What are primary immunodeficiencies?

Primary immunodeficiencies (PIDs) are a group of over 450 genetically-determined disorders in which components of the immune system are absent, reduced or dysfunctional from birth — not caused by external factors like HIV, chemotherapy or corticosteroids (which cause secondary immunodeficiency). PIDs range in severity from minor (selective IgA deficiency — usually asymptomatic; affects approximately 1 in 300-700 people) to life-threatening (SCID — invariably fatal without treatment; affects approximately 1 in 50,000-100,000). They typically manifest as: unusually frequent, severe or atypical infections; infections with organisms that normally do not cause disease (opportunistic); infections at unusual sites; poor response to standard antibiotic treatment.

What are the warning signs of PID?

The Jeffrey Modell Foundation 10 Warning Signs (for children): ≥4 ear infections per year; ≥2 serious sinus infections per year; ≥2 months on antibiotics with little effect; ≥2 pneumonias per year; failure to thrive; recurrent deep skin or organ abscesses; persistent oral thrush or fungal skin infection after age 1; need for IV antibiotics to clear infections; ≥2 deep-seated infections (meningitis, osteomyelitis, septicaemia, septic arthritis); family history of PID. For adults: prolonged or unusual infections; recurrent pneumonias; bronchiectasis of unknown cause; unusual pathogens (PCP in a non-HIV patient; unusual fungal infections; recurrent Salmonella bacteraemia). Any of these should prompt immunological investigation: FBC + differential, immunoglobulins (IgG, IgA, IgM), specific antibody responses to vaccines, lymphocyte subset counts, complement (CH50, C3, C4).

What is CVID and how is it treated?

Common variable immunodeficiency (CVID) is the most common clinically significant PID diagnosed in adults — typically presenting in the 20s-40s with a history of increasingly frequent or severe bacterial respiratory tract infections (sinusitis, pneumonia) despite antibiotic courses. Blood tests show: markedly low IgG (<7g/L in adults); usually low IgA and/or IgM; failure to mount specific antibody responses to vaccines. Treatment: immunoglobulin replacement therapy (IRT) — either IVIG (hospital infusion every 3-4 weeks) or SCIG (home self-administration weekly). IRT reduces serious bacterial infections by approximately 85-90% and prevents the development of chronic lung disease (bronchiectasis). It must be continued lifelong — like insulin for type 1 diabetes, it replaces a missing biological function.

What is SCID and how is it treated?

Severe combined immunodeficiency (SCID) is the most severe PID — a medical emergency. SCID infants lack functional T-cells (and usually B-cells and/or NK-cells) and will die from overwhelming infection within the first 1-2 years without treatment. Multiple genetic forms: X-linked SCID (IL2RG mutations — affects boys only; gamma-chain of cytokine receptors absent); ADA-SCID (adenosine deaminase enzyme deficiency — SCID + skeletal, neurological, and auditory abnormalities). Standard treatment: haematopoietic stem cell transplantation (HSCT) — providing a new immune system; best outcomes with a matched sibling donor, early (before infections), achieving >90% survival. Gene therapy (Strimvelis for ADA-SCID, EMA 2016): corrects the genetic defect in the patient's own stem cells — revolutionary for patients without a matched donor; first gene therapy approved for a genetic disease.

What is the importance of newborn screening for SCID?

SCID is uniformly fatal without treatment — but if identified before the first serious infection, treatment with HSCT or gene therapy can be curative. The T-cell receptor excision circle (TREC) assay on newborn dried blood spot samples detects SCID (and other severe T-cell deficiencies) with >95% sensitivity — before any clinical symptoms. If SCID is detected at birth: the baby is immediately placed in protective isolation; urgent immunology referral; HSCT or gene therapy arranged within weeks. Survival rate: >90% when transplanted in the first 3 months of life. Without newborn screening, most SCID babies present at 3-6 months with life-threatening infections after maternal antibody wanes — by which time infections have already caused organ damage. This is one of the strongest arguments for comprehensive newborn screening programmes.

How does GMJ News cover primary immunodeficiency?

GMJ News covers the 10 Warning Signs, CVID (most common adult PID), SCID (most severe), ADA-SCID gene therapy (Strimvelis 2016 — first approved gene therapy), TREC newborn screening, XLA (Bruton's disease), CGD (oxidative burst defect), immunoglobulin replacement (IVIG and SCIG), IUIS 2022 classification, and the 1:2,000 prevalence. PIDs are directly relevant to PHIG's rare disease programme, Georgia's newborn screening policy, and the hospital accreditation standards for infection management.

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Primary Immunodeficiency

Q: What is SCID and how is it treated?

