Clinical Immunology : Primary immunodeficiency

• Recognition: Primary Immunodeficiency - Overview | Warning Signs and When to Refer
• Antibody defects: Common Variable Immunodeficiency | X-linked Agammaglobulinaemia | Selective IgA Deficiency and Other Antibody Defects
• Combined and T-cell defects: Severe Combined Immunodeficiency | Syndromic Combined Immunodeficiencies | Hyper-IgE and Mucocutaneous Candidiasis | Susceptibility to Mycobacteria
• Phagocyte and complement defects: Chronic Granulomatous Disease | Other Phagocyte Defects and Congenital Neutropenia | Complement Deficiencies
• Immune dysregulation: Haemophagocytic Lymphohistiocytosis | Autoimmune and Lymphoproliferative Syndromes
• Treatment: Immunoglobulin Replacement Therapy | Antibiotics, Vaccines, Transplant and Gene Therapy
• Revision: Primary Immunodeficiencies at a Glance | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🛡️ Primary immunodeficiency - page 2 of the Clinical Immunology chapter. Primary immunodeficiencies (now often called inborn errors of immunity) are inherited defects of the immune system - over 450 genetic causes are known. They are individually rare but often diagnosed years late, by which time bronchiectasis or other organ damage has developed. Many present in adults (especially CVID), and many cause autoimmunity, inflammation or lymphoma as well as infection.
Your four questions for every patient with recurrent infection: Are the infections more frequent, severe, persistent or unusual than expected? Which organisms and sites point to which part of the immune system? Have secondary causes (drugs, HIV, cancer, protein loss) been excluded? Does the patient need immunoglobulin replacement, prophylaxis or a transplant?

Primary Immunodeficiency - Overview

• Classification (International Union of Immunological Societies - IUIS):
  • Predominantly antibody deficiencies - the commonest (about half) - CVID, XLA, selective IgA deficiency, specific antibody deficiency.
  • Combined immunodeficiencies (T and B cells) - SCID, hyper-IgM syndromes.
  • Syndromic combined immunodeficiencies - 22q11.2 deletion, Wiskott–Aldrich, ataxia telangiectasia, hyper-IgE syndrome.
  • Phagocyte defects - chronic granulomatous disease, leucocyte adhesion deficiency, congenital neutropenia.
  • Complement deficiencies.
  • Immune dysregulation - familial HLH, IPEX, APECED, ALPS.
  • Defects of innate immunity - mycobacterial susceptibility (IFN-γ/IL-12 pathway), chronic mucocutaneous candidiasis, herpes simplex encephalitis (TLR3).
  • Autoinflammatory disorders - periodic fever syndromes.
• Inheritance - many are X-linked (affecting boys - XLA, X-linked SCID, CGD, Wiskott–Aldrich, X-linked hyper-IgM) or autosomal recessive (more common with consanguinity); some are autosomal dominant.
• Not just infection - autoimmunity (cytopenias), granulomatous disease, enteropathy, lymphoproliferation and lymphoma, and allergy are common features.
• Diagnostic delay is common - average several years in CVID.
• UK registry - UK Primary Immunodeficiency Network (UKPIN) maintains a national registry and standards.

Warning Signs and When to Refer

• Suspect immunodeficiency with "SPUR" infections - Serious, Persistent, Unusual (organism or site) or Recurrent.
• Adult warning signs:
  • Two or more pneumonias or severe sinus infections a year, or bronchiectasis without another cause.
  • Need for frequent or IV antibiotics; poor response to antibiotics.
  • Infections with unusual organisms (PCP, atypical mycobacteria, Aspergillus, recurrent Neisseria).
  • Chronic diarrhoea or weight loss with infections; persistent giardia.
  • Unexplained autoimmune cytopenias, granulomas, splenomegaly or lymphadenopathy.
  • A family history of immunodeficiency or unexplained early deaths from infection.
• Child warning signs (e.g. Jeffrey Modell Foundation 10 warning signs) - 4 or more ear infections or 2 or more serious sinus infections or pneumonias in a year, 2 or more months of antibiotics with little effect, failure to thrive, recurrent deep skin or organ abscesses, persistent oral or skin candida after age 1, need for IV antibiotics, 2 or more deep-seated infections, family history.
• Infant red flags - lymphopenia (under 3.0 × 10⁹/L in infancy), persistent diarrhoea, failure to thrive, severe infections, delayed umbilical cord separation (over 3 weeks - leucocyte adhesion deficiency), complications from live vaccines (BCG, rotavirus).
• Refer to clinical immunology (paediatric or adult) - urgently for suspected SCID or HLH.

