AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

X-linked agammaglobulinemia
B-linked agammaglobulinemia
Hyper-IgM syndrome
Selective IgA deficiency
Antibody deficiency with normal serum immunoglobulins
Secondary immunodeficiency due to loss of IgG and IgA

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• In evaluating transient hypergammaglobulinemia of infancy (THI), serum IgG levels are decreased less than 2 SDs for age-adjusted reference range levels. Often, serum IgA levels are also decreased; however, IgM levels are typically within the reference range. Flow cytometry studies reveal that the percentages and numbers of CD3⁺ and especially CD4⁺ T cells may be slightly decreased but are typically normal. T-cell function assessed by delayed type hypersensitivity (DTH) and in vitro lymphoproliferative responses are normal. Percentages and numbers of CD19+ B cells may be increased; however, in the author's experience, CD27+ memory and CD27+IgD-IgM- switched B cells may be decreased.
• Antibody titers to protein immunizations (eg, tetanus toxoid, diphtheria toxoid, polio) are at normal or near-normal concentrations. This distinguishes THI from more serious B- and T-cell immunodeficiency disorders. However, antibody responses to viral respiratory infections may also be decreased. Furthermore, Dalal and Roifman (2001) reported that antibody responses following immunization may be normal but may not persist on serial determinations.⁶
• In contrast to responses to protein antigens, antibody responses to polysaccharide antigens are often abnormal. In children with THI older than 2 years, Wolpert and Knutsen (1998) observed poor antibody responses to the unconjugated pneumococcal vaccine (Pneumovax); in children with THI younger than 2 years, poor antibody response to the conjugated-pneumococcal vaccine (Prevnar) was observed.¹¹ Dorsey et al (2006) reported that immunizations to conjugated polysaccharide antigens are often subnormal in children with THI.¹ These authors observed decreased antibody responses to both conjugated H influenzae type B vaccine and S pneumoniae immunization in children with THI.
• The serum immunoglobulin pattern of decreased IgG and IgA levels resembles X-linked hyper-IgM (XL-HIGM type 1) syndrome, autosomal recessive CD40 deficiency HIGM (type 2), and common variable immunodeficiency. In HIGM and common variable immunodeficiency, mature B cells are present. In addition, memory and switched B cells are decreased in these conditions, which may be seen in THI as well. However, a severe antibody deficiency distinguishes these conditions from THI. Deficiency of T-cell CD40 ligand (gp39, CD154) is the genetic defect in XL-HIGM, and deficiency of B-cell CD40 is the genetic defect in HIGM type 3. CD40L and CD40 can be analyzed using flow cytometry.
• Deficiency of activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase (UNG) in B cells has been associated with autosomal recessive forms of HIGM that affect B cells (HIGM type 2). Gene analysis of these defects in HIGM can be analyzed by commercial laboratories that specialize in genetic defects.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Transient hypogammaglobulinemia of infancy (THI) treatment is conservative and depends on the severity of infections and the patient's response to therapy. Appropriate antibiotic treatment may be sufficient. However, given emerging evidence that THI is an intrinsic B-cell immunodeficiency, with antibody deficiencies to polysaccharide and conjugated-polysaccharide immunizations (eg, S pneumoniae), treatment with prophylactic antibiotics is reasonable.

Furthermore, in patients with THI who develop severe life-threatening infections or who develop recurrent respiratory tract infections despite antibiotic therapy, a trial of antibody replacement therapy in the form of intravenous immunoglobulin (IVIG) is indicated. Investigators have recommended IVIG for 6-12 months using the usual therapeutic dose of IVIG of 400-800 mg/kg intravenously every 3-4 weeks.^{3, 4} A subcutaneous form of gammaglobulin (Vivaglobin) has become available as an alternative to IVIG. The usual therapeutic dose is 100-200 mg/kg subcutaneously per week. 

Allergic rhinitis contributes to recurrent otitis media and sinusitis. If allergic rhinitis occurs, the child should be aggressively treated with topical nasal corticosteroids and antihistamines.

Routine immunizations are continued in children with THI. Recently, a conjugated heptavalent pneumococcal vaccine has been recommended for routine immunization in children beginning at age 2 months. Whether this immunization can significantly reduce otitis media in children with THI is unclear. The conjugated heptavalent pneumococcal vaccine covers approximately 85% of the serotype responsible for invasive pneumococcal infection in children.

