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Transient hypogammaglobulinaemia of infancy


A 14-month-old boy is brought to your GP clinic by his mother with recurrent upper respiratory tract infections. His mother reports that he attends full-time daycare and is ‘constantly sick.’

You note that one of your colleagues has seen him twice for acute otitis media this year.

What happens to serum immunoglobulin levels in early life?

IgG levels of maternal origin in the fetal circulation increase throughout pregnancy. At the end of gestation, fetal IgG levels exceed those in the maternal circulation, which indicates that the placenta develops an active transport mechanism for IgG molecules (1).

Evolution of maternal and serum IgG levels during pregnancy.

Maternal immunoglobulin G (IgG) is transported across the placenta, mainly in the third trimester. Because of this, babies born prematurely have less IgG.

After birth, the maternally derived IgG levels fall to a physiological nadir of 400 mg/dL at 3–6 months. At the same time, the infant’s production of IgG is not fully developed. Preterm babies have a more pronounced nadir. At the age of 1 year, IgA levels are approximately 20% of adult levels, IgG approximately 60% of adult levels and IgM approximately 75% of adult levels (2).

Immunoglobulin levels by age (from 3)

What are the clinical features of transient hypogammaglobulinaemia of infancy (THI)?

The usual clinical features include:

  • Upper respiratory tract infections in about two-thirds of patients, most commonly ear and sinus infections
  • Lower respiratory tract infections in approximately one-third of patients
  • Allergic manifestations in 30% of patients, namely asthma, eczema, food allergy
  • Gastrointestinal difficulties in 10% of patients, e.g. chronic diarrhoea, persistent vomiting, food allergy and/or intolerance

Typically, children have a combination of the above features.

Other less common or rare clinical features include:

  • Urinary tract infections
  • Opportunistic infections caused by fungi (e.g. Pneumocystis jiroveci pneumonia or chronic candida), staphylococcus
  • Severe invasive infections such as sepsis and meningitis
  • Severe varicella zoster infection

How is transient hypogammaglobulinaemia of infancy defined and diagnosed?

There are differing definitions of THI in the literature, but the following criteria are widely accepted:

Serum IgG level must be less than 2SD below the mean for age, with or without depression of IgA or IgM on two separate occasions.

Immunoglobulins and specific antibody formation must normalise usually during childhood.

Other primary immunodeficiency must be excluded.

THI can only be diagnosed retrospectively when age-adjusted immunoglobulin levels and specific antibody formation (function) have become normal, usually by the age of four years. There are no specific markers or a genetic signature.

In a normal population, 2.5% of individuals will fall below that value, and clinicians may encounter otherwise well children with low immunoglobulin levels and normal antibody responses to vaccine antigens with no increased susceptibility to infection.

Diagnosis of putative THI is based on clinical picture and investigations. Most infants with THI have a normal physical examination with none of the classic findings in other primary immunodeficiency diseases, although the tonsils and lymph nodes may be small.

THI is seen in two cohorts of patients:

Firstly, asymptomatic patients whose relatives have immunodeficiency are tested and found to have low IgG. These patients are not excessively prone to infection and would not otherwise have come to medical attention without the index case.

Secondly, those who present with clinically significant THI, frequent infections, and/or poor antibody responses to one or more vaccine antigens.

How common is transient hypogammaglobulinaemia of infancy?

The estimated incidence of THI is between 0.061 and 1.1 per 1000 live births (5,6). It is likely to be significantly underdiagnosed.

There is a male predominance (2:1). 60% of patients are diagnosed by one, and the remaining 40% are diagnosed after. Male predominance may be a genuine finding or suggest that the normal values we use for evaluation should reflect age and sex.

What investigations should be ordered?

 Immunoglobulins (IgG, IgA, IgM)

By definition, the IgG level is <2SD below the mean for age. The IgG level is typically less than 400 mg/dl. Over half of children with THI have IgG levels as low as 200 mg/dl.

Levels less than 100 mg/dl and/or pan-hypogammaglobulinemia (low IgM, IgA, and IgG) may suggest a permanent immunodeficiency.

Pneumococcal antibody serology, tetanus serology (adapted from 7)

Most children with THI produce normal antibodies to vaccines, including tetanus toxoid, diphtheria, conjugated Haemophilus influenza, hepatitis A and B vaccines, and measles, mumps and rubella vaccines.

Most infants will receive Prevenar 13 (conjugated pneumococcal vaccine) given on the immunisation schedule at 2m of age in Australia and will respond adequately.

Tetanus antigen given at the same age in Infanrix hexa is a potent vaccine, and lack of response suggests a more serious defect and should prompt a more comprehensive evaluation.

If protective antibodies are not found, i.e., if the child lacks protective antibodies against a prior vaccine, a booster shot can be given, and the antibody response can be checked four to six weeks later. If the antibody response is poor, repeat titres may be done in six months.

A lack of response to tetanus antigen, poor antibody responses, or frequent or severe infections should prompt additional studies and referral/consultation with an immunologist.

