Infection and immunity in Down syndrome: a trial of long-term low oral doses of zinc

To determine whether orally administered zinc supplements could correct the abnormal humoral and cell-mediated immunity of Down syndrome, we randomly assigned 64 children with Down syndrome, aged 1 to 19 years and living at home, to receive either zinc gluconate or placebo daily for 6-month periods with crossover from one regimen to another. Control subjects were siblings and age-matched, unrelated children. Serum zinc, copper, and measures of immune system competence were tested at 3- or 6-month intervals. Parents kept daily logs of clinical symptoms such as cough and diarrhea and of physician visits. Mean serum zinc concentrations increased to about 150% of baseline during zinc supplementation, but we found no effect on serum levels of copper, immunoglobulins, or complement; on lymphocyte number or subset distribution; or on in vitro response to mitogens. Children with Down syndrome who were receiving zinc had a trend toward fewer days or episodes of cough and fever but no change in other clinical variables. Long-term, low-dose oral zinc supplementation to improve depressed immune response or to decrease infections in children with Down syndrome cannot be recommended.     

Increased circulating apoptotic lymphocytes in children with Down syndrome

Down syndrome (DS) resembles immunodeficiency with increased infections, auto‐immune diseases, and hematological malignancies. Until now, immunological studies in DS mainly focused on T‐lymphocytes. We recently described a profound B‐lymphocytopenia in children with DS. This could be caused by increased apoptosis. Therefore, we determined expression of flowcytometric markers for apoptosis [Annexin‐V (AV) and propidium iodide (PI)] on peripheral lymphocytes in 72 children with DS and 32 age‐matched controls (AMC). Within the total lymphocyte compartment, apoptosis was more pronounced in DS; it increased with age. Moreover, apoptosis was highest within the B‐lymphocyte compartment which may be a contributing factor to the B‐lymphocytopenia found in DS. Pediatr Blood Cancer 2012; 59: 1310–1312. © 2012 Wiley Periodicals, Inc.     

Inadequate humoral immunogenicity to recombinant hepatitis B virus vaccine in biliary atresia children

This study aimed to investigate the primary immunogenicity and the long-term efficacy of recombinant hepatitis B virus (HBV) vaccine in biliary atresia (BA) children. Fifty BA infants (age, 11 +/- 3.9 mo), and 23 BA patients at childhood (age, 8.5 +/- 0.22 y) were included for the evaluation of HBV surface antibody (anti-HBs) levels after three doses of recombinant HBV vaccine immunization. Age- and gender-matched healthy infants (n = 50) and children (n = 23) were enrolled as the control group. Serum samples of the study populations were collected for HBV seromarkers determination. In the absence of hepatitis B virus core antibody and HBV surface antigen, serum anti-HBs level above 10 IU/L was considered adequate immunogenicity to HBV vaccine. The prevalence of adequate anti-HBs levels after recombinant HBV vaccine in BA infants was significantly lower than those of the controls (p = 0.006). There was no difference in the prevalence between childhood BA patients and their matched controls (p = 0.538). In conclusion, adequate primary humoral immunity after the standard doses of recombinant HBV vaccine in BA infants is hard to establish. However, once immunity is acquired, BA children have adequate anti-HBs titer in the long run.     

Intrinsic abnormalities of lymphocyte counts in children with down syndrome

OBJECTIVE: Down syndrome (DS) is associated with an increased frequency of infections, hematologic malignancies, and autoimmune diseases, suggesting that immunodeficiency is an integral part of DS that contributes significantly to the observed increased morbidity and mortality. We determined the absolute counts of the main lymphocyte populations in a large group of DS children to gain further insight into this immunodeficiency. STUDY DESIGN: In a large group of children with DS (n = 96), the absolute numbers of the main lymphocyte subpopulations were determined with 3-color immunophenotyping using the lysed whole-blood method. The results were compared with previously published data in healthy children without DS. RESULTS: In healthy children with DS, the primary expansion of T and B lymphocytes seen in healthy children without DS in the first years of life was severely abrogated. The T- lymphocyte subpopulation counts gradually reached more normal levels with time, whereas the B- lymphocyte population remained severely decreased, with 88% of values falling below the 10th percentile and 61% below the 5th percentile of normal. CONCLUSIONS: The diminished expansion of T and B lymphocytes strongly suggests that a disturbance in the adaptive immune system is intrinsically present in DS and is not a reflection of precocious aging. Thymic alterations have been described in DS that could explain the decreased numbers of T lymphocytes, but not the striking B lymphocytopenia, seen in these children.     

