Primary immunodeficiency disorders

• Primary immunodeficiency (also called an inborn error of immunity) is a genetically determined defect in one component of the immune system. It is present from birth, even when symptoms only appear later in life.
• These disorders are grouped by the part of immunity that fails: antibody (B-cell) defects, T-cell defects, combined B- and T-cell defects, phagocyte defects, and complement defects. Antibody defects are the most common group, accounting for 50 to 60% of diagnoses. ^[1]
• A child can have many infections without being immunodeficient; recurrent infections are far more often due to exposure, anatomy or another disease than to an immune defect. ^[2]
• Immunodeficiency is suspected when infections are unusually severe, complicated, in several sites, slow to clear, caused by unusual organisms, or cluster in the family, especially with onset in early infancy. ^[2]
• Diagnosis starts with simple tests (blood count, immunoglobulin levels, vaccine antibody titres, complement activity) and proceeds to specialised studies; severe T-cell and combined defects must be recognised in the newborn period because every week of delay increases risk. ^{[2] [3]}
• Treatment prevents infection, replaces missing immune components (immune globulin, stem cell transplant, enzyme replacement), and limits live vaccine use according to the immune defect. ^{[2] [4]}

By the end of this page you should be able to:

1. Define primary immunodeficiency and distinguish it from secondary immunodeficiency, and classify the common disorders by the immune compartment affected.
2. List the clinical clues that make an immunodeficient patient different from a child who simply has frequent infections, and recognise the red flags for urgent investigation.
3. Describe the pathophysiology and presentation of the Bruton, common variable, selective IgA, and hyper-IgM antibody disorders.
4. Describe DiGeorge syndrome and chronic mucocutaneous candidiasis as T-cell disorders, and explain why severe combined immunodeficiency is an emergency.
5. Describe ataxia-telangiectasia, Wiskott-Aldrich syndrome, and the common phagocyte disorders, and state which infections each predisposes to.
6. Read a complement deficiency table, predicting the infection pattern from the missing component.
7. Plan the stepwise investigation of suspected immunodeficiency and state the key laboratory thresholds.
8. Explain immune globulin replacement dosing, stem cell transplantation and the rules for live vaccine avoidance.

A primary immunodeficiency is a genetically determined defect in the development or function of one or more components of the immune system. ^[1] In 2022 the International Union of Immunological Societies reported that 485 inborn errors of immunity have been linked to primary immunodeficiency disorders, yet only about 20 to 30% of current disorders have an identified genetic mutation. ^[1] Secondary (acquired) immunodeficiency is far more common and results from another disease, infection, medication or malnutrition; separating the two is the first task of the assessment. ^{[1] [2]}

Primary immunodeficiencies are classified by the main immune compartment that is deficient. ^[1] This classification determines which infections occur, how the disease is investigated and how it is treated.

The percentages are from the 2024 MSD overview, which drew on registry data. ^[1] Together these five groups explain why primary immunodeficiency is really a collection of different diseases rather than one diagnosis, and why “immune deficiency” is an answer to “which part?” not just “how bad?”.

Some patients have a primary immunodeficiency syndrome, in which non-infectious findings (ataxia, telangiectasia, eczema, thrombocytopenia, facial and cardiac anomalies, hypocalcaemia) appear before or alongside the infections and may be the first clue. ^[1]

Taken together, symptomatic primary immunodeficiency occurs in about 1 person in 280 worldwide, varies between settings and is likely underdiagnosed. ^[1] About 70% of patients are under 20 years at onset of symptoms, and because transmission is often X-linked about 60% are male. ^[1] The serious defects present in infancy; the commonest symptomatic antibody defect, common variable immunodeficiency, usually appears between the ages of 20 and 40 years. ^[1] Complement deficiencies are the rarest and most delayed group, with a median age at diagnosis of 15 years. ^[6]

