Impaired specific antibody response and increased B-cell population in transient hypogammaglobulinemia of infancy

Division of Immunology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology (Impact Factor: 2.6). 12/2006; 97(5):590-5. DOI: 10.1016/S1081-1206(10)61085-X
Source: PubMed


Transient hypogammaglobulinemia of infancy (THI) is a heterogeneous disorder with poorly understood pathophysiology.
To better characterize THI and improve understanding of its pathophysiology.
Twenty-four children with hypogammaglobulinemia defined by an IgG level less than 2 SDs below the mean on 2 occasions, who did not have other immunologic diagnoses, were followed and retrospectively reviewed.
The average z-score for IgG level at presentation was -2.4 (mean age, 12 months; median age, 8 months), with a mean level of 254 mg/dL. Thirteen of 24 patients had IgA levels less than 2 SDs below the mean, 5 had IgM levels less than 2 SDs below the mean, and 7 of 23 had elevated IgE levels. Eighteen were followed up until their IgG levels normalized (mean age, 27 months; median age, 23 months), with 12 of 18 normalizing by 24 months and the remainder by 59 months. There was a significant association between presenting IgG z-score and duration of disease (P = .05). Five of the 18 patients had absolute CD19+ B-cell counts greater than the 95% percentile for age (P < .001), and the mean percentage and absolute CD19+ B-cell count across all patients were greater than those of the age-matched controls (P = .02). Most patients had nonprotective titers to Haemophilus influenzae type b vaccine, and one third had nonprotective titers to tetanus vaccine. Twenty patients carried at least one atopic diagnosis, and 13 of those had recurrent wheezing.
THI is associated with a number of immunologic abnormalities beyond just hypogammaglobulinemia. These abnormalities include impaired specific antibody responses and increased proportions of CD19+ B cells and may be suggestive of particular immunologic mechanisms that result in hypogammaglobulinemia.

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    • "Recurrent infections are the most common reasons for morbidity and hospitalization, and are frequently related to humoral immunodeficiencies. Physicians often prefer antibiotic prophylaxis or follow up without medication, but some authors proposed that the lack of specific antibodies should be used in the decision making process when treating THI patients with IVIg.7,15 Duse et al.16 suggested that IVIg should be used in severely symptomatic children in order to stop the vicious circle of infection-immunodeficiency. "
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    ABSTRACT: Transient hypogammaglobulinemia of infancy (THI) is characterized by recurrent infections and one or more reduced serum immunoglobulin levels. Typically, THI patients recover spontaneously, mostly within 30-40 months of age, but sometimes recovery may be delayed until 5-6 years of age. The use of intravenous immunoglobulin (IVIg) as an alternative to antibiotic prophylaxis remains contraversial also in symptomatic THI patients. In fact, some authors believe that IVIg therapy may cause a delay in the maturation of the humoral immune system because of the interference from passively transfered antibodies. The aim of this study was to investigate the effect of IVIg replacement on recovery from immunodeficiency in THI patients and determine new parameters in order to include these patients in IVIg therapy groups. In this retrospective study, 43 patients (65%) received IVIg replacement therapy while 23 patients (34.8%) showed spontaneous normalization without IVIg. The percentages of patients who had more than six times the number of febrile infections in a year decreased from 91% to 21% in the group receiving IVIg treatment. At admission, before being recruited to IVIg therapy, serum immunoglobulin G (IgG) levels and anti-hemophilus B (Hib) antibody titers were found to be significantly low in cases who were selected for IVIg replacement. The percentages of patients who did not have protective levels of anti-Hib, anti-rubella or anti-rubeola-IgG were also significantly high in IVIg cases. There was no statistically significant difference in the age at which IgG levels normalized between the IVIg and the non-IVIg group. Patients in the IVIg group and non-IVIg group reached normal IgG levels at the age of 42.9±22.0 and 40.7±19.8 months, respectively. In conclusion, IVIg infusions do not cause a delay in the maturation of the immune system in THI patients. Besides the well-established criteria, very low and non-protective specific antibody responses against previously applied vaccines are important factors to consider when selecting patients for IVIg therapy.
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    ABSTRACT: Hypogammaglobulinemia has been described as a secondary consequence of many disorders. It is also the seminal finding in many primary immune deficiencies. There are few studies examining the global etiologies of hypogammaglobulinemia. This study undertook a database discovery of all cases of laboratory-defined hypogammaglobulinemia identified in a large tertiary care pediatric hospital setting between August of 1990 until June of 2006. Eight thousand three hundred and four IgG levels were sent during that time frame. One thousand two hundred and ninety-five specimens from 680 individual patients exhibited hypogammaglobulinemia and these patients represent the study population. The majority of cases in whom an identifiable cause was found had pre-existing conditions and the IgG level was sent as part of a monitoring process. Of the 366 patients who had an IgG level obtained for diagnostic purposes, nearly half were found to have an immune deficiency. One hundred and seventy-two patients with an immune deficiency were identified. Seven percent of these had severe combined immune deficiency. Seventy-four percent of the immune deficient patients identified required active intervention with IVIG, bone marrow transplantation or other management (not including prophylactic antibiotics). Evaluating all patients with IgG levels less than half of the lower limit for age revealed 122 patients of whom 33% had a primary immune deficiency. This study provides a framework for considering causes of hypogammaglobulinemia. At the study institution, hypogammaglobulinemia was found most often as a secondary immune deficiency due to chemotherapy or from complex cardiac anomalies. The magnitude of the secondary hypogammaglobulinemia in a tertiary care setting requires public health consideration as these patients have an unknown risk of infection and an unknown risk of prolonged viral shedding; issues which could be important in epidemic settings.
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