Immunodeficiency Disorders

Definition, Etiology, PathogenesisTop

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

1) Inborn errors of immunity (IEI; previously known as primary immunodeficiencies [PIDs]): Rare conditions caused mostly by monogenetic 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 or other components of the innate immune system, or immune dysregulation. The overall prevalence of IEI is estimated at ~1 in 2000. Over 400 distinct disorders have been identified.

2) Secondary immunodeficiencies 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, immunosuppressive treatment, chemotherapy, and chimeric antigen receptor T [CAR-T] cell therapy), 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 classically manifest as frequent chronic and recurrent infections. The infections are more 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. Some patients may have atypical responses to common infections, such as hemophagocytic lymphohistiocytosis in the context of Epstein-Barr virus (EBV) infection. The diagnosis is sometimes obscured by false-negative results of serologic studies.

Another important presentation is systemic autoimmunity. This can manifest most commonly as autoimmune cytopenias, vasculitis, gut disease, or cutaneous involvement. Patients may be atopic and can also have manifestations of immune dysregulation and autoinflammation.

Clinical symptoms and signs of IEI usually appear in childhood, but it is not uncommon for the diagnosis to be made in adulthood. Some inborn disorders do not manifest immediately, and the delay in presentation is poorly understood.

DiagnosisTop

Immunodeficiency should be suspected in every person with recurrent or severe viral or bacterial infections, or with opportunistic infections. Unexplained evidence of autoimmunity or autoinflammation 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 require the guidance and expertise of specialized centers.

Warning signs of IEI 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) IEI 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 IEI.

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; assessment of T-cell, B-cell, and natural killer (NK)-cell counts (subpopulations) using flow cytometry; serum immunoglobulin (IgG, IgM, IgA) levels; titers of specific antibodies (against antigens of vaccines administered in childhood); HIV testing in the setting of severe viral infections, fungal infections, or both; serum protein electrophoresis (to exclude monoclonal gammopathies).

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

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; radiologic studies of the thymus; HIV testing.

2) Specialized studies: Determination of the type of T-cell or NK-cell dysfunction (or both; levels of adenosine deaminase and purine nucleoside phosphorylase); assessment of NK-cell 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 immunodeficiency panels, or whole genome sequencing in selected cases).

3. Assessment of phagocyte function:

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

2) Specialized studies: Neutrophil oxidative burst index (also called dihydrorhodamine reduction assay, previously assessed by nitroblue tetrazolium reduction assay), to assess oxidative processes in neutrophils; 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 complement component levels, typically C3 and C4 are readily available), mannose-binding lectin levels.

TreatmentTop

General recommendations: Table 1.

1. Avoid situations associated with a high risk of infection. Personal protective measures, such as hand washing, are recommended.

2. Treat the underlying condition in patients with secondary immunodeficiency or remove immunosuppressive medications if possible.

3. Administer intravenous immunoglobulin (IVIG) in patients with immunodeficiency associated with hypogammaglobulinemia and evidence of inadequate specific antibody production, 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 immunoglobulin (SCIG) 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 infusion reactions, and headache (including aseptic meningitis). Premedication with intravenous fluids, acetaminophen (INN paracetamol), and antihistamines, as well as systemic hydrocortisone, may be helpful in preventing or mitigating these reactions.

4. Prophylactic antimicrobial therapy: Amoxicillin (500 mg/d or 250-500 mg bid), trimethoprim/sulfamethoxazole (160 mg of trimethoprim once daily or 80-160 mg bid), or azithromycin 500 mg 3 times/wk. 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 jiroveci infections is recommended in patients with combined immunodeficiency displaying significantly defective leukocyte function, significantly decreased CD4⁺ cell counts, 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 <0.5×109/L). 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 sometimes 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 transplant is used in selected patients with profound or severe combined IEI and immune dysregulation.

8. Vaccinations in patients with immunodeficiency (see Immunization and Selected Vaccinations in Adults): Vaccination is typically ineffective in patients with humoral deficiency. Vaccination with attenuated live viruses (such as measles, mumps, rubella, and varicella) 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 and preferably platelet concentrates from cytomegalovirus-negative donors if local regulations allow it (irradiation is used to reduce lymphocyte counts in the concentrate).

10. Treatment of febrile neutropenia.

11. Immunosuppression: Some patients with immune dysregulatory disorders counterintuitively benefit from immune suppressive medications such as glucocorticoids, cyclosporine, and sirolimus, as well as pathway-targeted biologics, to improve their autoinflammatory symptoms.

TablesTop