💡 Clinical Pearl: A lymphocyte count is part of every FBC - and lymphopenia in an infant is often overlooked. A baby with persistent infections, diarrhoea or failure to thrive and a low lymphocyte count needs urgent assessment for SCID before any live vaccine is given.

Common Variable Immunodeficiency

• The commonest symptomatic primary antibody deficiency - about 1 in 25,000–50,000; usually presents in adults (peaks in childhood and 20s–40s); most cases have no single gene identified.
• Diagnosis (ESID criteria):
  • Low IgG with low IgA and/or IgM.
  • Poor vaccine responses (and/or low switched memory B cells).
  • Age over 4 years; secondary causes excluded.
• Infections - recurrent sinusitis, otitis, pneumonia (pneumococcus, Haemophilus), bronchiectasis, GI infections (giardia, campylobacter, norovirus), Mycoplasma arthritis.
• Non-infective complications (in up to half - major causes of death):
  • Autoimmunity - immune thrombocytopenia, autoimmune haemolytic anaemia, thyroid disease, pernicious anaemia, vitiligo.
  • Granulomatous–lymphocytic interstitial lung disease (GLILD) and granulomas in liver, spleen, lymph nodes (sarcoid-like - but low immunoglobulins).
  • Enteropathy - coeliac-like villous atrophy (serology falsely negative), chronic diarrhoea, malabsorption; nodular regenerative hyperplasia of the liver.
  • Lymphoproliferation - splenomegaly, lymphadenopathy; non-Hodgkin lymphoma (much increased risk) and gastric cancer.
• Treatment - lifelong immunoglobulin replacement; prompt antibiotics; airway clearance for bronchiectasis; treat complications (immunosuppression for GLILD - rituximab, steroids); regular CT, lung function, FBC and LFT monitoring.
• Serology is unreliable - patients can't make antibodies; use PCR for infection diagnosis (e.g. hepatitis, enteroviruses).

X-linked Agammaglobulinaemia

• Bruton's agammaglobulinaemia - BTK (Bruton tyrosine kinase) gene - B cells fail to mature; about 1 in 200,000 males.
• Presentation - boys well for the first 6 months (protected by maternal IgG), then recurrent bacterial infections - otitis, sinusitis, pneumonia, bacteraemia, meningitis; enteroviral meningoencephalitis (chronic, can be fatal); giardia; Mycoplasma arthritis.
• Clues - absent or very small tonsils and lymph nodes, very low IgG, IgA and IgM, absent B cells (CD19) on lymphocyte subsets, family history of affected males on the maternal side.
• Treatment - immunoglobulin replacement for life; antibiotics; avoid live oral polio vaccine (not used in the UK); bronchiectasis care.
• Autosomal recessive agammaglobulinaemia - similar disease in girls (other B-cell genes).
• BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) used for CLL and lymphoma cause a milder version of this effect - infections are common.

