BASICS
DESCRIPTION
- Immunodeficiency can be either primary or secondary (acquired). There are numerous causes; each may lead to increased risk of infections, autoimmune diseases, and cancers.
- Primary immunodeficiency disease (PID): an intrinsic defect in the immune system affecting receptor function, cytoplasmic enzymes, and gene regulatory proteins. These defects affect the maturation and function of B cells, T cells, phagocytes, the complement system, and NK cells. Depending on the defect, ≥1 organ systems are affected.
- B-cells: humoral immunodeficiencies: defects in antibody production typically presenting as recurrent sinopulmonary or gastrointestinal infections. Most common form of PID (~2/3). Typically not seen before 6 months of age due to maternal antibodies:
- IgA deficiency: most common primary immunodeficiency: Clinical symptoms range from asymptomatic/mild to severe. Sporadic more common than inherited. Spanish and Arabian populations are more at risk than European (~1:150 to 1:400+). Asians are at least risk (~1:2,600 to 1:18,000). Associated with autoimmune diseases such as rheumatoid arthritis (RA) (at any age) and systemic lupus erythematosus (SLE). Children <5 years presenting with IgA deficiency may outgrow it.
- Common variable immunodeficiency: a heterogeneous form of severe antibody deficiency. Low immunoglobulins (IgG, IgA, and/or IgM) leave patients susceptible to pyogenic infections. Moderate to severe clinical presentations are more common than mild/asymptomatic. Adult onset (mid-20s) is more common than childhood. Sporadic (~90%) is more common than inherited. Incidence for CVID 1:25,000 to 1:66,000. Northern European descent higher risk than African, Asian, and Hispanic. Men and women are at equal risk. Similar risks and family history as with IgA deficiency. Treatment helps prevent bronchiectasis, malabsorption, and vitamin deficiencies.
- X-linked agammaglobulinemia (XLA): Xq22; Bruton tyrosine kinase. Recurrent infections with encapsulated bacteria after birth are common. Growth and development are usually normal. All serum immunoglobulins are extremely low. T and NK cells' function are preserved. Tonsils, adenoids, and peripheral lymph nodes are diminished in size.
- Hyper-IgM syndrome (HIMG): Similar infections as XLA. Pneumocystis jiroveci pneumonia is possible as initial presentation. Defect of either B-cell isotype switching from IgM-secreting to IgG, A, or E (HIMG1-4: autosomal recessive [AR], NEMO) or helper T-cell inability to signal/activate B cells (X-linked: Xq26 and formerly a T-cell PID). Serum IgM concentration is polyclonal and normal to elevated.
- Other examples: defects in Ig heavy chain gene, hypogammaglobulinemia
- T cells (cellular-mediated immunodeficiencies): defects in maturation or function of T-lymphocytes Predisposed to infections such as Candida, parasite, and P. jiroveci:
- 22q11.2 deletion syndrome/DiGeorge syndrome: defect of embryogenesis. Involved structures include thymus, parathyroid, and aortic arch. De novo or autosomal dominant (AD). Prevalence is ~1:4,000. Normally diagnosed in infancy. Characteristics (CATCH 22): cardiac abnormalities, hypognathus, long philtrum, low set ears, hypertelorism, downward slanted eyes, "carp-shaped" mouth, thymic abnormalities (absent thymic shadow), cleft palate, hypoparathyroidism
- Immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX): classically presents as a syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. Involves neonatal-onset diabetes mellitus, hypothyroidism, enteritis (diarrhea/villous atrophy), hemolytic anemia and thrombocytopenia, and dermatitis. Death normally occurs by 1 to 2 years of age. Missense mutations in FOXP3 result in impaired development and function of CD4+, CD25, and regulatory T cells and may repress cytokine promoters.
