Evaluation of the Suspected Immunodeficiency in Children
Introduction to Pediatric Immunodeficiency
Immunodeficiency disorders in children represent a diverse group of conditions characterized by defects in the immune system's ability to fight infections. These disorders can be primary (genetic) or secondary (acquired). Early recognition and diagnosis are crucial for optimal management and prevention of complications.
Key points:
- Primary immunodeficiencies (PIDs) are rare, affecting approximately 1 in 2,000 live births
- Secondary immunodeficiencies are more common and can result from various factors such as malnutrition, medications, or infections (e.g., HIV)
- Over 400 distinct disorders have been identified, with new genetic defects continually being discovered
- Early diagnosis can significantly improve outcomes and quality of life for affected children
Clinical Presentation of Immunodeficiency in Children
The clinical presentation of immunodeficiency in children can vary widely, but certain patterns should raise suspicion:
- Recurrent infections: Frequency, severity, and unusual pathogens are key factors
- Failure to thrive: Poor growth and development often accompany immunodeficiency
- Family history: Many PIDs have genetic components
- Unusual complications from live vaccines
- Chronic diarrhea or malabsorption
- Autoimmune manifestations
Special Physical Features Associated With Immunodeficiency Disorders
DERMATOLOGIC
- Eczema: Wiskott-Aldrich syndrome, IPEX, hyper-IgE syndromes, hypereosinophilia syndromes, IgA deficiency
- Sparse and/or hypopigmented hair: Cartilage-hair hypoplasia, Chédiak-Higashi syndrome, Griscelli syndrome
- Ocular telangiectasia: Ataxia-telangiectasia
- Oculocutaneous albinism: Chédiak-Higashi syndrome
- Severe dermatitis: Omenn syndrome
- Erythroderma: Omenn syndrome, SCID, graft-vs-host disease, Comel-Netherton syndrome
- Recurrent abscesses with pulmonary pneumatoceles: Hyper-IgE syndromes
- Recurrent organ granulomas or abscesses, lung, liver, and rectum especially: CGD
- Recurrent abscesses or cellulitis: CGD, hyper-IgE syndrome, leukocyte adhesion defect
- Cutaneous granulomas: Ataxia telangiectasia, SCID, CVID, RAG deficiency
- Oral ulcers: CGD, SCID, congenital neutropenia
- Periodontitis, gingivitis, stomatitis: Neutrophil defects
- Oral or nail candidiasis: T-cell immune defects, combined defects (SCIDs); mucocutaneous candidiasis; hyper-IgE syndromes; IL-12, -17, -23 deficiencies; CARD9 deficiency; STAT1 deficiency
- Vitiligo: B-cell defects, mucocutaneous candidiasis
- Alopecia: B-cell defects, mucocutaneous candidiasis
- Chronic conjunctivitis: B-cell defects
EXTREMITIES
- Clubbing of nails: Chronic lung disease caused by antibody defects
- Arthritis: Antibody defects, Wiskott-Aldrich syndrome, hyper-IgM syndrome
ENDOCRINOLOGIC
- Hypoparathyroidism: DiGeorge syndrome, mucocutaneous candidiasis
- Endocrinopathies (autoimmune): Mucocutaneous candidiasis
- Diabetes, hypothyroid: IPEX and IPEX-like syndromes
- Growth hormone deficiency: X-linked agammaglobulinemia
- Gonadal dysgenesis: Mucocutaneous candidiasis
HEMATOLOGIC
- Hemolytic anemia: B- and T-cell immune defects, ALPS
- Thrombocytopenia, small platelets: Wiskott-Aldrich syndrome
- Neutropenia: Hyper-IgM syndrome, Wiskott-Aldrich variant, CGD
- Immune thrombocytopenia: B-cell immune defects, ALPS
SKELETAL
- Short-limb dwarfism: Short-limb dwarfism with T- and/or B-cell immune defects
- Bony dysplasia: ADA deficiency, cartilage-hair hypoplasia
Warning signs (Jeffrey Modell Foundation's 10 Warning Signs):
- Four or more new ear infections within one year
- Two or more serious sinus infections within one year
- Two or more months on antibiotics with little effect
- Two or more pneumonias within one year
- Failure of an infant to gain weight or grow normally
- Recurrent, deep skin or organ abscesses
- Persistent thrush in mouth or fungal infection on skin
- Need for intravenous antibiotics to clear infections
- Two or more deep-seated infections including septicemia
- A family history of PID
Initial Evaluation of Suspected Immunodeficiency
When immunodeficiency is suspected, a systematic approach to evaluation is essential:
- Comprehensive medical history:
- Detailed infection history (frequency, severity, pathogens)
- Growth and development milestones
- Family history of immunodeficiency or early deaths
- Medication history, including vaccinations
- Physical examination:
- Growth parameters (height, weight, head circumference)
- Lymphoid tissue evaluation (tonsils, adenoids, lymph nodes)
- Skin examination for rashes, abscesses, or telangiectasia
- Neurological assessment
- Review of previous medical records:
- Past laboratory results
- Imaging studies
- Growth charts
This initial evaluation helps guide further diagnostic testing and determines the urgency of referral to an immunologist.
