Overview
Definition:
Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited disorders that impair the innate or adaptive immune system, leading to increased susceptibility to infections, autoimmunity, and malignancy
These are distinct from secondary immunodeficiencies caused by external factors.
Epidemiology:
The estimated prevalence of all PIDs is approximately 1 in 1,200 live births, but some specific PIDs are much rarer
Early diagnosis and management are crucial for improving outcomes.
Clinical Significance:
Recognizing the warning signs of PID is critical for timely diagnosis and intervention, which can prevent life-threatening infections, reduce long-term morbidity, and improve quality of life for affected children
Understanding initial laboratory investigations guides further workup and specialist referral.
Warning Signs
Red Flags:
Eight warning signs for PIDs in children: 1
Four or more new-onset pneumonias in 1 year
2
Recurrent, severe, or persistent bacterial infections
3
Failure to thrive or poor growth
4
Recurrent deep organ or skin abscesses
5
Persistent oral or skin candidiasis beyond 1 year of age
6
Need for intravenous antibiotics to clear infections
7
Two or more serious infections (e.g., meningitis, sepsis, osteomyelitis) within the first year of life
8
Family history of PIDs or unexplained deaths early in infancy.
Infection Patterns:
Atypical or unusual infections, infections with opportunistic pathogens (e.g., Pneumocystis jirovecii, Candida, Aspergillus), and recurrent sinopulmonary infections (otitis media, sinusitis, pneumonia, bronchitis) are common
Non-infectious manifestations like autoimmune diseases, allergic disorders, and increased risk of malignancies are also important clues.
Other Indicators:
Recurrent gastrointestinal problems (diarrhea, malabsorption), lymphadenopathy, hepatosplenomegaly, and skin rashes can also be associated with PIDs, depending on the underlying defect.
Initial Diagnostic Approach
History Taking:
Detailed history focusing on the number, frequency, severity, and type of infections
Inquire about antibiotic use, hospitalization, and response to treatment
Ask about family history of recurrent infections, autoimmune diseases, allergies, or early infant deaths
Assess growth and development, and inquire about gastrointestinal symptoms, skin rashes, and autoimmune manifestations.
Physical Examination:
General assessment for signs of malnutrition, chronic illness, or dysmorphic features
Evaluate for lymphadenopathy (size, consistency, mobility), hepatosplenomegaly, and skin lesions (eczema, pustules, candidiasis)
Assess tonsil and adenoid size, and listen for lung and heart sounds for signs of infection or chronic lung disease.
Screening Investigations:
Initial screening laboratory tests include: Complete Blood Count (CBC) with differential to assess for lymphopenia, neutropenia, or eosinophilia
Quantitative Immunoglobulins (IgG, IgA, IgM) to assess humoral immunity
and Isohemagglutinin titers (anti-A, anti-B) in infants over 1 year old as a marker of functional B cell activity (absence suggests impaired antibody production).
Further Investigations Guidance:
Based on clinical suspicion and initial results, further investigations may include: specific antibody responses to vaccines (e.g., tetanus, pneumococcal), lymphocyte subset analysis (flow cytometry to quantify T, B, and NK cells), complement levels (CH50, C3, C4), and assessment of neutrophil function (e.g., nitroblue tetrazolium test or dihydrorhodamine assay).
Common Pid Types And Labs
B Cell Defects:
Most common group (e.g., Common Variable Immunodeficiency - CVID, X-linked Agammaglobulinemia - XLA)
Presentation: Recurrent bacterial infections, particularly sinopulmonary
Initial Labs: Low IgG, IgA, IgM
poor or absent specific antibody responses to vaccines
XLA shows absent B cells on flow cytometry.
T Cell Defects:
Less common but more severe (e.g., Severe Combined Immunodeficiency - SCID, DiGeorge Syndrome)
Presentation: Severe, opportunistic infections, failure to thrive, chronic diarrhea, skin rashes
Initial Labs: Profound lymphopenia (low T cells on flow cytometry), impaired cell-mediated immunity
SCID requires urgent hematopoietic stem cell transplantation.
Phagocyte Defects:
e.g., Chronic Granulomatous Disease (CGD)
Presentation: Recurrent deep-seated bacterial and fungal infections (abscesses of skin, lungs, liver, lymph nodes)
Initial Labs: Normal CBC and immunoglobulins
Diagnosis confirmed by neutrophil function tests (e.g., DHR assay).
Complement Defects:
e.g., C1, C2, C4 deficiencies
Presentation: Recurrent infections, particularly Neisseria species
autoimmune manifestations (SLE-like syndrome)
Initial Labs: Low levels of specific complement components
normal immunoglobulin levels.
Management Principles
Infection Control:
Prompt and appropriate antibiotic therapy for all infections
Prophylactic antibiotics and antifungals may be indicated
Avoidance of live attenuated vaccines in patients with significant T-cell defects.
Immunoglobulin Replacement Therapy:
Intravenous Immunoglobulin (IVIg) or Subcutaneous Immunoglobulin (SCIg) is the mainstay for most B-cell defects to prevent infections
Dosage and frequency are individualized based on trough IgG levels and clinical response.
Hematopoietic Stem Cell Transplantation:
Curative option for severe PIDs, particularly SCID and CGD, if performed early
Gene therapy is emerging as an alternative for some PIDs.
Supportive Care:
Nutritional support, management of autoimmune complications, and psychological support for patients and families are essential
Genetic counseling is also important.
Key Points
Exam Focus:
The 8 warning signs for PID are high-yield
Differentiate between B-cell, T-cell, phagocyte, and complement defects and their typical presentations and initial lab findings
Understand the role of IVIg/SCIg and when HSCT is indicated.
Clinical Pearls:
Always consider PID in a child with recurrent, severe, or unusual infections, especially if there is a family history
Early referral to a pediatric immunologist is crucial
Never underestimate the significance of failure to thrive in the context of recurrent infections.
Common Mistakes:
Missing one or more of the warning signs
Delaying investigation due to attributing recurrent infections solely to environmental factors or common childhood illnesses
Incorrect interpretation of initial lab results, particularly immunoglobulin levels and CBC
Prescribing live vaccines inappropriately.