶、体重不增或生长发育极度迟缓和PID家族史对PID有预警意义,中耳炎、中枢神经系统感染和反复呼吸道感染在抗体缺陷为主的免疫缺陷中较为多见, 深部脓肿、卡介苗接种后异常反应对CGD有预警意义。慢性反复发作性腹泻对PID预警作用值得进一步关注。     

儿童原发性免疫缺陷病35例临床分析

目的：了解儿童原发性免疫缺陷病（PID）的临床特点。方法：对2005年9月至2008年12月收治的35例PID患儿的临床资料进行分析,包括现病史,个人史,家族史,临床表现,实验室检查,诊断情况,住院期间治疗和转归等情况。结果：35例PID中,T、B细胞联合免疫缺陷病6例,X连锁无丙种球蛋白血症4例,选择性IgG亚类缺陷22例,常见变异性免疫缺陷病1例,慢性肉芽肿病2例。全部病例均有发热,并伴反复感染,感染部位主要是呼吸道和消化道,其中部分患儿生长发育落后于正常同龄儿。采用人血丙种球蛋白输注、抗感染等综合治疗,除2例放弃治疗,1例转外院治疗外,其余均好转出院。结论：对反复感染或伴发自身免疫性疾病,长期使用抗生素无效的患儿,应详细询问病史、家族史,注意PID的可能,及早进行免疫功能测定,以利于早期识别和诊断。［中国当代儿科杂志,2010,12（8）：625-629］     

小儿脓毒症相关性脑病的临床诊断与治疗探讨

目的 探讨脓毒症相关性脑病患儿的早期临床诊断与治疗策略.方法 对9例脓毒症相关性脑病患儿,根据其临床表现,按个体化原则采用早期综合加强策略控制脓毒症外,尽早大剂量血浆、丙种球蛋白(IVIG)调整免疫平衡,并加用小剂量甘露醇、鲁米那等保护脑功能并积极控制抽搐状态.结果 9例脓毒症患儿存活6例,死亡3例.结论 针对脓毒症复杂的病理生理和免疫失衡,运用早期综合加强策略控制脓毒症,防止多器官功能不全加重,早期诊断和治疗脓毒症相关性脑病,可显著提高存活率,降低病死率.     

X-连锁无丙种球蛋白血症临床分析及基因诊断

目的分析X-连锁无丙种球蛋白血症(XLA)的临床特点及Bruton酪氨酸激酶(BTK)的基因突变情况。方法回顾分析通过基因检测确诊的20例XLA患儿的临床资料,以及采用Sanger测序方法分析BTK基因的突变情况。结果 20例患儿均为男性,发病年龄6～54月龄,平均(26.3±14.61)月龄;基因诊断确诊年龄26～168月龄,平均(64.7±38.22)月龄;诊断周期中位数为27.5月龄(3～114月龄)。临床表现以呼吸道感染为主,其中18例诊断为肺炎,另外2例为消化道感染。免疫功能检测示成熟B淋巴细胞缺如或比例显著降低,血清IgG、IgA及IgM水平明显降低。基因检测提示错义突变10例,无义突变4例,移码突变3例,内含子剪切位点突变2例,剪接突变1例。20例患儿明确诊断后均给予静脉输注丙种球蛋白替代治疗,感染频次均显著减少,均无后遗症。结论对反复严重、特殊部位感染的男童,尤其是有相关家族史的患儿,尽早行免疫功能筛查,并行基因检测明确诊断及遗传咨询。     

造血干细胞移植治疗原发性免疫缺陷病研究进展

原发性免疫缺陷病(PID)是一类遗传性全身免疫系统缺陷病,患儿通常很早发病,以反复致命的感染为主要表现.近年来对PID的认识从表型到基因型不断深入,对PID的治疗从有效的支持疗法缓解感染症状,到通过异基因造血干细胞移植治愈PID也有了长足的进步.目前基因治疗尚处于前期临床研究阶段.该文对异基因造血干细胞移植治疗PID的种类、干细胞来源、预处理方案及远期预后等方面进行综述.     

造血干细胞移植治疗原发性免疫缺陷病研究进展

原发性免疫缺陷病(PID)是一类遗传性全身免疫系统缺陷病,患儿通常很早发病,以反复致命的感染为主要表现.近年来对PID的认识从表型到基因型不断深入,对PID的治疗从有效的支持疗法缓解感染症状,到通过异基因造血干细胞移植治愈PID也有了长足的进步.目前基因治疗尚处于前期临床研究阶段.该文对异基因造血干细胞移植治疗PID的种类、干细胞来源、预处理方案及远期预后等方面进行综述.     