Selective IgA Deficiency and Other Antibody Defects

• Selective IgA deficiency - the commonest primary immunodeficiency (about 1 in 500 white Europeans); IgA under 0.07 g/L with normal IgG and IgM, age over 4.
  • Most are asymptomatic; some have recurrent sinopulmonary or GI infections (giardia), especially with IgG2 subclass or specific antibody deficiency.
  • Associations - coeliac disease (10–20 times more common - and tTG-IgA serology is falsely negative: check total IgA and use IgG-based tests - IgG tTG or DGP), autoimmune disease, allergy; can evolve into CVID.
  • Transfusion reactions - rarely, anti-IgA antibodies cause anaphylaxis to blood products - IgA-deficient blood products if anti-IgA antibodies are present (specialist advice).
  • No specific treatment - prompt antibiotics; immunoglobulin replacement only if there's an additional antibody defect.
• Specific antibody deficiency - normal immunoglobulin levels but poor response to polysaccharide vaccines (pneumococcal) - recurrent respiratory infections; prophylactic antibiotics or immunoglobulin.
• Transient hypogammaglobulinaemia of infancy - delayed normal antibody production; normal vaccine responses; resolves by 2–4 years.
• Hyper-IgM syndromes - failure of class switching - X-linked CD40 ligand deficiency (commonest) - low IgG and IgA, normal or high IgM; bacterial infections plus Pneumocystis, Cryptosporidium (sclerosing cholangitis and liver disease), neutropenia - co-trimoxazole prophylaxis, immunoglobulin, boil drinking water; stem cell transplant. Autosomal recessive forms (AID, UNG) have no PCP risk.
• Activated PI3K delta syndrome (APDS) - infections, bronchiectasis, lymphoproliferation, EBV and CMV viraemia - leniolisib (PI3Kδ inhibitor).

Severe Combined Immunodeficiency

• A paediatric emergency - absent or non-functional T cells (and often B or NK cells); about 1 in 40,000–75,000 births; fatal within the first 1–2 years without treatment.
• Causes - X-linked IL2RG (common gamma chain - commonest in boys), ADA deficiency (adenosine deaminase - also skeletal and neurological features), RAG1/2, IL7R, Artemis, JAK3 and others.
• Presentation (usually first months of life):
  • Persistent infections - Pneumocystis pneumonia, persistent viral infections (RSV, adenovirus, parainfluenza, CMV), oral and nappy-area candida.
  • Chronic diarrhoea and failure to thrive.
  • Disseminated BCG or vaccine-strain rotavirus infection after live vaccines.
  • Skin rash - Omenn syndrome (erythroderma, lymphadenopathy, eosinophilia, high IgE) or maternal T-cell engraftment (GVHD-like).
• Tests - lymphopenia (often under 2.0 × 10⁹/L - but may be normal if B cells or maternal T cells are present), very low or absent T cells on subsets, low immunoglobulins (IgG may be maternal), absent thymus on chest X-ray, poor T-cell proliferation, genetics.
• Immediate management:
  • No live vaccines (BCG, rotavirus, MMR); only irradiated, CMV-negative blood products (transfusion-associated GVHD).
  • Protective isolation; co-trimoxazole (PCP) and antifungal prophylaxis; immunoglobulin replacement; stop breastfeeding if mother is CMV-positive (specialist advice).
  • Urgent referral to a supra-regional SCID centre (Great Ormond Street or Newcastle).
• Curative treatment - haematopoietic stem cell transplant (best before infection - survival over 90% if done early); gene therapy for ADA-SCID; enzyme replacement (PEG-ADA) as a bridge.
• Newborn screening with TREC assay on the blood spot - under in-service evaluation in England (see Genetics chapter); vital because BCG is given to some babies in the first weeks.

Syndromic Combined Immunodeficiencies

• 22q11.2 deletion syndrome (DiGeorge) - thymic hypoplasia - most have mild T-cell deficiency that improves; complete DiGeorge (athymia - rare) needs thymus transplant (Great Ormond Street). Also conotruncal heart defects, hypocalcaemia, cleft palate (see Genetics chapter). Use irradiated blood until T-cell function is known.
• Wiskott–Aldrich syndrome - X-linked (WAS) - triad of:
  • Thrombocytopenia with small platelets (bleeding - bloody diarrhoea, petechiae, intracranial haemorrhage).
  • Eczema.
  • Recurrent infections (encapsulated bacteria, viruses).
  • Plus autoimmunity and lymphoma; low IgM, high IgA and IgE; poor polysaccharide responses - stem cell transplant or gene therapy.
• Ataxia telangiectasia - autosomal recessive (ATM - DNA repair):
  • Progressive cerebellar ataxia from toddler age, oculocutaneous telangiectasia (conjunctivae, from 3–6 years), oculomotor apraxia.
  • Sinopulmonary infections, low IgA and IgG2, lymphopenia.
  • Raised AFP (diagnostic clue), radiosensitivity (avoid unnecessary X-rays and CT; reduced radiotherapy doses), very high risk of leukaemia and lymphoma; heterozygous carriers have increased breast cancer risk.
• Other DNA repair defects - Nijmegen breakage syndrome (microcephaly), Bloom syndrome.
• Cartilage–hair hypoplasia - short-limbed dwarfism, fine sparse hair, T-cell defect (Amish and Finnish populations).

