Overview
Definition:
Severe Combined Immunodeficiency (SCID) refers to a group of rare, inherited genetic disorders characterized by profound defects in both T-cell and B-cell mediated immunity, leading to a severely compromised immune system
Infants with SCID are highly susceptible to opportunistic infections from bacteria, viruses, and fungi, and often do not survive their first year of life without intervention.
Epidemiology:
SCID affects approximately 1 in 58,000 live births worldwide
The incidence varies slightly by population and genetic background
In India, while specific large-scale screening data is emerging, the global incidence suggests a significant number of affected infants born annually.
Clinical Significance:
Early diagnosis and prompt treatment are critical for SCID
Without intervention, infants develop recurrent, severe infections that can be life-threatening
Newborn screening (NBS) has become a cornerstone for identifying affected infants before they become symptomatic, allowing for timely referral and definitive management, most commonly hematopoietic stem cell transplantation (HSCT) or gene therapy
Protective isolation is crucial for preventing life-threatening infections in infants awaiting diagnosis or definitive treatment.
Clinical Presentation
Symptoms:
Failure to thrive
Recurrent, severe, and persistent infections, including pneumonia, sepsis, diarrhea, skin infections, and oral thrush that does not respond to standard treatment
Opportunistic infections are common
Lymphadenopathy and tonsillar hypertrophy are typically absent due to the T-cell defect.
Signs:
Generalized lymphopenia, specifically T-cell deficiency
Absence of lymphoid tissue (thymus, lymph nodes, tonsils) on imaging
Normal or elevated absolute lymphocyte count (ALC) can be misleading
enumeration of lymphocyte subsets is key
Presence of severe infections despite appropriate antibiotic therapy.
Diagnostic Criteria:
Confirmed SCID diagnosis relies on laboratory confirmation of severely impaired T-cell receptor excision circle (TREC) levels, absent or severely reduced T-cell numbers, and absent or significantly impaired B-cell function (low or absent immunoglobulins, poor response to vaccines)
Genetic testing confirms the specific gene mutation responsible for the SCID phenotype.
Diagnostic Approach
History Taking:
Detailed birth history including any consanguinity
Family history of infant deaths, recurrent infections, or known primary immunodeficiencies
Detailed history of infant's health: feeding patterns, number and type of infections, response to prior treatments, vaccination status (which are often contraindicated if SCID is suspected)
Red flags include persistent thrush, severe diarrhea, pneumonia, or sepsis unresponsive to antibiotics.
Physical Examination:
Thorough physical examination focusing on signs of infection
Palpate for lymphadenopathy and check for tonsils
Assess skin for signs of infection
Evaluate for failure to thrive
Absence of palpable lymph nodes or tonsils in a young infant should raise suspicion for SCID.
Investigations:
Initial screening: TREC analysis (via dried blood spot) for T-cell lymphopenia
Confirmation: Complete blood count with differential, lymphocyte subset analysis (CD3, CD4, CD8, CD19, CD56), serum immunoglobulin levels (IgG, IgA, IgM), and specific antibody responses to vaccinations (e.g., tetanus, pneumococcus) if the infant is old enough
Genetic testing for specific SCID-causing mutations
Viral and bacterial cultures for suspected infections.
Differential Diagnosis:
Other causes of recurrent infections in infancy:Transient hypogammaglobulinemia of infancy, DiGeorge syndrome (22q11.2 deletion), Wiskott-Aldrich syndrome, Ataxia-telangiectasia, other severe combined immunodeficiencies, acquired immunodeficiencies (e.g., HIV infection, though rare in neonates in India without specific risk factors).
Newborn Screening And Early Detection
Screening Programmes:
Many developed countries have implemented SCID NBS programs using TREC analysis on dried blood spots collected at routine newborn screening
TRECs are DNA circles formed during T-cell development
their absence indicates a defect in T-cell maturation
A positive screen (low TREC count) requires urgent confirmatory testing.
Importance Of Timeliness:
Early detection through NBS is crucial
Infants identified before symptom onset have significantly better outcomes with HSCT
Delay in diagnosis leads to increased morbidity and mortality due to infections and potential damage to organs from infection.
Interpretation Of Results:
A low TREC count on NBS is a screening indication, not a diagnosis
It requires immediate follow-up with confirmatory laboratory testing: lymphocyte subset analysis to quantify T, B, and NK cells and genetic testing to identify the underlying mutation.
Protective Isolation And Management
Protective Isolation Measures:
Strict protective isolation is paramount for infants with suspected or confirmed SCID
This includes: placing the infant in a private room with positive pressure ventilation, strict hand hygiene for all caregivers, use of personal protective equipment (gowns, gloves, masks) by healthcare workers and visitors, avoiding contact with individuals who are ill, and limiting visitors
Breast milk should be pasteurized if there is any risk of CMV transmission, or formula feeding may be preferred.
Antimicrobial Prophylaxis:
Prophylactic antibiotics, antifungals (e.g., fluconazole), and antivirals (e.g., acyclovir) are often initiated empirically to prevent common opportunistic infections while awaiting diagnosis or treatment
Pneumocystis jirovecii pneumonia (PCP) prophylaxis (e.g., trimethoprim-sulfamethoxazole) is critical.
Hematopoietic Stem Cell Transplantation Hsct:
HSCT is the gold standard treatment for SCID
Early HSCT (ideally before 3-6 months of age, and before any serious infections) offers the best chance of cure
Matched sibling donors are preferred, followed by matched unrelated donors or haploidentical donors
Gene therapy is an alternative for specific SCID subtypes where gene correction is feasible.
Supportive Care:
Nutritional support is vital, as malabsorption and diarrhea are common
Intravenous immunoglobulin (IVIG) replacement therapy may be used for B-cell defects to provide passive immunity and manage infections while awaiting definitive treatment
Careful monitoring for any signs of infection is ongoing.
Key Points
Exam Focus:
NBS for SCID relies on TREC analysis
Low TRECs indicate a T-cell defect
SCID infants lack both T and B cell function
Clinical presentation is dominated by severe, recurrent infections
HSCT is the definitive treatment
timing is critical for survival
Protective isolation prevents life-threatening infections.
Clinical Pearls:
Always consider SCID in infants with recurrent severe infections, failure to thrive, and absent lymphoid tissue
Absence of lymphadenopathy or tonsillar hypertrophy in an infant with severe infections is a major clue
Never give live vaccines (e.g., rotavirus, oral polio, BCG) to infants with suspected or confirmed SCID.
Common Mistakes:
Delaying confirmatory testing after a positive NBS TREC result
Administering live vaccines to at-risk infants
Misinterpreting normal lymphocyte counts without subset analysis
Failing to implement strict protective isolation measures promptly.