Transient Hypogammaglobulinemia of Infancy 

Updated: Aug 06, 2019
Author: Alan P Knutsen, MD; Chief Editor: Harumi Jyonouchi, MD 



Transient hypogammaglobulinemia of infancy (THI) is a relatively common primary immunodeficiency disease that affects infants and young children.[1] 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 with or without decreased immunoglobulin A (IgA) and immunoglobulin M (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 protein immunizations.[2] In addition, other primary immunodeficiency disorders need to be excluded. These levels usually increase to the reference range by age 2–6 years in children with THI. Abnormalities of T-cell help have been identified as a cause of THI, but 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.[3]


Pathophysiology of THI is unknown. Siegal et al.[4] 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. Subsequent studies have reported normal percentages and numbers of CD4+ T cells.[5, 3] Dorsey et al reported that the percentage and number of CD19+ B cells are increased.[3]

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 and conjugated Haemophilus influenzae type B immunizations are decreased.[3, 5] 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.[6] These decreased antibody responses probably account for the increased susceptibility to infections in children with THI.

In 1997, Kowalczyk et al.[7] reported increased synthesis of tumor necrosis factor (TNF)-α, TNF-β, and interleukin (IL)-10 (but not IL-1, IL-4, and IL-6) in patients with THI. When peripheral blood mononuclear cells were stimulated with pokeweed mitogen (PWM), TNF-α and TNF-β 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-α, TNF-β, and IL-10 was observed in patients with THI.

In addition, interferon-gamma (IFN-γ) Th1 T cells were increased in these patients. Furthermore, after normalization of the patients' IgG levels, TNF-α and TNF-β 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.

Artac et al.[8] reported reduced CD19 expression on B cells of patients with THI. The B-cell antigen receptor (BCR) is associated with co-receptors CD19, CD21, CD81, and CD225, which play a critical role in B-cell response. Though CD19 expression was reduced, CD21 and CD81 expressions were normal. IgM+ memory and class-switched B cells were decreased. They hypothesized that since CD19+ complex regulates B-cell activation following BCR-antigen stimulation, that this may lead to hypogammaglobulinemia.

Dalal et al.[5, 9] have identified 3 patterns of antibody responses in patients with low IgG and IgA levels in early infancy. 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.



The exact frequency of THI is unknown, although it has been estimated to be 0.061-1.1 cases per 1,000 live births.[10, 11, 12] In a nationwide survey in Japan, THI comprised 18.5% of primary immunodeficiency disorders.[13] In this author's experience, THI is a relatively common diagnosis in children referred for evaluation of recurrent infections.[14]


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.


THI is a congenital immunodeficiency disorder that manifests after the infant catabolizes maternal-derived IgG, typically by age 6 months. Most children outgrow this condition by age 2 years, when serum IgG, IgA, and immunoglobulin M (IgM) concentrations normalize, as do antibody responses to both protein and polysaccharide antigens; however, some children take up to age 6 years to outgrow THI.

THI occurs in people of all races.

Whelan et al.[15] and Ji-hong et al.[16] reported a male preponderance with a male-to-female ratio of approximately 2:1. McGeady reported in a review of 19 published series of 10 or more THI patients, the mean percentage of males was 65% with a range of 52–78%.[17]  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[10]  reported increased family history of severe combined immunodeficiency (SCID).


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.




Patients with THI may be symptomatic or asymptomatic. 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.[15] Infants with THI typically begin to experience increasingly frequent and recurrent otitis media, sinusitis, and bronchial infections. Life-threatening infections with polysaccharide-encapsulated bacteria may occur but are unusual. Dalal et al.[9] reported that upper respiratory tract infections occurred in most patients and pneumonia occurred in 23% of patients.[5] In a prospective study of 77 children with THI, Moschese et al.[18] reported infections in 91%, allergies in 47%, and autoimmune diseases of hemolytic anemia and neutropenia in 4% of patients. 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[9] , other investigators have reported increased incidence of atopic diseases, such as food allergy, asthma, and allergic rhinitis.[11, 14, 3] GI allergic-related symptoms may also occur.

Hematologic abnormalities have also been reported in THI; these included neutropenia and thrombocytopenia.[9] One patient developed acute lymphocytic leukemia (ALL).


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.


The cause(s) of THI is unknown. Investigators have identified abnormalities in T cells, B cells, and monocytes in THI. 

T-cell abnormalities

Siegal et al.[4] reported decreased CD4+ T-helper cell numbers and function and decreased T cell help of B-cell synthesis of IgG and IgA in THI; subsequent studies have been able to confirm this. Kowalczyk et al.[7]  reported that THI lymphocytes synthesize increased TNF-α, TGF-β, and IL-10 with PHA stimulation, proposing that this suppressed Ig synthesis. When the IgG levels normalized in THI so did the cytokine imbalance.   Subsequently, Kowalcyk et al.[19] proposed that there was increased TH1 bias in THI with increased TNF-α, TNF-β, IL-10, IL-12 in CD4+ T cells and increased IL-12 and IL-18 synthesis. Rutkowska et al.[20] reported that CD4+CD25high FoxP3+ T regulatory cells were increased in patients with THI; whereas they are decreased in patients with CVID.​ Furthermore, as THI resolved T regulatory cells decrease to normal. This may be useful then in differentiating THI from CVID and following THI patients as the IgG levels normalize. The mechanism of this is unknown. 