Hyper-IgE and Mucocutaneous Candidiasis

• Autosomal dominant hyper-IgE syndrome (Job syndrome - STAT3):
  • Severe eczema from the newborn period.
  • "Cold" staphylococcal abscesses (skin and lungs - little inflammation or fever).
  • Recurrent pneumonia with pneumatoceles (lung cysts - Aspergillus and Pseudomonas colonisation).
  • Very high IgE (often over 2,000 IU/mL), eosinophilia.
  • Non-immune features - coarse facial features, retained primary teeth, scoliosis, minimal trauma fractures, joint hypermobility, vascular aneurysms.
  • Treatment - anti-staphylococcal prophylaxis (co-trimoxazole or flucloxacillin), antifungals, skin care, immunoglobulin; stem cell transplant in some.
• DOCK8 deficiency (autosomal recessive hyper-IgE) - severe eczema, severe viral skin infections (warts, molluscum, herpes), food allergy, cancers - stem cell transplant.
• Chronic mucocutaneous candidiasis - persistent candida of skin, nails and mucosa:
  • STAT1 gain of function and IL-17 pathway defects.
  • APECED (autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy - AIRE gene, autosomal recessive - autoimmune polyglandular syndrome type 1) - candidiasis, hypoparathyroidism and Addison's disease (the classic triad), plus other autoimmunity; anti-interferon antibodies.
• Atopic dermatitis alone can cause high IgE - hyper-IgE syndrome is suggested by the combination with abscesses, pneumatoceles and skeletal features.

Susceptibility to Mycobacteria

• Mendelian susceptibility to mycobacterial disease (MSMD) - defects in the IL-12/IFN-γ axis (IFNGR1/2, IL12RB1, STAT1 loss of function) - disseminated BCG or non-tuberculous mycobacterial infection (e.g. M. avium complex), severe TB, Salmonella infection.
• Adult-onset - anti-IFN-γ autoantibodies (more common in people of South-East Asian ancestry) - disseminated NTM, salmonella, VZV.
• GATA2 deficiency (MonoMAC) - monocytopenia, B and NK lymphopenia, disseminated NTM, HPV warts, pulmonary alveolar proteinosis, myelodysplasia and AML - stem cell transplant.
• Treatment - prolonged antimycobacterial therapy; IFN-γ therapy for some IL-12 pathway defects; avoid BCG in affected families.
• Acquired mycobacterial susceptibility - HIV, anti-TNF therapy, corticosteroids, transplant, CKD, diabetes (see page 3).

Chronic Granulomatous Disease

• Phagocytes can't kill some bacteria and fungi - defective NADPH oxidase (no respiratory burst); about two thirds X-linked (CYBB - gp91phox), others autosomal recessive.
• Infections with catalase-positive organisms - Staphylococcus aureus, Aspergillus (the commonest cause of death), Burkholderia cepacia, Serratia, Nocardia, Salmonella.
• Sites - liver abscesses, lymphadenitis, pneumonia, skin abscesses, osteomyelitis, perianal abscesses.
• Inflammation and granulomas - Crohn's-like colitis, gastric outlet and urinary tract obstruction by granulomas; poor wound healing.
• Diagnosis - dihydrorhodamine (DHR) flow cytometry (absent oxidative burst); genetic testing; check carrier mothers (risk of discoid lupus and mild infections).
• Management:
  • Lifelong prophylaxis - co-trimoxazole (antibacterial) and itraconazole (antifungal); IFN-γ in some.
  • Aggressive treatment of infections - drainage, prolonged antibiotics and antifungals.
  • Avoid mouldy hay, compost, mulch, gardening and building sites (Aspergillus exposure).
  • Haematopoietic stem cell transplant - curative; gene therapy in trials.

