Transient hypogammaglobulinemia of infancy (THI) is a primary immunodeficiency caused by a transitory drop of the levels of immunoglobulin G (IgG) in an infant beginning between 5 and 24 months of age. Levels typically return to reference range at ages 2 to 6 years. IgG is produced at low levels by the fetus, and it is the only immunoglobulin to cross the placenta. At birth, an infant's IgG level is equivalent to that of its mother. Shortly after birth, infants begin to produce their own IgG, and levels gradually increase to their expected value around 6 months of age. This process overlaps with the declining maternal IgG levels.
Physiologic hypogammaglobulinemia is expected and occurs between 3 to 6 months when maternal levels are low, and infant production is low. This physiologic response is typically not clinically significant. In cases of THI, the IgG levels remain significantly lower (two standard deviations) in infants after 6 months of age. Clinically, THI may be characterized by recurrent infections, although some patients remain asymptomatic. The presence of adequate or mildly low serum levels of IgA and IgM levels may also occur. This combination rules out a diagnosis of X-linked agammaglobulinemia. However, other immunodeficiencies such as common variable immunodeficiency are not completely excludable until the transient period is over, and IgG levels return to normal. Diagnosis is usually confirmed retrospectively. Males are more affected than females by a ratio of 2 to 1. The cause and frequency of THI are unknown. Treatment with antibiotics and replacement immunoglobulin therapy is of foremost importance in the management of symptomatic infants.
There exact cause of transient hypogammaglobulinemia of infancy is unknown. Proposed mechanisms include 1) malfunctioning T cells that fail to stimulate the appropriate synthesis of antibodies by B cells, 2) suppression of IgG production by maternal IgG, 3) low production of critical cytokines, and 4) genetic variations in families prone to immunodeficiency.
The estimated frequency of transient hypogammaglobulinemia varies between studies. In some studies, it is the most common IgG deficiency in childhood. Research has described it worldwide, and it is thought to be highly underdiagnosed due to variations in the criteria for diagnosis. THI has been reported to be more common in males. More than half of the patients are diagnosed by age 1 and the remaining after the age of 5. Initial low IgM and IgA levels were associated with slow recovery. Patients with longer duration of breastfeeding recover earlier.
Although not fully elucidated, the presence of maternal immunosuppressive antibodies (IgG) crossing the placenta, that disrupt the humoral immune system of the neonate is one suggestion. This inhibition can cause a reduced level of not only IgG but also IgM and IgA, as seen in some cases.
Some studies indicate that patients with THI have a normal number of B lymphocytes but a transient impaired function of T-lymphocytes associated with immunoglobulin synthesis. It stresses the importance of B and T cell cooperation to result in a proper immune response.
In transient hypogammaglobulinemia of infancy, most patients experience upper and lower respiratory tract infections and allergic disorders. More severe manifestations include urinary tract infections, gastroenteritis, and invasive infections. Physical exam findings are consistent with the specific type of infection.
Some infants remain asymptomatic with a diagnosis following immunologic evaluation for other reasons or family history.
The laboratory investigation of a patient with transient hypogammaglobulinemia of infancy includes the assessment of both immunoglobulin levels, B-cell quantitative assessment, antibody testing, immunophenotyping, and T cell function and he and other studies as follows:
Quantitative Serum Immunoglobulins
In THI, IgG is at least two standard deviations below expected controls. IgA and IgM may or may not present as decreased.
Detection of isohemagglutinins (IgM)
IgG antibodies (post-exposure)
IgG antibodies (post-immunization)
Most infants with THI produce normal antibodies to vaccines including diphtheria, tetanus, hepatitis A and B vaccines, conjugated Haemophilus influenzae, measles, mumps, and rubella vaccines. In the U.S., most children receive the conjugated pneumococcal vaccine, and they respond well. If after vaccination with a potent vaccine such as tetanus follows a lack of response, a thoroughly immunological study should be done to diagnose an early immunodeficiency disorder.
Blood Lymphocyte T Subpopulations
B-cell Quantitative Assessment
T cell and B cell function reports as normal in most studies.
Other tests may be necessary as clinically indicated to exclude other causes.
Transient hypogammaglobulinemia of infancy treatment is conservative.
Due to the frequency of ear infections, the placement of tympanostomy tubes should be considered. Functional endoscopic sinus surgery (FESS) for chronic sinusitis may also be a consideration.
Differential diagnosis of transient hypogammaglobulinemia of infancy includes:
The prognosis of transient hypogammaglobulinemia of infancy depends on the severity of the immunodeficiency. The prognosis for those who are symptomatic or present with mild disease is good with no significant morbidity. Patients with severe disease may be affected with opportunistic infections, atopy or autoimmunity, and have a more complicated course but, by definition, THI should completely resolve. Few patients may present a condition similar to X-linked agammaglobulinemia and must receive treatment with antimicrobials and IVIG for life.
Complications of transient hypogammaglobulinemia of infancy include:
A pediatrician and a clinical immunologist are necessary in cases of severe transient hypogammaglobulinemia of infancy. Consults with other specialists such as an infectious disease specialist and allergist may also be relevant.
Parents of children with transient hypogammaglobulinemia of infancy should receive education regarding the risk of infections. Compliance with medications, including antibiotics, immunoglobulins, and antihistamines, is needed to reduce complications from transient hypogammaglobulinemia of infancy.
Transient hypogammaglobulinemia of infancy may present in infancy with recurrent infections, atopy, autoimmunity, and gastrointestinal disorders. The management can be complex, given the spectrum of disease manifestations involving multiple organ systems. It should be managed by an interprofessional team that includes an immunologist, infectious disease specialist, nurses, pediatrician, pharmacist, an allergist, and a primary care physician, all collaborating across disciplines to achieve optimal patient results. [Level V] The key is to identify immunoglobulin deficiency and initiate prompt treatment.
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