- Combined immunodeficiencies: Defects in the cellular effector and humoral mechanisms directly involving a combination of B and T lymphocytes and NK cells. Typically present as failure to thrive, often associated with diarrhea and severe eczema:
- Severe combined immunodeficiency (SCID): Depending on genetic mutation, patients may have absent T cells with/without impairment to B cells and/or NK cells. Presents in infancy with failure to thrive, recurrent or persistent thrush, and gastrointestinal illnesses. Prevalence 1/50,000 to 100,000. If treatment is unsuccessful or delayed, death normally occurs before 1 to 2 years of age. X-linked, AR, and known mutations in adenosine deaminase deficiency gene, purine nucleoside phosphorylase deficiency gene, interleukin-Ī³ chain, JAK3, CD45, ZAP70, RAG1, and RAG2.
- Others: Wiskott-Aldrich syndrome (X-linked), MHC II deficiency, and ataxia telangiectasia (AR)
- Phagocytic immunodeficiencies: defects in the function and/or quantity of phagocyte cells. Recurrent pyogenic infections with staphylococcal species, Aspergillus, Klebsiella, and Pseudomonas. Granuloma formation and poor wound healing are common.
- Chronic granulomatous disease: 90% inherited disorder (X-linked and AR) of phagocytic cells; results from an inability of phagocytes to undergo respiratory burst (key enzyme: NADPH oxidase). Recurrent life-threatening bacterial and fungal infections, often involving lymph nodes, liver, spleen, and skin. Normally occurs early in life. X-linked: mutation of cytochrome gp91 or b558 genes, called CYBB. AR: chromosome 7, NCF1 (p47phox) gene.
- Leukocyte adhesion deficiency: an AR disorder resulting in a dysfunction of cell surface adhesion. The defect is in CD18, important in stabilizing macrophage interaction with T cells and bacterial opsonization. Delayed separation of the umbilical cord may be seen in the neonatal period. Later in life, recurrent pyogenic infections without pus formation are common.
- Glucose-6-phosphate dehydrogenase deficiency: X-linked (Xq28) defect preventing generation of NADPH via the hexose monophosphate shunt. Lack of NADPH oxidase produces a clinical picture similar to CGD. Differs by a later age of onset (>10 years): commonly presents as hemolytic anemia
- Myeloperoxidase deficiency: facilitates the oxidation of chloride and iodide by hydrogen peroxide. Deficiency results in the attenuation of bactericidal PMNs activity. Most individuals are asymptomatic, but some may have recurrent candidal infections. AR: 17q21.3-q23
- Other examples: Ch ©diak-Higashi syndrome and lazy leukocyte syndrome
- Complement deficiencies: inherited or acquired and complete or partial
- Classical (C1, C4, C2): immune complex diseases (e.g., discoid or systemic lupus erythematosus, pneumococcal infections)
- Alternative (properdin, factor B, factor D): severe fulminant pyogenic neisserial infections with a high mortality rate
- Mannose-binding lectin: recurrent infections, accelerated course of SLE and RA
- Other examples: C3, factor H, and factor I (pyogenic bacterial infections). Terminal pathway C5-C9 (neisserial and bacterial infections)
- Gene regulatory protein defects
- (STAT 1) Chronic mucocutaneous candidiasis: a heterogenous group of disorders involving recurrent Candida infections. May occur anywhere on the body and at any point in life. Disease can be familial (STAT1: AD). Although Candida is the defining infection, it may include others. Endocrine abnormalities are common.
- (STAT 3) Hyper-IgE syndrome: Recurrent severe staphylococcal abscesses (skin, lungs, and viscera). Characteristic facial features include prominent forehead, deep-set eyes, broad nasal bridge, wide fleshy nasal tip, mild prognathism, facial asymmetry, and hemihypertrophy. Extremely high serum IgE, elevated serum IgD, and normal concentrations of IgG, IgA, and IgM. STAT3 gene mutation (AD with incomplete penetrance).
- Secondary immunodeficiency disease: either acquired as a result of age, malnutrition, pregnancy, illness (autoimmune, cancers, leukemias, HIV), treatment(s) (chemotherapy, corticosteroids, immunosuppressants, radiation), or injury (burns, trauma). May be transient (newborn) or permanent (HIV). More common than PID and tends to occur later in life
GENERAL PREVENTION
- Early identification is key to prevent infection and possible comorbidity. For newborns with known family history, consider genetic counseling and prenatal diagnostic testing.
