Hypogammaglobulinemia
Hypogammaglobulinemia: Excerpt from The 5-Minute Pediatric Consult
Timothy Andrews, MD
Hypogammaglobulinemia - BASICS
Hypogammaglobulinemia - description
Humoral immunodeficiency signified by low or absent immunoglobulin levels, as compared with age-matched controls, and defective specific antibody production
Hypogammaglobulinemia - DIAGNOSIS
Hypogammaglobulinemia - signs & symptoms
Hypogammaglobulinemia - history
Detailed history for recurrent infection is key to evaluating suspected humoral immunodeficiency.
- Patients with humoral immunodeficiencies usually present with recurrent infections owing to encapsulated bacteria, such as Haemophilus influenzae type B and Streptococcus pneumoniae.
- It is important to rule out hypogammaglobulinemia in patients with recurrent infections, because replacement therapy with IV IgG is readily available.
- Patients with hypogammaglobulinemia usually present after 3–6 months of age.
- Late onset of infections may be more consistent with common variable immunodeficiency.
- Recurrent severe infections such as meningitis, sepsis, and osteomyelitis: Some of the congenital immunodeficiency syndromes are signified by specific infections such as chronic meningoencephalitis with echoviruses, vaccine-associated poliomyelitis, and Pneumocystis carinii pneumonia.
- Familial history of immunodeficiencies: Previously affected males suggests an X-linked inheritance pattern.
- Early infant deaths owing to overwhelming infection may indicate a previously undiagnosed congenital immunodeficiency.
- Many of the congenital immunodeficiencies have associated arthritis, autoimmune disease, chronic lung disease, and GI manifestations.
Hypogammaglobulinemia - physical exam
Patients should be examined for signs of acute and chronic infections.
- Growth parameters: Children with significant, recurrent infections and GI disease related to immunodeficiency may present with failure to thrive.
- Signs of chronic otitis media or conjunctival recurrent disease: Patients with X-linked agammaglobulinemia frequently have signs of chronic conjunctivitis.
- Gingivitis and stomatitis may occur with the neutropenia-associated hypogammaglobulinemia syndromes.
- Lymphoid tissue: Absence of tonsillar tissue and palpable lymph nodes is suggestive of X-linked agammaglobulinemia.
- Lymphadenopathy and tonsillar hypertrophy:
- Can be seen in hyper-IgM syndrome and common variable immunodeficiency
- Persistently enlarged nodes should be investigated.
- Wheezes, rales may signify acute pneumonia or chronic lung disease.
- Hepatosplenomegaly or masses:
- May be seen in hyper-IgM syndrome and common variable immunodeficiency
- Abdominal masses should be investigated promptly to rule out malignancy.
- Arthritis, clubbing:
- Arthritis can be seen in patients with X-linked agammaglobulinemia and common variable immunodeficiency.
- Clubbing can be seen in the presence of chronic lung disease/bronchiectasis.
Hypogammaglobulinemia - tests
Hypogammaglobulinemia - lab
- CBC with differential: Autoimmune hemolytic anemia, neutropenia, and thrombocytopenia can be seen in X-linked agammaglobulinemia, hyper-IgM, and common variable immunodeficiency.
- Quantitative immunoglobulin levels:
- Each isotype should be measured (IgG, IgA, IgM, IgE).
- Normal or elevated IgM level in face of low to absent IgG, IgA is characteristic of hyper-IgM syndrome.
- Serial testing of immunoglobulins: Should be done in infants suspected of transient hypogammaglobulinemia to document subsequent normalization of immunoglobulin levels
- Qualitative antibody levels:
- Isohemagglutinins are primarily IgM antibodies to the main blood groups.
- Should be present in normal patients, but will be absent in patients with AB blood type
- Presence is inconstant in children <1 year of age.
- Antibody titers to tetanus, diphtheria, Streptococcus pneumoniae, and Haemophilus influenzae type B measured postvaccination: Ability to mount a protective antibody response to childhood vaccinations may indicate a less severe clinical course in hypogammaglobulinemia.
- Test: B-cell enumeration:
- Numbers of peripheral B cell will be decreased to absent in X-linked agammaglobulinemia and in autosomal recessive agammaglobulinemia.