Other Phagocyte Defects and Congenital Neutropenia

• Leucocyte adhesion deficiency type 1 (ITGB2 - CD18 - autosomal recessive):
  • Neutrophils can't leave the blood - very high neutrophil count but no pus at infection sites.
  • Delayed umbilical cord separation (over 3 weeks) and omphalitis, severe periodontitis, necrotic skin ulcers, poor wound healing.
  • Stem cell transplant.
• Chédiak–Higashi syndrome (LYST) - partial oculocutaneous albinism, giant granules in neutrophils, recurrent pyogenic infections, bleeding, peripheral neuropathy, high risk of HLH.
• Severe congenital neutropenia (ELANE, HAX1 - Kostmann) - neutrophils under 0.5 × 10⁹/L from birth; omphalitis, skin and deep infections, mouth ulcers - G-CSF; risk of myelodysplasia and AML.
• Cyclic neutropenia (ELANE) - neutropenia every 21 days with fever, mouth ulcers and infections.
• Benign ethnic neutropenia (Duffy-null associated neutrophil count) - lower neutrophil counts (often 1.0–1.5) in people of African and Middle Eastern ancestry with the Duffy-null phenotype - no increased infection; avoid unnecessary investigation or withholding of treatment (e.g. clozapine, chemotherapy thresholds adjusted).
• Myeloperoxidase deficiency - common, usually asymptomatic.

Complement Deficiencies

• Management of complement deficiency - vaccinate (MenACWY, MenB, pneumococcal, Hib); consider prophylactic penicillin; emergency antibiotics and an alert card; screen siblings; manage SLE in early component deficiency.

Haemophagocytic Lymphohistiocytosis

• A life-threatening hyperinflammatory syndrome - uncontrolled activation of cytotoxic T cells and macrophages with a cytokine storm.
• Primary (familial) HLH - infancy or childhood - perforin (PRF1), UNC13D, STX11; also Chédiak–Higashi, Griscelli, X-linked lymphoproliferative disease (SH2D1A, XIAP - triggered by EBV).
• Secondary HLH (adults - commoner) - triggered by infection (EBV, CMV, HIV, TB, leishmaniasis), malignancy (lymphoma - especially T-cell and NK), autoimmune disease (macrophage activation syndrome in Still's disease, SLE), CAR-T therapy and checkpoint inhibitors.
• Features (HLH-2004 criteria - 5 of 8):
  1. Fever.
  2. Splenomegaly.
  3. Cytopenias (2 or more lines).
  4. High triglycerides and/or low fibrinogen.
  5. Haemophagocytosis in bone marrow, spleen or lymph node.
  6. Low or absent NK cell activity.
  7. Ferritin 500 micrograms/L or more (often over 10,000).
  8. Raised soluble CD25 (soluble IL-2 receptor).
• Other clues - liver dysfunction, raised LDH, coagulopathy, neurological features, rash; HScore estimates probability in adults.
• Treatment - urgent haematology and immunology input; treat the trigger; dexamethasone and etoposide (HLH-94 protocol); anakinra (especially MAS), ciclosporin, emapalumab (anti-IFN-γ), ruxolitinib; stem cell transplant for primary or refractory HLH.

⚠️ Safety Pearl: Fever, cytopenias, splenomegaly and a very high ferritin that "isn't responding to antibiotics" - think HLH. Check ferritin, triglycerides, fibrinogen and LFTs, and involve haematology the same day; untreated HLH is rapidly fatal.