Frequency of lower respiratory tract infections in relation to adaptive immunity in children with Down syndrome compared to their healthy siblings

Aim: Children with Down syndrome (DS) experience respiratory tract infections (RTIs) more frequently than healthy children. We investigated whether this is related to different immunological characteristics associated with DS. Methods: The study group consisted of 22 children with DS and 22 of their healthy, age‐range matched siblings. Data were collected on infections and hospitalizations because of lower RTIs. Immunoglobulin and IgG subclass levels in blood, as well as lymphocyte and T cell (subset) counts, were determined. Results: The children with DS had a significantly higher frequency of lower RTIs and related hospitalization than their siblings. We also found significantly reduced IgG2 levels as well as significantly lower counts of total lymphocytes, CD4⁺ T lymphocytes, CD4⁺ invariant natural killer (iNKT) cells and regulatory T cells in the DS group. Conclusion: In children with DS, reduced levels of IgG2, total lymphocytes, T lymphocytes, iNKT cells and regulatory T cells might contribute to their higher susceptibility to lower RTIs.     

Immunological patterns in young children with Down syndrome: is there a temporal trend?

Down syndrome is associated with an increased susceptibility to infections due to a deficiency of both specific and nonspecific immunity. AIM: The aim of the study was to analyze the temporal trends, if any, of some variables related to the immunological status of children affected by Down syndrome. METHODS: Heparinized blood samples were obtained by venipuncture in 30 children with Down syndrome, who were regularly followed in our department and analyzed for hematologic values, lymphocyte subpopulations, immunoglobulin dosage and zinc level. Results were compared with those of the normal population. RESULTS: In the first 5 years of life, we observed a progressive decrease in the medium values of lymphocytes, CD4(+) and plasma zinc levels, and an increase in CD8(+), immunoglobulin A, immunoglobulin G, immunoglobulin M and natural killer, but generally without exceeding the interval of normality. CONCLUSIONS: In Down syndrome children, the immune cellular status is similar to the normal population as far as white blood cell, lymphocyte, CD4(+), CD8(+), natural killer and immunoglobulins are concerned. Plasma level of zinc is normal from birth until 5 years but with a temporal trend of progressive reduction. This observation supports the hypothesis that a pharmacological supplementation may be necessary in Down syndrome children only after 5 years of age.     

Age-related patterns of thyroid-stimulating hormone response to thyrotropin-releasing hormone stimulation in Down syndrome.

Thyroid function in subjects with Down syndrome was studied using the thyrotropin-releasing hormone test. Forty-seven infants and children with Down syndrome were investigated. Ages ranged from 1 month to 7 years; there were 26 boys and 21 girls. Fourteen of the subjects with Down syndrome who had an exaggerated thyroid-stimulating hormone response to thyrotropin-releasing hormone stimulation had two or more annual follow-up tests. The remaining 33 subjects who only underwent one thyrotropin-releasing hormone test were compared with 22 age-matched controls (11 boys and 11 girls). Mean basal thyroxine 4 and triiodothyronine 3 values were in the normal ranges. All thyroid antibody titers were negative. Mean basal thyroid-stimulating hormone levels of subjects with Down syndrome were significantly higher than those of controls for all ages, even though there was a decline in thyroid-stimulating hormone levels in both groups. Peak thyroid-stimulating hormone response levels were significantly greater in the subjects with Down syndrome than in the controls. Longitudinal study of the 14 children with Down syndrome with an exaggerated thyroid-stimulating hormone response showed that the response remained exaggerated until the third year of life, when it declined to normal levels. Thyroid dysfunction during the growth spurt of infancy or delayed maturation of the hypothalamic pituitary thyroid axis are proposed mechanisms.     

Hepatitis C virus infection and interferon therapy in patients with Down syndrome.

