Basics

Description

Immunodeficiencies generally represent a defect in host defense. Less common deficiencies represent defects in the regulation of immune function. Congenital and acquired forms exist.

  • Defects in antibody production: often characterized by frequent sinopulmonary infections with typical organisms
    • X-linked agammaglobulinemia
      • Onset of symptoms after 6 months of age; sinopulmonary infections with typical bacterial pathogens
      • Markedly decreased immunoglobulins (Ig) and B cells. Tonsils are absent.
    • Hyper-IgM syndromes: several forms
      • Usually present with recurrent bacterial infections in infancy; Pneumocystis jiroveci is seen; intermittent neutropenia is common.
      • Decreased IgG, IgE, IgA with normal or increased IgM
    • Common variable immunodeficiency (CVID)
      • Usually presents with recurrent bacterial infections; most commonly arises in the 2nd or 3rd decade (but seen at all ages)
      • Ig levels and function gradually decline; autoimmunity is common.
    • IgA deficiency
      • Most common congenital immunodeficiency (1:600); most are asymptomatic.
      • Symptoms seen at any age; typically sinopulmonary infections; increased risk of allergy, autoimmune disease, and reactions to blood products
    • Transient hypogammaglobulinemia of infancy
      • A developmental delay of Ig production; function is intact; typically resolves between 1 and 2 years of age
  • T-cell defects: most often characterized by persistent viral infections or opportunistic infections
    • Severe combined immunodeficiency (SCID)
      • Most common presentation is a respiratory virus that fails to clear or chronic diarrhea.
      • Failure to thrive, thrush, and P. jiroveci pneumonia are also common.
      • Many states now have SCID newborn screening; patients identified have no symptoms.
    • Combined immune deficiencies
      • Several forms
      • Children exhibit increased severity of a broad range of infections, opportunistic infections, and unusual autoimmunity.
    • Chromosome 22q11.2 deletion syndrome
      • See “DiGeorge Syndrome.”
    • Chronic mucocutaneous candidiasis
      • Multiple forms of this disorder
      • One form is also called autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) and has an 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 infections; modest predisposition to other infections
    • 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 bacterial or fungal infections are characteristic.
    • Autoimmune neutropenia of infancy
      • Most common neutrophil defect of childhood; usually detected at ~6 to 12 months of age
      • Often resolves by 2 years of age
    • Congenital neutropenia
      • Infections may be skin infections or sinopulmonary.
      • Patients have either persistently absent or markedly low neutrophil counts.
      • Some patients will have 21-day cycles of neutropenia—cyclic neutropenia.
    • Leukocyte adhesion deficiency
      • ~10% have delayed separation of the umbilical cord.
      • Most common presentations are recurrent skin ulcers and periodontitis.
      • Spontaneous peritonitis occurs.
    • Chronic granulomatous disease (CGD)
      • Recurrent skin abscesses common, deep hepatic abscesses, and pulmonary infections
      • Typical organisms are Staphylococcus aureus, Burkholderia, Serratia, Nocardia, mycobacteria, Aspergillus, and Candida.
      • Age of onset is usually 1 to 3 years.
  • Innate defects in signaling: typically present with severe bacterial or viral infections in early infancy
    • IRAK4 and MyD88 deficiencies
      • Associated with staphylococcal, streptococcal, or pseudomonal sepsis/meningitis
      • Clostridial infections are also seen.
    • Herpes simplex encephalitis is associated with several gene defects.
  • Macrophage activation defects
    • Associated with atypical mycobacteria. Salmonella is also seen.
    • Biopsies may reveal poorly formed granulomas.
  • Complement deficiency
    • Deficiencies of C5 to C9 are associated with Neisseria infections.
    • Deficiencies of C1, C2, and C4 are associated with lupus and recurrent bacterial infections.
    • C3 deficiency associated with glomerulonephritis and severe recurrent infections
    • Defects in complement regulatory proteins are associated with atypical hemolytic uremic syndrome (HUS) or hereditary angioedema.
  • Immunodeficiency syndromes
    • Ataxia telangiectasia
      • Progressive cerebellar ataxia during infancy; ocular telangiectasias at about 5 to 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
      • Ig levels are variable but responses to vaccines often poor; small platelets and thrombocytopenia
    • Hyper-IgE syndrome
      • Recurrent infections of the skin and lungs; S. aureus is a major cause of infection, and pulmonary infections typically heal with pneumatoceles.
    • X-linked lymphoproliferative syndrome
      • Four main types of presentation and two genetic types: 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
      • Multiple defects in cytotoxic function; presents with fever, pancytopenia, and hepatosplenomegaly; usually <5 years of age
    • Ectodermal dysplasia with immune deficiency
      • Two forms. Variable ectodermal dysplasia and variable immune deficiency. Ig levels are variable as are responses to vaccines.
      • Susceptibility to mycobacteria, Pneumocystis, and common bacterial pathogens
  • Secondary immunodeficiencies include the following:
    • HIV infection
    • Malignancy
    • Viral suppression
    • Nephrotic syndrome
    • Protein-losing enteropathy
    • Malnutrition
    • Medications
    • Splenectomy
    • Complex cardiac anomalies

