OVERVIEW: What every practitioner needs to know

Are you sure your patient has transient hypogammaglobulinemia of infancy? What are the typical findings for this disease?

Transient hypogammaglobulinemia of infancy (THI) is a relatively common primary immunodeficiency disease that affects infants and young children. THI is characterized by decreased serum immunoglobulin (Ig)G levels with or without decreased IgA and IgM levels less than 2 standard deviations (SDs) from age-adjusted reference range levels in infants older than 6 months of age in the first years of life but with normal to near-normal antibody responses to immunization with protein antigens.

Other primary immunodeficiency disorders also need to be excluded. The IgG levels usually increase to the normal 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.

Patients with THI may be symptomatic or asymptomatic. Children with THI typically begin to experience increasingly frequent and recurrent otitis media, sinusitis, and bronchial infections. Approximately 5% of infants with THI are symptomatic when they are younger than 6 months, 50% become symptomatic at 6-12 months, and 25% become symptomatic when they are older than 12 months. Dalal et al reported that recurrent upper respiratory tract infections occurred in most patients and recurrent pneumonia occurred in 23% of patients.

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Life-threatening infections such as bacteremia, sepsis, or meningitis resulting from polysaccharide-encapsulated bacteria (S. pneumoniae, H. influenzae) may occur but are unusual. Infrequently, severe varicella, persistent oral candidiasis, or other opportunistic infections have been seen.

What other disease/condition shares some of these symptoms?

Diagnosis and Management of Transient Hypogammaglobulinemia of Infancy

Other B-cell immunodeficiencies must be excluded. These include X-linked agammaglobulinemia (Bruton agammaglobulinemia), common variable immunodeficiency (CVID), and hyper-IgM syndromes (HIGM). Combined T- and B-cell immunodeficiency must be excluded, such as severe combined immunodeficiency (SCID).

Decreased serum IgG and IgA levels may also occur in disorders of serum protein loss, such as protein-losing enteropathy (PLE) and nephrotic syndrome, and these conditions must also be excluded.

What caused this disease to develop at this time?

The cause of THI is unknown.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

IgG, IgA, IgM serum levels should be ordered. The serum IgG level is decreased to less than 2 SD for age-adjusted reference range levels. Often, serum IgA levels are also decreased; however, IgM levels are typically within the reference range.

Antibody titers to protein immunizations (eg, tetanus toxoid, diphtheria toxoid, polio) are normal or nearly normal. This distinguishes THI from most of the more serious B- and T-cell immunodeficiency disorders.

Antibody responses to polysaccharide antigens are often abnormal. Specific immunization with purified polysaccharide H. influenzae type B vaccine (unconjugated vaccine) and/or unconjugated polysaccharide of S. pneumoniae (Pneumovax) are often subnormal in children with THI.

Memory and switched B cells. CD19+CD27+ memory B cells and IgM-IgD-CD27+ switched B cells are decreased in many of the B-cell immunodeficiencies, such as CVID, HIGM syndrome, and selective antibody deficiency. Decreased memory and switched B cells have been observed in some children younger than 5 years with symptomatic THI.

CD3+, CD4+, CD8+ T cells and T-cell function. Determination of CD3+, CD4+, CD8+ T-cell percentages and absolute numbers by flow cytometry and measurement of T-cell function either by delayed-type hypersensitivity skin testing to Candida albicans and tetanus toxoid and/or in vitro lymphoproliferative responses to mitogens and antigens should be performed as well to exclude a T-cell immunodeficiency.

Would imaging studies be helpful? If so, which ones?

Imaging studies are not helpful except as indicated to assist in the diagnosis of infection associated with THI.

If you are able to confirm that the patient has this disease, what treatment should be initiated?

Treatment of THI is conservative and depends on the severity of infections and the patient’s response to therapy. Appropriate antibiotic treatment for individual specific infections may be sufficient. However, given emerging evidence that THI is an intrinsic B-cell immunodeficiency, with antibody deficiencies to polysaccharide immunizations (eg, S. pneumoniae), a trial of prophylactic antibiotics is often considered necessary in the patient with THI who is having more frequent or serious recurrent infections.

In patients with THI in whom severe life-threatening infections or recurrent respiratory tract infections develop despite antibiotic therapy, a trial of antibody replacement therapy in the form of intravenous immunoglobulin (IVIG) is indicated. A trial of IVIG consists of the usual therapeutic dose of 400-800 mg/kg intravenously every 3-4 weeks for 6-12 months, with an objective reevaluation of risks and benefit.

A subcutaneous form of gammaglobulin (SCGG) has become available as an alternative to IVIG. The usual therapeutic dose is 100-200 mg/kg subcutaneously per week. AS with IVIG, a time-limited trial on this therapy, followed by an objective reassessment of clinical benefit, is indicated.

What are the adverse effects associated with each treatment option?