BACKGROUND: The clinical features of hepatitis C virus (HCV)-associated liver diseases, or the efficacy of interferon (IFN) therapy in children with Down syndrome (DS) remain to be elucidated. The purpose of the present paper was to survey the features of liver diseases in this subset of children and evaluate the efficacy of IFN treatment in those patients. METHODS: A questionnaire was sent to 41 members of the Japan Society of Pediatric Hepatology. Ten of them reported on 11 patients with DS who had concomitant chronic HCV infection, providing information on liver disease and the response to IFN treatment. RESULTS: Interferon therapy of 24 weeks duration using natural IFN-alpha was instituted in six of the 11 patients with DS, but none of the six patients cleared HCV-RNA from their serum. Among 12 age- and sex-matched control children who were treated with IFN using the same regimen against chronic HCV infection, half of them had a favorable response to IFN therapy with a sustained clearance of HCV-RNA from their serum. The major baseline features including alanine aminotransferase levels, HCV genotype and viral load were not apparently different between the six patients with DS and the 12 controls. CONCLUSIONS: IFN therapy for HCV infection in patients with DS may be unfavorable as compared with non-DS children.     

Thymic deficiency in Down's syndrome.

Children with Down's syndrome (DS) often have small and abnormal thymuses, with lymphocyte depletion, diminution of the cortex, and loss of corticomedullary demarcation--a picture resembling thymic involution. Besides this, they have markedly enlarged Hassall's corpuscles, some surrounded by a sheath of lymphocytes. Patients with DS are known to have increased numbers of respiratory infections; they also have a higher incidence of lymphatic leukemia than do individuals who do not have DS. Studies of cell-mediated (thymic-dependent) immunity demonstrate that children with DS have both diminished numbers of T cells as well as functional deficiency of these cells.     

Age-related difference in immune responses to respiratory syncytial virus infection in young children

There have been longitudinal studies of the developmental change of the immune system during the first year of life. The aim of this study was to investigate if there is any age-related difference in cytokine responses to respiratory syncytial virus (RSV) infection between the patients under 6 months of age and the patients over 12 months of age compared with age-matched controls. Forty-five children < or =24 months of age who were admitted with acute RSV bronchiolitis were enrolled. The patients were divided into two groups: the infants < or =6 months old and the young children > or =12 months old. Immune response to RSV infection was determined by measuring the serum concentrations of cytokines and compared with age-matched controls. Serum samples were obtained on admission and analyzed for interferon (IFN)-gamma, interleukins (IL)-10, -13, and -4 using ELISA. Comparing the cytokine levels of two control groups, both IFN-gamma and IL-13 were lower in the children > or =12 months of age than in the infants < or =6 months of age. IL-10 and IL-4 showed no significant changes with age. Comparing with age-matched controls, IFN-gamma levels were significantly higher in RSV group > or =12 months of age, but showed a tendency toward lower levels in RSV group < or =6 months of age. Both IL-10 and IL-13 levels were significantly higher in RSV group > or =12 months of age, but showed no significant difference in RSV group < or =6 months of age. Our study demonstrated a significant age-related difference in immune response to RSV infection during early life. It suggests that the developmental changes in cytokine responses to RSV infection may be considered in the control of RSV bronchiolitis in young children.     

不同年龄肺炎支原体肺炎患儿胸片与实验室检查特点比较

目的探讨不同年龄肺炎支原体肺炎(MPP)患儿表现为大叶性肺炎和支气管肺炎时,血常规、血清C反应蛋白(CRP)及体液免疫各项指标的变化。方法 MPP患儿211例,根据年龄分为1个月～6岁组和≥6岁组,同时依据胸片表现分为大叶性肺炎组和支气管肺炎组。入院初检测血常规、CRP及体液免疫指标。结果≥6岁组患儿MPP大叶性肺炎发生率为45.92%,高于1个月～6岁组的22.12%(χ2=13.4,P<0.001)。在1个月～6岁组中,大叶性肺炎患儿外周血淋巴细胞比例低于支气管肺炎患儿(P<0.05);而在≥6岁组患儿中,两者差异无统计学意义(P>0.05)。≥6岁组大叶性肺炎患儿的血清IgA、IgM含量低于支气管肺炎患儿(P<0.05)。两个年龄组大叶性肺炎患儿的血清CRP含量均高于支气管肺炎患儿(P<0.05)。结论年长儿MPP以大叶性肺炎多见,可能是年长儿MP感染后机体全身炎症反应强烈的表现之一,MP感染后淋巴细胞减少和早期特异性抗体产生不足也可能与大叶性肺炎的发生有关。     