Most primary immunodeficiencies are single-gene disorders inherited in an autosomal recessive, autosomal dominant or X-linked pattern. ^{[1] [2]} An X-linked defect should be suspected when there is a family history of childhood death or similar infections in a maternal uncle. ^[2] Consanguinity and founder populations change local prevalence. Environmental and secondary factors (nutrition, chronic disease, immunosuppressive treatment) cause acquired defects; they must be excluded before calling a defect primary. ^{[1] [2]}

No modifiable risk factor is known for the inherited forms. Practical clues to an X-linked defect come from the family history rather than from any test result: affected males related through the maternal line, early male deaths, or a pattern of infection in boys that stops at sisters. ^[2]

The immune system has layers. Antibodies (produced by B cells) opsonise encapsulated bacteria and neutralise viruses in the blood and secretions. T cells orchestrate the response, kill virus-infected cells and help B cells mature. Phagocytes engulf and kill organisms, especially staphylococci and gram-negative bacteria. Complement proteins mark organisms for destruction and rupture membranes. A defect at any layer removes the protection that layer provided, and the result is predictable infection with the organisms that layer normally controls. ^{[1] [2]}

Maternal antibodies cross the placenta and protect the infant for the first 6 to 9 months. ^[2] A T-cell defect therefore shows itself before 6 months, a combined defect between 6 and 12 months, and a pure antibody defect later, once maternal antibody has gone. ^[2] This timing clue is one of the most useful in paediatrics.

Antibody defects are the largest group and the least dangerous to life, but they are the commonest cause of chronic lung and sinus disease in immunodeficient patients. ^[1] They present with recurrent sinopulmonary infection with encapsulated bacteria: otitis media, sinusitis, pneumonia, and bronchiectasis if untreated. Viral respiratory illness is normal in these children; what is abnormal is the bacterial superinfection and the failure to clear it. ^{[1] [2]}

Bruton X-linked agammaglobulinaemia is caused by a mutation in the Bruton tyrosine kinase (BTK) gene, is X-linked and usually presents in male infants after maternal antibody has faded, from about 6 months of age. ^{[1] [2]} Tonsils, adenoids and peripheral lymph nodes are very small or absent despite frequent infections, because B cells never develop. ^[2] Infections are recurrent and often severe: otitis media, sinusitis, pneumonia, cellulitis, septic arthritis, osteomyelitis and enteroviral meningoencephalitis. ^[1]

Two problems are characteristic. First, infections with live-attenuated oral poliovirus vaccine or with echoviruses and coxsackieviruses can cause persistent central nervous system disease. ^[1] Second, the risk of bronchiectasis and of some cancers is increased later, even with treatment. ^[1] Inheritance is X-linked, so a careful family history and genetic counselling matter. ^[2]

Common variable immunodeficiency is the most common symptomatic antibody defect. ^[1] B cells are present but fail to mature, so immunoglobulin G (and usually IgA and IgM) is low, antibody responses are poor and patients present with recurrent bacterial sinopulmonary infection, bronchiectasis, malabsorption, nodular lymphoid hyperplasia, splenomegaly, autoimmune disease and granulomatous lung disease. ^[1] It is diagnosed most often between the ages of 20 and 40 years, but can appear in children or much later. ^{[1] [2]} Mutations are sporadic in most cases. ^[1]

Because T-cell function can also be impaired, some patients develop opportunistic infection. About 10% develop gastric carcinoma or lymphoma. Autoimmune cytopenias and granulomatous disease can also occur. ^{[1] [2]} Live vaccine avoidance and careful investigation of unexplained cytopenia are therefore part of routine follow-up. ^[2]

Selective IgA deficiency is the commonest primary immunodeficiency overall, but many patients are entirely asymptomatic. ^[1] When symptomatic, patients have recurrent sinopulmonary infection, diarrhoea, allergy and autoimmunity (celiac disease, inflammatory bowel disease, systemic lupus erythematosus, chronic active hepatitis). ^{[1] [2]} IgA is profoundly useful at mucosal surfaces; its absence is usually tolerated because IgM compensates in the blood, which is why most patients are well. ^[1]

One rare but serious risk is anaphylaxis to blood products in patients who have formed anti-IgA antibodies. ^[1] These patients need washed or IgA-deficient blood products if transfusion is required. ^{[1] [2]} Treatment otherwise resembles that of other antibody defects.

