Symptomatic hypogammaglobulinemia in infancy and childhood – clinical outcome and in vitro immune responses

BACKGROUND: Symptomatic hypogammaglobulinemia in infancy and childhood (SHIC), may be an early manifestation of a primary immunodeficiency or a maturational delay in the normal production of immunoglobulins (Ig). We aimed to evaluate the natural course of SHIC and correlate in vitro lymphoproliferative and secretory responses with recovery of immunoglobulin values and clinical resolution. METHODS: Children, older than 1 year of age, referred to our specialist clinic because of recurrent infections and serum immunoglobulin (Ig) levels 2 SD below the mean for age, were followed for a period of 8 years. Patient with any known familial, clinical or laboratory evidence of cellular immunodeficiency or other immunodeficiency syndromes were excluded from this cohort. Evaluation at 6- to 12-months intervals continued up to 1 year after resolution of symptoms. In a subgroup of patients, in vitro lymphocyte proliferation and Ig secretion in response to mitogens was performed. RESULTS: 32 children, 24 (75%) males, 8 (25%) females, mean age 3.4 years fulfilled the inclusion criteria. Clinical presentation: ENT infections 69%, respiratory 81%, diarrhea 12.5%. During follow-up, 17 (53%) normalized serum Ig levels and were diagnosed as transient hypogammaglobulinemia of infancy (THGI). THGI patients did not differ clinically or demographically from non-transient patients, both having a benign clinical outcome. In vitro Ig secretory responses, were lower in hypogammaglobulinemic, compared to normal children and did not normalize concomitantly with serum Ig's in THGI patients. CONCLUSIONS: The majority of children with SHIC in the first decade of life have THGI. Resolution of symptoms as well as normalization of Ig values may be delayed, but overall the clinical outcome is good and the clinical course benign

The Role of Helminth Infection and Environment in the Development of Allergy: A Prospective Study of Newly-Arrived Ethiopian Immigrants in Israel

<div><p>Helminth infection may be protective against allergy and account for the low prevalence of allergy in developing countries. We studied prospectively the prevalence of allergy in Ethiopian immigrants with heavy helminth infection on arrival in Israel, and again after a year of adjustment to an urban industrialized setting, to explore the roles of helminth infection, changed environment and background immunity on the manifestations of allergy. 126 newly arrived Ethiopian immigrants were studied at baseline and 115 after a year of follow up in Israel. Allergic symptoms, Skin prick tests (SPT), Tuberculin (PPD) skin tests, stool and blood samples were obtained for determining parasites, blood IgE and eosinophil levels, respectively. Anti-helminthic therapy was offered to the entire infected individuals, but only 50/108 (46.3%) took the medication. At baseline, there was a significant negative association between helminth infection and allergy, 4/18 (22.2%) of uninfected participants were allergic compared to 7/108 (6.5%) of helminth-infected participants (p = 0.028), as well as between helminth infection and SPT reactivity, 12/18 (66.6%) of uninfected participants compared to 43/108 (39.8%) of helminth-infected participants (p = 0.033). After one year, a significant general increase in allergy and SPT was observed. While only 11/126 (8.7%) were allergic at baseline, 30/115 (26.1%) became allergic at follow-up (p<0.0001), and while 55/126 (43.7%) were SPT+ at baseline, 79/115 (68.7%) became SPT+ at follow-up (p<0.001). A twofold increase in allergen sensitization was also observed after one year in Israel, particularly for dust mites, grasses and olive tree (p<0.001). These results show that: a) Helminth infection is significantly associated with low allergy and low SPT reactivity; b) One year after immigration to Israel, allergy and SPT reactivity increased significantly in all immigrants; c) Higher increases in positive SPT and allergy were observed after a year in the group that remained infected with helminths, even though they had a lowered helminth load; d) The reasons for the increased allergy one year after immigration needs further investigation but probably reflects the combined influence of the decreased helminth load and novel environmental factors.</p></div

Individual allergen sensitization.

<p>(A) Proportion of individuals reacting between 0 and 10 different allergens (McNemar’s test) and (B) Number of allergen sensitizations per individual in the different helminth infections (HI) groups, at baseline and after a year. The distribution of the number of different allergens per individual causing positive SPT responses are represented by the boxes that represent 75% of the data values. The horizontal black line across the box marks the median value. The error bar shows the 90^th percentile of the population. Individual data-points falling beyond that boundary are shown as dots. HI (+,+): individuals with persistent infection after a year, HI (+,-): individuals infected with helminths on arrival and not infected after a year, and HI (-,-): individuals in whom no helminths were found on arrival and after a year. Statistical differences between the groups are shown, p values <0.05 (*), <0.01 (**), and <0.001 (***). ns: not significant. Wilcoxon signed ranks test.</p

Flow chart of the study design.

<p>The groups are divided according to the status of helminth infection (HI) as helminth-infected (HI+) or helminth-uninfected (HI-) on arrival, and compared each individual between entry and after one year of follow up, then divided into three groups according to their HI status: persistent HI [HI(+,+) 69 individuals (60%)], eradicated HI [HI(+,-) 28 individuals (24.3%)], and those without HI [HI (-,-) 18 individuals (15.7%)].</p

Allergy after one year.

<p>The prevalence of allergy (asthma and or allergic rhinitis), positive skin prick test (SPT) and delayed type hypersensitivity responses (PPD) in the whole cohort (A), and in the different groups (B), showing the association between helminth infections (HI) on arrival and after a year in Israel. Helminth infected individuals (n) were divided into three groups; HI (+,+): Individuals infected with helminths on arrival and in whom the infection persisted after a year, HI (+,-): Individuals infected with helminths on arrival that were not infected after a year, and HI (-,-): Individuals in whom no helminths were found on arrival and after a year. Statistical p values <0.05 (*), <0.01 (**), and <0.001 (***). McNemar’s test.</p

Helminth infections (HI) and the prevalence of allergy.

<p>Asthma and/or allergic rhinitis, positive skin prick test (SPT +) and delayed type hypersensitivity responses (PPD +) in the new Ethiopian immigrants on arrival to Israel. (A) The number of individuals in each group (n) and the statistical difference (p), between helminth infected (HI +) and non-infected (HI -) individuals. (B) The prevalence of allergic individuals at baseline and their HI status in absence of helminths (HI-) or in their presence (HI+), differences are shown for individuals with mono or multiple parasites infections. (C) The proportion of skin prick test (SPT) reactivity with the different allergens related to the HI status, is shown at baseline. Statistical p values <0.05 (*), <0.01 (**), and <0.001 (***). Chi square and Fisher’s exact test.</p

Response to allergens.

<p>Prevalence of allergen sensitizations by positive skin prick test (SPT +) to the different allergens are shown at baseline and after a year for the whole cohort. Dust mites <i>dermatophagoides pteronyssinus</i> (DP) and <i>dermatophagoides farina</i> (DF); feather mix (Feath); cockroach (Cockr); cat pelt; dog epithelium; pollens of grass mix; weed mix, olive and cypress trees. Statistical p values <0.05 (*), <0.01 (**), and <0.001 (***). McNemar’s test.</p