Antibiotics: The potential adverse reactions to antibiotics, whether administered for acute infections or prophylactically, include drug allergy, selection of antibiotic-resistant bacteria, and gastrointestinal disorders. Gastrointestinal problems may include Clostridium difficile infection and antibiotic-induced diarrhea. The use of probiotics, such as Lactobacillus, may be helpful in alleviating the antibiotic-induced diarrhea resulting from alteration of bacterial flora.

IVIG/SCGG: Side effects of IVIG therapy include infusion reactions that include fever, chills, fever, and backache. This typically occurs from infusing the IVIG at a rapid rate and often responds to simply slowing the infusion rate. Headaches either during or after the IVIG adminstration are common and can be troublesome to treat.

Anaphylactic and anaphylactoid reactions to IVIG may occur, requiring immediate treatment. Other serious adverse events related to IVIG administration include aseptic meningitis/encephalitis, renal failure, hyperviscosity syndrome, and thromboembolic events. The suspected causes of these adverse events include high osmolality of the IVIG preparation, sucrose-containing IVIG, and high-dose IVIG therapy. Transmission of hepatitis C virus is a risk, but improved processing has lessened this risk significantly.

The side effects of SCGG are typically redness and swelling at the subcutaneous administration site, which usually resolves within 24-48 hours.

The duration of treatment with IVIG/SCGG that might be necessary and beneficial is uncertain. Therefore it is important to discontinue IVIG/SCGG periodically and reevaluate the patient’s B-cell immune system about every 6-12 months. Serial measurements of memory and switch B cells may also be helpful. When these levels improve, discontinuation of IVIG/SCGG and close clinical follow-up and reevaluation is indicated.

What are the possible outcomes of this disease?

The majority of children “outgrow” THI between 2 and 6 years of age. Dorsey and Orange reported that normalization of IgG levels occurred at a mean age of 27 months, with a median age of 23 months. The IgG levels in this study normalized in 50% of patients with THI by 24 months of age and in an additional 25% by 5 years of age, but 25% failed to normalize by 5 years of age.

What causes this disease and how frequent is it?

The exact frequency of THI is unknown, although it has been estimated to be 0.061-1.1 cases/1000 live births. In a nationwide survey in Japan, THI composed 18.5% of primary immunodeficiency disorders. Whelan et al and Ji-hong et al reported a male preponderance with a male-female ratio of approximately 2:1.

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 reported an increased family history of SCID.

Siegal et al reported decreased CD4+ T-helper cell function and B-cell synthesis of IgG and IgA in THI.

Kowalczyk et al reported an imbalance of increased tumor necrosis factor (TNF)-α, TNF-β, and interleukin (IL)-10 synthesis. Increased TNF-α and TNF-β suppressed in vitro IgG and IgA synthesis. IL-10–induced IgG switching may be responsible for THI.

What complications might you expect from the disease or treatment of the disease?

The major complications are related to recurrent/chronic infections. These include mastoiditis, perforated tympanic membranes, chronic sinusitis, recurrent pneumonias, and bronchiectasis. Rarely, serious life-threatening infections may occur such as sepsis and meningitis.

How can this disease be prevented?

Transient hypogammaglobulinemia of infancy cannot be prevented.

What is the evidence?

Dorsey, MJ, Orange, JS. “Impaired specific antibody response and increased B-cell population in transient hypogammaglobulinemia of infancy”. Ann Allergy Asthma Immunol. vol. 97. 2006. pp. 590-5.

Dalal, I, Reid, B, Nisbet-Brown, E. “The outcome of patients with hypogammaglobulinemia in infancy and early childhood”. J Pediatr. vol. 133. 1998. pp. 144-6.

Wolpert, J, Knutsen, AP. “Natural history of selective antibody deficiency to bacterial polysaccharide antigens in children”. Pediatr Asthma Allergy Immunol. vol. 12. 1998. pp. 183-91.

Dogu, F, Ikinciogullari, A, Babacan, E. “Transient hypogammaglobulinemia of infancy and early childhood: outcome of 30 cases”. Turk J Pediatr. vol. 46. 2004. pp. 120-4.

Ji-hong, Q, Jian-xing, Z, Xiao-dong, Z. “Clinical features and follow-up of Chinese patients with symptomatic hypogammaglobulinemia in infancy”. Chin Med J. vol. 122. 2009. pp. 1877-83.

Cano, F, Mayo, DR, Ballow, M. “Absent specific viral antibodies in patients with transient hypogammaglobulinemia of infancy”. J Allergy Clin Immunol. vol. 85. 1990. pp. 510-3.

Siegel, RL, Issekutz, T, Schwaber, J. “Deficiency of T helper cells in transient hypogammaglobulinemia of infancy”. N Engl J Med. vol. 305. 1981. pp. 1307-13.

Kowalczyk, D, Mytar, B, Zembala, M. “Cytokine production in transient hypogammaglobulinemia and isolated IgA deficiency”. J Allergy Clin Immunol. vol. 100. 1997. pp. 556-62.

Whelan, MA, Hwan, WH, Beausoleil, J. “Infants presenting with recurrent infections and low immunoglobulins: characteristics and analysis of normalization”. J Clin Immunol. vol. 26. 2006. pp. 7-11.