Allergic factors associated with the development of asthma and the influence of cetirizine in a double-blind, randomised, placebo-controlled trial: First results of ETA®

There is a common progression known as the allergic march from atopic dermatitis to allergic asthma. Cetirizine has several antiallergic properties that suggest a potential effect on the development of airway inflammation and asthma in infants with atopic dermatitis. Methods. Over a two year period, 817 infants aged one to two years who suffered from atopic dermatitis and with a history of atopic disease in a parent or sibling were included in the ETAC^® (Early Treatment of the Atopic Child) trial, a multi-country, double-blind, randomised, placebo-controlled trial. The infants were treated for 18 months with either cetirizine (0.25mg/ kg b.i.d.) or placebo. The number of infants who developed asthma was compared between the two groups. Clinical and biological assessments including analysis of total and specific IgE antibodies were performed. Results. In the placebo group, the relative risk (RR) for developing asthma was elevated in patients with a raised level of total IgE (≥ 30 kU/I) or specific IgE (≥ 0.35 kUA/I) for grass pollen, house dust mite or cat dander (RR between 1.4 and 1.7). Compared to placebo, cetirizine significantly reduced the incidence of asthma for patients sensitised to grass pollen (RR = 0.5) or to house dust mite (RR = 0.6). However, in the population that included all infants with normal and elevated total or specific IgE (intention-to-treat - ITT), there was no difference between the numbers of infants developing asthma while receiving cetirizine or placebo. The adverse events profile was similar in the two treatment groups. Discussion. Raised total IgE level and raised specific IgE levels to grass pollen, house dust mite or cat dander were predictive of subsequent asthma. Cetirizine halved the number of patients developing asthma in the subgroups sensitised to grass pollen or house dust mite (i.e. 20% of the study population). In view of the proven safety of the drug, we propose this treatment as a primary pharmacological intervention strategy to prevent the development of asthma in specifically sensitised infants with atopic dermatitis.     

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孤独症谱系障碍(autistic-spectrum disorders,ASDs)近年来患病率逐年攀升至1%左右,其症状往往伴随终生,成为严重威胁儿童健康和发展的神经发育性疾患;注意缺陷多动障碍(attention deficit hyperactivity disorder,ADHD)是儿童期最常见的精神障碍,国内报道患病率为4.13%～5.83%,其症状可延续至青少年期,甚至到成年期[1]。这两类精神障碍在成年期的临床表现、共患病、治疗策略和预后与儿童期有哪些不同呢?本文通过回顾相     

EXCITING NEW TREATMENT APPROACHES FOR PATHYPHYSIOLOGIC MECHANISMS OF SICKLE CELL DISEASE

During the past several decades, our understanding of the complex pathophysiology of vasoocclusion associated with sickle cell disease has improved greatly. Interaction of genes, hemoglobin molecules, red cell membrane and metabolic changes, cell-cell interactions and cell-plasma interactions, red cell adhesion to vascular endothelium, activation of coagulation, and vascular reactivity play a role in vaso occlusion. Penicillin prophylaxis of pneumococcal infections and appropriate use of blood transfusions and other supportive measures improved survival of sickle cell patients. Hydroxyurea made a major impact on sickle cell therapy when it was shown to decrease acute painful episodes, acute chest syndrome, and the need for blood transfusion in adults. Significant experience in the use of hydroxyurea has been accumulated in older children. The benefits and risks of hydroxyurea for younger children and long-term risks in all patients will be evaluated in future investigations. Other promising therapies include butyrate compounds, clotrimazole, magnesium supplementation, poloxamer 188, antiadhesion agents, anticoagulant approaches, and nitric oxide. Hemopoietic transplantation remains the only curative therapy. However, several transgenic mouse models are available for studies of gene therapy or other treatment approaches on biochemical, cellular, and pathologic effects of mutant genes.     

Infiltrations of Epstein-Barr virus-carrying cells in granular lymphocyte-proliferative disorders corresponding to chronic active Epstein-Barr virus infection

A 21-year-old man with granular lymphocyte-proliferative disorders (GLPD) associated with chronic active Epstein-Barr virus (EBV) infection is described. Chromosomal analyses revealed several clonal abnormalities and two of them were mainly repetitious. High copy numbers of monoclonal EBV genome were also detected in the proliferative large granular lymphocytes (LGLs), indicating the monoclonal expansion of EBV-infected LGLs. The patient had an indolent course for several years, and there was no evidence of infiltrations of his bone marrow until the end stage. At autopsy, microscopic studies revealed marked infiltrations of LGL in the liver and spleen, and the infiltrating cells were NK-cell immunophenotype. The infiltrated LGLs showed latency I.     