- Usually normal in other hypogammaglobulinemia syndromes
- Total lymphocyte count T- lymphocyte number and function are normal
Hypogammaglobulinemia - imaging
Chest and sinus radiography and CT scans:
- May be helpful in evaluating for acute and chronic disease
- Bronchiectasis can be a long-term sequela of chronic pulmonary infection.
Hypogammaglobulinemia - differencial diagnosis
- Selective IgA deficiency: For details, refer to the topics “Common Variable Immunodeficiency (CVID)” and “Immunoglobulin A Deficiency.”
- X-linked agammaglobulinemia (Bruton agammaglobulinemia):
- X-linked hyper IgM: Hyper IgM syndrome type:
- Defect is caused by mutations in the gene encoding the CD40 ligand surface molecule on T cells. This leads to defective T-cell signaling for B-cell immunoglobulin class switching.
- Normal to elevated IgM levels with low to absent IgG, IgA, and IgE
- Recurrent upper respiratory tract infections, otitis, pneumonia, sinusitis
- Associated complications include autoimmune hemolytic anemia/thrombocytopenia/neutropenia, opportunistic infections with Pneumocystis carinii, and lymphoproliferative disease.
- CD40 mutation: Hyper IgM syndrome type 3
- Type I integral membrane glycoprotein encoded by gene chromosome 20 defect results in defective B-cell class switching.
- Autosomal recessive form of hyper IgM clinically similar to X-linked hyper IgM
- Activation-dependent cytidine deaminase mutation: Hyper IgM syndrome type 2
- Activation-dependent cytidine deaminase is an RNA-editing enzyme encoded by a gene on chromosome 12p13 expressed in germinal center B cells.
- Deficiency causes impaired terminal differentiation of B cells and failure of isotype switching.
- Extreme elevation of IgM with low to absent IgG, IgA, and IgE
- Lymphoid hyperplasia, unlike X-linked hyper IgM in which there is minimal lymphoid tissue
- Older at age of onset
- No susceptibility to Pneumocystis carinii
- Transient hypogammaglobulinemia of infancy:
- Difficult to differentiate this from the normal physiologic nadir of IgG that occurs between 3 and 6 months of age owing to the loss of maternally derived immunoglobulin. This nadir is normally short lived.
- Affected infants have abnormally prolonged delay in the onset of their own immunoglobulin production to compensate for this nadir.
- Cause is unknown.
- Self-limited; most infants recover by 18–36 months
- Clinical course is typically benign. Therapy with IV immunoglobulin should be considered only in infants with severe recurrent infections.
- This syndrome is frequently seen in infants with a familial history of severe combined immunodeficiency or other immunodeficiencies.
- Selective IgG subclass deficiency (the 4 subclasses of IgG, in decreasing order of serum levels: IgG1, IgG2, IgG3, and IgG4):
- Total serum IgG levels can be normal even when 1 subclass is low or absent.
- Deficiency of IgG3 is most common in adults, whereas deficiency of IgG2 is seen more frequently in children.
- IgG2 deficiency has been associated with an inability to respond to polysaccharide antigens.
- Clinical significance of IgG subclass deficiency has not been fully defined. Many patients have an increased frequency of upper and lower respiratory tract infections, whereas others are asymptomatic.
- No consensus on standard therapy for these patients in regard to replacement IV immunoglobulin
- Kappa-chain deficiency:
- Absence of the kappa subtype of light chains in immunoglobulin molecules
- Described in 2 families
- Associated with variable defects in specific antibody formation
- Immunodeficiency with thymoma:
- Viruses:
- Epstein-Barr virus
- Cytomegalovirus
- Congenital rubella
- Mechanism by which antibody responses and immunoglobulin production are altered in infected patients is not clearly defined.
- Infectious mononucleosis:
- Has been associated with defective specific antibody responses to neoantigens and impaired in vitro B-cell function in normal individuals. These defects are transient and resolve within 6–8 weeks after the onset of the disease.
- A disastrous response to Epstein-Barr virus infection is seen in X-linked lymphoproliferative syndrome. These patients develop fatal infectious mononucleosis, marrow aplasia, B-cell lymphoma, and agammaglobulinemia.
