| Transient Hypogammaglobulinemia of Infancy | |
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Edited by Ann O'Neill, Shigeoka, MD, Associate Clinical Professor, Department of Pediatrics, Division of Immunology-Rheumatology, University of Utah School of Medicine, Primary Children's Medical Center; Robert Konop, PharmD, Pediatric Clinical Pharmacy Specialist Manager, Clinical Assistant Professor, Section of Clinical Pharmacy, Regions Hospital; Bettina C Hilman, MD, Chief, Pulmonary and Allergy, Professor, Department of Pediatrics, Louisiana State University Medical Center; Daniel Rauch, MD, Program Director, Assistant Professor, Department of Pediatrics, Albert Einstein College of Medicine, Jacobi Medical Center; and Maureen Strafford, MD, Director, Associate Professor, Department of Anesthesiology and Pediatrics, New England Medical Center, The Floating Hospital for Children
| Author's Email: | Alan P Knutsen, MD | Topic Last Updated: |
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| Editor's Email: | Ann O'Neill, Shigeoka, MD | 06/26/2000 11:14:19 |
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Background: Transient hypogammaglobulinemia of infancy (THI) is a relatively common primary immunodeficiency disorder affecting infants and young children. Following birth, maternal IgG is catabolized and there is a gradual accumulation of IgG synthesized by the infant. Thus, the physiological nadir of serum levels is typically reached at 3- to 6 months of age. Transient hypogammaglobulinemia of infancy is characterized by decreased serum IgG and IgA levels less than 2 standard deviation of the age-adjusted normal levels in the first years of life, which increase to a normal levels usually between 2 to 6 years of age.
Pathophysiology: Siegal et al reported that there was decreased T helper function in THI that accounted for decreased synthesis of IgG and IgA and that there was not an intrinsic B cell defect. This is in contrast to other B cell immunodeficiency disorders, such as Bruton's agammaglobulinemia and common variable immunodeficiency disease, in which there is an intrinsic B cell defect accounting for the hypogammaglobulinemia. In THI, antibody responses to immunizations are readily detectable, though may be decreased compared to normal controls. In our studies, antibody responses to bacterial polysaccharide antigens, S. pneumoniae immunizations, are decreased. Thus, this disorder may represent a maturational defect of T helper function of B-cell IgG synthesis and response to bacterial polysaccharide antigens.
Frequency:
Mortality/Morbidity: Patients with THI have an increased frequency of upper respiratory infections, especially otitis media and sinusitis, but usually do not have pneumonias or life-threatening bacterial infections.
Race: THI occurs in all races.
Sex: The inheritance of THI is unknown and affects males and female equally. There is frequently a family history of THI. In addition, there may be a family history of other primary immune deficiency disorders, such as SCID.
Age: THI is a congenital immune deficiency disorder that manifests itself after maternal-derived IgG is catabolized by the infant, typically 6 months of age. Children typically "outgrow" this disorder between 3 to 6 years of age. At this time serum IgG, IgA and IgM concentrations are normal as well as antibody responses to both protein and polysaccharide antigens.
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History: Patients with THI typically have an onset of increased frequency of infections beginning at approximately 6 months of age. The infections involve recurrent otitis media, sinusitis, bronchitis. Pneumonias and life-threatening infections with polysaccharide encapsulated bacteria are unusual. Since T cell immunity is intact, infections with opportunistic microorganisms are not observed. Since antigen-specific antibody responses are largely intact, this probably accounts for the lack of serious bacterial infection observed in THI. Typically after age 3, the frequency of infections diminishes even if serum immunoglobulin levels have not normalized. There is an increased incidence of atopy in patients with THI, such as allergic rhinitis and asthma.
Physical: Physical examination is largely normal. In Bruton's agammaglobulinemia and common variable immunodeficiency disease, peripheral lymphoid node and tonsillar tissue is decreased in size. In THI, tonsils and lymph nodes are normal, which aids in differentiating THI from other congenital intrinsic B cell immune defects.