Clinical Aids to the Diagnosis of Immunodeficiency
Suggestive of B-Cell Defect (Humoral Immunodeficiency)
- Recurrent bacterial infections of the upper and lower respiratory tracts
- Recurrent skin infections, meningitis, osteomyelitis secondary to encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Neisseria meningitidis)
- Paralysis after vaccination with live-attenuated poliovirus
- Reduced levels of immunoglobulins
Suggestive of T-Cell Defect (Combined Immunodeficiency)
- Systemic illness after vaccination with any live virus or bacille Calmette-Guérin (BCG)
- Unusual life-threatening complication after infection with benign viruses (e.g., giant cell pneumonia with measles, varicella pneumonia)
- Chronic oral candidiasis after age 6 months
- Chronic mucocutaneous candidiasis
- Graft-versus-host disease after blood transfusion
- Reduced lymphocyte counts for age
- Low levels of immunoglobulins
- Absence of lymph nodes and tonsils
- Small thymus
- Chronic diarrhea
- Failure to thrive
- Recurrent infections with opportunistic organisms
Suggestive of Macrophage Dysfunction
- Disseminated atypical mycobacterial infection, recurrent Salmonella infection
- Fatal infection after BCG vaccination
Congenital Syndromes With Immunodeficiency
- Ataxia-telangiectasia: ataxia, telangiectasia
- Autoimmune polyglandular syndrome: hypofunction of one or more endocrine organs, chronic mucocutaneous candidiasis
- Cartilage-hair hypoplasia: short-limbed dwarfism, sparse hair, neutropenia
- Wiskott-Aldrich syndrome: thrombocytopenia, male gender, eczema
- Chédiak–Higashi syndrome: oculocutaneous albinism, nystagmus, recurrent bacterial infections, peripheral neuropathies
- DiGeorge syndrome (22q deletion syndrome): unusual facies, heart defect, hypocalcemia
Suggestive of Asplenia
- Heterotaxia
- Complex congenital heart disease
- Howell-Jolly bodies on blood smear
- Sickle cell anemia
Laboratory Testing for Pediatric Immunodeficiency
Laboratory testing is crucial for diagnosing and characterizing immunodeficiencies. The approach typically involves:
- First-line screening tests:
- Complete blood count (CBC) with differential
- Quantitative immunoglobulins (IgG, IgA, IgM, IgE)
- Lymphocyte subsets (T, B, and NK cells)
- CH50 or CH100 (complement function)
- Second-line tests (based on initial results and clinical suspicion):
- Specific antibody responses to vaccines
- Lymphocyte proliferation assays
- Neutrophil function tests
- Individual complement component levels
- Cytokine production assays
- Advanced diagnostic tests:
- Flow cytometry for specific cell markers
- Genetic testing (targeted sequencing or whole exome/genome sequencing)
- Enzyme assays (e.g., for adenosine deaminase deficiency)
Interpretation of results should always be done in the context of the child's age, as normal values vary significantly during development.