反复呼吸道感染儿童细胞免疫与体液免疫状况

目的探讨反复呼吸道感染（RRI）患儿细胞与体液免疫状况,为临床进行免疫治疗提供依据。方法用流式细胞仪对23例RRI患儿进行外周血淋巴细胞亚群检测;同时进行免疫球蛋白（IgA、IgG、IgM）及补体C3、C4水平检测。结果与健康人群比较,RRI患儿血清IgG及IgA各有1例降低,血清IgM降低7例;补体C3降低3例,C4降低1例。RRI患儿外周血CD8较健康对照组明显增高（P=0）,CD4/CD8较健康对照组明显降低（P=0.002）。结论RRI患儿存在体液免疫功能降低,细胞免疫功能失调亦非常显著。     

Prolonged impairment of cellular immunity in children with intrauterine growth retardation.

Cellular immunity was studied in 17 newborn infants, in eight children aged 1 to 5 years with intrauterine growth retardation, and in age-matched control subjects. At birth T and B peripheral blood lymphocytes were decreased, and delayed cutaneous hypersensitivity to phytohemagglutinin was diminished. In vitro PHA-induced lymphocyte proliferation was similar to that in control subjects but was greater than in healthy adults. In later childhood the numbers of T lymphocytes were normal, but their proliferative capacity was significantly reduced and cutaneous hypersensitivity was minimal or absent. Prolonged impairment of cellular immunity in these children may explain their increased susceptibility to infection and inadequate response to immunization, and predispose to the development of allergic, autoimmune, and neoplastic disease.     

Antibody Response Determined with Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC), Neutralizing Antibody, and Varicella Skin Test in Children with Natural Varicella and After Varicella Immunization

Humoral and cellular immune responses were examined in 115 children with varicella and in 21 children who had been immunized with live varicella vaccine. Antibody determined with antibody-dependent cell-mediated cytotoxicity (ADCC) was detected earlier than neutralizing antibody (NT) in both groups. While humoral and cellular immunity were detected simultaneously in the natural varicella group, cellular immunity was detected earlier than humoral immunity in the immunized group. This suggests that ADCC, rather than NT, is involved in the early stages of recovery from varicella-zoster virus (VZV) infection.     

癫(癎)的免疫学研究进展

癫(癎)为临床常见综合征,近年来,关于癫(癎)的免疫学发病机制已逐渐被人们所认识,包括体液免疫和细胞免疫两个方面.体液免疫异常主要包括细胞因子、自身抗体及免疫球蛋白等的变化,细胞免疫异常则表现为淋巴细胞亚群、淋巴细胞增殖带及NK细胞等的变化.除外周血的异常,癫(癎)患者的脑脊液检查也可发现各项免疫指标的变化.抗癫癎药物...     

Cytokine release of peripheral blood mononuclear cells in children with chronic hepatitis B virus infection.

BACKGROUND: Immune response to hepatitis B virus (HBV) antigens or mitogens in Asian children with chronic HBV infection who are mainly perinatally infected has not been studied in connection with the production of various cytokines, although these patients are considered to be less responsive to antiviral therapy. METHODS: The production of the cytokines interferon (IFN)-gamma, lymphotoxin, interleukin (IL)-4, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta by peripheral blood mononuclear cells (PBMCs) was studied in 17 hepatitis B surface antigen (HBsAg) carrier children with raised alanine transferase levels (group 1), 17 HBsAg carrier children with normal alanine transferase levels (group 2), and 20 healthy noncarrier control subjects (group 3). RESULTS: Hepatitis B core antigen (HBcAg)-stimulated IFN-gamma production was significantly higher in group 1 than in groups 2 and 3, serum HBeAg cleared within 1 year in five of eight children in group 1 with stimulation indexes higher than 3, and HBcAg-induced IL-4 secretion was minimal in all groups. Interferon-gamma produced by PBMCs stimulated by purified HBsAg did not differ among the three groups. Higher lymphotoxin production by PBMCs stimulated by HBcAg was also noted in groups 1 and 2 than in group 3. Lipopolysaccharide (LPS)-stimulated TNF-alpha production by PBMCs was significantly higher in group 1 than in group 2. There was no association between HBeAg-anti-HBe status and production of various cytokines. No differences were seen in the profile of cytokines induced by HBV antigens or LPS in children of carrier mothers compared with children of HBsAg-negative mothers. CONCLUSION: Increased IFN-gamma production resulting from HBcAg-specific T-helper lymphocyte type 1 response, and increased TNF-alpha production may contribute to cell-mediated antiviral immune response in children with chronic hepatitis B. In HBV carrier children, the ability to produce the studied cytokines is related to whether an endogenous immune attempt to eliminate HBV infection emerges in the patients but is not related to the different modes of acquisition of HBV infection.     