Causes: Siegal et al reported that CD4+ T helper cells and function on B cell IgG and IgA synthesis were decreased in THI. We have reported that there is a selective antibody deficiency to bacterial polysaccharide antigens, e.g., S. pneumoniae immunizations, in patients with THI, IgA/IgG-2 and IgG-2 subclass deficiency. In infants and young children this appeared to be a maturational defect, as the majority of children "outgrew" this deficiency. Thus, THI may represent a maturation defect affecting CD4+ T cells and/or CD1 antigen presenting cells.
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Other Problems to be Considered:
THI needs to be differentiated from other hypogammaglobulinemic diseases that are due to intrinsic B-cell immune deficiencies. In THI, mature B cells are present and antibody responses to protein antigens are intact. This distinguishes THI from X-linked agammaglobulinemia (Bruton's gammaglobulinemia), which is due to a defect of B cell tyrosine kinase (BTK) which interfers with the differentiation of bone marrow stem into mature B cells. Thus, in Bruton's agammaglobulinemia there are no mature B cell in the periphery, near absence of serum IgG, IgA and IgM, and a severe antibody deficiency. In the other intrinsic B cell immune deficiency disorders, mature B cell are present but antigen-specific antibody responses to protein and bacterial polysaccharide antigens are absent to markedly diminished. In protein-losing enteropathies and nephrotic syndrome, serum IgG and IgA levels are decreased, but so is serum albumin and the clinical symptoms are usually obvious.
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Lab Studies:
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Procedures:
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Medical Care: The treatment of THI is conservative and depends upon the severity of infections and response to therapy. Often, appropriate antibiotic treatment is sufficient. Sometimes prophylactic antibiotics are given to prevent. Only rarely is antibody replacement therapy with IVIG given. If allergic rhinitis is present, this should be aggressively treated with topical nasal corticosteroids and antihistamines as this will contribute to recurrent otitis media and sinusitis.
Surgical Care: None needed.
Consultations: Allergy/Immunology consultation.
Diet: No special diet required.
Activity: No restriction of activities.
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Appropriate antibiotics for bacterial infections. Often prophylactic antibiotic usuage will decrease the infections. Only rarely is IVIG needed when the patient continues to have infections despite antibiotics.
Drug Category: Antibiotics - Antibiotics that have coverage for S. pneumoniae, H. influenzae, and C. moraxella are chosen. Typically, these include amoxacillin, 2nd generation cephalosporins, clarithomycin.Drug Category: intravenous immunoglobulin (IVIG) - IVIG is an intravenous preparation of IgG antibodies with trace amount of other plasma proteins, such as IgA. Treatment with IVIG is antibody replacement therapy.
| Drug Name | IVIG - The dosage of IVIG is 300-600 mg/kg of body weight. IVIG is given as an intravenous infusion beginning at a slow rate and gradually increasing the infusion rate. Potential side-effects on IVIG therapy are allergic reactions, e.g. anaphylaxis, urticaria. More common are rate-related reactions, consisting of fever, chills, muscle aches, nausea, and vomiting. |
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| Pregnancy | A - Safe in pregnancy |
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CME Question 1: Which of the following are characteristic of transient hypogammaglobulinemia of infancy? A: Low serum IgG, IgA and IgM concentrations B: Absent B-cells C: Normal antibody titers to protein antigens D: Normal T-helper cell number and function E: Abnormal T-cell cell mediated immunity
The correct answer is C: In THI, serum IgG and IgA levels are low, but IgM levels are normal. Mature B-cells are normal. Antibody responses to protein antigens, such as tetanus toxoid, are normal. The pathophysiology of THI is due to decreased T helper functions
CME Question 2: Which of the following is not true of transient hypogammaglobulinemia of infancy? A: Family history of immune deficiency B: Personal history of atopic diseases C: Susceptibility to invasive life-threatening bacterial infections D: Susceptibility to recurrent/chronic upper respiratory tract infections E: IVIG antibody replacement therapy is sometimes used
The correct answer is C: Serious life-threatening infectins typically do not occur in THI. Antibody responses to antigens are normal or near normal for age and afford protection.
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NOTE:
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