Transient Hypogammaglobulinemia of Infancy

Article Author:
Angel Justiz Vaillant
Article Editor:
Allecia Wilson
6/16/2019 12:32:20 PM
PubMed Link:
Transient Hypogammaglobulinemia of Infancy


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.[1][2]


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.[3][4][5]


The estimated frequency of transient hypogammaglobulinemia varies between studies.  In some studies, it is the most common IgG deficiency in childhood.[6] 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.[7]


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.[1]

History and Physical

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.

Typical symptomatic presentations include [2][3][4]:   

  • Sinus pulmonary infections
  • Bacteremia
  • Meningitis
  • Otitis media
  • Arthritis
  • Septicemia
  • Bronchiectasis
  • Recurrent tonsillitis
  • Pyodermitis
  • Purulent conjunctivitis
  • Failure to thrive
  • Aphthous stomatitis 
  • Diarrhea
  • Loss of weight   
  • Recurrent abscess      
  • Loss of weight 
  • Autoimmunity
  • Atopy
  • Sinus pulmonary infections
  • Viral infections
  • Neutropenia
  • Persistent vomiting
  • Fungal infection (candidiasis)

Some infants remain asymptomatic with a diagnosis following immunologic evaluation for other reasons or family history.

Treatment / Management

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[5][6][7][8]

Quantitative Serum Immunoglobulins

  • IgG
  • IgM
  • IgA
  • IgG1
  • IgG2
  • IgG3
  • IgG4

In THI, IgG is at least two standard deviations below expected controls.[9] IgA and IgM may or may not present as decreased.

Antibody Activity

Detection of isohemagglutinins (IgM)

  • Anti-type A blood
  • Anti-type B blood

IgG antibodies (post-exposure)

  • Rubella
  • Measles
  • Varicella Zoster

IgG antibodies (post-immunization)

  • Tetanus toxoid
  • Diphtheria toxoid
  • Pneumococcal polysaccharide
  • Polio

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.

Other assays

  • Serum protein electrophoresis

Blood Lymphocyte T Subpopulations

  • Total lymphocyte count
  • T lymphocytes (CD3, CD4, and CD8)
  • CD4/CD8 ratio

B-cell Quantitative Assessment

  • Levels of CD19
  • Levels of CD20
  • Levels of CD21
  • Levels of CD81
  • Levels of CD 225

T cell and B cell function reports as normal in most studies.

Microbiological Studies

  • Cerebrospinal fluid (culture, chemistry, and histopathology)
  • Blood culture
  • Stool culture
  • Sputum examination

Other Investigations 

  • DNA testing 
  • Complete blood cell count   
  • Chest x-ray
  • Diagnostic ultrasound
  • CT scan

Other tests may be necessary as clinically indicated to exclude other causes.

Differential Diagnosis

Differential diagnosis of transient hypogammaglobulinemia of infancy includes:

  • X-linked (Bruton) agammaglobulinemia: recurrent bacterial infections affect boys, and genetic studies may reveal the presence of Bruton tyrosine kinase (BTK) mutations).[10]
  • Common variable immunodeficiency: recurrent bacterial infections usually later in life (second-fourth decade).  Diagnosis is verified once all causes of immunodeficiency have been ruled out.[11]


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[12]:

  • Fungal infections including oral candidiasis 
  • Bacteremia
  • Premature death
  • Anaphylaxis 
  • Chronic diarrhea
  • Neutropenia


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. 

Deterrence and Patient Education

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. 

Pearls and Other Issues

  • Transient hypogammaglobulinemia of infancy (THI) is a transitory immunodeficiency of childhood characterized by low (at least two standard deviations) IgG levels.
  • THI typically presents during the first year of life with recurrent upper and lower respiratory tract infections.
  • Atopy is a common manifestation.
  • The primary differential diagnoses include X-linked agammaglobulinemia and common variable immunodeficiency.
  • The diagnosis of THI confirmed retrospectively when IgG levels have returned to expected levels.
  • Antibiotic prophylaxis and immune globulin replacement therapy may be necessary for patients with severe and recurrent infections.

Enhancing Healthcare Team Outcomes

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. 


[1] Siemińska I,Rutkowska-Zapała M,Bukowska-Strakova K,Gruca A,Szaflarska A,Kobylarz K,Siedlar M,Baran J, The level of myeloid-derived suppressor cells positively correlates with regulatory T cells in the blood of children with transient hypogammaglobulinaemia of infancy. Central-European journal of immunology. 2018;     [PubMed PMID: 30799989]
[2] Keles S,Artac H,Kara R,Gokturk B,Ozen A,Reisli I, Transient hypogammaglobulinemia and unclassified hypogammaglobulinemia: 'similarities and differences'. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2010 Aug;     [PubMed PMID: 20609138]
[3] Whelan MA,Hwan WH,Beausoleil J,Hauck WW,McGeady SJ, Infants presenting with recurrent infections and low immunoglobulins: characteristics and analysis of normalization. Journal of clinical immunology. 2006 Jan;     [PubMed PMID: 16418798]
[4] Wang LJ,Yang YH,Lin YT,Chiang BL, Immunological and clinical features of pediatric patients with primary hypogammaglobulinemia in Taiwan. Asian Pacific journal of allergy and immunology. 2004 Mar;     [PubMed PMID: 15366655]
[5] Wang HC,Whelan MA,McGeady SJ,Yousef E, A 5-month-old boy with recurrent respiratory infections, failure to thrive, and borderline elevated sweat chloride levels. Allergy and asthma proceedings. 2006 May-Jun;     [PubMed PMID: 16913275]
[6] Eroglu FK,Aerts Kaya F,Cagdas D,Özgür TT,Yılmaz T,Tezcan İ,Sanal Ö, B lymphocyte subsets and outcomes in patients with an initial diagnosis of transient hypogammaglobulinemia of infancy. Scandinavian journal of immunology. 2018 Oct;     [PubMed PMID: 30152873]
[7] Rutkowska M,Trzyna E,Lenart M,Szaflarska A,Pituch-Noworolska A,Kobylarz K,Siedlar M, 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. Clinical immunology (Orlando, Fla.). 2013 Oct;     [PubMed PMID: 23899993]
[8] Karaca NE,Aksu G,Gulez N,Yildiz B,Azarsiz E,Kutukculer N, New laboratory findings in Turkish patients with transient hypogammaglobulinemia of infancy. Iranian journal of allergy, asthma, and immunology. 2010 Dec;     [PubMed PMID: 21131704]
[9] Dalal I,Reid B,Nisbet-Brown E,Roifman CM, The outcome of patients with hypogammaglobulinemia in infancy and early childhood. The Journal of pediatrics. 1998 Jul     [PubMed PMID: 9672529]
[10] Suri D,Rawat A,Singh S, X-linked Agammaglobulinemia. Indian journal of pediatrics. 2016 Apr;     [PubMed PMID: 26909497]
[11] Nasa M,Mishra SR,Lipi L,Sud R, Common variable immunodeficiency syndrome with chronic diarrhoea. BMJ case reports. 2019 Mar 31;     [PubMed PMID: 30936343]
[12] Hong R, Transient hypogammaglobulinemia of infancy. The Journal of pediatrics. 1978 Mar;     [PubMed PMID: 75969]