B-cell abnormalities

A number of defects in B cell numbers, memory and switch B cells have been identified, which are further discussed in the section on Laboratory Studies.

Monocyte abnormalities

Kowalcyk et al.[21] reported decreased CD40 expression on monocytes of patients with THI, possibly resulting in decreased colligation of Th CD40L and B cell CD40 stimulation necessary for class switching and memory B cell development. 

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. Decreased total 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.





Laboratory 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[9]  reported that antibody responses following immunization may be normal but may not persist on serial determinations.

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[14]  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.[14] Dorsey et al.[3] (2006) reported that immunizations to conjugated polysaccharide antigens are often subnormal in children with THI. These authors observed decreased antibody responses to both conjugated H influenzae type B vaccine and S pneumoniae immunization in children with THI.

Memory and switched B cells should be analyzed. 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 (SAD). Note the following:

  • Bukowska-Strakova et al.[22] analyzed memory and switched B cells in CVID, THI and selective IgA deficiency (SIgAD). Memory and switched B cells were typically decreased in 56 children with CVID but normal in 37 children with THI and in 39 children with SIgAD compared to age-matched control children age 0–7 years. However, they did observe in some children younger than 5 years with symptomatic THI, decreased memory, and switched B cells.

  • Moschese et al.[23, 18] reported decreased CD27+ memory B cells and decreased IgM-IgD-CD27+ switched B cells in children with THI older than 2 years. The investigators postulated that these children may have a permanent immunodeficiency later in life.

  • Karaca et al. [24] on the other hand found normal numbers of T cells, B cells including memory and switched B cells in 101 infants with THI. 
  • Recently, Rutkowska et al.[20] reported that CD4+CD25highFoxP3+ T-regulatory (Treg) cells were increased in patients with THI; whereas they are decreased in patients with CVID. Furthermore, as THI resolved, T-regulatory cells decreased to normal. This may be useful in differentiating THI from CVID and following THI patients as the IgG levels normalize. The mechanism of this is unknown.

  • Van Winkle et al.[25] reported that when the sum of IgG, IgA, and IgM levels is less than 81% of the sum of lower limit of age-adjusted IgG, IgA, and IgM levels, then resolution of THI is prolonged.

The phenotype of decreased IgG and decreased specific antibody deficiency has been associated with mutations of CD20, CD21, and CD81.[26, 27, 28] 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.[29]  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.



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. Recently, Memmedova et al.[30] reported that IVIG treatment in children with THI significantly decreased infections. Furthermore, IVIG therapy did not prolong resolution of THI. 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.[5, 6] Subcutaneous forms of gammaglobulin (Hizentra, Gammagard 10%, Gamunex c) have 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.[31]

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.


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.


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


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 Summary

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.


Class Summary

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

Immune globulin, intravenous (Carimune NF, Gammagard S/D, Gammagard liquid, Gammar-P, Gammaplex, Gamunex, Optigam, Polygam S/D, Privigen)

Purified preparation of gamma globulin derived from large pools of human plasma. Comprises 4 antibody subclasses.

Potential adverse effects include allergic reactions (eg, anaphylaxis, urticaria) because of IgE or anti-IgA antibodies. In a risk-benefit analysis, allergic reactions with IVIG administration in THI probably warrant discontinuation of IVIG. In severe B-cell immunodeficiency diseases in which IVIG is critical to care, premedication with corticosteroids and antihistamines (diphenhydramine) is usually successful in avoiding a reaction. In addition, the different IVIG preparations contain different amounts of IgA. Select an IVIG preparation with the least amount of IgA (eg, Gammagard SD). Contact manufacturer for specific lots low in IgA.

Immune globulin, subcutaneous (Hizentra, Gammagard liquid, Gamunex C, Xembify)

IgG antibodies that neutralize a wide variety of bacterial and viral agents. Neutralizes circulating myelin antibodies through anti-idiotypic antibodies; downregulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade. Hizentra and Xembify are a 20% (ie, 200-mg/mL) SC injectables. Gammagard liquid and Gamunex c are 10% (ie, 100 mg/mL) SC injectables.


Class Summary

These agents are used to induce active immunity.

Pneumococcal 7-valent conjugate vaccine (Prevnar)

Sterile solution of saccharides of capsular antigens of S pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F individually conjugated to diphtheria CRM197 protein. These 7 serotypes have been responsible for >80% of invasive pneumococcal disease in children < 6 years in the United States. Also accounted for 74% of penicillin-nonsusceptible S pneumoniae (PNSP) infections and 100% of pneumococci infections with high-level penicillin resistance. Customary age for first dose is 2 mo, but can be given as young as 6 wk.

Preferred sites of IM injection include the anterolateral aspect of the thigh in infants or deltoid muscle of upper arm in toddlers and young children. Do not inject vaccine in gluteal area or areas where there may be a major nerve trunk or blood vessel.

Number of 0.5 mL doses for series initiated at age 7-11 mo is 3 (4 wk apart; third dose after first birthday), at age 12-23 mo is 2 doses (2 mo apart), for age 2-9 y is one dose.

Minor illnesses, such as a mild upper respiratory tract infection, with or without low-grade fever are not generally contraindications.



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.


Questions & Answers


What is transient hypogammaglobulinemia of infancy (THI)?

What is the pathophysiology of transient hypogammaglobulinemia of infancy (THI)?

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