Transient hypogammaglobulinemia of infancy

INTRODUCTION — Transient hypogammaglobulinemia of infancy (THI) was classically described as an accentuation and prolongation of the "physiologic" immunoglobulin nadir that is normally observed during the first three to six months of life (figure 1) [1,2]. However, there remains no full agreement among immunologists regarding the definition of THI due to the absence of specific markers or a genetic signature. While some use sweeping inclusion criteria such as a reduction in any immunoglobulin (immunoglobulin G [IgG], immunoglobulin A [IgA], immunoglobulin M [IgM]), beyond the physiologic nadir [2-7], most agree that low IgG is essential for considering the diagnosis [8-12].

This topic reviews the clinical features, diagnosis, and management of THI. Other humoral immune defects are reviewed in greater detail separately. (See "Primary humoral immunodeficiencies: An overview".)

DEFINITIONS — The definition proposed by the International Union of Immunological Societies (IUIS) committee [13], calling for obligatory low IgG and IgA in THI, poses multiple challenges. It excludes all cases of isolated, transient low IgG (4 to 45 percent of cases of classically defined THI [3,8,10,14]) and also includes other entities such as hyper-IgM syndrome and common variable immunodeficiency (CVID) [15].

The European Society for Immunodeficiencies (ESID) has proposed the term "unclassified hypogammaglobulinemia" for children in the first three years of life with low IgG levels, reserving THI for those children that recover by age four years [16]. The ESID definition includes children with borderline low IgG levels.

The authors of this topic use a more conservative definition, which, on one hand, is flexible enough to include most cases historically considered to have THI but sufficiently restrictive to prevent confusion with other possible conditions. It encompasses low serum IgG levels in the presence or absence of low IgA or IgM (consistent with the ESID criteria) and normalization of IgG levels, as well as specific antibodies (if low initially), over time [17]. Hypogammaglobulinemia associated with a reduction in circulating B cells, abnormal cellular immunity, and syndromic features is excluded from the definition of THI.

EPIDEMIOLOGY — The estimated incidence of THI, using the more conservative definition, is between 0.061 and 1.1 per 1000 live births [4,18]. Some cohorts demonstrated a disproportionate number of male infants (up to 70 percent) [3,14,19], but this finding was not supported by other studies [12,20,21].

PATHOGENESIS — The molecular basis underlying THI remains elusive [2,8-10,22-29], although there are ongoing attempts to determine the pathogenesis of this disorder.

A defect in B cell CD19 expression was proposed as a possible cause of reduced immunoglobulin production in THI in a single study [30]. However, other groups have found increased numbers of circulating CD19⁺ B cells in patients with THI [31]. This discordant result may be explained by the difference in study populations. The first study was performed on a highly consanguineous population, while the second study was done on a presumed genetically heterogeneous North American group. A CD19 defect as a cause for THI is also challenged by the findings that B cell development and in vitro immunoglobulin production are normal in THI [11,32] but not in CD19 deficiency [33]. In addition, CD5⁺ B cells are normal in THI but low in CD19 deficiency [30].

Alternatively, a reduced immunoglobulin switch defect was found by some investigators [33,34] but not others [35]. However, this theory cannot be reconciled with the normal in vitro immunoglobulin production [23] and the temporary nature of THI [34]. Similarly, an abnormality in the Fc gamma receptor does not appear to underlie the transient low IgG levels [34].

CLINICAL MANIFESTATIONS — The clinical manifestations of THI have remained consistent in large surveys and prospective studies [15,19,36]. Most patients suffer upper and lower respiratory tract infections (40 to 90 percent), and the second most common feature is allergic disorders (approximately 30 to 50 percent). Rare manifestations include urinary tract infections, gastroenteritis, and invasive infections [19,20,30], as well as developmental delay and cardiac defects [31].

Recurrent or unusual infections — Most infants with THI are identified because immunoglobulin measurement was performed due to a history of recurrent infections starting early in life. The spectrum of infections ranged from recurrent upper respiratory infections (URIs), otitis media, bronchitis, and urinary tract infections to severe, invasive infections, such as bacteremia and bacterial meningitis [9,19,21-23]. The initial indication for immunologic evaluation was recurrent URIs in one-half of these patients. Other indications included recurrent gastroenteritis, severe varicella, and prolonged oral thrush [8].

Atopic features — Atopic manifestations are frequently reported in patients with THI [4,6-8]. These include increased immunoglobulin E (IgE) concentrations and food allergy [37]; symptoms of either atopic disease or food allergy/intolerance without a history of recurrent infections [18]; and severe eczema (along with sensitization to certain common food allergens) that resolved with systemic glucocorticoids, relapsed with topical corticosteroids, and ultimately resolved with normalization of IgG levels [38].

