Immunodeficiency Disorders

Chapter: Immunodeficiency Disorders
McMaster Section Editor(s): Judah A. Denburg
Section Editor(s) in Interna Szczeklika: Andrzej Hellmann, Bogdan Ochrem
McMaster Author(s): Elli Rosenberg, Judah A. Denburg
Author(s) in Interna Szczeklika: Jacek Roliński, Tomasz Sacha
Additional Information

Definition, Etiology, PathogenesisTop

Immunodeficiency disorders are associated with dysfunctions of the immune system. They are classified as:

1) Primary (hereditary) immune deficiencies: Rare conditions caused mostly by genetic defects of the immune system that can lead to an abnormal production of antibodies (most frequently common variable immunodeficiency), abnormal cellular response, abnormal phagocytosis, deficiencies in the complement system, or immune dysregulation. The overall prevalence of primary immunodeficiency is estimated at ~1 in 2000. Over 300 distinct disorders have been identified.

2) Secondary immune deficiencies caused by external factors or diseases: These are usually mixed (including an impaired specific immune response [humoral and cellular] and impaired nonspecific immune response [eg, abnormalities of the complement system]). Key etiologic factors include medications (anticonvulsants, nonsteroidal anti-inflammatory drugs, immunosuppressive treatment, and chemotherapy), infections (HIV, measles, herpes simplex virus, bacterial infections [including mycobacteria], parasitic infections [malaria]), malignancy (chronic lymphocytic leukemia, Hodgkin lymphoma, monoclonal gammopathies, solid tumors), metabolic disturbances (diabetes mellitus, renal failure, liver failure, malnutrition), autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, Felty syndrome), burns, environmental exposure (ionizing radiation, chemicals), pregnancy, stress, asplenia, splenic dysfunction, cirrhosis, and aging.

Clinical FeaturesTop

Immunodeficiency disorders manifest as frequent chronic and recurrent infections. The infections are severe, frequently atypical and prolonged, and sometimes resistant to antimicrobial treatment. They may be due to pathogens that rarely cause serious infections in immunocompetent persons, such as Mycobacterium avium, Cryptosporidium parvum, cytomegalovirus, or Candida albicans. For humoral immunodeficiencies, recurrent respiratory tract and paranasal sinus infections caused by encapsulated bacteria (eg, Haemophilus influenzae, Streptococcus pneumoniae) are characteristic. The diagnosis is frequently obscured by false-negative results of serologic studies.

Another important presentation is systemic autoimmunity. This can manifest as autoimmune cytopenias, vasculitis, gut disease, or cutaneous involvement. Allergic reactions to antimicrobial agents and food allergens are frequently observed.

Clinical symptoms and signs of primary immunodeficiencies usually appear in childhood, but it is not uncommon for the diagnosis to be made in adulthood.

DiagnosisTop

Immunodeficiency should be suspected in every person with recurrent or severe viral and/or bacterial infections, or with opportunistic infections. Unexplained evidence of autoimmunity can act as an additional clue. In such patients perform the studies reviewed below to assess the specific aspects of immune response, beginning with screening tests and proceeding towards more specialized studies. Once suspected, the diagnosis and management of immunodeficiency frequently requires the guidance and expertise of specialized centers.

Warning signs of primary immunodeficiency (PID) for adults:

1) Six signs by the European Society for Immunodeficiencies (2008):

a) At least 4 infections requiring antibiotics within a year (otitis, bronchitis, sinusitis, pneumonia).

b) Recurring infections or an infection requiring prolonged antibiotic therapy.

c) At least 2 severe bacterial infections (osteomyelitis, meningitis, septicemia, cellulitis).

d) At least 2 radiologically proven episodes of pneumonia within 3 years.

e) Infection with an unusual localization or unusual pathogen.

f) PID in the family.

