SUMMARY
1. Transient Hypogammaglobulinemia of Infancy (THI) refers to a prolongation of the physiologic hypogammaglobulinemia which typically occurs between 3-6 months of life.
2. THI is characterized by low IgG levels but normal or low normal vaccine antigen responses. In one study of 24 patients, most had low H. Influenzae titers and one-third had low tetanus titers. THI remains a diagnosis of exclusion and the absence of other primary immunodeficiencies (XLA, HIGM, CVID) must be documented.
3. Many patients with THI are asymptomatic. However, some patients can present with recurrent bacterial sinopulmonary infections.
4. Laboratory testing reveals low IgG levels (2 SD or more below the mean) with decreased or normal IgM and IgA levels. Vaccine responses are normal or low normal (patients with CVID have low IgG and absent vaccine response). Patients with low vaccine antibody levels should be revaccinated and levels re-checked 4-6 weeks later.
5. Spontaneous improvement in IgG levels typically occurs by 18 months of age. However, recovery may not occur in some patients until 5 years of age.
6. It should be noted that the normal physiologic IgG nadir is significantly more pronounced in premature infants (maternal IgG transfer peaks during the 3rd trimester). However, most typically do not have an increased incidence of infections despite low IgG levels.
7. Patients who are asymptomatic do not require therapy. Antibiotic prophylaxis (ex. amoxicillin 20 mg/kg divided twice daily) can be considered for patients who suffer from recurrent sinopulmonary infections
8. In rare cases, IVIG replacement therapy can be considered for patients who continue to have severe infections despite antibiotic prophylaxis therapy. This therapy should not be continued indefinitely - cessation of IVIG within 1-2 years to assess endogenous antibody levels and vaccine responses is recommended.
9. Patients suspected of having THI should be followed longitudinally and have quantitative immunoglobulin levels and vaccine antibody responses checked every 6-12 months until resolution can be documented.
OVERVIEW
Transient Hypogammaglobulinemia of Infancy (THI) refers to a prolongation of the physiologic hypogammaglobulinemia which typically occurs between 3-6 months of life.
THI is characterized by low IgG levels but normal or low normal vaccine antigen responses. In one study of 24 patients, most had low H. Influenzae titers and one-third had low tetanus titers. THI remains a diagnosis of exclusion and the absence of other primary immunodeficiencies (XLA, HIGM, CVID) must be documented.
Many patients with THI are asymptomatic. However, some patients can present with recurrent bacterial sinopulmonary infections.
Laboratory testing reveals low IgG levels (2 SD or more below the mean) with decreased or normal IgM and IgA levels. Vaccine responses are normal or low normal (patients with CVID have low IgG and absent vaccine response). Patients with low vaccine antibody levels should be revaccinated and levels re-checked 4-6 weeks later.
Spontaneous improvement in IgG levels typically occurs by 18 months of age. However, recovery may not occur in some patients until 5 years of age.
PATHOGENESIS
At birth, most serum IgG is maternally derived from trans-placental transfer which begins during the 2nd trimester of pregnancy and peaks during the 3rd trimester (levels are equal to maternal IgG levels at birth). Maternal IgG gradually declines and a physiologic nadir is reached around 6 months of age until the infant's endogenous IgG production begins to develop. In patients with THI, this endogenous IgG production is delayed and prolonged hypogammaglobulinemia occurs.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis for hypogammaglobulinemia includes the following conditions:
1. Common Variable Immune Deficiency (CVID)
2.X-lined and autosomal agammaglobulinemia
3.Hyper IgM syndrome
EVALUATION
THI should be suspected in infants or toddlers who present with low IgG. Patients may be asymptomatic or have recurrent sinopulmonary infections.
Step 1: Quantitative Humoral Evaluation
-Quantitative immunoglobulins (IgG, IgM, IgA)
-Flow cytometry for B-cell, T-cell, and NK cell numbers
-In THI the IgG level is more 2 SD or more below the mean. IgM and IgA levels may be normal or decreased.
-The total B cell numbers are normal in THI. This helps to distinguish it from other causes of hypogammaglobulinemia such as X-linked agammaglobulinemia. T and NK cell numbers are normal.
Step 2: Functional Humoral Evaluation
-Antibody titers to vaccine antigens
-Protein and polysaccharide vaccine antibody responses should be measured (ex. Tetanus, Diphtheria, H. Influenzae type B, and Pneumococcus). If serum antibody titers are low, patients can be vaccinated with repeat titers drawn 4-6 weeks later.
-Antibody titers are generally present in THI (in contrast to CVID) but decreased responses to protein antigens (Hib and Tetanus) have also been reported.
MANAGEMENT
Patients who are asymptomatic do not require therapy. Antibiotic prophylaxis can be considered for patients who suffer from recurrent sinopulmonary infections. Two sample prophylaxis regimens are listed below:
-Amoxicillin 20mg/kg divided twice daily. Maximum of 500mg twice daily.
-Azithromycin 10mg/kg once weekly. Maximum of 1 gram once weekly.
In rare cases, IVIG replacement therapy can be considered for patients who continue to have severe infections despite antibiotic prophylaxis therapy. This therapy should not be continued indefinitely cessation of IVIG within 1-2 years to assess endogenous antibody levels and vaccine responses is recommended.
Patients suspected of having THI should be followed longitudinally and have quantitative immunoglobulin levels and vaccine antibody responses checked every 6-12 months until resolution can be documented.
RESOURCES
Literature Resources
1. Ozen 2010
Outcome of Hypogammaglobulinemia in children
2. Dorsey 2006
Impaired specific antibody response and increased B cell population in THI