Asymptomatic — Some infants with THI are asymptomatic, and the diagnosis is recognized because they had an immune evaluation, including screening of serum immunoglobulin levels, due to a family history of primary immunodeficiency [4,25].

LABORATORY FINDINGS — The laboratory hallmarks of THI include the following:

●Serum immunoglobulins – IgG is at least two standard deviations (SDs) below the mean for age-matched controls, with or without diminished levels of IgA or IgM. There is some variability in normal levels and SDs at different institutions and diagnostic laboratories.

●Specific antibodies – Most patients with THI have normal antibody responses to infections or to immunizations at presentation, while the remainder normalize by the time of resolution of THI [12,31]. In addition to normal antibodies found against protein antigens (such as tetanus), antipolysaccharide antibodies also appear comparable with controls in most [4,5,26], but not all [8,16], children. (See "Assessing antibody function as part of an immunologic evaluation".)

●Immunophenotyping and T cell function – Most studies have found intact lymphocyte subpopulations, including the level of memory and class-switched B cells [5,8,9,22,26]. In addition, studies have shown normal in vitro responses to mitogens [5,8,9,22,26] and normal production of IgG [23]. There are some cases of contrary findings; however, those patients may have other classified immunodeficiencies rather than THI. As examples, a single study reported transient numeric and functional abnormalities of CD4⁺ T cells [23], and a few other single-center studies have described lower or higher than normal expression of CD19 expressing B cells [30,31]. Another group identified reduced numbers of circulating IgM⁺ and "switched" (IgM^-IgD^-) memory B cells and an inability to produce IgG in vitro in some patients [15,39], a feature commonly observed in common variable immunodeficiency (CVID) [11,40,41]. Another group reported that, while the proportion of regulatory T cells (Tregs) in children with THI were significantly increased compared with controls, primary memory B cells were reduced. Additionally, the proportion of CD127 in CD3⁺ and CD3⁺CD4⁺ T cells were significantly reduced in patients with THI compared with controls [42].

●Hematologic abnormalities – Hematologic manifestations are uncommon. Transient neutropenia was reported in two series [4,8], and a case of permanent neutropenia and another patient who developed acute lymphoblastic leukemia were also reported [8].

DIAGNOSIS — The diagnosis of THI cannot be made at presentation but rather is made retrospectively. It is one of several possible diagnoses considered in the heterogeneous population of young children presenting with recurrent infections and low immunoglobulins.

The diagnosis is dependent upon obligatory criteria:

●Serum IgG level must be recorded at more than two standard deviations (SDs) below age-matched controls with or without diminished levels of other serum immunoglobulins on at least two occasions.

●Immunoglobulins, as well as specific antibody formation, must normalize, usually during childhood or rarely during adolescence.

●Other defined immunodeficiencies, as well as syndromes, should be excluded. (See 'Differential diagnosis' below.)

In order to establish the diagnosis, the following assessment is required:

●History of type of past infections and a thorough physical examination (to exclude syndromes). (See "Laboratory evaluation of the immune system" and "Approach to the child with recurrent infections" and "Syndromic immunodeficiencies".)

●Measurement of serum IgG, IgA, and IgM, as well as specific antibodies.

●Immunophenotyping and/or proliferative response to mitogens should be assessed in suspected cases in order to exclude cellular immunodeficiency or agammaglobulinemia (X linked or autosomal recessive).

DIFFERENTIAL DIAGNOSIS — THI at presentation should be distinguished from other permanent forms of hypogammaglobulinemia [2]. Cases of X-linked or autosomal recessive agammaglobulinemia can be identified with relative ease by identifying low to absent B cells on flow cytometry and by confirming the diagnosis with genetic analysis [43-45]. However, more challenging are rare, leaky forms of these genetic defects that may present with circulating B cells, although antibody production is still aberrant [46,47]. (See "Flow cytometry for the diagnosis of primary immunodeficiencies", section on 'B cells' and "Agammaglobulinemia" and "Primary humoral immunodeficiencies: An overview".)

Early-onset common variable immunodeficiency (CVID) should also be considered in the differential diagnosis in patients after the age of two years. The common denominator with this heterogeneous group of patients is low immunoglobulins (IgG and IgA), but an inability to produce specific antibodies sets this condition apart from THI. The overlap in presentation between these disorders can be observed in patients with CVID who gradually lose the ability to form antibodies and cases with THI who initially lack antibodies but eventually resolve. (See "Common variable immunodeficiency in children".)

Low immunoglobulins are also seen in patients with severe combined immunodeficiency. However, unlike THI, they distinctly present with very low lymphocyte counts, severe and recurrent viral or fungal infections, and failure to thrive. (See "Severe combined immunodeficiency (SCID): An overview".)