2) Ten signs by the Jeffrey Modell Foundation endorsed by Immunodeficiency Canada:

a) At least 2 new ear infections within a year.

b) At least 2 new sinus infections within a year in the absence of allergy.

c) One pneumonia episode per year for >1 year.

d) Chronic diarrhea with weight loss.

e) Recurrent viral infections (colds, herpes, warts, condylomata).

f) Recurrent need for intravenous antibiotics to clear infections.

g) Recurrent deep abscesses of the skin or internal organs.

h) Persistent thrush or fungal infection on skin or elsewhere.

i) Infection with normally harmless tuberculosis-like bacteria.

j) A family history of PID.

Diagnostic Tests

1. Assessment of humoral immune response:

1) Screening tests: Complete blood count (CBC) with differential cell count; basic liver and kidney function tests; serum protein electrophoresis (to exclude monoclonal gammopathies); serum immunoglobulin (IgG, IgM, IgA) levels; titers of specific antibodies (against antigens of vaccines administered in childhood); HIV testing.

2) Specialized studies: Measurement of titers of specific antibodies before and after vaccinations (including assessment of the response to polysaccharide and protein vaccines); IgG subclass measurement; assessment of B-cell counts (subpopulations) using flow cytometry; assessment of in vitro immunoglobulin synthesis in response to mitogens.

2. Assessment of cellular immune response:

1) Screening tests: CBC with differential cell count; assessment of T-cell, B-cell, and NK-cell counts (subpopulations) using flow cytometry; skin tests to assess delayed cutaneous hypersensitivity (response to intradermal administration of antigens, eg, BCG, purified protein derivative); radiologic studies of the thymus; HIV testing.

2) Specialized studies: Determination of the type of T-cell and/or NK-cell dysfunction (levels of adenosine deaminase and purine nucleoside phosphorylase); assessment of NK cytotoxic activity; in vitro proliferation in response to mitogen or antigen stimulation; cytokine synthesis and secretion in response to mitogen or antigen stimulation; expression of surface markers after mitogen stimulation; assessment of 22q11 and 10p11 deletions using a fluorescence in situ hybridization assay; genetic analysis (including whole genome sequencing in select cases).

3. Assessment of phagocyte function:

1) Screening tests: CBC with differential cell count; microscopic assessment of neutrophils using standard staining.

2) Specialized studies: Dihydrorhodamine reduction assay or nitroblue tetrazolium reduction assay (to assess oxidative processes in phagocytes); assessment of adhesive molecules using flow cytometry; chemotaxis studies; phagocytosis studies using flow cytometry; cytochemical studies performed to assess activity of granulocyte peroxidase and glucose-6-phosphate dehydrogenase; bone marrow aspiration with a quantitative and morphological assessment of the myeloid lineage.

4. Assessment of the complement system:

1) Screening tests: Total hemolytic complement activity (CH50); activity of the complement alternative pathway (AH50).

2) Specialized studies: Concentrations or activities of respective complement components (serum C1-C9 levels, C1 esterase inhibitor).

TreatmentTop

1. Avoid situations associated with a high risk of infection.

2. In patients with secondary immunodeficiency, treat the underlying condition.

3. Administer intravenous immunoglobulins (IVIGs) in patients with immunodeficiency associated with hypogammaglobulinemia or agammaglobulinemia. The half-life of IgG is ~21 days, so it is recommended to administer IVIG every 21 to 28 days to maintain protective IgG levels (≥500 mg/dL). In patients with agammaglobulinemia or severe IgG deficiency (<200 mg/dL), consider administering a loading dose of 1 g/kg. Protective IgG levels are achieved in the majority of patients who receive IVIG 300 to 600 mg/kg every 3 weeks or 400 to 800 mg/kg every 4 weeks. However, the doses of IVIG necessary to maintain protective IgG levels and to achieve clinical improvement vary greatly among patients. Subcutaneous immunoglobulins (SCIGs) may also be used, usually once a week, until the protective IgG levels are achieved and subsequently at lower maintenance doses.