Autoimmune and Lymphoproliferative Syndromes

• IPEX syndrome (FOXP3 - X-linked - absent regulatory T cells) - Immune dysregulation, Polyendocrinopathy (neonatal type 1 diabetes, thyroiditis), Enteropathy (severe watery diarrhoea), X-linked; eczema - stem cell transplant.
• APECED (AIRE) - see Hyper-IgE and Mucocutaneous Candidiasis above.
• Autoimmune lymphoproliferative syndrome (ALPS) - defective FAS-mediated apoptosis - chronic lymphadenopathy and splenomegaly, autoimmune cytopenias, raised "double-negative" (CD4−CD8−) T cells, lymphoma risk - sirolimus, mycophenolate.
• CTLA4 haploinsufficiency and LRBA deficiency - CVID-like antibody deficiency with autoimmunity, enteropathy and lymphocytic infiltration - abatacept (CTLA-4–Ig) is targeted therapy.
• Autoinflammatory diseases (innate immunity) - periodic fevers:
  • Familial Mediterranean fever (MEFV - recessive) - 1–3 day episodes of fever, serositis (peritonitis, pleurisy), arthritis, erysipelas-like rash; AA amyloidosis if untreated - colchicine.
  • TRAPS, CAPS (cryopyrin - urticaria-like rash, deafness), mevalonate kinase deficiency (hyper-IgD) - IL-1 blockade.
  • VEXAS syndrome (somatic UBA1 - older men) - fevers, chondritis, vasculitis, macrocytic anaemia, myelodysplasia.

Immunoglobulin Replacement Therapy

• Indications - primary antibody deficiencies with low IgG and/or poor vaccine responses (CVID, XLA, hyper-IgM, SCID until transplant), selected secondary antibody deficiency (see page 3).
• Product - pooled human IgG from thousands of donors (blood product - record batch numbers; donor exposure; UK plasma sourcing).
• Routes:
  • Intravenous (IVIG) - every 3–4 weeks in hospital or at home.
  • Subcutaneous (SCIG) - weekly or fortnightly at home (self-infused) - fewer systemic reactions, steadier levels; facilitated SCIG (with hyaluronidase) monthly.
• Dose - typically about 0.4–0.6 g/kg/month, adjusted to clinical response and trough IgG (aim usually for a trough above the lower limit of normal - higher in bronchiectasis).
• Adverse effects:
  • Infusion reactions - headache, chills, flushing, back pain (rate-related - slow the infusion; premedication).
  • Aseptic meningitis, thrombosis (MI, stroke, VTE - hydrate, slow rates in high-risk), acute kidney injury (especially sucrose-containing products), haemolysis (anti-A and anti-B - blood groups A and AB), neutropenia.
  • Anaphylaxis - rare (anti-IgA in IgA-deficient patients).
  • Interference with serology - passive antibodies (e.g. positive hepatitis B core antibody) for weeks after infusion.
• High-dose IVIG for immunomodulation (ITP, Guillain–Barré, Kawasaki disease, CIDP, myasthenic crisis) is a different use (see page 6) - NHS England commissioning criteria apply to all immunoglobulin use.

Antibiotics, Vaccines, Transplant and Gene Therapy

• Prophylactic antibiotics - e.g. azithromycin (bronchiectasis), co-trimoxazole (PCP - T-cell defects, hyper-IgM, CGD), penicillin (complement and asplenia), antifungals (CGD, SCID).
• Rapid treatment of infection - a rescue antibiotic pack, a lower threshold for admission, sputum culture, longer courses.
• Vaccination:
  • Inactivated vaccines are safe (but may be less effective; patients on immunoglobulin get passive protection).
  • Live vaccines are contraindicated in significant T-cell and combined defects (SCID, complete DiGeorge, Wiskott–Aldrich, hyper-IgM) and in XLA and CVID (on immunoglobulin) - BCG, MMR, varicella, yellow fever, live influenza (nasal), oral typhoid, rotavirus; seek specialist advice.
  • Live vaccines are generally safe in complement and IgA deficiency (BCG avoided in CGD and MSMD).
  • Household contacts should be fully vaccinated (including influenza and MMR).
• Haematopoietic stem cell transplant - curative for SCID, CGD, Wiskott–Aldrich, LAD, HLH, IPEX, CD40L deficiency and others.
• Gene therapy - ADA-SCID (Strimvelis), X-linked SCID and Wiskott–Aldrich (trials and specialist access); thymus transplant for athymia.
• Monitoring - lung function, CT for bronchiectasis, FBC and LFTs, lymphoma surveillance; transition from paediatric to adult immunology services.
• Genetic counselling - X-linked and recessive conditions (carrier testing, prenatal diagnosis, PGT).

Primary Immunodeficiencies at a Glance

Spot the Diagnosis

Exam-style Scenarios