MM Esser, Immunology Unit National Health Laboratory Service Tygerberg, Division Medical Microbiology, Department of Pathology, Stellenbosch University, Cape Town, South Africa

Introduction :

Transient hypogammaglobulinaemia of infancy (THI) which affects infants and young children, is a relatively frequent primary immunodeficiency. It was first described as a clinical entity by Gitlin and Janeway.1Normal newborn infants rely on passively transferred maternal immunoglobulins in the first 3-6 months of life, when they reach a nadir of immunoglobulin G (IgG),until sufficient production of their own antibodies. Serum immunoglobulin A (IgA) may be variably low, immunoglobulin M (IgM) levels are very rarely reduced and B cell numbers are normal. (Figure 1) Antibody responses to protein immunizations arenormal or near normal.

THI in the majority, represents an exaggerated and prolonged,self-limited form of this physiological nadir of hypogammaglobulinaemia, after 6 months of age of otherwise normal infants. Immunoglobulins (Igs) are multifunctional in immunity and essential for interactions of antigen with cellular and humoral effectors. Consequently low Ig levels, even if regarded as physiological, may precipitate susceptibility to infections. THI may mimic a diagnosis of primary immunodeficiency (PID) or rarely it may even evolve into true PID. A good understanding of the development of infant immunity, specifically the humoral immune response assists with the interpretation of the normal changes in immunoglobulin levels of the neonate and infant and assists to differentiate it from an emerging PID.


The definition of THI according to the European Society of Immunodeficiency Diseases (ESID) Clinical Criteria 2014 describes the condition as:

“ Serum IgG below age-related normal value detected in the first three years of life (measured at least twice) AND defined causes of hypogammaglobulinaemia have been excluded AND spontaneous resolution approximately after the 4th birthday. “2

For PID registry classifications these patients will initially be registered as unclassified hypogammaglobulinaemia and then changed to THI, if there is spontaneous resolution before age 4 years.

Hencethe confirmed diagnosis of THI can only be made retrospectively.


The etiology of THI remains unknown. THI has been observed more commonly in male infants, estimated to be as frequent as 0.061-1.1 cases per 1000 life births and is thought to represent an exaggeration of the physiological process of immune maturation by most.Some authors however regard THI as reflecting a diverse group of errors of the immune system which include documentation of reduced CD19 expression with decreased memory B cell numbers and transient elevation of circulating regulatory T cells.3,4THI must be differentiated from true hypogammaglobulinaemia where IgG levels are 2 or more standard deviations below the normal mean levels for age and where B cell numbers may be low. B cells proportion is similar to that in adults at birth, the B cell absolute number is however significantly higher in infancy than in adulthood. Despite this, the normal neonate has immature antigen specific immune responses and relies on actively transferred third trimester maternal transplacental IgG for protection from infection in the first part of life. Hence the expected nadir of IgG at 3-6 months of life can be much lower in a premature infant, especially if born before 32 weeks of age. IgA, IgM and IgE serum levels are normally low even in term infants because these immunoglobulins cannot cross the placenta. IgA and IgM production takes place in the fetus to neoantigens, and IgM can be stimulated significantly by in utero infections.  Switching of Ig isotypes is also delayed when challenged in infancy. This manifests with earlier ability to respond to T cell-dependent and only later T cell-independent response maturation of antibody formation.

Clinical picture and Investigations:

The investigation for recurrent infections which commonly occur during the physiological IgG nadir of even normal infancy or the routine screening for other causes may alert to the diagnosis. Infections if they occur are usually respiratory and mostly limited to the upper respiratory tract, they become less frequent with age and pneumonia is uncommon. Although 2.5% of infants may fall below the 95% confidence range for normal serum IgG levels, it is a rarely diagnosed. The true incidence is therefore unknown. THI also does not impair the ability to produce specific antibodies to T-dependent antigens (eg tetanus or diphtheria toxoid) but the response to polysaccharide antigens may be transiently impaired/not sustained and require repeat vaccinations (eg pneumococcal vaccine). The majority of THI infants develop normal Ig levels by 24 months of age, but this may be delayed even until around 48 months. Infants who fail to achieve any normalization of Ig levels after 24 months, continue to have infections or develop autoimmune manifestations and have reduced IgM production and reduced switched memory B cells are diagnosed as having true hypogammaglobulinaemia and may be presenting as emerging Common Variable Immunodeficiency (CVID). Therefore the diagnosis of THI cannot be made with confidence until full resolution of the clinical and laboratory findings.5

Treatment and Follow up:

With a working diagnosis of THI, parents need to be reassured of the transient nature of the problem, but a plan of follow up should be structured with limited investigations to document the maturation and ultimate diagnosis of THI. Serial Ig measurements and if available vaccine antibody responses are indicated to document eventual resolution of the hypogammaglobulinaemia and a functional humoral immune response. Until resolution, suspected bacterial infections need to be treated promptly with appropriate antibiotics. Atopic manifestations including asthma which appear to be more common in THI should be treatedappropriately. Immunoglobulin replacement is only very rarely required and is not indicated if the infant is otherwise healthy.

Key messages :

1) The diagnosis of THI is provisional until age 4 years and must be followed up until serum Ig levels normalize.
2) In THI the B cell must be greater than 2% of peripheral blood lymphocytes, to differentiate from agammaglobulinaemia.
3) Where available, it is useful to document antibody vaccine responses to protein antigens which should be protective in THI.


Figure 1


  • GitlinD,Janeway CA. Agammaglobulinemia: Congenital, acquired and transient forms.ProgHematol 1956;1:318-329.
  • ESID Registry - Working definitions for clinical diagnosis of PID. March 5, 2014
  • Artac H, Kara R, Gokturk B, Reisli I. Reduced CD19 expression and decreased memory B cell numbers in transient hypogammaglobulinemia of infancy. ClinExp Med 13(4):257-263.
  • Rutkowska M, Trzyna E, Lenart M et al. The elevated number of circulating regulatory T cells in patients with transient hypogammaglobulinemia of infancy is not associated with any abnormalities in the genes encoding the TGF-β receptors. ClinImmunol 2013; 149:83–85.
  • Ovadia A, DalalI.Transienthypogammaglobulinemia of infancy (Review).LymphoSign 2014;1(1):1-9



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