- Proper hygiene and nutrition for all ages regardless of type of immunodeficiency
- For certain secondary immunodeficiencies such as HIV and hepatitis B and C, emphasize safe needle practices and safe sexual practices.
DIAGNOSIS
HISTORY
- A complete personal and family history are key to correct diagnosis. Recurrent respiratory infections are the most common clinical manifestations of PID (1,2).
- 10 signs of possible primary immunodeficiency
- ≥4 new ear infections in 1 year
- ≥2 serious sinus infections in 1 year
- ≥2 months on antibiotics with little effect
- ≥2 pneumonias within 1 year
- Failure to thrive
- Recurrent deep skin or organ abscesses
- Persistent thrush or fungal infections on skin
- Need for IV antibiotics to clear an infection
- ≥2 deep-seated infections (e.g., sepsis)
- Family history of primary immunodeficiency
- Infection history and other clues
- Pneumococcus, Haemophilus influenzae, and so forth: Think B-cell defect.
- PCP, Candida, parasites: Think T-cell defect.
- Aspergillus, Klebsiella, Pseudomonas: Think PMN defect.
- Meningococcus: Think complement defect.
- Family history: similar symptoms, known PID, autoimmune diseases, early infant deaths, cancers, or hemolytic diseases
- Newborn screening: 30 States, DC, and Navajo Nation screen for SCID. Screen uses an assay for T-cell receptor excision circles (TRECs) by PCR. Positive test require immediate flow cytometry. Positive patients should be treated until flow cytometry is complete (3).
PHYSICAL EXAM
Varies with condition. Focus on skin, sinopulmonary, and gastrointestinal exam. Assess for lymphadenopathy.
DIAGNOSIS TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Complete blood count with differential
- Serum protein electrophoresis for immunoglobulin levels, including IgG, IgA, IgM, and IgE
- X-rays or CT scans as indicated (if there is concern for SCID or DiGeorge, absent thymic shadow, PNA, abscesses)
Follow-Up Tests & Special Considerations
- Consultation with a geneticist or an immunologist before ordering special testing is appropriate (4,5).
- Flow cytometry to examine lymphocyte subsets (CD4, CD8, CD3, CD19, CD20) (4,6): helps to detect deficiency in T, B, NKT, and NK cells
- B-cell antibody responses to vaccines (e.g., pneumococcus): helps assess humoral antigen response
- T-cell enumeration, mitogen/antigen stimulation, FISH
- Combined immunodeficiencies: T-cell enumeration, mitogen/antigen stimulation, ADA/PNP activity, ZAP 70, and IL2-Ī³ chain evaluation
- Phagocyte immunodeficiencies: nitroblue tetrazolium test, dihydrorhodamine reductase test, chemiluminescence, granule biopsy, chemotaxis assay
- Complement deficiencies: CH50, AH 50, individual complement components
- NK cell deficiency: NK cell function test
TREATMENT
GENERAL MEASURES
- Avoid live viral vaccines in patients with severe cellular or antibody immunodeficiencies. This includes intranasal influenza, varicella, zoster, measles, mumps, rubella, oral polio, smallpox, Bacille Calmette-Gu ©rin, and yellow fever.
- Consult the CDC's Advisory Committee on Immunization Practices (ACIP) for up-to-date recommendations (7).
- Patients receiving (or who have received) immunoglobulin replacement therapy (IgG) in the past 6 months are considered passively immune and do not require vaccination.
- Transfuse irradiated, CMV-negative blood products in patients with cellular or combined defects.
- Bone marrow, stem cell, or thymic transplants for certain immunodeficiencies such as SCID, MHC II, and so forth.
MEDICATION
- Highly variable depending on form and severity of PID or acquired immunodeficiency
- Antibiotics, antivirals, antifungal, antiparasitic agents: Specific to organism if known, broad coverage until known; may need prophylactic or chronic medications
- Immunoglobulin replacement therapy for humoral deficiencies (e.g., CVID, XLA, HIMG)
ISSUES FOR REFERRAL
Refer individuals suspected of a primary immunodeficiency to a clinical immunologist.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Varies according to deficiency
- Recurrence of infections or failure to fully treat current infection
- Decline in respiratory function
- Patients on IgG should have levels checked regularly (<600 at risk for infections).
