Timo Klemola

Clinical spectrum of X-linked hyper-IgM syndrome

We report the clinical and immunologic features and outcome in 56 patients with X-linked hyper-IgM syndrome, a disorder caused by mutations in the CD40 ligand gene. Upper and lower respiratory tract infections (the latter frequently caused by Pneumocystis carinii), chronic diarrhea, and liver involvement (both often associated with Cryptosporidium infection) were common. Many patients had chronic neutropenia associated with oral and rectal ulcers. The marked prevalence of infections caused by intracellular pathogens suggests some degree of impairment of cell-mediated immunity. Although lymphocyte counts and in vitro proliferation to mitogens were normal, a defective in vitro proliferative response to antigens was observed in some patients, and additional defects of cell-mediated immunity may be presumed on the basis of current knowledge of CD40-ligand function. All patients received regular infusions of immunoglobulins. Four patients underwent liver transplantation because of sclerosing cholangitis, which relapsed in there. Three patients underwent bone marrow transplantation. Thirteen patients (23%) died of infection and/or liver disease. X-linked hyper-IgM syndrome, once considered a clinical variant of hypogammaglobulinemia, is a severe immunodeficiency with significant cellular involvement and a high mortality rate.

Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease.

The hematopoietic-specific transmembrane protein tyrosine phosphatase CD45 functions to regulate Src kinases required for T- and B-cell antigen receptor signal transduction. So far, there have been no reports to our knowledge of a human deficiency in a tyrosine-specific phosphatase. Here, we identified a male patient with a deficiency in CD45 due to a large deletion at one allele and a point mutation at the other. The point mutation resulted in the alteration of intervening sequence 13 donor splice site. The patient presented at 2 months of age with severe combined immunodeficiency disease. The population of peripheral blood T lymphocytes was greatly diminished and unresponsive to mitogen stimulation. Despite normal B-lymphocyte numbers, serum immunoglobulin levels decreased with age. Thus, CD45 deficiency in humans results in T- and B-lymphocyte dysfunction.

Superior relative efficacy of live attenuated influenza vaccine compared with inactivated influenza vaccine in young children with recurrent respiratory tract infections.

Background: Young children have a high incidence of influenza and influenza-related complications. This study compared the efficacy and safety of cold-adapted influenza vaccine, trivalent (CAIV-T) with trivalent inactivated influenza vaccine (TIV) in young children with a history of recurrent respiratory tract infections (RTIs). Methods: Children 6 to 71 months of age were randomized to receive 2 doses of CAIV-T (n = 1101) or TIV (n = 1086), 35 ± 7 days apart before the start of the 2002–2003 influenza season and were followed up for culture-confirmed influenza, effectiveness outcomes, reactogenicity, and adverse events. Results: Overall, 52.7% (95% confidence interval [CI] = 21.6%–72.2%) fewer cases of influenza caused by virus strains antigenically similar to vaccine were observed in CAIV-T than in TIV recipients. Greater relative efficacy for CAIV-T was observed for the antigenically similar A/H1N1 (100.0%; 95% CI = 42.3%–100.0%) and B (68.0%; 95% CI = 37.3%–84.8%) strains but not for the antigenically similar A/H3N2 strains (−97.1%; 95% CI = −540.2% to 31.5%). Relative to TIV, CAIV-T reduced the number of RTI-related healthcare provider visits by 8.9% (90% CI = 1.5%–15.8%) and missed days of school, kindergarten, or day care by 16.2% (90% CI = 10.4%–21.6%). Rhinitis and rhinorrhea, otitis media, and decreased appetite were the only events that were reported more frequently in CAIV-T subjects. There was no difference between groups in the incidence of wheezing after vaccination. Conclusions: CAIV-T was well tolerated in these children with RTIs and demonstrated superior relative efficacy compared with TIV in preventing influenza illness.

Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma.

Background: Despite their potential for increased morbidity, 75% to 90% of asthmatic children do not receive influenza vaccination. Live attenuated influenza vaccine (LAIV), a cold-adapted, temperature-sensitive, trivalent influenza vaccine, is approved for prevention of influenza in healthy children 5 to 19 years of age. LAIV has been studied in only a small number of children with asthma. Methods: Children 6 to 17 years of age, with a clinical diagnosis of asthma, received a single dose of either intranasal CAIV-T (an investigational refrigerator-stable formulation of LAIV; n = 1114) or injectable trivalent inactivated influenza vaccine (TIV; n = 1115) in this randomized, open-label study during the 2002–2003 influenza season. Participants were followed up for culture-confirmed influenza illness, respiratory outcome, and safety. Results: The incidence of community-acquired culture-confirmed influenza illness was 4.1% (CAIV-T) versus 6.2% (TIV), demonstrating a significantly greater relative efficacy of CAIV-T versus TIV of 34.7% (90% confidence interval [CI] 9.4%–53.2%; 95% CI = 3.9%–56.0%). There were no significant differences between treatment groups in the incidence of asthma exacerbations, mean peak expiratory flow rate findings, asthma symptom scores, or nighttime awakening scores. The incidence of runny nose/nasal congestion was higher for CAIV-T (66.2%) than TIV (52.5%) recipients. Approximately 70% of TIV recipients reported injection site reactions. Conclusions: CAIV-T was well tolerated in children and adolescents with asthma. There was no evidence of a significant increase in adverse pulmonary outcomes for CAIV-T compared with TIV. CAIV-T had a significantly greater relative efficacy of 35% compared with TIV in this high-risk population.