OUTCOME — By definition, THI should completely resolve, with return to normal serum immunoglobulin levels and response to immunizations by age four years [48]. Resolution of recurrent infections usually occurs by 9 to 15 months of age, while IgG levels typically normalize by two to four years of age [8,29,31,48-50]. Rarely, resolution may span up to three decades [8,51] and may include a transient phase during which IgG subclasses (especially IgG2) are temporarily low, although the utility of measuring IgG subclasses in this context clinically is unclear.

TREATMENT — Most patients with THI are observed and treated for infections as needed. However, patients with more frequent and/or more severe infections can be treated with antibiotic prophylaxis or immune globulin replacement therapy.

Antibiotic prophylaxis — Antibiotic prophylaxis is reserved for patients with recurrent respiratory and/or ear infections. The most commonly used options are a single daily dose of trimethoprim-sulfamethoxazole (5 mg/kg of the trimethoprim component), twice-daily amoxicillin (20 mg/kg per dose), or azithromycin (10 mg/kg weekly or 5 mg/kg every other day) [17]. (See "Acute otitis media in children: Prevention of recurrence", section on 'Antibiotic prophylaxis'.)

Immune globulin replacement therapy — Most patients with THI have only mild infections and do not require immune globulin replacement. Replacement therapy is reserved for patients with recurrent, severe infections who fail to respond to antibiotic prophylaxis [48]. (See "Immune globulin therapy in inborn errors of immunity" and "Overview of intravenous immune globulin (IVIG) therapy".)

Immune globulin replacement therapy is used extensively, and the preparation has been shown to be safe [46]. Still, a decision to use this treatment should take the following into consideration:

●It is an expensive treatment.

●It is a blood product, and, as such, it may potentially transmit new and previously unrecognized infective agents despite extensive inactivation methods [52].

●Mild adverse reactions are commonly associated with its administration. However, rarely, more severe reactions such as thromboembolic events have been reported. (See "Immune globulin therapy in inborn errors of immunity" and "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis".)

●Administering immune globulin replacement therapy may theoretically delay the endogenous synthesis of the patient's own immunoglobulins [53]. This was not observed among 43 patients with THI compared with 23 untreated controls [48].

Most patients with THI are treated with immune globulin replacement therapy for short periods of time, ranging from a single injection up to 18 months of therapy [12,22,54]. Cessation of treatment is usually based upon the frequency and severity of infection and increase of immunoglobulins other than IgG. After discontinuation of therapy, patients should be followed periodically until a complete clinical and laboratory resolution is accomplished and sustained. (See 'Diagnosis' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY

●Definition – Transient hypogammaglobulinemia of infancy (THI) is a diagnosis of exclusion that is established in retrospect after any laboratory findings and clinical manifestations have resolved. It occurs in the absence of other immunodeficiency conditions. Although transient, it persists beyond six months of age. (See 'Introduction' above and 'Diagnosis' above.)

●Clinical manifestations – Patients with THI typically present in infancy with recurrent upper respiratory infections (URIs). Urinary tract infections, gastroenteritis, and invasive infections are less frequent. Some patients may be asymptomatic. Up to one-third of patients with THI have atopic features, including allergic respiratory features and food allergies. (See 'Clinical manifestations' above.)

●Laboratory findings – Patients with THI have immunoglobulin G (IgG) levels that fall at least two standard deviations (SDs) below the mean for age-matched controls, with or without diminished values of other immunoglobulin isotypes. Specific antibodies to immunizations or infections are adequate in most patients at presentation and, in those with initially low levels, normalize with resolution of THI. (See 'Laboratory findings' above.)

●Differential diagnosis – The primary disorders to exclude are permanent forms of hypogammaglobulinemia, including X-linked or autosomal recessive agammaglobulinemia and common variable immunodeficiency (CVID). (See 'Differential diagnosis' above.)

●Outcome – Infections and immunoglobulin levels resolve in most patients by two to four years of age. Rarely, resolution may be delayed beyond the first decade of life. (See 'Outcome' above.)

●Antibiotic prophylaxis in patients with recurrent sinopulmonary infections – Antibiotic prophylaxis is reserved for patients with recurrent respiratory and/or ear infections. The most commonly used options are a single daily dose of trimethoprim-sulfamethoxazole (5 mg/kg of the trimethoprim component), twice-daily amoxicillin (20 mg/kg per dose), or azithromycin (10 mg/kg weekly or 5 mg/kg every other day). (See 'Treatment' above.)

●Immune globulin replacement therapy in patients with recurrent severe infections – Immune globulin replacement therapy is reserved for patients with THI who have recurrent, severe infections and fail a trial of antibiotic prophylaxis. (See 'Treatment' above and "Immune globulin therapy in inborn errors of immunity".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.