- Monitor for comorbid malignancies and/or autoimmune conditions.
- Malnutrition
PATIENT EDUCATION
- Immune Deficiency Foundation, 40 West Chesapeake Ave. Suite 308, Towson, MD 21204. Tel: (800) 296-4433. www.primaryimmune.org.
PROGNOSIS
Highly variable; depends on specific deficiency and compliance with preventive and active treatments
COMPLICATIONS
- Immunoglobulin replacement therapy: allergic reactions, increased risk of thrombosis
- Transplants: graft-versus-host disease, infection
- Frequent/prophylactic antibiotic use predisposes to the development of resistant stains
REFERENCES
11 Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005;94(5 Suppl 1):S1-S63.22 Notarangelo LD. Primary immunodeficiencies. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S182-S194.33 Kwan A, Church JA, Cowan MJ, et al. Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California: results of the first 2 years. J Allergy Clin Immunol. 2013:132(1):140-150.44 Oliveira JB, Fleisher TA. Laboratory evaluation of primary immunodeficiencies. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S297-S305.55 Orange JS, Ballow M, Stiehm ER, et al. Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2012;130(Suppl 3):S1-S24.66 Meyer-Bahlburg A, Renner ED, Rylaarsdam S, et al. Heterozygous signal transducer and activator of transcription 3 mutations in hyper-IgE syndrome result in altered B-cell maturation. J Allergy Clin Immunol. 2012;129(2):559-562.77 Principi N, Esposito S. Vaccine use in primary immunodeficiency disorders. Vaccine. 2014;32(30):3725-3731.
ADDITIONAL READING
- Bousfiha AA, Jeddane L, Ailal F, et al. Primary immunodeficiency diseases worldwide: more common than generally thought. J Clin Immunol. 2013;33(1):1-7.
- Chinen J, Shearer WT. Secondary immunodeficiencies, including HIV infection. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S195-S203.
CODES
ICD10
- D84.9 Immunodeficiency, unspecified
- D80.9 Immunodeficiency with predominantly antibody defects, unspecified
- D80.2 Selective deficiency of immunoglobulin A [IgA]
- D83.9 Common variable immunodeficiency, unspecified
- D89.9 Disorder involving the immune mechanism, unspecified
- D83.0 Com variab immunodef w predom abnlt of B-cell nums & functn
- D80.4 Selective deficiency of immunoglobulin M [IgM]
- D80.3 Selective deficiency of immunoglobulin G [IgG] subclasses
- D80.1 Nonfamilial hypogammaglobulinemia
- D80.0 Hereditary hypogammaglobulinemia
- D80.5 Immunodeficiency with increased immunoglobulin M [IgM]
ICD9
- 279.3 Unspecified immunity deficiency
- 279.00 Hypogammaglobulinemia, unspecified
- 279.01 Selective IgA immunodeficiency
- 279.06 Common variable immunodeficiency
- 279.09 Other deficiency of humoral immunity
- 279.04 Congenital hypogammaglobulinemia
- 279.03 Other selective immunoglobulin deficiencies
- 279.02 Selective IgM immunodeficiency
- 279.05 Immunodeficiency with increased IgM
SNOMED
- Immunodeficiency disorder (disorder)
- Hypogammaglobulinemia (finding)
- Selective immunoglobulin A deficiency
- common variable agammaglobulinemia (disorder)
- Humoral immune defect
- Congenital hypogammaglobulinemia
- Hyperimmunoglobulin M syndrome
- Selective immunoglobulin M deficiency
CLINICAL PEARLS
- Patients with immunodeficiencies may appear healthier than they are due to an attenuated inflammatory response.
- Patients with humoral deficiencies may have comorbid autoimmune illnesses with normal antibody testing.
- Patients with T-cell deficiencies may not react to purified protein derivative testing for TB.
- Consider immunodeficiency disease in patients presenting with unexplained recurrences of respiratory illness.