Common adverse effects that can be anticipated with parenteral immunoglobulins include local injection site reactions, systemic allergic reactions, and headache (including aseptic meningitis). Premedication with intravenous fluids, acetaminophen (INN paracetamol), and antihistamines may be helpful in preventing these reactions.

4. Prophylactic antimicrobial therapy: Amoxicillin (500 mg/d or 250-500 mg bid), sulfamethoxazole/trimethoprim (160 mg of trimethoprim once daily or 80-160 mg bid), or azithromycin 500 mg/kg once weekly. If these agents are ineffective, use clarithromycin 500 mg/d or amoxicillin + clavulanic acid 875 mg or 1000 mg once daily. Prophylactic antimicrobial therapy is indicated in patients with severe or moderate hypogammaglobulinemia in whom administration of IgG does not prevent frequent infections and in patients with severe deficiency of IgA or subclasses of IgG causing frequent infections. Prophylaxis of Pneumocystis jirovecii infections is recommended in patients with combined immunodeficiency displaying significantly defective leukocyte function and in patients undergoing intensive immunosuppressive treatment.

5. Hematopoietic growth factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte and macrophage colony-stimulating factor [GM-CSF]) are used in patients with severe neutropenia (absolute neutrophil count <500/microL). These agents may reduce the duration of neutropenia of various etiologies (including severe congenital neutropenia, cyclic neutropenia, and AIDS) and reduce the severity and duration of infections. They should be considered in patients with neutropenia and poor performance status who are at high risk of infectious complications, particularly if they have previously undergone anticancer treatment and developed complications in the form of infection or febrile neutropenia. Dosage of hematopoietic growth factors for G-CSF: filgrastim 3.45 to 11.5 microg/kg/d subcutaneously, lenograstim 150 microg/m2; for GM-CSF, use 250 microg/m2/d IV or subcutaneously.

6. Interferon alpha and interferon gamma are used in patients with congenital defects of humoral response, cell-mediated immune response (abnormalities of the interleukin 12/interferon gamma axis), or phagocytosis.

7. Allogeneic hematopoietic stem cell transplantation is used in selected patients with severe (and usually combined) PID.

8. Vaccinations in patients with immunodeficiency (see Immunoprophylaxis of Infectious Diseases in Adults): Vaccination with attenuated viruses (such as measles, mumps, and rubella) should be avoided in patients with defective cellular immunity. Every patient with asplenia or hyposplenism should receive vaccines against encapsulated bacteria (S pneumonia, Neisseria meningitidis, H influenzae type b) and yearly vaccination against influenza. Recommend vaccination of close contacts of an immunodeficient patient against most common infectious diseases (in particular against influenza).

9. Transfusions of blood cell concentrates: In patients with defects of cell-mediated immune response, transfuse only irradiated packed red blood cells or platelet concentrates from cytomegalovirus-negative donors (irradiation is used to reduce lymphocyte counts in the concentrate).

10. Treatment of febrile neutropenia.

TablesTop

Table. General recommendations on treatment of primary immunodeficiency disorders

Type of immunodeficiency

IVIG/SCIG

Allogeneic HSCT

Other treatments

Approximate prevalence (select examples)

Immunodeficiency affecting predominantly antibodies

+

– (+ for select cases of CVID)

– Avoidance of live vaccines (except SIGAD, IGGSD, THI)

– Antibiotic prophylaxis: all immunodeficiencies of this type if infections continue despite IVIG

– Immunomodulators: CVID

– Pneumococcal vaccination: SIGAD, IGGSD, SAD

SIGAD, 1:200

CVID, 1:20,000

XLA, 1:200,000

Combined immunodeficiency (including well-defined immunodeficiency syndromes)

+

+

– Avoidance of live vaccines: all immunodeficiencies of this type

– Avoidance of nonirradiated blood or products: all immunodeficiencies of this type