Development of immune response to cow's milk proteins in infants receiving cow's milk or hydrolyzed formula

BACKGROUND Development of humoral and cellular immune responses to orally administered antigens in human beings is poorly understood, although antigen administration has been suggested as a treatment for hypersensitivity disorders and autoimmune diseases. OBJECTIVE The purpose of the study was to investigate the development of systemic immune response in infants fed with formula containing whole cows milk proteins or hydrolyzed formula containing casein peptides. METHODS In a double-blind trial, 10 infants received cows milk-based formula, and 10 infants received a casein hydrolysate formula until the age of 9 months. Blood samples were taken at the ages of 6, 9, and 12 months. Cellular responses were assessed by proliferation assay of peripheral blood mononuclear cells to cows milk proteins (beta-lactoglobulin, bovine serum albumin, and alpha-casein). Humoral responses to the same proteins were measured by ELISA for IgG antibodies. RESULTS Feeding infants with cows milk-based formula induced systemic humoral and cellular responses to cows milk proteins. T-cell response later declined, supporting the concept of oral tolerization. Exposure to cows milk proteins after the age of 9 months resulted in depressed cellular and humoral responsiveness to these proteins. CONCLUSION Our results support the view that induction of oral tolerance in human beings is an age-dependent phenomenon.

Feeding a soy formula to children with cow's milk allergy: The development of immunoglobulin E-mediated allergy to soy and peanuts

Peanut allergy has been associated with the intake of soy milk or a soy formula. We studied the development of immunoglobulin E antibodies specific to soy and peanuts and of allergic reactions caused by peanuts, in children with confirmed cows milk (CM) allergy fed either a soy formula or an extensively hydrolyzed formula (EHF). One hundred and seventy infants with documented CM allergy (CMA) were randomly assigned to receive either a soy formula or an EHF. The children were followed to the age of 4 yr. Peanut‐specific immunoglobulin E was measured at the age of 4. A detailed history of the occurrence of allergic reactions caused by peanuts was recorded by the parents. Soy‐specific immunoglobulin E antibodies were measured at the time of diagnosis and at the ages of 1, 2 and 4 yr. Immunoglobulin E antibodies to soy (≥0.35 kU/l) were found in 22 of 70 children fed the soy formula, and in 14 of 70 of the children fed the EHF (p = 0.082). In an open challenge with soy at the age of 4, no immediate reactions were observed. One of 72 children from the soy group had a delayed reaction. immunoglobulin E antibodies to peanuts (≥0.35 kU/l) were found in 21 of 70 children fed the soy formula and 17 of 69 infants fed the EHF (p = 0.717). The incidence of reported peanut allergy in the soy group was two of 72 (3%) and four of 76 (5%) in the EHF group (p = 0.68). Development of immunoglobulin E‐associated allergy to soy and peanuts was rare in our study group of milk allergic children. The use of a soy formula during the first 2 yr of life did not increase the risk of development of peanut‐specific immunoglobulin E antibodies or of clinical peanut allergy.

Combined T regulatory cell and Th2 expression profile identifies children with cow's milk allergy

The role of T regulatory cells in spontaneous recovery from cows milk allergy (CMA) is unclear. We investigated the mRNA expression of 12 T-cell markers and the protein expression of CD4, CD25, CD127, FoxP3 after in vitro beta-lactoglobulin stimulation of peripheral blood mononuclear cells from children with persisting CMA (n=16), early recovery (n=20) or no atopy (n=21). Artificial neural networks with exhaustive search for all marker combinations revealed that markers FoxP3, Nfat-C2, IL-16 and GATA-3 distinguished patients with persisting CMA most accurately from other study groups. FoxP3 mRNA expression following beta-lactoglobulin stimulation was highest in children with persisting CMA. Also the FoxP3 intensity in CD4(+) CD25(high)CD127(low) cells was higher in children with CMA compared with non-atopic children. The expression profile of both Th2- and T regulatory cell-related genes thus reflects the clinical activity of CMA. Tolerance, in contrast, is not characterized by activation of circulating T regulatory cells.