Immune Deficiency
Kathleen E. Sullivan. MD, PhD
Immune Deficiency - BASICS
Immune Deficiency - description
Immunodeficiencies represent a defect in host defense.
- Can be either congenital or acquired
- Brief descriptions of congenital or primary immunodeficiencies follow.
- Defects in antibody production: Most often characterized by very frequent infections with typical organisms at typical sites
- X-linked agammaglobulinemia: Onset of symptoms after 6 months of age; sinopulmonary infections with typical bacterial pathogens. Markedly decreased immunoglobulins and B cells are characteristic. Tonsils are absent.
- Hyper-IgM syndrome: Usually presents with recurrent bacterial infections; Pneumocystis jiroveci is seen in some infants; intermittent neutropenia is common. Decreased IgG, IgE, IgA with normal or increased IgM
- Common variable immunodeficiency: Usually presents with recurrent bacterial infections; most commonly arises in the 2nd or 3rd decade of life (but is seen in all ages). Immunoglobulin levels and function gradually decline; often an associated mild T-cell defect
- IgG subclass deficiency: IgG2 subclass deficiency is seen as a transient developmental delay in the acquisition of humoral immunity. May also precede the development of common variable immunodeficiency and can rarely be seen as an isolated defect
- IgA deficiency: The most common congenital immunodeficiency (1:500); most are asymptomatic. Symptoms can be seen at any age; typically sinopulmonary infections; increased risk of allergy, autoimmune disease, and anaphylaxis from blood products
- Transient hypogammaglobulinemia of infancy: A developmental delay of immunoglobulin production; function is intact; typically resolves between 9 and 15 months of age.
- T-cell defects: Most often characterized by persistent viral infections of opportunistic infections.
- Severe combined immunodeficiency: Most common presentation is a respiratory virus that fails to clear or chronic diarrhea. Failure to thrive, thrush, and Pneumocystis jiroveci pneumonia are also common; see “Failure to Thrive,” “Pneumocystis carinii” Pneumonia.
- Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome): See “DiGeorge Syndrome.”
- Chronic mucocutaneous candidiasis: There are multiple forms of this disorder. One form is also called autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) and has a very strong association with polyendocrinopathies and ectodermal dysplasia. The other types are more likely to have an associated T-cell defect. Infants have extensive or recurrent Candida; predisposition to other infections is modest.
- IPEX (immunodeficiency, polyendocrinopathy, enteropathy, X-linked syndrome): Diarrhea associated with villous atrophy and a T cell infiltrate, progressive autoimmune destruction of endocrine organs. Infections can be severe but the autoimmune manifestations predominate.
- Neutrophil defects: Staphylococcus, pseudomonas, unusual bacteria or fungal infections are characteristic
- Autoimmune neutropenia of infancy: Most common neutrophil defect of childhood; usually detected at ~6–12 months of age; often resolves by 2 years of age
- Congenital neutropenia: Infections may be skin infections or sinopulmonary; patients have either absent or markedly low neutrophil counts, which are consistent.
- Leukocyte adhesion deficiency: ~10% have delayed separation of the umbilical cord; most common presentations are recurrent skin ulcers and periodontitis. Spontaneous peritonitis.
- Chronic granulomatous disease: Recurrent skin abscesses common, deep hepatic abscesses, and pulmonary abscesses also seen. Typical organisms are Staphylococcus aureus, Burkholderia, mycobacteria, Aspergillus and Candida are also seen; age of onset is usually 1–3 years.
- Macrophage activation defects: Universally associated with atypical mycobacteria. Salmonella also seen. Biopsies may reveal poorly formed granulomas.
- Complement deficiency: Deficiencies of C5–C9 are associated with Neisseria infections; deficiencies of C1, C2, C4 are associated with lupus and recurrent bacterial infections. C3 deficiency is associated with glomerulonephritis and severe recurrent infections. Defects in complement regulatory proteins are associated with atypical HUS.
- Immunodeficiency syndromes
- Ataxia telangiectasia: Progressive cerebellar ataxia beginning at ~2 years of age; ocular telangiectasias beginning at about 5–15 years of age; recurrent sinopulmonary infections; α-fetoprotein is elevated, IgA and IgG2 are diminished.
- Wiskott-Aldrich syndrome: Clinical triad of eczema, thrombocytopenia, and recurrent infections. IgM low; IgG normal or slightly low; IgA and IgE elevated; platelets range from 20,000–90,000 and are small.
- Hyper-IgE syndrome: Recurrent infections of the skin, lungs, middle ears, and sinuses; S. aureus is a major cause of infection, and pulmonary infections typically heal with pneumatoceles.