– Avoidance of CMV-positive blood or cells: all immunodeficiencies of this type

– Antibiotic prophylaxis: all immunodeficiencies of this type

– Antifungal prophylaxis: SCID, HIGM, HIES, ICD4L

– Splenectomy: WAS

– Glucocorticoids: WAS

– Thymus transplantation: DGS

– G-CSF, GM-CSF: ICD4L, HIGM

– Gene therapy for IL2RG, ADA deficiency, WAS

SCID, 1:50,000

WAS, 1:100,000

DGS, 1:5000

HIES, 1:100,000

HIGM, 1:500,000

ICD4L, very rare

Immunodysregulation disorders

+

+

– Avoidance of live vaccines: all immunodeficiencies of this type

– Antibiotic prophylaxis: all immunodeficiencies of this type

– Chemotherapy (as in lymphoproliferative neoplasms): XLP, GS

– Chemotherapy (associated with allogeneic HSCT): CHS

XLP, 1:1,000,000

 

Phagocyte defects

+

– Avoidance of live vaccines: all immunodeficiencies of this type

– Antibiotic prophylaxis: all immunodeficiencies of this type

– IFN-gamma: CGD, disorders of IL-12/IFN-gamma axis

– Surgical or dental debridement: CGD, LAD

– Antifungal prophylaxis: CGD, LAD

– G-CSF: neutropenia

– Antituberculous agents: disorders of IL-12/IFN-gamma axis

CGD, 1:200,000

LAD, very rare

Primary immunodeficiencies of the innate immune system

– (+ for WHIM)

+

– Avoidance of live vaccines: all immunodeficiencies of this type

– Antibiotic prophylaxis: all immunodeficiencies of this type

– G-CSF and GM-CSF: WHIM

– Antifungal agents: CMCC

– Antiviral agents: NK-cell deficiency

CMCC (diverse group of diseases), up to 1:10,000

WHIM, very rare

Complement deficiencies

– Antibiotic prophylaxis: all complement deficiencies

– Pneumococcal vaccine: deficiency of C1a, C1r, C2, C3, C4

– Meningococcal vaccine: deficiency of C5, C6, C7, C8, C9

– Immunomodulators (IFN-gamma): deficiency of C1a, C2, C4, factors H and I

C2 deficiency, 1:20,00

C4 deficiency, very rare

C5-C9 deficiency, variable, up to 1:2000

 

Adapted from: Bonilla FA, Khan DA, Ballas ZK, et al; Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; and the Joint Council of Allergy, Asthma & Immunology. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015 Nov;136(5):1186-205.e1-78. doi: 10.1016/j.jaci.2015.04.049. Epub 2015 Sep 12. PubMed PMID: 26371839.

ADA, adenine deaminase; CGD, chronic granulomatous disease; CHS, Chédiak-Higashi syndrome; CMCC, chronic mucocutaneous candidiasis; CMV, cytomegalovirus; CVID, common variable immunodeficiency; DGS, DiGeorge syndrome; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating factor; GS, Griscelli syndrome; HIES, hyper-IgE syndrome; HIGM, hyper-IgM syndrome; HSCT, hematopoietic stem cell transplantation; ICD4L, idiopathic CD4 lymphocytopenia; IFN-gamma, interferon gamma; IGGSD, IgG subclass deficiency; IL, interleukin; IL2RG, IL2 receptor gamma; IVIG, intravenous immunoglobulin; LAD, leukocyte adhesion deficiency; SAD, specific antibody deficiency; SCID, severe combined immunodeficiency; SCIG, subcutaneous immunoglobulin; SIGAD, selective IgA deficiency; THI, transient hypogammaglobulinemia of infancy; WAS, Wiskott-Aldrich syndrome; WHIM, warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis; XLA, X-linked agammaglobulinemia; XLP, X-linked lymphoproliferative syndrome.

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