In studies of healthy children, the pneumococcal vaccine significantly eliminated invasive infections but reduced the frequency of otitis media by only 20%. Sorensen et al have reported that a significant percentage of children with a selective antibody deficiency to bacterial polysaccharide antigens following immunization with the unconjugated vaccine (Pneumovax) develop protective antibody levels following immunization to the conjugated vaccine (Prevnar), with a reduction in infections.¹³

Surgical Care

Many of these children are referred to otolaryngologists for placement of tympanostomy tubes for recurrent otitis media and functional endoscopic sinus surgery (FESS) for chronic sinusitis. Tympanostomy tubes are of uncertain benefit in the prevention of recurrent otitis media, and the potential adverse anatomic and audiologic sequelae of tube placement must be considered. Likewise, some have suggested that FESS is not the cure for chronic sinusitis but that the underlying immunodeficiency disease must be appropriately treated.

Consultations

These children need to be referred to an allergist, immunologist, or both to evaluate for THI and to ascertain that another immunodeficiency is not present. A definitive diagnosis of THI is a retrospective diagnosis when the immunodeficiency resolves. These patients need to be evaluated over time.

Atopic diseases associated with THI need to be looked for and treated.

Diet

No special diet is required unless a food allergy is present.

Activity

The child should not attend a daycare center to reduce his or her increased susceptibility to infections. However, physicians need to consider each family's dynamics and economic situation when giving this recommendation.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Choose antibiotics to cover S pneumoniae, H influenzae, and Moraxella catarrhalis (eg, amoxicillin, second-generation cephalosporins, clarithromycin). Often, prophylactic antibiotics decrease infections. IVIG is rarely needed and is used only when the patient continues to have infections despite antibiotics.

Drug Category: Immunoglobulins

IVIG or subcutaneous immune globulin is used for antibody replacement therapy.

Drug Category: Vaccines

These agents are used to induce active immunity.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Confirm initial diagnosis by measuring serum immunoglobulin levels annually until levels normalize.
• As discussed above, treatment of infections and modalities to reduce infections should be instituted. Treatment of allergic disorders should also be instituted.
• With appropriate treatment, these children can be considered healthy. The prognosis for transient hypogammaglobulinemia of infancy (THI) is quite good. Most children outgrow this immune deficiency when aged 2-6 years. However, THI is a diagnosis that is made retrospectively when serum immunoglobulin levels normalize and all antibody responses are normal.
• The immune system is periodically evaluated, usually at yearly intervals.

Prognosis

• Long-term prognosis for patients with THI is excellent; the immune system becomes normal in patients by age 2-6 years.
• Serious life-threatening infections in patients with THI are rare.