Severe combined immunodeficiency (SCID) is the most severe PID — a medical emergency. SCID infants lack functional T-cells (and usually B-cells and/or NK-cells) and will die from overwhelming infection within the first 1-2 years without treatment. Multiple genetic forms: X-linked SCID (IL2RG mutations — affects boys only; gamma-chain of cytokine receptors absent); ADA-SCID (adenosine deaminase enzyme deficiency — SCID + skeletal, neurological, and auditory abnormalities). Standard treatment: haematopoietic stem cell transplantation (HSCT) — providing a new immune system; best outcomes with a matched sibling donor, early (before infections), achieving >90% survival. Gene therapy (Strimvelis for ADA-SCID, EMA 2016): corrects the genetic defect in the patient's own stem cells — revolutionary for patients without a matched donor; first gene therapy approved for a genetic disease.

GMJ News knowledge hub · last reviewed September 2026 · Georgian Medical Journal

Summary Statistics Glossary GMJ news FAQ Documents Organizations Research

Primary immunodeficiencies (PIDs) — a heterogeneous group of over 450 monogenic disorders in which components of the innate or adaptive immune system are absent or dysfunctional from birth — cause recurrent, severe or unusual infections that should trigger immune workup after 2 or more serious infections in 12 months, or any single infection with an unusual pathogen or clinical course, representing an often unrecognised but treatable cause of childhood mortality and morbidity globally (approximately 1 in 2,000 live births by recent estimates) (WHO). Common variable immunodeficiency (CVID) — the most common symptomatic PID in adults — and severe combined immunodeficiency (SCID — “bubble boy disease”) — the most life-threatening PID, with the first FDA-approved gene therapy (Strimvelis 2016; then lentiviral ADA-SCID gene therapies) representing one of medicine’s most inspiring therapeutic stories.

Key messages

Warning signs — "2 or more serious infections in 12 months"

The 10 Warning Signs of Primary Immunodeficiency (Jeffrey Modell Foundation): 4+ ear infections in 1 year; 2+ serious sinus infections in 1 year; 2+ months on antibiotics with little effect; 2+ pneumonias in 1 year; failure of an infant to gain weight or grow normally; recurrent deep skin or organ abscesses; persistent thrush or fungal infection after age 1; need for IV antibiotics to clear infections; 2+ deep-seated infections (meningitis, osteomyelitis, septicaemia); family history of PID.

CVID — most common symptomatic PID in adults

Common variable immunodeficiency (CVID) — low IgG (and usually low IgA and/or IgM) with impaired specific antibody responses to vaccines — is the most common symptomatic PID diagnosed in adults (typically age 20-40). Presents with recurrent sinopulmonary infections (bacterial — encapsulated organisms; Pneumocystis jirovecii). Treatment: lifelong regular immunoglobulin replacement (IVIG every 3-4 weeks, or subcutaneous SCIG weekly). Prognosis greatly improved with therapy.

SCID — "bubble boy disease" — the most severe PID

Severe combined immunodeficiency (SCID): absence of functional T, B and/or NK cells — the most severe PID, inevitably fatal without treatment. Multiple genetic forms: ADA-SCID (adenosine deaminase deficiency — most common); X-linked SCID (IL2RG mutations — most common X-linked PID, affecting boys only). Standard treatment: haematopoietic stem cell transplantation (HSCT). Gene therapy: Strimvelis (ADA-SCID, EMA 2016 — first approved gene therapy for a genetic disease); lentiviral gene therapies for multiple SCID forms.

Newborn screening for SCID — the critical intervention

SCID is now included in newborn screening programmes in many HICs (using the TREC — T-cell receptor excision circle — assay). Early detection (before first serious infection) dramatically improves HSCT outcomes — survival >90% when transplanted within the first 3 months of life, before infections cause organ damage. WHO advocates universal SCID newborn screening.

Immunoglobulin replacement — the cornerstone of B-cell PID treatment

Immunoglobulin replacement therapy (IRT) provides IgG antibodies from pooled human plasma donors — replacing what patients with B-cell PIDs cannot produce. Two routes: IVIG (intravenous immunoglobulin): infusion every 3-4 weeks at hospital or home; SCIG (subcutaneous immunoglobulin): weekly self-administered injection at home — most common route now due to convenience and stable IgG levels. Target trough IgG level: >8g/L (higher in those with structural lung disease). Reduces serious bacterial infections by approximately 85-90%.

X-linked agammaglobulinaemia (XLA) — Bruton's disease

XLA (BTK gene mutations): complete absence of mature B cells and immunoglobulins; affects boys exclusively. Presents at 6-9 months when maternal IgG wanes — recurrent bacterial infections of sinuses, lungs, joints. No risk of opportunistic infections (T-cells are normal). Treatment: lifelong immunoglobulin replacement. XLA patients who go undiagnosed may develop chronic lung disease (bronchiectasis), arthritis and enteroviral encephalitis (poliovirus — must avoid OPV vaccine).