Initial Screening Immunologic Testing of the Child With Recurrent Infections
Complete Blood Count, Differential, and Erythrocyte Sedimentation Rate
- Absolute lymphocyte count: Normal result rules against T-cell defect
- Absolute neutrophil count: Normal result rules against congenital or acquired neutropenia and (usually) both forms of leukocyte adhesion deficiency, in which elevated counts are present even between infections
- Platelet count: Normal result excludes Wiskott-Aldrich syndrome
- Howell-Jolly bodies: Absence rules against asplenia
- Erythrocyte sedimentation rate: Normal result indicates chronic bacterial or fungal infection unlikely
Screening Tests for B-Cell Defects
- IgG, IgA, IgM: Low in most antibody defects
- Isohemagglutinins: Low in agammaglobulinemia
- Antibody titers tetanus, diphtheria, Haemophilus influenzae, and pneumococcus: Low in most antibody defects
Screening Tests for T-Cell Defects
- Absolute lymphocyte count: Normal result indicates T-cell defect unlikely
- Flow cytometry: Examine for the presence of naïve T cells (CD3+ CD45RA+ cells)
Screening Tests for Phagocytic Cell Defects
- Microscopy: Abnormal in some neutropenias
- Respiratory burst assay: Abnormal in chronic granulomatous disease
Screening Test for Complement Deficiency
- CH50: Nearly absent in classical pathway and terminal component deficiencies
- AH50: Nearly absent in alternative pathway and terminal component deficiencies
Specific Immunodeficiency Evaluations
Depending on the suspected type of immunodeficiency, specific evaluations may be necessary:
- B cell defects:
- Specific antibody titers pre- and post-vaccination
- B cell subsets analysis
- Genetic testing for known mutations (e.g., BTK for X-linked agammaglobulinemia)
- T cell defects:
- T cell receptor excision circles (TRECs) analysis
- T cell proliferation assays
- HLA typing (for severe combined immunodeficiency)
- Phagocyte disorders:
- Dihydrorhodamine (DHR) flow cytometry test for chronic granulomatous disease
- Neutrophil chemotaxis and phagocytosis assays
- Complement deficiencies:
- Alternative and classical pathway assays
- Individual complement component levels
These specialized tests are typically performed in conjunction with an immunologist and may require referral to a specialized center.
Laboratory Tests in Immunodeficiency
B-CELL DEFICIENCY
- Screening Tests: IgG, IgM, IgA, and IgE levels, Isohemagglutinin titers, Ab response to vaccine antigens (e.g., tetanus, diphtheria, pneumococci, Haemophilus influenzae)
- Advanced Tests: B-cell enumeration (CD19 or CD20), Biopsies (e.g., lymph nodes), Ab responses to boosters or to new vaccines
- Research/Special Tests: Advanced B-cell phenotyping, Ab responses to special antigens (e.g., bacteriophage φX174), mutation analysis
T-CELL DEFICIENCY
- Screening Tests: Lymphocyte count, Chest x-ray examination for thymic size, TRECs
- Advanced Tests: T-cell subset enumeration (CD3, CD4, CD8), Proliferative responses to mitogens, antigens, allogeneic cells, 22q11.2 deletion analysis
- Research/Special Tests: Advanced flow cytometry, Enzyme assays (e.g., ADA, PNP), Mutation analysis, T-cell activation studies
PHAGOCYTIC DEFICIENCY
- Screening Tests: WBC count, morphology, Respiratory burst assay
- Advanced Tests: Adhesion molecule assays (e.g., CD11b/CD18, selectin ligand)
- Research/Special Tests: Macrophage functional testing, Mutation analysis
COMPLEMENT DEFICIENCY
- Screening Tests: CH50 activity
- Advanced Tests: AH50 activity
- Research/Special Tests: Specific component assays
Management and Referral of Pediatric Immunodeficiency
Management of pediatric immunodeficiency requires a multidisciplinary approach:
- Referral criteria:
- Presence of multiple warning signs
- Abnormal screening test results
- Family history of known PID
- Severe or life-threatening infections
- Initial management:
- Prophylactic antibiotics when indicated
- Immunizations (avoid live vaccines if T cell deficiency is suspected)
- Nutritional support
- Treatment of acute infections
- Specialized treatments:
- Immunoglobulin replacement therapy
- Hematopoietic stem cell transplantation
- Gene therapy (for specific disorders)
- Enzyme replacement therapy (e.g., PEG-ADA for ADA deficiency)
- Long-term follow-up:
- Regular monitoring of growth and development
- Surveillance for complications (e.g., malignancies, autoimmune disorders)
- Psychosocial support for patients and families
Early referral to a pediatric immunologist is crucial for accurate diagnosis and optimal management. Coordination between primary care providers and specialists is essential for comprehensive care.