The hyper-IgM syndromes are characterised by normal or high IgM with low IgG, IgA and IgE, because B cells cannot switch isotype. ^[1] The common X-linked form is due to deficiency of CD40 ligand. ^[1] It looks at first like agammaglobulinaemia (recurrent pyogenic sinopulmonary infection) but with more frequent Pneumocystis jirovecii pneumonia, cryptosporidiosis, severe neutropenia and lymphoid hypoplasia. ^{[1] [2]} B cells are present but stuck producing IgM, T cells cannot help them change, and the patient is exposed to opportunistic organisms more typical of a T-cell defect. ^[2] Rarer autosomal recessive forms (AID or UNG deficiency; CD40 deficiency) add lymphoid hyperplasia or hypoplasia. ^[1] These patients need immune globulin replacement and careful management of neutropenia and liver disease (cryptosporidial cholangitis). ^{[1] [2]}

T-cell defects account for only 5 to 10% of primary immunodeficiencies but are far more dangerous, because T cells control viruses, fungi, intracellular organisms and the antibody response. ^[1] Infections are viral, fungal or mycobacterial; antibody levels fall too, because B cells depend on T-cell help. ^[1] Three particular findings point to a T-cell problem: opportunistic infection; graft versus host disease after blood transfusion; and severe or persistent infection after a live-attenuated vaccine or after BCG. ^[2]

DiGeorge syndrome (22q11.2 deletion syndrome; a small deletion on chromosome 10p13 gives a similar picture) is a syndrome of conotruncal heart disease, abnormal facies, thymic hypoplasia or aplasia, cleft palate and hypoparathyroidism with hypocalcaemic tetany, plus recurrent infection and developmental delay. ^{[1] [2]} The level of immunodeficiency depends on how much thymic tissue is present. Most patients have partial defects that improve with age as the thymus grows; a few have complete absence of T cells and need urgent intervention. ^{[1] [2]} Hypocalcaemia and cardiac disease are the emergencies in the newborn period; the immune defect dominates management in the first year. ^[1] Live vaccines are avoided until immune studies are normal, and blood products should be irradiated and from cytomegalovirus-negative donors to prevent graft versus host disease. ^[2]

Chronic mucocutaneous candidiasis is a T-cell defect presenting with persistent or recurrent candidal infection of skin, nails and mucous membranes, with onychomycosis and sometimes autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (hypoparathyroidism, adrenal insufficiency). ^{[1] [2]} Inheritance is autosomal dominant or recessive (STAT1 dominantly; AIRE recessively). ^[1] The infection is usually confined to mucosa and skin, which is the clue that this is a selective T-cell problem rather than SCID; nevertheless invasive candidiasis must be excluded. ^{[1] [2]} Treatment uses antifungals, and endocrine autoimmunity must be screened for and treated. ^{[1] [2]}

Severe combined immunodeficiency (SCID) is the most severe primary immunodeficiency: T cells are absent or very low, and B cells and natural killer cells may be low, normal or high but cannot function without T-cell help. ^{[3] [1]} It is fatal in infancy unless diagnosed and treated early. ^[3]

All forms of SCID obey the same clinical clock: by 6 months of age most infants develop systemic candidiasis, persistent viral infection, Pneumocystis jirovecii pneumonia and diarrhoea, with failure to thrive; some develop graft versus host disease from maternal lymphocytes or transfused T cells. ^[3] The thymus is tiny or absent, and lymphoid tissue is reduced. ^[3]

The commonest form is X-linked, from a mutation in the interleukin-2 receptor gamma chain gene, phenotype T negative, B positive, natural killer negative. ^[3] Adenosine deaminase deficiency is the second commonest and produces a T-negative, B-negative, natural killer-negative picture with bony abnormalities. ^[3] Other causes include IL-7 receptor alpha, RAG1 and RAG2, JAK3, CD45 and Artemis mutations. ^{[1] [3]} Omenn syndrome (leaky SCID) adds erythroderma, desquamation, alopecia, lymphadenopathy, hepatosplenomegaly, eosinophilia and a very high IgE. ^{[1] [3]}

