Definition and epidemiology
Primary immunodeficiencies (PIDs), now termed inborn errors of immunity (IEI), are a heterogeneous group of more than 480 monogenic disorders affecting development or function of the immune system. They predispose to recurrent or severe infection, immune dysregulation (autoimmunity, lymphoproliferation), and in some, malignancy. Individually rare but collectively not uncommon, they are under-recognised, particularly in settings with high background infection rates. In India, high consanguinity raises the prevalence of autosomal-recessive forms such as severe combined immunodeficiency (SCID), and BCG vaccination at birth means disseminated BCG (BCGosis) can be the sentinel presentation of a severe T-cell defect.
Clinical features
The classic phenotype is the child with infections that are too frequent, too severe, too persistent, too unusual in organism or site, or that respond poorly to treatment. The Jeffrey Modell Foundation 10 warning signs remain a practical screen: ≥4 new ear infections in a year; ≥2 serious sinus infections in a year; ≥2 months of antibiotics with little effect; ≥2 pneumonias in a year; failure to thrive; recurrent deep skin or organ abscesses; persistent oral or skin thrush after age 1; need for intravenous antibiotics to clear infections; ≥2 deep-seated infections including septicaemia; and a family history of PID. Non-infective clues — early-onset autoimmunity, granulomas, unexplained cytopenias, eczema with thrombocytopenia, or characteristic syndromic features — are equally important and may dominate.
Diagnosis
A first-tier workup is widely available and high-yield: full blood count with differential (absolute lymphocyte and neutrophil counts; lymphopenia in an infant is SCID until proven otherwise), serum immunoglobulins (IgG, IgA, IgM, IgE), and vaccine-specific antibody responses. Second-tier testing — lymphocyte subsets by flow cytometry, complement (CH50/AH50), neutrophil oxidative burst (DHR for chronic granulomatous disease), and targeted genetic testing — is directed by the phenotype. Newborn screening using T-cell receptor excision circles (TRECs) detects SCID before infections occur and is expanding internationally. Diagnostic frameworks from ESID and the IUIS classification structure this evaluation.
See the full criteria: Immunodeficiency
Red flags
- Infant with persistent lymphopenia, failure to thrive and infections — treat as possible SCID and refer urgently (a pediatric emergency)
- Disseminated BCG or atypical mycobacterial infection
- Severe or recurrent infection with opportunistic organisms (Pneumocystis, invasive fungal, CMV)
- Two or more deep-seated infections or unexplained bronchiectasis
- Combination of infection with autoimmunity, granuloma or lymphoproliferation
Management overview
Suspected PID warrants referral to clinical immunology. While awaiting definitive diagnosis, avoid live vaccines (BCG, OPV, rotavirus, MMR, varicella) and use irradiated, leukoreduced, CMV-safe blood products if transfusion is needed. Cornerstones of treatment include immunoglobulin replacement for antibody deficiencies, antimicrobial prophylaxis, aggressive treatment of intercurrent infection, and management of immune dysregulation. Hematopoietic stem cell transplantation is curative for SCID and several combined immunodeficiencies, with outcomes best when performed early and before infectious complications; gene therapy is established for selected disorders. Family counselling and genetic testing of relatives are integral.
References
- Jeffrey Modell Foundation. 10 Warning Signs of Primary Immunodeficiency.
- Bousfiha A, et al. J Clin Immunol. 2022 (IUIS phenotypical classification update).
- ESID clinical diagnostic criteria and warning signs.
Decision support for qualified clinicians only — verify against current primary guidelines and your clinical judgement.