Overview
Definition:
Primary antibody deficiencies (PADs) are a group of inherited disorders characterized by defects in the development or function of B lymphocytes and/or plasma cells, leading to impaired production of immunoglobulins (antibodies)
This results in increased susceptibility to recurrent infections, particularly bacterial ones affecting the sinopulmonary tract and gastrointestinal system
Intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) therapy are cornerstone treatments for many PADs, aiming to replace deficient antibodies and provide passive immunity.
Epidemiology:
PADs are the most common type of primary immunodeficiency disorders (PIDs), affecting approximately 1 in 2,000 live births worldwide
The most common PAD is Common Variable Immunodeficiency (CVID), followed by Selective IgA Deficiency and X-linked Agammaglobulinemia (XLA)
The prevalence varies among different ethnic groups and geographical regions
Early diagnosis and treatment are crucial for improving outcomes.
Clinical Significance:
PADs pose a significant clinical challenge due to the severity and frequency of infections
Untreated or inadequately treated patients are at risk of chronic lung disease, autoimmune disorders, inflammatory conditions, and an increased incidence of certain malignancies
Immunoglobulin replacement therapy (IRT) with IVIG or SCIG significantly reduces infection rates, improves quality of life, and prevents long-term complications, making it vital for pediatric residents and DNB/NEET SS candidates to understand
It is a critical component of managing patients with recurrent infections and suspected immunodeficiency.
Clinical Presentation
Symptoms:
Recurrent bacterial infections, typically involving the sinopulmonary tract (sinusitis, otitis media, pneumonia) and gastrointestinal tract (diarrhea, malabsorption)
Infections are often severe, prolonged, and may not respond well to standard antibiotic therapy
Fever
Sepsis
Autoimmune manifestations such as autoimmune hemolytic anemia, thrombocytopenia, or inflammatory arthritis may also be present
Growth failure in children.
Signs:
Physical examination may reveal signs of chronic infection such as nasal polyps, chronic otitis media with effusion, or lung crackles
Generalized lymphadenopathy may be absent or minimal in some types like XLA due to B-cell defects
Signs of dehydration or malnutrition in severe cases
Signs of autoimmune phenomena.
Diagnostic Criteria:
Diagnosis is typically based on a combination of clinical history, physical examination, and laboratory investigations
Key laboratory findings include low serum levels of one or more immunoglobulin classes (IgG, IgA, IgM) and/or subclasses, and a poor or absent response to vaccination with polysaccharide antigens
Specific diagnostic criteria for individual PADs (e.g., CVID, XLA) are well-defined by expert groups like the International Union of Societies for the Study of Immunodeficiencies (IUIS).
Diagnostic Approach
History Taking:
Detailed history of recurrent infections, including site, frequency, severity, and response to antibiotics
History of opportunistic infections
Family history of similar infections or immunodeficiency
Presence of autoimmune diseases or allergies
History of vaccinations and response
Growth and development in children
Any chronic diarrhea or malabsorption.
Physical Examination:
Thorough examination focusing on signs of chronic infection (nasal, ear, pulmonary findings)
Assessment of lymph nodes, spleen, and liver
Evaluation for signs of autoimmune disease or skin conditions
Assessment of growth parameters (height, weight, head circumference) and nutritional status.
Investigations:
Complete blood count (CBC) with differential to assess for lymphopenia or other hematological abnormalities
Serum immunoglobulin levels (IgG, IgA, IgM, IgE) to screen for hypogammaglobulinemia
Serum immunoglobulin subclasses
Specific antibody titers to vaccine antigens (e.g., tetanus, pneumococcal) to assess B-cell function
Lymphocyte subset analysis (flow cytometry) to enumerate B cells, T cells, and NK cells
Genetic testing for specific PADs when indicated (e.g., BTK gene for XLA).
Differential Diagnosis:
Secondary antibody deficiencies due to underlying conditions like malnutrition, certain malignancies (leukemia, lymphoma), nephrotic syndrome, or medications (e.g., chemotherapy, immunosuppressants)
Other primary immunodeficiency disorders not primarily affecting antibody production
Recurrent infections due to non-immunodeficiency causes like anatomical abnormalities or allergies.