Diagnosis rests on lymphopenia, a very low T-cell count and absent lymphocyte proliferative responses to mitogens. ^{[2] [3]} In the United States all newborns are screened with the T-cell receptor excision circle test precisely to catch SCID before infection begins. ^[2] Management is reverse isolation, prophylactic immune globulin, antibiotics against Pneumocystis and antifungals, and then hematopoietic stem cell transplantation as soon as possible. ^{[2] [3]} Early diagnosis transforms outcome: if SCID is diagnosed by 3 months of age, survival after transplantation with either HLA-identical or rigorously T-cell-depleted haploidentical marrow is 96%, and transplantation from a matched sibling restores immunity in 90 to 100% of cases. ^[3] Pre-transplantation chemotherapy is unnecessary because the patient has no T cells to reject the graft. ^{[2] [3]} ADA-deficient patients who cannot be transplanted may receive polyethylene glycol-modified bovine ADA, and gene therapy has proved successful. ^[3]

Ataxia-telangiectasia is an autosomal recessive disorder (ATM gene) producing progressive cerebellar ataxia, oculocutaneous telangiectasia, recurrent sinopulmonary infection, endocrine abnormalities (gonadal dysgenesis, testicular atrophy, diabetes) and a markedly increased cancer risk. ^{[1] [2]} Onset of ataxia is usually in early childhood; telangiectasias appear later. ^[2] Both humoral and cellular immunity are impaired, so infections are bacterial (sinopulmonary) and patients are vulnerable to lymphoma and leukaemia. ^{[1] [2]} Live vaccines must be avoided, and malignancy surveillance is a lifelong part of care. ^{[2] [4]}

Wiskott-Aldrich syndrome is an X-linked recessive disease (WASP gene) presenting with the triad of pyogenic and opportunistic infection, eczema and thrombocytopenia with small platelets, plus bloody diarrhoea, recurrent respiratory infection and increased risk of cancer after the age of 10 years. ^{[1] [2]} Thrombocytopenia in a male infant with eczema is the bedside clue. ^[2] Infection is with encapsulated bacteria, herpesviruses and opportunistic organisms; immunoglobulin (especially IgM) and cellular function are both reduced. ^{[1] [2]} Treatment is immune globulin replacement, prophylactic antibiotics, and stem cell transplantation in severe disease; transplantation requires pre-transplantation chemotherapy because T-cell function is partly preserved. ^[2]

Hyper-IgE syndrome (Job syndrome) is caused by autosomal dominant STAT3 mutations or autosomal recessive DOCK8 or TYK2 mutations. ^{[1] [2]} Features include recurrent staphylococcal abscesses of skin, lungs, joints and viscera, pulmonary pneumatoceles, pruritic dermatitis, coarse facies, delayed shedding of primary teeth, osteopenia with recurrent fractures, and high serum IgE with eosinophilia. ^{[1] [2]} Infections are staphylococcal and later fungal. ^{[1] [2]} Management targets Staphylococcus (prophylaxis, antiseptics, intermittent drainage) and optimises skin care; DOCK8 deficiency is treated with stem cell transplantation. ^{[1] [2]}

Phagocyte defects make up 10 to 15% of primary immunodeficiencies and present with cutaneous staphylococcal and gram-negative infection, abscesses and granulomas. ^[1] The classic clues are “staph and gram-negatives,” delayed cord separation, poor wound healing and granulomatous obstruction. ^{[1] [2]}