Evaluation of the Suspected Immunodeficiency in Children
- Q: What are the four main categories of primary immunodeficiencies? A: B cell (antibody) deficiencies, T cell deficiencies, combined immunodeficiencies, and phagocyte disorders
- Q: Which clinical sign is often the first indicator of a possible immunodeficiency in children? A: Recurrent or severe infections
- Q: What is the most common type of primary immunodeficiency? A: Antibody deficiencies
- Q: Which laboratory test is typically used as an initial screening for antibody deficiencies? A: Serum immunoglobulin levels (IgG, IgA, IgM)
- Q: What is the gold standard test for assessing T cell function? A: Lymphocyte proliferation assay
- Q: Which immunodeficiency is characterized by the absence of B cells but normal T cell numbers? A: X-linked agammaglobulinemia (XLA)
- Q: What is the typical age of presentation for severe combined immunodeficiency (SCID)? A: Within the first few months of life
- Q: Which vaccine is contraindicated in children with suspected severe T cell deficiencies? A: Live vaccines, especially BCG and oral polio vaccine
- Q: What test is used to screen newborns for SCID in many countries? A: T cell receptor excision circle (TREC) assay
- Q: Which clinical feature is often associated with Wiskott-Aldrich syndrome? A: Eczema, thrombocytopenia, and recurrent infections
- Q: What is the most common cause of secondary immunodeficiency in children worldwide? A: Malnutrition
- Q: Which test is used to assess the function of the classical complement pathway? A: CH50 assay
- Q: What is the characteristic feature of Hyper-IgM syndrome? A: Normal or elevated IgM levels with low IgG, IgA, and IgE levels
- Q: Which imaging study is often used to evaluate for the presence of a thymus in suspected T cell deficiencies? A: Chest X-ray or CT scan
- Q: What is the primary treatment for most antibody deficiencies? A: Immunoglobulin replacement therapy
- Q: Which test is used to assess neutrophil function in suspected phagocyte disorders? A: Nitroblue tetrazolium (NBT) test or dihydrorhodamine (DHR) assay
- Q: What is the most definitive test for diagnosing specific gene defects in primary immunodeficiencies? A: Genetic testing
- Q: Which immunodeficiency is characterized by absent T cells but normal B cell numbers? A: DiGeorge syndrome (22q11.2 deletion syndrome)
- Q: What is the role of vaccination response assessment in evaluating suspected immunodeficiencies? A: To assess the ability to produce specific antibodies against antigens
- Q: Which clinical feature is often associated with chronic granulomatous disease (CGD)? A: Recurrent catalase-positive bacterial and fungal infections
- Q: What is the typical pattern of inheritance for X-linked SCID? A: X-linked recessive
- Q: Which test is used to assess the alternative complement pathway? A: AH50 assay
- Q: What is the most common presenting symptom of common variable immunodeficiency (CVID) in children? A: Recurrent sinopulmonary infections
- Q: Which growth chart parameter is important to monitor in children with suspected immunodeficiency? A: Weight-for-age and height-for-age percentiles
- Q: What is the role of flow cytometry in evaluating suspected immunodeficiencies? A: To enumerate and characterize lymphocyte subsets
- Q: Which test is used to assess the ability of T cells to produce cytokines? A: Intracellular cytokine staining
- Q: What is the primary treatment for severe combined immunodeficiency (SCID)? A: Hematopoietic stem cell transplantation
- Q: Which immunodeficiency is characterized by the triad of ataxia, telangiectasia, and immunodeficiency? A: Ataxia-telangiectasia
- Q: What is the role of serum protein electrophoresis in evaluating suspected immunodeficiencies? A: To assess for the presence of monoclonal gammopathies or absence of gamma globulin fraction
- Q: Which test is used to assess the function of natural killer (NK) cells? A: NK cell cytotoxicity assay