HUMORAL IMMUNITY AGAINST HEPATITIS B,TETANUS, AND DIPHTHERIA FOLLOWING CHEMOTHERAPY FOR HEMATOLOGIC MALIGNANCIES: A Report and Review of Literature

Malignancy and its treatment are major causes of secondary immunodeficiency in childhood. The authors investigated the effects of chemotherapy on humoral immunity against hepatitis B, tetanus, and diphtheria in children with hematologic malignancies. The authors recruited 54 patients with hematologic malignancies after the completion of chemotherapy (group A), 25 patients with newly diagnosed hematologic malignancies before initiation of chemotherapy (group B), and 74 healthy controls (group C). All participants had been vaccinated against hepatitis B, tetanus, and diphtheria according to the Iranian national vaccination scheme. Patients in group A achieved protective levels of diphtheria and hepatitis B antibodies significantly less frequently than the other 2 groups and protective levels of tetanus antibody significantly less frequently than group C (P <.05). After controlling for age, the association observed for tetanus lost its significance, but chemotherapy was a significant and independent predictor of failure to achieve protective levels of antibodies against diphtheria (odds ratio [OR] = 7.7, P < .001) and hepatitis B (OR = 3.13, P = .008). These results indicate that chemotherapy has independent adverse effects on vaccine-induced antibody protection against diphtheria and hepatitis B.     

Contact pressure distribution features in Down syndrome infants in supine and prone positions, analyzed by photoelastic methods

BACKGROUND: Local force distribution supporting the bodyweight of infants with Down syndrome (DS) appears to be different from that of healthy controls. The purpose of the present study was to establish methods to assess this force distribution and to allow therapeutic evaluation of neurological development in DS infants prior to walking. METHODS: Contact pressure distribution patterns in supine and prone positions were measured by photoelastic methods and were compared between DS infants and healthy controls. The DS group included eight subjects, seven with regular trisomy 21, and one with a Robertson translocation. The controls consisted of 14 neonates, four 4-month-old infants and eight 7-month-old infants. RESULTS: In both groups, head loading ratio decreased as age advanced but the decrement was less in the test group than in the control group. When the bodyweight loading ratios were measured in two different lying positions, that is, prone and supine, the ratios for prone generally tended to be smaller than those for supine in the controls. This kind of difference between prone and supine was not seen in the DS group. The bodyweight is somewhat sustained with limbs and the limbs loading ratios in the DS group were always significantly lower than in the controls. CONCLUSION: Coordinated development of weight-supporting limbs seems to be poor in the DS group.     

Hematological Studies in Children with Down Syndrome

Previous studies have reported erythrocyte macrocytosis in adults and children with Down syndrome (DS), the significance of which remains unclear. We compared hematological parameters of 50 DS children aged 2 to 15 years, divided into three age groups, with those of 68 aged-matched healthy children. Patients with DS had a significantly increased mean corpuscular volume (MCV) and hemoglobin in all groups when compared with the controls. Erythrocyte creatine content, hexokinase (Hk) activity, erythrocyte and serum folates, vitamin B₁₂, haptoglobin, serum iron, and ferritin were tested. All of these parameters were not significantly different from those of the control group. We conclude that macrocytosis may not be an expression of reduced red cell survival but rather of an altered folate remethylation pathway, secondary to enhanced cystathionine β-synthase (CBS) activity, the gene for which is present on chromosome 21.