Chronic granulomatous disease is a defect of the respiratory burst that kills catalase-positive organisms. ^{[1] [2]} Inheritance is X-linked (gp91phox, CYBB) or autosomal recessive (p22phox, p47phox, p67phox). ^[1] Patients develop granulomatous lesions of lung, liver, lymph nodes and gastrointestinal or genitourinary tract (causing obstruction), lymphadenitis, hepatosplenomegaly, skin and organ abscesses, osteomyelitis, pneumonia and infection with staphylococci, gram-negative bacteria and Aspergillus. ^{[1] [2]} Diagnosis is the dihydrorhodamine or nitroblue tetrazolium respiratory burst assay. ^[2] Management is aggressive treatment of infection, granuloma management, prophylactic antibiotics (trimethoprim and sulfamethoxazole is used for many phagocyte defects) and prophylactic antifungals as advised by specialist teams. ^[2] Stem cell transplantation is curative in selected patients. ^[2]

Chediak-Higashi syndrome is an autosomal recessive defect (LYST gene) with oculocutaneous albinism, recurrent infection, fever, jaundice, hepatosplenomegaly, lymphadenopathy, neuropathy, pancytopenia and a bleeding diathesis. ^{[1] [2]} Giant granules in neutrophils are the diagnostic hallmark. ^[2] Infection control is poor because phagocytes kill slowly. Progressive lymphoproliferative disease develops in many patients, and stem cell transplantation is recommended before that stage. ^{[1] [2]} Live bacterial vaccines are contraindicated, and the defect in interferon-driven immunity means live viral vaccines are also avoided. ^[4]

Leukocyte adhesion deficiency type 1 is an autosomal recessive defect of CD18 (ITGB2 gene); type 2 affects the GDP-fucose transporter. ^{[1] [2]} Neutrophils cannot migrate into tissue, so patients have soft-tissue infection, periodontitis, poor wound healing, delayed separation of the umbilical cord, striking leukocytosis and no pus. ^{[1] [2]} Type 2 adds developmental delay. ^[1] Because the defect is in migration rather than killing, infection can be severe despite a high white cell count. ^[2] Stem cell transplantation is the curative option. ^[2]

Complement defects are the rarest group, 2% or fewer of primary immunodeficiencies, but they are important because their infection pattern is distinctive. ^{[1] [6]} Most are autosomal recessive; C1 inhibitor deficiency is dominant, properdin deficiency is X-linked. ^{[1] [6]} The defect is in opsonisation, killing and clearance of immune complexes, giving either recurrent infection or autoimmune disease (especially systemic lupus erythematosus and glomerulonephritis). ^[1]

The practical rule, from the 2024 complement review, is this: the later in the cascade the block, the more specific the infection pattern. ^[6]

The list combines the MSD table of complement deficiencies with the 2024 complement review's pathway grouping. ^{[1] [6]} Inherited complement deficiencies have an estimated prevalence of about 0.03% and are estimated to make up 2 to 10% of all inborn errors of immunity. ^[6] A slight male predominance (about 56%) probably reflects the several X-linked properdin cases in the largest reported cohort; median age at diagnosis is 15 years. ^[6]

Diagnosis starts with functional screens. CH50 measures total classical pathway activity and AH50 total alternative pathway activity; low CH50 with normal AH50 suggests an early classical component defect, low AH50 with normal CH50 an alternative pathway defect, and both low a C3, C5-C9 or regulatory defect. ^{[2] [6]} Individual factor concentrations are then measured by immunoassay in reference laboratories, with genetic testing for family counselling. ^{[2] [6]}

Management has no curative replacement: immune globulin and fresh plasma are not used routinely, because missing proteins are not effectively or permanently replaced and antibody formation or anaphylaxis can occur. ^[6] Management therefore is vaccination against encapsulated bacteria (pneumococcal, Haemophilus influenzae type b and all meningococcal serogroups) as early as possible and repeated through life, consideration of prophylactic antibiotics (penicillin has proved effective in terminal defects) and an emergency plan for fever or meningism. ^[6] Patients are monitored for autoimmune disease. ^[6]

There is no single screening test that catches all primary immunodeficiency. The usual approach is history, examination and then labs keyed to the suspected compartment. ^[2]

Red flags for primary immunodeficiency, and the findings that push a clinician from “watch and wait” to “investigate now,” are: ^[2]