LUTEINIZING HORMONE RECEPTOR MUTATIONS IN DISORDERS OF SEXUAL DEVELOPMENT AND CANCER

Human male sexual development is regulated by chorionic gonadotropin (CG) and luteinizing hormone (LH). Aberrant sexual development caused by both activating and inactivating mutations of the human luteinizing hormone receptor (LHR) have been described. All known activating mutations of the LHR are missense mutations caused by single base substitution. The most common activating mutation is the replacement of Asp-578 by Gly due to the substitution of A by G at nucleotide position 1733. All activating mutations are present in exon 11 which encodes the transmembrane domain of the receptor. Constitutive activity of the LHR causes LH releasing hormone-independent precocious puberty in boys and the autosomal dominant disorder familial male-limited precocious puberty (FMPP). Both germline and somatic activating mutations of the LHR have been found in patients with testicular tumors. Activating mutations have no effect on females. The molecular genetics of the inactivating mutations of the LHR are more variable and include single base substitution, partial gene deletion, and insertion. These mutations are not localized and are present in both the extracellular and transmembrane domain of the receptor. Inactivation of the LHR gives rise to the autosomal recessive disorder Leydig cell hypoplasia (LCH) and male hypogonadism or male pseudohermaphroditism. Severity of the clinical phenotype in LCH patients correlates with the amount of residual activity of the mutated receptor. Females are less affected by inactivating mutation of the LHR. Symptoms caused by homozygous inactivating mutation of the LHR include polycystic ovaries and primary amenorrhea.     

Resurgence of measles in Singapore: profile of hospital cases

OBJECTIVE: To ascertain the profile of cases of measles seen at a general hospital during a recent outbreak that occurred despite a measles vaccination program. METHODOLOGY: A retrospective study from January 1991 to March 1998. All patients with measles (ICD code 055. 9) seen at the emergency unit or as inpatients were included. RESULTS: There were 87 cases identified. The diagnosis was clinical in all and proven serologically in 71%. Eighty-five per cent of the cases occurred between January 1997 and March 1998. There was a bi-modal age distribution with peaks in the very young (相似文献   

Personality profiles and heart rate variability (vagal tone) in children with recurrent abdominal pain

The aim of the study was to explore psychological factors and autonomic activity in children with recurrent abdominal pain and to compare them with those in a control group of healthy children. The Personality Inventory for Children was used for assessment of developmental, emotional and psychosocial factors in 25 children with recurrent abdominal pain (age, 7-15 y). Parasympathetic and sympathetic functions in these children and in 23 healthy control subjects (age, 7-13 y) were also investigated, non-invasively using a computerized polygraph. Vagal tone (parasympathetic function) was indexed by calculation of respiratory sinus arrhythmia in beats/min. Skin conductance (sympathetic function) was recorded by the constant current method. On the Personality Inventory for Children, 16 patients had high scores on somatic concern. Several patients had scores in the clinical range for depression, withdrawal and anxiety, but the mean scores for these personality profile scales were well within the normal range of healthy children. Interestingly, there was a spike on the L (Lie)-scale for most of the patients and 15 patients had scores above or close to the clinical cut-off value. As compared with the scores in healthy children, vagal tone and sympathetic tone were normal. Conclusion: Many children with recurrent abdominal pain have scores in the clinical range for depression, withdrawal, anxiety and L-scale indicating coping problems, denial and a trend towards somatic concern that may contribute to the evolution of abdominal pain. Autonomic nerve activity was not disturbed in these children.     

Overcoming surfactant inhibition with polymers

Inhibition of the function of pulmonary surfactant in the alveolar space is an important element of the pathophysiology of many lung diseases, including meconium aspiration syndrome, pneumonia and acute respiratory distress syndrome. The known mechanisms by which surfactant dysfunction occurs are (a) competitive inhibition of phospholipid entry into the surface monolayer (e.g. by plasma proteins), and (b) infiltration and destabilization of the surface film by extraneous lipids (e.g. meconium-derived free fatty acids). Recent data suggest that addition of non-ionic polymers such as dextran and polyethylene glycol to surfactant mixtures may significantly improve resistance to inhibition. Polymers have been found to neutralize the effects of several different inhibitors, and can produce near-complete restoration of surfactant function. The anti-inhibitory properties of polymers, and their possible role as an adjunct to surfactant therapy, deserve further exploration.     

Understanding infant formula

The World Health organisation recommends breast feeding infants for the first six months of life. When this breast feeding does not occur either through parental choice or medical need, infant formulas will be required. There is a bewildering array of formulas on the UK market for many different requirements. When faced with an unsettled infant many parents (and healthcare professionals) will experiment with the infant formula available and then attend the paediatric clinic looking for help and advice. It is therefore essential that paediatricians understand what milks are available and what the key differences between different products are. This review attempts to provide a simple guide through many of the formulations currently available in the UK; and offers advice for the dietary management of the child with extra calorie requirements, infants with cow's milk protein allergy, gastro oesophageal reflux disease, apparent unresolved hunger and infantile colic. Whatever the underlying condition, there is likely to be an infant formula that is suitable in this generation of ever expanding formulations.