- HIV, cytomegalovirus, and rubella infections have been associated with abnormal specific antibody responses.
Drugs:
- Immunosuppressive/chemotherapeutic agents, phenytoin
- Associated defects in immune function and antibody production usually resolve after therapy is discontinued.
Other:
- Protein-losing enteropathy
- Intestinal lymphangiectasia
- Nephrotic syndrome
- The hypogammaglobulinemia is owing to direct loss through the GI tract or kidneys.
- Lymphoreticular malignancies have been associated with various immune defects and decreased immunoglobulin production.
Hypogammaglobulinemia - TREATMENT
Hypogammaglobulinemia - general measures
- Prompt and appropriate antibiotic therapy is an important part of routine treatment.
- May be a role for prophylactic antibiotics in patients with persistent recurrent infections
- Replacement therapy with IV immunoglobulin is the primary therapeutic modality for X-linked agammaglobulinemia, hyper-IgM syndrome, and common variable immuno-deficiency.
- Usual initiating doses are 200–400 mg/kg every 3–4 weeks.
- Nadir IgG levels should be >300 mg/dL.
Hypogammaglobulinemia - FOLLOW UP
Hypogammaglobulinemia - prognosis
Therapy is usually lifelong in patients with documented humoral immunodeficiency.
Patients receiving IV immunoglobulin therapy should not receive routine vaccinations; they are passively immunized with the therapy.
Hypogammaglobulinemia - bibliography
- Conley ME, Rohrer J, Minegishi Y. X-linked agammaglobulinemia. Clin Rev Allergy Immunol. 2000;19:183–204.
- Ferrari S, Giliani S, Insalaco A, et al. Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci U S A. 2001;98:12614–12619.
- Huston DP, Kavanaugh AF, Rohane PW, et al. Immunoglobulin deficiency syndromes and therapy. J Allergy Clin Immunol. 1991;87:1–17.
- Minegishi Y, Lavoie A, Cunningham-Rundles C, et al. Mutations in activation-induced cytidine deaminase in patients with hyper IgM syndrome. Clin Immunol. 2000;97:203–210.
- Ochs HD, Smith CI. X-linked agammaglobinemia: A clinical and molecular analysis. Medicine. 1996;75:287–299.
Ochs HD, Stiehm ER, Winkelstein JA. Antibody Deficiencies In: Stiehm ER, ed. Immunologic Disorders in Infants and Children. 5th ed. Philadelphia, Pa: WB Saunders; 2004:356–426.- Rosen FS, Cooper MD, Wedgwood RJP. The primary immunodeficiencies. N Engl J Med. 1995;333:431–440.
- Schaffer FM, Ballow M. Immunodeficiency: The office work-up. J Respir Dis. 1995;16:523–541.
- Skull S, Kemp A. Treatment of hypogammaglobulinaemia with intravenous immunoglobulin, 1973–1993. Arch Dis Child. 1996;74:527–530.
- Woroniecka M, Ballow M. Office evaluation of children with recurrent infection. Pediatr Clin North Am. 2000;47:1211–1224.
Hypogammaglobulinemia - CODES
Hypogammaglobulinemia - icd9
- 279.00 Hypogammaglobulinemia, unspecified Agammaglobulinemia NOS
- 279.04 Congenital hypogammaglobulinemia
- Agammaglobulinemia: Bruton’s type X-linked
- 279.09 Other transient hypogammaglobulinemia of infancy
Hypogammaglobulinemia - FAQ
- Q: When should I make a referral?
- A: Refer any patient suspected of having a primary humoral immunodeficiency to a specialist in allergy and immunology. These are patients with chronic disease who require prolonged follow-up and good communication between the referring physician and specialist.
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Book Source Details
- Book Title: The 5-Minute Pediatric Consult
- Author(s): M. William Schwartz MD; et al.
- Year of Publication: 2008
- Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.
More About Common Variable Immunodeficiency
More Medical Textbooks Online about Common Variable Immunodeficiency
Review other book chapters online related to Common Variable Immunodeficiency:
Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.
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More About This Book:
Title: The 5-Minute Pediatric Consult
Authors: M. William Schwartz MD; et al.
Publisher: Lippincott Williams & Wilkins
Copyright: 2008
ISBN: 0-7817-7577-9
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