• Infections that are severe, complicated, in more than one location, or refractory to standard treatment (needing repeated oral antibiotics or any intravenous antibiotics). ^[2]
• Infections caused by unusual organisms or occurring in unusually large number in the family. ^[2]
• Onset before 6 months of age (suggests a T-cell defect) or between 6 and 12 months (combined or antibody defect). ^[2]
• Chronic diarrhoea with failure to thrive in an infant, especially from adenovirus or Cryptosporidium. ^[2]
• Skin lesions (eczema, warts, abscesses, pyoderma, alopecia), oral or oesophageal thrush, oral ulcers or periodontitis. ^[2]
• A family history of childhood death or of infections in a maternal uncle (X-linked inheritance). ^[2]
• Secondary findings such as those of a syndrome (ataxia, telangiectasia, facial and cardiac anomalies, hypocalcaemia, thrombocytopenia, eczema). ^{[1] [2]}

The age at onset is the single most useful clue. ^[2] “Clue infections” point to the compartment: recurrent pneumococcal or Haemophilus infection suggests antibody or C2/IRAK-4 deficiency; Pneumocystis, cryptosporidiosis or toxoplasmosis suggests T-cell disease; staphylococcal and gram-negative or fungal infection suggests phagocyte defects or hyper-IgE; recurrent Neisseria points to terminal complement deficiency; Giardia suggests antibody deficiency; familial autoimmunity suggests CVID or selective IgA deficiency. ^[2] Live-attenuated vaccine infection and graft versus host disease after transfusion are strong evidence of T-cell disease. ^[2]

On examination, remember that tonsils, adenoids and peripheral lymph nodes are small or absent in X-linked agammaglobulinaemia, X-linked hyper-IgM, SCID and other T-cell defects despite repeated infection. ^[2] In chronic granulomatous disease the nodes are large and often suppurative. ^[2] Delayed umbilical cord separation suggests leukocyte adhesion deficiency. ^[2] An absent thymic shadow on chest radiograph suggests a T-cell defect, especially before infection has shrunk the thymus. ^[2]

Start with tests that screen each compartment rather than one that names a disease: ^[2]

• Full blood count with differential. A neutrophil count under 1200 per microlitre suggests congenital or cyclic neutropenia; lymphocytes under 2000 per microlitre at birth, under 4500 at 9 months, or under 1000 in older children and adults suggests T-cell disease; persistent leukocytosis between infections occurs in leukocyte adhesion deficiency; thrombocytopenia in a male infant suggests Wiskott-Aldrich syndrome. ^[2]
• Quantitative IgG, IgM, IgA (and IgE). IgG under 200 mg/dL (under 2 g/L) usually marks significant antibody deficiency, but similar levels can occur in protein-losing states. ^[2] Normal Ig levels do not exclude antibody dysfunction, which is why antibody responses are also tested. ^[2]
• Vaccine responses. Isohaemagglutinin titres (anti-A at least 1:8, anti-B at least 1:4) assess IgM function, and a less-than-twofold rise in IgG 2 to 3 weeks after vaccine antigens suggests antibody deficiency regardless of immunoglobulin level. ^[2] Natural antibodies (antistreptolysin O) can be used too. ^[2]
• Delayed-type hypersensitivity skin testing with Candida, with a positive induration greater than 5 mm at 24 to 72 hours excluding T-cell disease; a negative test is unhelpful if there has been no prior exposure. ^[2]
• Complement: C3, C4, CH50 and, where indicated, AH50. ^[2]
• Newborns: TREC screening identifies impaired T-cell development. ^{[2] [3]}

Advanced testing (lymphocyte phenotyping by flow cytometry, T-cell proliferation to mitogens, oxidative burst by dihydrorhodamine for chronic granulomatous disease, mutation analysis) follows from these. ^[2] If first tests are normal but the clinical picture persists, repeat them, because some deficiencies evolve, and many abnormalities are transient effects of infection, medication or other factors. ^[2] Gene sequencing panels are now widely available and 485 causative mutations are recognised, changing how diagnosis is made and how prognosis is given. ^{[1] [2]}

Prenatal diagnosis is possible for several disorders once the family mutation is known, using chorionic villus sampling, cultured amniotic cells or fetal blood. ^[2]

Normal first tests do not fully exclude disease; a minimally affected infant may have normal results early, and antibody defects can evolve for years before they become abnormal. ^[2] This is why clinical judgement matters more than any single laboratory number.