Epidemiology

Primary immune deficiencies range from the common (1:600) to the very rare (1:1,000,000).

  • 1:600 for IgA deficiency in Caucasians
  • 1:3,000 for chromosome 22q11.2 deletion syndrome
  • 1:20,000 for common variable immune deficiency
  • 1:50,000 for SCID
  • 1:200,000 for CGD

Risk Factors

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 SCID, X-linked CGD, X-linked lymphoproliferative syndrome (two types), IPEX, Wiskott-Aldrich syndrome, NF-kappa B Essential Modulator (NEMO) deficiency. All of these have autosomal recessive phenocopies or may be seen in females with altered X inactivation.
  • Autosomal dominant
    • Hyper-IgE syndrome, chromosome 22q11.2 deletion syndrome, some macrophage activation defects
  • Polygenic
    • IgA deficiency and CVID

Diagnosis

History

  • Question: Family history?
  • Significance: X-linked disorders are common.
  • Question: Number and duration of infections?
  • Significance: to determine whether the problem is one of clearance or frequency
  • Question: Types of infections?
  • Significance: Infections of skin are frequently due to neutrophil problems, whereas recurrent infections of a single site imply an anatomic problem. Opportunistic infections are associated with both neutrophil defects (unusual bacteria and fungi) and T-cell defects (opportunistic viruses).
  • HIV risk factors

Physical Exam

Examination should be directed at defining organ damage as a result of infection, the presence of any current infections, syndromic features, signs of autoimmune disease, and the characterization of accessible lymphoid organs, liver, and spleen.

Differential Diagnosis

  • Chronic inflammation of mucous membranes such as that due to reflux or allergies can lead to recurrent infections.
  • Immunocompromised status due to chemotherapy and immunosuppressive drugs
  • Malnutrition
  • Intercurrent viral infections such as Epstein-Barr virus and cytomegalovirus
  • Medications such as antiseizure drugs and corticosteroids can cause IgA deficiency or hypogammaglobulinemia.
  • Inborn errors of metabolism
  • Chromosomal syndromes
  • Protein loss can be associated with hypogammaglobulinemia.
  • HIV infection

Diagnostic Tests and Interpretation

  • Test: IgG, IgA, IgM, IgE levels, and responses to vaccines such as diphtheria and tetanus
  • Significance: Recurrent sinopulmonary infections with typical organisms are associated with defects in antibody production.
  • Test: evaluation of T-cell production and function—T-cell enumeration and lymphocyte proliferation studies
  • Significance: T-cell defects will often have low T-cell numbers.
  • Test: evaluation of neutrophil numbers and function—a CBC with differential, morphologic exam of neutrophils, and a measure of respiratory burst
  • Significance: Neutropenia is the most common type of neutrophil defect followed by CGD.
  • Test: special studies designed to test the function of the toll-like receptor signaling complex
  • Significance: Innate defects, such as IRAK4, MyD88, and NEMO deficiencies, can be detected.
  • Test: a CH50
  • Significance: A CH50 will detect most of the structural component deficiencies. Special studies are needed for defects of the alternative pathway and the regulatory proteins.
  • Test: CBC with differential; IgG, IgA, and IgM levels; and diphtheria and tetanus titers
  • Significance: In certain patients, it may be difficult to differentiate between viral processes and bacterial processes. In these cases, a CBC with differential; IgG, IgA, and IgM levels; and diphtheria and tetanus titers are a useful screen to evaluate for the most common immunodeficiencies.

