This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.
![Cover of StatPearls](/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-statpearls-lrg.png)
StatPearls [Internet].
Show detailsContinuing Education Activity
Transient hypogammaglobulinemia of infancy (THI) is a type of antibody deficiency that affects infant and children typically below the age of 6 years. It characteristically demonstrates recurrent bacterial infections and can be treated with antibiotics or replacement immunoglobulin therapy. This activity reviews the clinical evaluation, diagnosis, and management of THI.
Objectives:
- Review the clinical presentation of infants with THI immunodeficiency.
- Describe the epidemiology and proposed pathophysiology of THI.
- Outline the treatment and management options available for THI.
- Summarize interprofessional team strategies for improving care coordination and communication to improve outcomes.
Introduction
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]
Etiology
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]
Epidemiology
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 the age of one year and the remaining after the age of five years. Initial low IgM and IgA levels were associated with slow recovery. Patients with longer duration of breastfeeding recover earlier.[7]
Pathophysiology
Transient hypogammaglobinemia of infancy may represent an exaggerated physiologic nadir when maternal IgG begins to decrease and before the child begins to synthesize their own immunoglobulin. Although the mechanism is 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, to include food allergies. 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.
Evaluation
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 type B, measles, mumps, and rubella vaccines. In the U.S., most children receive the conjugated pneumococcal vaccine, and they respond well. If a patient fails to respond to an immunization such as tetanus, 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.
Treatment / Management
Medical Care
Transient hypogammaglobulinemia of infancy treatment is conservative.
- Antibiotic treatment with prophylactic antibiotics is reasonable if children begin to experience infections.
- In patients who develop severe life-threatening infections or recurrent respiratory tract infections despite antibiotic therapy, a trial of antibody replacement therapy in the form of intravenous immunoglobulin (IVIG) is indicated.
- If allergic rhinitis occurs, treat with topical nasal corticosteroids and antihistamines.
Surgical Care
Due to the frequency of ear infections, the placement of tympanostomy tubes should be considered. Functional endoscopic sinus surgery (FESS) for chronic sinusitis may also be a consideration.
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).[14]
- 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.[15]
Prognosis
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
Complications of transient hypogammaglobulinemia of infancy include[16]:
- Fungal infections including oral candidiasis
- Bacteremia
- Premature death
- Anaphylaxis
- Chronic diarrhea
- Neutropenia
- Food Allergies
Consultations
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.
References
- 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. Cent Eur J Immunol. 2018;43(4):413-420. [PMC free article: PMC6384417] [PubMed: 30799989]
- 2.
- Keles S, Artac H, Kara R, Gokturk B, Ozen A, Reisli I. Transient hypogammaglobulinemia and unclassified hypogammaglobulinemia: 'similarities and differences'. Pediatr Allergy Immunol. 2010 Aug;21(5):843-51. [PubMed: 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. J Clin Immunol. 2006 Jan;26(1):7-11. [PubMed: 16418798]
- 4.
- Wang LJ, Yang YH, Lin YT, Chiang BL. Immunological and clinical features of pediatric patients with primary hypogammaglobulinemia in Taiwan. Asian Pac J Allergy Immunol. 2004 Mar;22(1):25-31. [PubMed: 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 Asthma Proc. 2006 May-Jun;27(3):285-8. [PubMed: 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. Scand J Immunol. 2018 Oct;88(4):e12709. [PubMed: 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. Clin Immunol. 2013 Oct;149(1):83-5. [PubMed: 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. Iran J Allergy Asthma Immunol. 2010 Dec;9(4):237-43. [PubMed: 21131704]
- 9.
- Dalal I, Reid B, Nisbet-Brown E, Roifman CM. The outcome of patients with hypogammaglobulinemia in infancy and early childhood. J Pediatr. 1998 Jul;133(1):144-6. [PubMed: 9672529]
- 10.
- Ameratunga R, Ahn Y, Steele R, Woon ST. Transient hypogammaglobulinaemia of infancy: many patients recover in adolescence and adulthood. Clin Exp Immunol. 2019 Nov;198(2):224-232. [PMC free article: PMC6797871] [PubMed: 31260083]
- 11.
- Bellutti Enders F, Conti F, Candotti F, Angelini F. [Transient hypogammaglobulinemia of infancy]. Rev Med Suisse. 2017 Apr 05;13(557):739-742. [PubMed: 28722362]
- 12.
- Breslin ME, Lin JH, Roberts R, Lim KJ, Stiehm ER. Transient hypogammaglobulinemia and severe atopic dermatitis: Open-label treatment with immunoglobulin in a case series. Allergy Rhinol (Providence). 2016 Jan;7(2):69-73. [PMC free article: PMC5010435] [PubMed: 27470901]
- 13.