- X-linked lymphoproliferative syndrome: 4 main types of presentation: Acute Epstein-Barr virus infection with hemophagocytosis, lymphoma, hypogammaglobulinemia, and aplastic anemia. Family history is key to diagnosis.
- Chédiak-Higashi syndrome: Pigmentary dilution, progressive neuropathy, and frequent infections; associated with a hemophagocytic process. Neutrophil counts are low and neutrophils have giant inclusions.
- Familial hemophagocytic lymphohistiocytosis: A defect in natural killer cell function; presents with fever, pancytopenia, and hepatosplenomegaly; usually <5 years of age
- Secondary immunodeficiencies include:
- HIV infection
- Malignancy
- Viral suppression
- Nephrotic syndrome
- Protein losing enteropathy
- Malnutrition
- Medications
- Splenectomy
Immune Deficiency - epidemiology
Immune Deficiency - prevalence
Most common immunodeficiency is IgA deficiency, with an estimated prevalence of 1:500 people:
- 1:3,000 for chromosome 22q11.2 deletion syndrome (DiGeorge syndrome)
- 1:60,000 for SCID
- 1:200,000 for chronic granulomatous disease
Immune Deficiency - risk factors
Immune Deficiency - genetics
The immunodeficiencies are generally autosomal recessive, although there are several important exceptions:
- X-linked: (Properdin deficiency, X-linked agammaglobulinemia, X-linked hyper-IgM, X-linked severe combined immunodeficiency, X-linked chronic granulomatous disease, X-linked lymphoproliferative syndrome, IPEX, Wiskott-Aldrich syndrome). All of these have autosomal recessive phenocopies or may be seen in females with altered X inactivation.
- Autosomal dominant: Hyper-IgE syndrome, some macrophage activation defects
- Polygenic: IgA deficiency and common variable immunodeficiency
Immune Deficiency - pathophysiology
- B-cell dysfunction: Leads to antibody deficiency; poor opsonization of bacteria, loss of immunologic memory. The hallmark of B-cell disorders is recurrent infections with organisms typical for that age group.
- T-cell dysfunction: Loss of cytolytic activity against viruses, loss of cytokines required for regulation of the immune response. Patients are vulnerable to viral infections, chronic indolent infections such as fungi, and opportunistic infections. May have autoimmune disease due to impaired regulation of self reactivity
- Neutrophil disorders: Due to either qualitative or quantitative dysfunction; impaired phagocytosis of bacteria and fungi
- Macrophage activation defects: Defects in gamma interferon signaling or IL-12 signaling lead to impaired killing of intracellular organisms.
- Complement deficiency: Complement serves as a major opsonin to tag pathogens for removal and can directly kill Gram-negative organisms. Complement deficiencies are associated with SLE (due to defective clearance of apoptotic debris), infections with encapsulated organisms (due to defective opsonization), infections with Neisserial species (due to defective cytolysis).
Immune Deficiency - DIAGNOSIS
Immune Deficiency - signs & symptoms
Immune Deficiency - history
- Family history (X-linked disorders)
- Number and duration of infections (to determine whether the problem is one of clearance, or frequency)
- Types of infections (infections of skin are frequently due to neutrophil problems, whereas recurrent infections of a single site implies an anatomic problem). Opportunistic infections are associated with both neutrophil defects (unusual bacteria and fungi) and T-cell defects (opportunistic viruses).
- HIV risk factors
Immune Deficiency - physical exam
- The physical examination should be directed at defining organ damage as a result of infection, the presence of any current infections, the presence of any syndromic features, the presence of signs of autoimmune disease, and the characterization of accessible lymphoid organs.
- Examination of lymph nodes, tonsils, liver, and spleen will reveal hypoplasia or expansion.
- Clinical pearls:
- Boys with X-linked agammaglobulinemia and X-linked hyper-IgM do not have tonsils and adenoids.
- Children and adults with hyper-IgE syndrome develop abscesses that are not painful.
Immune Deficiency - tests
- A patient with recurrent sinopulmonary infections with typical organisms could have a defect in antibody production. Therefore, laboratory evaluations should focus on the quantity and function of antibodies: IgG, IgA, IgM, IgE levels, and responses to vaccines such as diphtheria and tetanus.
- Chronic viral infections or opportunistic infections suggest a T-cell defect. These patients will benefit from an evaluation of T-cell production and function: T-cell enumeration and lymphocyte proliferation studies.
- Neutrophil disorders typically present with skin abscesses or ulcers or deep infections with Staphylococcus or fungi. Patients with these problems will benefit from an evaluation of neutrophil numbers and function. A CBC and differential, morphologic examination of neutrophils and a measure of respiratory burst are appropriate.