Full blood count

Haematological abnormalities in THI are uncommon, but a complete blood count with differential may suggest a primary immunodeficiency.

B and T lymphocyte subsets

Indicated if there is lymphopaenia, persistent or severe fungal or opportunistic infections, failure to thrive, chronic diarrhoea, or severe skin disease.


Chest or sinus X-ray may be helpful in a child with a chronic respiratory tract infection. In THI, the chest X-ray is usually normal, and the thymus is typically normal in size.

What is the differential diagnosis?

THI should be distinguished from other permanent forms of hypogammaglobulinemia, such as CVID or X-linked agammaglobulinaemia (XLA).

  • CVID: Typically, these patients cannot produce protective levels of specific antibodies with variable immunoglobulin concentrations, and most have some impairment in cellular immunity.
  • XLA: Typically, XLA can be easily differentiated from THI. XLA has a severe deficiency of all Ig isotypes, an inability to produce antibodies, an absence of normal peripheral lymphoid tissues, an absence or a very low number of circulating B lymphocytes, and severe pyogenic infections starting in the first to second year of life.

What is the pathogenesis of transient hypogammaglobulinaemia of infancy?

The pathogenesis is unknown, but proposed causes for THI include:-

(1) suppressive maternal antibodies (IgG) which cross the placenta and suppress foetal immunoglobulin production; (2) genetic variation in certain families with a propensity to immunodeficiency;
(3) abnormal T-lymphocytes that fail to stimulate antibody production by B-cells;
(4) unbalanced cytokine production;
(5) abnormal or immature B-cells.


What is the treatment of transient hypogammaglobulinemia of infancy?

Counselling is the main treatment required for asymptomatic patients. Immunoglobulins should be repeated approximately every six months to ensure they normalise.

The main objective for children with clinically significant THI is preventing and treating infection. Judicious reduction of exposure to infection and prompt and appropriate treatment of respiratory infections are warranted.

Antimicrobial prophylaxis may be prescribed if recurrent respiratory and ear infections occur during the respiratory infection season. Bactrim (5 mg/kg of the trimethoprim component) or amoxicillin (40 mg/kg) are suggested options.

Immunoglobulin replacement is reserved for rare instances of recurrent, severe infections only.

Immunisations should be given as per the schedule.

What is the prognosis of transient hypogammaglobulinemia of infancy?

Most children with THI develop normal IgG levels by age 4, but many normalise before this, and some children’s IgG levels do not normalise until adolescence.

Most suffer from increased episodes of otitis media and upper and lower respiratory infections.


Hazes JMW, Coulie PG, Geenen V, Vermeire S, Carbonnel F, Louis E, et al. Rheumatoid arthritis and pregnancy: evolution of disease activity and pathophysiological considerations for drug use. Rheumatol Oxf Engl. 2011 Nov;50(11):1955–68.

Jolliff CR, Cost KM, Stivrins PC, Grossman PP, Nolte CR, Franco SM, et al. Reference intervals for serum IgG, IgA, IgM, C3, and C4 as determined by rate nephelometry. Clin Chem. 1982 Jan;28(1):126–8.

Charles Janeway, Travers P, Walport, Mark, Shlomchik, Mark. Immunobiology. 6th ed. Garland Science; 2004. 800 p.

Dalal, Ilan and Roifman, Chaim. Transient hypogammaglobulinemia of infancy [Internet]. 2018 [cited 2018 Oct 30]. Available from:

Walker AM, Kemp AS, Hill DJ, Shelton MJ. Features of transient hypogammaglobulinaemia in infants screened for immunological abnormalities. Arch Dis Child. 1994 Mar;70(3):183–6.

Tiller TLJ, Buckley RH. Transient hypogammaglobulinemia of infancy: review of the literature, clinical and immunologic features of 11 new cases, and long-term follow-up. J Pediatr. 1978 Mar;92(3):347–53.

Blaese, R. Michael et. al. Immune Deficiency Foundation Patient and Family Handbook for Primary Immunodeficiency Diseases [Internet]. 5th ed. Towson, USA; 2013 [cited 2018 Oct 30]. 276 p. Available from:


  • Clementine David is a trainee in Clinical Immunology and Allergy with an unrivalled affiliation for gelato. While an Aussie at heart, she is currently residing as an expat in Hong Kong’s Happy Valley, balancing her time between antigens and Octonauts.


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1 thought on “Transient hypogammaglobulinaemia of infancy”

  1. Hi Clementine, very interesting article. My little daughter had low values of all 3 IGs (152 IGG, 4 IGA, 40 IGM mg/dl) when she was 4,5 months old (she is 6 months now). As you can imagine we are very worried that this could be a permanent deficit. I am not asking you for a diagnose, but wondering if there are chances that this could be a transitory disorder (maybe you are are aware on relevant statistics). My understanding is that she is so young that it could be hard to differentiate btw the IGs that are coming from her mother vs those she actually produce.
    Thanks a lot