Key statistics

~1 in 2,000

live births estimated to have a clinically significant primary immunodeficiency

ESID/IPOPI

450+

distinct PIDs identified and classified (IUIS classification 2022)

IUIS 2022

TREC assay

newborn screening for SCID — >90% survival if treated before infections

ESID/Newborn

EMA 2016

Strimvelis — first approved gene therapy for a genetic disease (ADA-SCID)

EMA 2016

85-90%

reduction in serious bacterial infections with immunoglobulin replacement

ESID/IPOPI

10 signs

Jeffrey Modell Foundation Warning Signs of PID — clinical screening tool

JMF

Primary immunodeficiency spectrum — by immune component affected

Source: IUIS 2022. Predominantly antibody deficiencies are most common; combined T+B deficiencies most severe.

Glossary of key terms

CVID (Common Variable Immunodeficiency)
ESID/IPOPIThe most common serious PID — characterised by: markedly reduced serum IgG (<7g/L in adults) + low IgA and/or IgM + failure to make specific antibodies to vaccines (tetanus, pneumococcus). Diagnosis typically in the 20s-40s after a pattern of recurrent sinopulmonary infections. Genetics: mostly unknown; a small proportion have monogenic causes (ICOS, TACI, BAFFR mutations). Complications beyond infections: autoimmune cytopenias; granulomatous disease (lung, liver, gut); lymphoid hyperplasia; elevated cancer risk (lymphoma, gastric carcinoma). Treatment: IVIG or SCIG lifelong — dramatically reduces infections and prevents complications.

Gene therapy for SCID
EMA/FDAADA-SCID (adenosine deaminase deficiency): Strimvelis (GSK/OrchaGen) — ex vivo retroviral gene therapy; CD34+ stem cells from patient collected, corrected with functional ADA gene, reinfused. EMA-approved 2016 — first approved gene therapy for a genetic disease in Europe. >90% enzyme activity restoration; no ADA-SCID disease recurrence in trial participants. Tisagenlecleucel (lentiviral ADA-SCID gene therapy, Orchard Therapeutics) — follow-on therapy with improved safety profile. X-linked SCID (IL2RG mutations): multiple lentiviral gene therapy programmes in trials; some early approvals pending. Game-changing for families who lack a matched donor for HSCT.

Bruton's agammaglobulinaemia (XLA)
ESID/GeneticsX-linked agammaglobulinaemia: caused by mutations in BTK (Bruton tyrosine kinase gene) — essential for B-cell development. Result: complete block in B-cell maturation at the pro-B cell stage → no circulating B cells, no immunoglobulins. Presentation: 6-9 months (when maternal IgG wanes) with recurrent bacterial infections — particularly encapsulated organisms (Pneumococcus, H. influenzae, Streptococcus). T-cell function: normal (no opportunistic infections). Treatment: lifelong IVIG or SCIG. Avoid live vaccines (OPV — poliovirus can cause vaccine-derived polio). BTK inhibitors (ibrutinib, zanubrutinib) — approved for B-cell lymphomas — deplete normal B cells, causing iatrogenic XLA-like antibody deficiency; these patients require immunoglobulin monitoring.

Chronic granulomatous disease (CGD)
ESID/ImmunologyA phagocyte defect (not antibody deficiency) — mutations in NADPH oxidase components (most commonly CYBB — X-linked CGD, affecting boys; also autosomal recessive forms) → neutrophils cannot produce the "oxidative burst" → cannot kill catalase-positive organisms after phagocytosis. Infections: recurrent abscesses and pneumonias from catalase-positive organisms — Staphylococcus aureus; Aspergillus (most dangerous); Burkholderia cepacia; Serratia; Nocardia. Granuloma formation (obstructing hollow organs — oesophagus, gut, urinary tract). Treatment: daily prophylactic antibiotics (trimethoprim-sulfamethoxazole) and antifungals (itraconazole); HSCT is curative; IFN-gamma (reduces infection frequency in some patients).

TREC (T-cell receptor excision circle) assay
Newborn screeningT-cell receptor excision circles (TRECs) are small circular DNA fragments excised during T-cell receptor gene rearrangement in the thymus — present in naive T-cells, absent in SCID (where T-cell development is absent or severely impaired). The TREC assay on dried blood spots from newborn heel-prick samples: quantifies TRECs by qPCR; low or absent TRECs → SCID screen positive → urgent immunology referral. Sensitivity >95% for severe T-cell lymphopaenia. Now included in newborn screening in USA (all 50 states), many European countries, Israel, Australia. Identifies SCID and other severe T-cell deficiencies before first life-threatening infection.

Subcutaneous immunoglobulin (SCIG)
ESID/TreatmentAn increasingly preferred alternative to IVIG for patients with antibody deficiencies: administered subcutaneously (into abdominal fat, thigh or upper arm) weekly or biweekly via a small needle and infusion pump — can be self-administered at home. Advantages over IVIG: more stable serum IgG levels (no peaks and troughs); no need for IV access; patient independence; home administration; higher trough IgG levels with equivalent dose. Disadvantages: local reactions (erythema, swelling at injection site — usually mild and transient); weekly administration (more frequent than 3-4 weekly IVIG). Most patients with CVID and XLA can be managed on home SCIG.