eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Transient Hypogammaglobulinemia of Infancy

Author: Alan P Knutsen, MD, Professor of Pediatrics, Allergy and Immunology, Director of Pediatric Clinical Immunology Laboratory, Department of Pathology, St Louis University Health Sciences Center
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Updated: Jun 20, 2008

Introduction

Background

Transient hypogammaglobulinemia of infancy (THI) is a relatively common primary immunodeficiency disease that affects infants and young children. Following birth, maternal immunoglobulin G (IgG) is catabolized, and IgG synthesized by the infant gradually accumulates. Serum levels typically reach their physiologic nadir in infants aged 3-6 months. THI is characterized by decreased serum IgG and immunoglobulin A (IgA) levels less than 2 standard deviations (SDs) from age-adjusted reference range levels in the first years of life but with normal to near-normal antibody responses to protein immunizations. These levels usually increase to the reference range by age 2-6 years in children with THI. Recent studies suggest that THI may be an intrinsic B-cell defect with abnormal antibody responses, especially to Streptococcus pneumoniae, respiratory viruses, and Haemophilus influenzae type B.¹

Pathophysiology

Pathophysiology of THI is unknown. Siegal et al reported that decreased T-helper function in THI accounted for decreased synthesis of IgG and IgA and that no intrinsic B-cell defect was present.² Subsequent studies have reported normal percentages and numbers of CD4+ T cells.^3,1   Dorsey et al reported that the percentage and number of CD19+ B cells are increased;¹ however, in the author's experience, both CD27+ memory B cells and CD27+IgD- switched B cells are decreased.  

Antibody responses in THI vary; the responses to protein immunizations are typically normal, but the responses to polysaccharide and conjugated polysaccharide antigens are typically decreased. Antibody responses to protein immunizations are readily detected in THI, although responses may be lower than healthy controls. In the author's studies, antibody responses to bacterial polysaccharide antigens (S pneumoniae immunizations) were decreased.

Numerous subsequent studies have confirmed that antibody responses to both conjugated and unconjugated S pneumoniae immunizations are decreased.^3,1 Furthermore, antibody titers to viral respiratory infections (eg, influenza virus A and B; adenovirus; mycoplasma; respiratory syncytial virus; parainfluenza virus 1, 2, and 3) were decreased.⁴ These decreased antibody responses probably account for the increased susceptibility to infections in children with THI. 

In 1997, Kowalczyk et al reported increased synthesis of tumor necrosis factor (TNF)-a, TNF-b, and interleukin (IL)-10 (but not IL-1, IL-4, and IL-6) in patients with THI.⁵  When peripheral blood mononuclear cells were stimulated with pokeweed mitogen (PWM), TNF-a and TNF-b inhibited IgG and IgA synthesis. These studies were subsequently confirmed by examination of intracellular cytokine synthesis by Th1/Th2 cells. In CD4+ T cells, increased intracellular expression of TNF-a, TNF-b, and IL-10 was observed in patients with THI.

In addition, interferon-gamma (IFN-g) Th1 T cells were increased in these patients. Furthermore, after normalization of the patients' IgG levels, TNF-a and TNF-b synthesis was decreased, but IL-10 synthesis was unchanged. The authors concluded that an imbalance of increased TNF-α that suppressed IgG and IgA synthesis and IL-10–induced IgG switching may be responsible for THI. 

Dalal et al have identified 3 patterns of antibody responses in patients with low IgG and IgA levels in early infancy.^6,3 In group 1, IgG and IgA levels and antibody responses normalize; this is classified as THI. In group 2, patients continue to have low IgG levels and abnormal protective antibody responses; this is classified as common variable immunodeficiency. In group 3, IgG levels normalize, but protective antibody responses are transient; this is classified as dysgammaglobulinemia. 