- Complement deficiencies: A CH50 will detect most of the structural component deficiencies. Special studies are needed for defects of the alternative pathway and the regulatory proteins.
- In certain patients it may be difficult to differentiate between viral processes and bacterial processes. In these cases, a CBC and differential, IgG, IgA, IgM levels, and diphtheria and tetanus titers are a useful screen to evaluate for the most common immunodeficiencies.
Immune Deficiency - differencial diagnosis
- Chronic inflammation of mucous membranes such as that due to reflux or allergies can lead to recurrent infections.
- Secondary immunodeficiency:
- Immunocompromise due to chemotherapy and immunosuppressive drugs
- Malnutrition, intercurrent viral infections such as Epstein-Barr virus and cytomegalovirus, toxin exposure, and medications such as Dilantin and gold:
- Inborn errors of metabolism
- Chromosomal syndromes
- HIV infection
Immune Deficiency - TREATMENT
Immune Deficiency - general measures
- Suspected severe combined immunodeficiency requires isolation, cytomegalovirus negative/irradiated blood products, and a prompt evaluation.
- IV immunoglobulin replacement:
- X-linked agammaglobulinemia
- Hyper-IgM
- Common variable immunodeficiency
- IgG subclass deficiency (infrequently)
- Probiotics can be useful for patients exposed to frequent antibiotics.
Immune Deficiency - medication
Prophylactic antibiotics/antifungals:
- IgG subclass deficiency
- Chronic mucocutaneous candidiasis
- Ataxia telangiectasia
- Hyper-IgE syndrome
- Chronic granulomatous disease
Immune Deficiency - surgery
- Bone marrow transplantation:
- Severe combined immunodeficiency (SCID)
- Wiskott-Aldrich syndrome
- X-linked lymphoproliferative syndrome
- Chédiak-Higashi syndrome
- Familial hemophagocytic lymphohistiocytosis
- Thymus transplantation:
- Severe chromosome 22q11.2 deletion syndrome (DiGeorge syndrome)
Immune Deficiency - FOLLOW UP
Immune Deficiency - prognosis
- Most antibody deficiencies have an excellent prognosis. Transient or developmental deficiencies of IgG or IgG subclasses typically resolve by 2 years of age.
- Antibody deficiencies such as X-linked agammaglobulinemia or common variable immunodeficiency have a good prognosis with IV IG treatment.
- The treatment of neutrophil disorders remains problematic, and most children with chronic granulomatous disease will not have a full life expectancy.
- Patients with T-cell disorders for whom bone marrow transplantation is not performed can do well if the defect is mild and if they do not suffer from autoimmune disease, malignancy, or recurrent infections.
Immune Deficiency - complications
- Bronchiectasis
- Deafness
- Autoimmune disease:
- Lymphoreticular malignancies occur in patients with T-cell disorders.
- Live viral vaccines administered to patients with T-cell dysfunction can result in unchecked viremia.
- Oral polio vaccine administered to patients with agammaglobulinemia can cause meningoencephalitis.
Immune Deficiency - bibliography
- Conley ME, Notarangelo L, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Clin Immunol. 1999;93:190–197.
- Noroski L, Shearer WT. Screening for primary immunodeficiencies in the clinical immunology laboratory. Clin Immunol Immunopathol. 1998;86:237–245.
Immune Deficiency - CODES
Immune Deficiency - icd9
- 279.00 Hypogammaglobulinemia
- 279.04 Congenital antibody deficiency
Immune Deficiency - FAQ
- Q: I have many patients with recurrent episodes of green rhinorrhea. Do these episodes all need to be treated with antibiotics, and should the child have an immunologic evaluation?
- A: Many viral infections cause green rhinorrhea and thus do not require antibiotics. Children with no other infections may be safely observed.
- Q: Does a child with thrush require evaluation?
- A: A child with severe thrush in the absence of risk factors should have an evaluation for T-cell dysfunction, HIV, and the possibility of chronic mucocutaneous candidiasis of childhood. Moderate thrush or recurrent simple thrush does not require evaluation unless it is occurring in an older child.
- Q: A newborn in my practice still has his umbilical cord attached at 6 weeks of age. Is that abnormal, and does it require an evaluation for leukocyte adhesion deficiency?
- A: A completely healthy-appearing cord at 6 weeks of age does not require any evaluation.
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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.
Other Book Chapters Related to Immune deficiency
Read excerpts from these other book chapters related to Immune deficiency:
Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Williams & Wilkins.
More About Causes of Immune deficiency
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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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