Treatment

Prophylactic antimicrobials

  • Chronic mucocutaneous candidiasis
  • Hyper-IgE syndrome
  • CGD

General Measures

  • Suspected SCID requires isolation, cytomegalovirus-negative/irradiated blood products, and a prompt evaluation for hematopoietic stem cell transplant (HSCT).
  • Ig replacement (either IV or SC)
    • X-linked agammaglobulinemia
    • Hyper-IgM
    • CVID
  • Specific strains of probiotic supplements may be useful for antibiotic-associated diarrhea.
  • Hand washing to prevent infections
  • Prophylactic antibiotics can be useful.

Diagnostic Procedures/Other

  • Hematopoietic stem cell transplantation
    • SCID
    • Wiskott-Aldrich syndrome
    • X-linked lymphoproliferative syndrome
    • Chédiak-Higashi syndrome
    • Familial hemophagocytic lymphohistiocytosis
    • Selected cases of hyper-IgM, CGD, macrophage activation defects
  • Thymus transplantation
    • Severe chromosome 22q11.2 deletion syndrome (DiGeorge syndrome)

Ongoing Care

Prognosis

  • Most antibody deficiencies have an excellent prognosis. Transient or developmental deficiencies of IgG or IgG subclasses typically resolve by 2 years of age.
  • Some patients with CVID can develop malignancy or autoimmune disease, and this defines the prognosis.
  • The treatment of neutrophil disorders remains problematic; most children with CGD will not have full life expectancy. HSCT can be curative.
  • 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.

Complications

  • Bronchiectasis
  • Deafness
  • Autoimmune disease
  • Lymphoreticular malignancies occur in patients with T-cell disorders.
  • Live viral vaccines administered to patients with significant T-cell dysfunction can result in disease.
  • Oral polio vaccine administered to patients with agammaglobulinemia can cause meningo-encephalitis.

Additional Reading

  1. Ballow M. Approach to the patient with recurrent infections. Clin Rev Allergy Immunol. 2008;34(2):129–140.  [PMID:18330724]
  2. Fischer A. Human primary immunodeficiency diseases. Immunity. 2007;27(6):835–845.  [PMID:18093537]
  3. Immunodeficiency Search. www.immunodeficiencysearch.com. Accessed June 8, 2018.
  4. Picard C, Al-Herz W, Bousfiha A, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies expert committee for primary immunodeficiency 2015. J Clin Immunol. 2015;35(8):696–726.  [PMID:26482257]
  5. Slatter MA, Gennery AR. Primary immunodeficiency syndromes. Adv Exp Med Biol. 2010;685:146–165.  [PMID:20687503]

Codes

ICD-9

  • 279.3 Unspecified immunity deficiency
  • 279.03 Other selective immunoglobulin deficiencies
  • 279.06 Common variable immunodeficiency
  • 279.04 Congenital hypogammaglobulinemia
  • 279.8 Other specified disorders involving the immune mechanism

ICD-10

  • D84.9 Immunodeficiency, unspecified
  • D80.9 Immunodeficiency with predominantly antibody defects, unspecified
  • D83.9 Common variable immunodeficiency, unspecified
  • D80.0 Hereditary hypogammaglobulinemia
  • D80.8 Other immunodeficiencies with predominantly antibody defects
  • D84.8 Other specified immunodeficiencies

SNOMED

  • 234532001 Immunodeficiency disorder (disorder)
  • 124950009 Deficiency of immunoglobulin (disorder)
  • 23238000 common variable agammaglobulinemia (disorder)
  • 267460002 Congenital hypogammaglobulinemia

FAQ

  • 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. If there is clinical suspicion of leukocyte adhesion deficiency, a CBC can be performed to identify neutrophilia.
  • Q: Which immunodeficiencies are associated with absent tonsils and adenoids?
  • A: Boys with X-linked agammaglobulinemia and X-linked hyper-IgM have absent tonsils and adenoids.
  • Q: Which immunodeficiency is associated with abscesses that are not painful?
  • A: Children and adults with hyper-IgE syndrome develop abscesses that are not painful.

Authors

Kathleen E. Sullivan, MD, PhD


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TY - ELEC T1 - Immune Deficiency ID - 617120 ED - Cabana,Michael D, BT - 5-Minute Pediatric Consult UR - https://peds.unboundmedicine.com/pedscentral/view/5-Minute-Pediatric-Consult/617120/all/Immune_Deficiency PB - Wolters Kluwer ET - 8 DB - Pediatrics Central DP - Unbound Medicine ER -