- Memmedova L, Azarsiz E, Edeer Karaca N, Aksu G, Kutukculer N. Does intravenous immunoglobulin therapy prolong immunodeficiency in transient hypogammaglobulinemia of infancy? Pediatr Rep. 2013;5(3):e14. [PMC free article: PMC3812531] [PubMed: 24198926]
- 14.
- Suri D, Rawat A, Singh S. X-linked Agammaglobulinemia. Indian J Pediatr. 2016 Apr;83(4):331-7. [PubMed: 26909497]
- 15.
- Nasa M, Mishra SR, Lipi L, Sud R. Common variable immunodeficiency syndrome with chronic diarrhoea. BMJ Case Rep. 2019 Mar 31;12(3) [PMC free article: PMC6453328] [PubMed: 30936343]
- 16.
- Hong R. Transient hypogammaglobulinemia of infancy. J Pediatr. 1978 Mar;92(3):521-2. [PubMed: 75969]
Disclosure: Angel Justiz Vaillant declares no relevant financial relationships with ineligible companies.
Disclosure: Allecia Wilson declares no relevant financial relationships with ineligible companies.
- Continuing Education Activity
- Introduction
- Etiology
- Epidemiology
- Pathophysiology
- History and Physical
- Evaluation
- Treatment / Management
- Differential Diagnosis
- Prognosis
- Complications
- Consultations
- Deterrence and Patient Education
- Pearls and Other Issues
- Enhancing Healthcare Team Outcomes
- Review Questions
- References
- A prospective study on children with initial diagnosis of transient hypogammaglobulinemia of infancy: results from the Italian Primary Immunodeficiency Network.[Int J Immunopathol Pharmacol. ...]A prospective study on children with initial diagnosis of transient hypogammaglobulinemia of infancy: results from the Italian Primary Immunodeficiency Network.Moschese V, Graziani S, Avanzini MA, Carsetti R, Marconi M, La Rocca M, Chini L, Pignata C, Soresina AR, Consolini R, et al. Int J Immunopathol Pharmacol. 2008 Apr-Jun; 21(2):343-52.
- A case of IgG subclass deficiency with the initial presentation of transient hypogammaimmuno-globulinemia of infancy and a review of IgG subclass deficiencies.[J Med Assoc Thai. 2003]A case of IgG subclass deficiency with the initial presentation of transient hypogammaimmuno-globulinemia of infancy and a review of IgG subclass deficiencies.Nettagul R, Visitsunthorn N, Vichyanond P. J Med Assoc Thai. 2003 Jul; 86(7):686-92.
- Transient hypogammaglobulinemia and unclassified hypogammaglobulinemia: 'similarities and differences'.[Pediatr Allergy Immunol. 2010]Transient hypogammaglobulinemia and unclassified hypogammaglobulinemia: 'similarities and differences'.Keles S, Artac H, Kara R, Gokturk B, Ozen A, Reisli I. Pediatr Allergy Immunol. 2010 Aug; 21(5):843-51. Epub 2010 Jul 1.
- Review A Systematic Review of the Clinical Diagnosis of Transient Hypogammaglobulinemia of Infancy.[Children (Basel). 2023]Review A Systematic Review of the Clinical Diagnosis of Transient Hypogammaglobulinemia of Infancy.Justiz-Vaillant AA, Hoyte T, Davis N, Deonarinesingh C, De Silva A, Dhanpaul D, Dookhoo C, Doorpat J, Dopson A, Durgapersad J, et al. Children (Basel). 2023 Aug 8; 10(8). Epub 2023 Aug 8.
- Review The four most common pediatric immunodeficiencies.[Adv Exp Med Biol. 2007]Review The four most common pediatric immunodeficiencies.Stiehm RE. Adv Exp Med Biol. 2007; 601:15-26.
- Transient Hypogammaglobulinemia of Infancy - StatPearlsTransient Hypogammaglobulinemia of Infancy - StatPearls
- crybb3.S crystallin beta B3 S homeolog [Xenopus laevis]crybb3.S crystallin beta B3 S homeolog [Xenopus laevis]Gene ID:446319Gene
- f2rl1.S coagulation factor 2 (thrombin) receptor-like 1 S homeolog [Xenopus laev...f2rl1.S coagulation factor 2 (thrombin) receptor-like 1 S homeolog [Xenopus laevis]Gene ID:496339Gene
- Taxonomy Links for Nucleotide (Select 298896633) (1)Taxonomy
Your browsing activity is empty.
Activity recording is turned off.
See more...