Patient Education

• Inform parents that THI is an immunodeficiency that eventually self-corrects because it is a maturational immunodeficiency.
• Also inform parents that patients are unlikely to have serious life-threatening infections.
• In addition, many infants with THI have or develop concomitant allergic diseases.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to differentiate transient hypogammaglobulinemia of infancy (THI) from other, more severe, forms of B-cell immunodeficiency such as Bruton agammaglobulinemia, common variable immunodeficiency, and HIGM has serious consequences because patients with more severe B-cell defects are susceptible to serious life-threatening bacterial infections that require IVIG therapy.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Dorsey MJ, Orange JS. Impaired specific antibody response and increased B-cell population in transient hypogammaglobulinemia of infancy. Ann Allergy Asthma Immunol. Nov 2006;97(5):590-5. [Medline].
2. Siegel RL, Issekutz T, Schwaber J, et al. Deficiency of T helper cells in transient hypogammaglobulinemia of infancy. N Engl J Med. Nov 26 1981;305(22):1307-13. [Medline].
3. Dalal I, Reid B, Nisbet-Brown E, Roifman CM. The outcome of patients with hypogammaglobulinemia in infancy and early childhood. J Pediatr. Jul 1998;133(1):144-6. [Medline].
4. Cano F, Mayo DR, Ballow M. Absent specific viral antibodies in patients with transient hypogammaglobulinemia of infancy. J Allergy Clin Immunol. Feb 1990;85(2):510-3. [Medline].
5. Kowalczyk D, Mytar B, Zembala M. Cytokine production in transient hypogammaglobulinemia and isolated IgA deficiency. J Allergy Clin Immunol. Oct 1997;100(4):556-62. [Medline].
6. Dalal I, Roifman CM. Hypogammaglobulinemia of infancy. Immunol Allergy Clin North Am. 2001;21:129-39.
7. Tiller TL, Buckley RH. Transient hypogammaglobulinemia of infancy: review of the literature, clinical and immunologic features of 11 new cases, and long-term follow-up. J Pediatr. Mar 1978;92(3):347-53. [Medline].
8. Walker AM, Kemp AS, Hill DJ, Shelton MJ. Features of transient hypogammaglobulinaemia in infants screened for immunological abnormalities. Arch Dis Child. Mar 1994;70(3):183-6. [Medline].
9. Dressler F, Peter HH, Muller W, Rieger CH. Transient hypogammaglobulinemia of infancy: Five new cases, review of the literature and redefinition. Acta Paediatr Scand. Sep 1989;78(5):767-74. [Medline].
10. Hayakawa H, Iwata T, Yata J, Kobayashi N. Primary immunodeficiency syndrome in Japan. I. Overview of a nationwide survey on primary immunodeficiency syndrome. J Clin Immunol. Jan 1981;1(1):31-9. [Medline].
11. Wolpert J, Knutsen AP. Natural history of selective antibody deficiency to bacterial polysaccharide antigens in children. Pediatr Asthma, Allergy, Immunol. 1998;12:183-191.
12. Hsueh KC, Chiu HH, Lin HC, et al. Transient hypogammaglobulinemia of infancy presenting as Staphylococcus aureus sepsis with deep neck infection. J Microbiol Immunol Infect. Apr 2005;38(2):141-4. [Medline].
13. Sorensen RU, Leiva LE, Giangrosso PA, et al. Response to a heptavalent conjugate Streptococcus pneumoniae vaccine in children with recurrent infections who are unresponsive to the polysaccharide vaccine. Pediatr Infect Dis J. Aug 1998;17(8):685-91. [Medline].
14. Castigli E, Wilson SA, Scott S, et al. TACI and BAFF-R mediate isotype switching in B cells. J Exp Med. Jan 3 2005;201(1):35-9. [Medline].
15. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. Jul 1999;92(1):34-48. [Medline].
16. Dogu F, Ikinciogullari A, Babacan E. Transient hypogammaglobulinemia of infancy and early childhood: outcome of 30 cases. Turk J Pediatr. Apr-Jun 2004;46(2):120-4. [Medline].
17. Kowalczyk D, Baran J, Webster AD, Zembala M. Intracellular cytokine production by Th1/Th2 lymphocytes and monocytes of children with symptomatic transient hypogammaglobulinaemia of infancy (THI) and selective IgA deficiency (SIgAD). Clin Exp Immunol. Mar 2002;127(3):507-12. [Medline].
18. Mayer L, Posnett DN, Kunkel HG. Human malignant T cells capable of inducing an immunoglobulin class switch. J Exp Med. Jan 1 1985;161(1):134-44. [Medline].
19. McGeady SJ. Transient hypogammaglobulinemia of infancy: need to reconsider name and definition. J Pediatr. Jan 1987;110(1):47-50. [Medline].
20. Oxelius VA. IgG subclass pattern in primary immunodeficiency disorders. Monogr Allergy. 1986;19:156-63. [Medline].
21. Salzer U, Maul-Pavicic A, Cunningham-Rundles C, et al. ICOS deficiency in patients with common variable immunodeficiency. Clin Immunol. Dec 2004;113(3):234-40. [Medline].
22. Sneller MC. Common variable immunodeficiency. Am J Med Sci. Jan 2001;321(1):42-8. [Medline].
23. Sneller MC, Strober W, Eisenstein E, et al. NIH conference. New insights into common variable immunodeficiency. Ann Intern Med. May 1 1993;118(9):720-30. [Medline].
24. Whelan MA, Hwan WH, Beausoleil J, et al. Infants presenting with recurrent infections and low immunoglobulins: characteristics and analysis of normalization. J Clin Immunol. Jan 2006;26(1):7-11. [Medline].

Article Last Updated: Jun 20, 2008