Frequency

United States

The exact frequency of THI is unknown, although it has been estimated to be 0.061-1.1 cases per 1,000 live births.^7,8,9  In a nationwide survey in Japan, THI comprised 18.5% of primary immunodeficiency disorders.¹⁰ In this author's experience, THI is a relatively common diagnosis in children referred for evaluation of recurrent infections.¹¹

Mortality/Morbidity

People with THI have increased frequency of upper respiratory tract infections, especially otitis media and sinusitis, and, occasionally, pneumonia. Life-threatening bacterial infections may occur but are infrequent.

Race

THI occurs in people of all races.

Sex

THI inheritance is unknown, and the male-to-female ratio is equal. Patients frequently have a family history of THI and may have a family history of other primary immunodeficiency diseases, such as selective IgA deficiency and common variable immunodeficiency. Tiller and Buckley (1978) reported increased family history of severe combined immunodeficiency (SCID).⁷

Age

THI is a congenital immunodeficiency disorder that manifests after the infant catabolizes maternal-derived IgG, typically by age 6 months. Most children aged 2-6 years outgrow this condition when serum IgG, IgA, and immunoglobulin M (IgM) concentrations normalize, as do antibody responses to both protein and polysaccharide antigens.

Clinical

History

At approximately age 6 months, infants with transient hypogammaglobulinemia of infancy (THI) typically begin to experience increasingly frequent and recurrent otitis media, sinusitis, and bronchial infections. Life-threatening infections with polysaccharide-encapsulated bacteria are unusual. Dalal et al (1998) reported that upper respiratory tract infections occurred in most patients and pneumonia occurred in 23% of patients.³ Infrequently, severe varicella, persistent oral candidiasis, sepsis, and meningitis were seen.

Because antigen-specific antibody responses are largely intact, this likely accounts for the lack of serious bacterial infections observed in THI. In children older than 3 years, the frequency of infections typically diminishes, even if serum immunoglobulin levels have not yet normalized. T cell immunity is intact, and infections with opportunistic microorganisms do not usually occur.

Although some investigators reported that atopic disease is not frequently associated with THI,⁶ , other investigators have reported increased incidence of atopic diseases, such as food allergy, asthma, and allergic rhinitis.^8,11,1 GI allergic-related symptoms may also occur.

Hematologic abnormalities have also been reported in THI; these included neutropenia and thrombocytopenia.⁶ One patient developed acute lymphocytic leukemia (ALL).

Physical

Physical examination findings are typically normal. Tonsils, adenoids, and lymph nodes are normal in patients with THI, which helps to differentiate THI from other congenital intrinsic B-cell immune defects. In X-linked infantile agammaglobulinemia (Bruton agammaglobulinemia) and common variable immunodeficiency, peripheral lymph nodes, tonsillar tissue, and adenoid tissue are hypotrophic. However, hypertrophic tonsillar tissue and splenomegaly may be present in as many as 25% of patients with common variable immunodeficiency. In hyper-IgM syndrome (HIGM), lymphoid hyperplasia and splenomegaly is uniformly present. Growth is typically normal in patients with THI, as it is in most primary B-cell immunodeficiencies.

Causes

The cause of THI is unknown. Siegal et al (1981) reported decreased CD4⁺ T-helper cell function and B-cell synthesis of IgG and IgA in THI; subsequent studies have been able to confirm this.² Kowalczyk et al (1997) reported an imbalance of increased TNF and IL-10 synthesis.¹² Antibody responses to protein antigens are normal or near normal; however, a selective antibody deficiency to bacterial polysaccharide antigens (eg, S pneumoniae immunizations, H influenzae type B) is present with IgA deficiency and IgG-2 subclass deficiency. Increased B cells and decreased memory and switched B cells have been observed. Because most children "outgrow" their immunodeficiency, it appears to be a maturational defect in infants and young children. Therefore, THI may represent a maturational defect affecting CD4⁺ T cells, B cells, and/or antigen-presenting cells.

• Search for CME/CE on This Topic »

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• White Blood Cell Function (Pediatrics: General Medicine)
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• Hypogammaglobulinemia (Allergy and Immunology)