A Prospective Study on Children with Initial Diagnosis of Transient Hypogammaglobulinemia of Infancy: Results from the Italian Primary Immunodeficiency Network

Abstract

Transient hypogammaglobulinemia of infancy (THI) is a heterogeneous disorder characterized by reduced serum IgG levels in early infancy. A putative diagnosis is initially made after exclusion of other causes of hypogammaglobulinemia while a definitive diagnosis of THI can only be made a posteriori in patients with normalization of IgG levels. The aim of this study is to characterize clinical and immunological features of children with an initial diagnosis of THI in correlation to natural outcome, and to assess predictive laboratory parameters of clinical evolution for this disorder. We prospectively analysed clinical and immunological characteristics of 77 THI children at initial diagnosis and of 57 patients at follow-up. Memory B cell subsets and in vitro immunoglobulin production were evaluated. Seventy patients (91 percent) showed clinical symptoms. Patients suffered from infections (91 percent), allergies (47 percent) and autoimmune disease (4 percent). During follow-up 41/57 children (72 percent) normalized IgG values, mostly within 24 months of age (p less than 0.001), allowing the diagnosis of THI. The 16 children who did not normalize their IgG levels showed a higher frequency of severe infections and autoimmune disease (p less than 0.01). Moreover, they expressed a reduced frequency of IgM and switched memory B cells (p less than 0.01) and an inability to produce IgG in vitro (p less than 0.02). We conclude that most patients with an initial diagnosis of THI spontaneously recover within 24 months of age and have a benign clinical course, while a subgroup of children with undefined hypogammaglobulinemia share a clinical and immunological profile with other primary immunodeficiencies. Early recognition of children with hypogammaglobulinemia during infancy who are likely to suffer from permanent immunodeficiencies later in life would allow prompt and appropriate laboratory and clinical interventions.

Evolution of Hypogammaglobulinemia in Premature and Full-Term Infants

“…In agreement with the literature (13,(15)(16), the main clinical feature in patients with THI were respiratory infections; however, all children had a benign clinical course. Five patients underwent IVIG because they had severe clinical symptoms in winter, a period of high morbidity.…”

Phenotypic Parameters Predict Time to Normalization in Infants with Hypogammaglobulinemia

“…It is important to discriminate between infants who are likely to have early resolution of hypogammaglobulinemia and infants who are likely to have persistence because there is evidence that infants with prolonged unresolved hypogammaglobulinemia are more likely to have recurrent infection and autoimmune problems. [7] This study confirms an easily understood hypothesis: infants with mild or moderate decreases in initial aggregate immunoglobulin levels or IgG levels alone are more likely to outgrow their immunologic deficiency and to do so sooner when compared to infants with greater decreases in immunoglobulin levels. Not surprisingly, infants with higher initial aggregate immunoglobulin levels have a greater probability of prompt resolution.…”

“…[6] Without question, some Infants with hypogammaglobulinemia will not have resolution of their deficiency and those infants with persistent hypogammaglobulinemia may be at increased risk for recurrent infection and autoimmune disease. [7] At the time of initial recognition of hypogammaglobulinemia in an infant, since this may be physiologic, immunologists are often finding with clinically relevant questions regarding the likely duration of hypogammaglobulinemia. Previous studies have shown that males are more likely than females to have resolution of hypogammaglobulinemia during infancy, [8] however, other than this observation, there has been little information that would allow an informed prediction about the probable time to resolution to hypogammaglobulinemia.…”

Five years of experience in transient hypogammaglobulinemia of infancy

“…Bu olgularda, serum IgG düzeyi yaşa göre ortalamanın 2 standart sapma değerinin altındadır. Daha sonra Ig düzeyleri yükselir ve genelde yaşamın 30.-40. aylarında normal değere ulaşır (3,7) . Bazı olgularda bu süre 6 yaşına kadar da uzayabilir (6) .…”