Management
Initial Management:
Prompt and aggressive treatment of acute infections with appropriate antibiotics
Prophylactic antibiotics may be used in some cases while awaiting diagnosis or if IRT is not yet established
Early referral to a pediatric immunologist is critical.
Medical Management:
Immunoglobulin replacement therapy (IRT) is the mainstay of treatment for symptomatic PADs
IVIG is administered intravenously every 3-4 weeks
SCIG can be administered subcutaneously weekly or bi-weekly at home
Dosing is typically 300-600 mg/kg per infusion/cycle, adjusted based on clinical response and trough IgG levels (aiming for trough IgG > 5-7 g/L)
Management also includes prompt treatment of acute infections, monitoring for complications, and management of associated autoimmune or inflammatory conditions.
Supportive Care:
Nutritional support and monitoring for growth and development
Pulmonary physiotherapy for chronic lung disease
Vaccinations: Live attenuated vaccines are generally contraindicated
inactivated vaccines are recommended but may have reduced efficacy
Genetic counseling for affected families
Education on infection prevention and recognition of early signs of illness.
Complications
Early Complications:
Infusion-related reactions to IVIG/SCIG (fever, chills, headache, anaphylaxis, aseptic meningitis)
Thrombotic events
Acute renal failure
Hemolysis
Infection transmission (rare).
Late Complications:
Chronic sinopulmonary disease (bronchiectasis, lung fibrosis)
Autoimmune disorders
Malignancies (lymphoma, gastrointestinal cancers)
Chronic diarrhea and malabsorption
Neurological complications
Splenomegaly
Liver disease.
Prevention Strategies:
Careful monitoring during IVIG infusions, slow infusion rates, and premedication for infusion reactions
Adequate hydration and monitoring of renal function
Education of patients and caregivers on signs of infection and prompt medical attention
Regular pulmonary function tests and chest imaging to monitor for chronic lung disease
Screening for autoimmune manifestations and malignancies.
Prognosis
Factors Affecting Prognosis:
Timeliness of diagnosis and initiation of IRT
Severity of underlying PAD
Development of chronic organ damage (lung, liver, gut)
Presence of autoimmune complications
Compliance with therapy
Response to treatment.
Outcomes:
With timely diagnosis and effective IRT, most patients with PADs can experience a significant reduction in infection rates and improve their quality of life
Many can achieve normal growth and development and lead relatively healthy lives
However, chronic complications like bronchiectasis or autoimmune disease can impact long-term outcomes.
Follow Up:
Lifelong monitoring by a pediatric immunologist is essential
Regular clinical assessment, monitoring of immunoglobulin levels and trough IgG levels, assessment of response to therapy, and screening for complications (pulmonary, autoimmune, oncological)
Regular review of vaccination status and management of any intercurrent illnesses.
Key Points
Exam Focus:
Recognize recurrent infections suggestive of PADs
Differentiate between common PADs (XLA, CVID, IgA deficiency) based on age and immunoglobulin pattern
Understand the principles of IRT (IVIG vs
SCIG), dosing, and monitoring
Identify complications of PADs and IRT
Recall indications for genetic testing.
Clinical Pearls:
A child with recurrent sinopulmonary infections unresponsive to standard antibiotic therapy should raise suspicion for PID, particularly PAD
Always check serum immunoglobulins in such cases
SCIG offers convenience for home administration and potentially fewer infusion reactions than IVIG
Early diagnosis and treatment are paramount to prevent irreversible organ damage.
Common Mistakes:
Delayed diagnosis due to attributing recurrent infections to common childhood illnesses
Inadequate IRT dosing or frequency, leading to persistent infections or sub-optimal trough IgG levels
Failure to screen for or manage associated autoimmune phenomena or chronic organ damage
Over-reliance on prophylactic antibiotics without considering IRT.