The principles are the same across primary immunodeficiency: avoid infection, treat infection early, replace what is missing, and match live vaccine use to immune capacity. ^[2]

Environmental advice matters and is often skipped: good hand hygiene, avoiding unsafe water and soil exposure, dental hygiene, and early treatment of sinus and lung infection. ^[2] Live-virus vaccines must not be given (varicella, rotavirus, measles-mumps-rubella, zoster, yellow fever, oral polio, intranasal influenza, BCG); non-live vaccines (pneumococcal, meningococcal, DTaP, hepatitis B, Haemophilus influenzae type b) are given and their effect varies with the degree of immunodeficiency. ^{[2] [4]} Inactivated, recombinant and subunit vaccines are considered safe in severe immune suppression; the concern with them is effectiveness, not safety. ^[4]

Patients at high risk (SCID, chronic granulomatous disease, Wiskott-Aldrich syndrome, asplenia) or at risk of specific infection (Pneumocystis in T-cell defects) receive prophylactic antibiotics, classically trimethoprim and sulfamethoxazole 5 mg/kg by mouth twice daily. ^[2] Blood products should be cytomegalovirus-negative, leucocyte-depleted and irradiated to prevent graft versus host disease. ^[2]

After appropriate cultures, treat early and empirically against the likely organisms, and drain abscesses surgically when needed. ^[2] Infections that are self-limited in healthy people (respiratory viruses, herpes simplex, varicella, influenza, respiratory syncytial virus) can be severe and persistent in immunodeficient patients, and antivirals may be lifesaving. ^[2] Do not wait for confirmation before starting treatment in a neutropenic or T-cell-deficient patient. ^[2] A useful maxim is to treat the likely organism, not the cultured one, because culture lags behind clinical decline. ^[2]

Immune globulin replacement is the backbone of antibody-deficiency care. Intravenous immune globulin 400 mg/kg once monthly is standard, started at a low infusion rate; some patients need higher or more frequent doses, and 800 mg/kg monthly is used when conventional doses fail, especially with chronic lung disease. ^[2] The aim is an IgG trough above 600 mg/dL (6 g/L). ^[2] Subcutaneous immune globulin 100 to 150 mg/kg weekly can be given at home and usually has fewer systemic side effects. ^[2] Immune globulin treats the antibody gap but not the lymphoid defect; it should not be regarded as a cure and is not a substitute for transplantation in T-cell disease. ^[2]

Hematopoietic stem cell transplantation is the definitive treatment for lethal T-cell and combined defects. Pre-transplantation chemotherapy is unnecessary in patients without T cells (SCID), but is needed where T cells are partly preserved (Wiskott-Aldrich syndrome, combined immunodeficiency with inadequate but not absent T-cell function). ^[2] Haploidentical parental marrow, umbilical cord blood and matched unrelated donors extend the option, with irradiated products and cytomegalovirus-negative status. Overall post-transplant survival is at least 80%. ^{[2] [3]}

Further options are disease-specific: enzyme replacement with polyethylene glycol-modified bovine adenosine deaminase, and gene therapy, which has succeeded in ADA-deficient SCID (and, with caution, in X-linked SCID) and is under study in chronic granulomatous disease, X-linked agammaglobulinaemia and hyper-IgM. ^[3] Gene therapy is promising but not routine for most disorders, and early transplantation remains the standard for SCID. ^{[3] [2]}

The central safety rule is that severe cell-mediated immunodeficiency contraindicates all live attenuated vaccines. ^{[4] [5]} Primary immunodeficiencies then separate neatly into three patterns: ^[4]

• Severe antibody defects (such as Bruton agammaglobulinaemia and CVID): oral polio, smallpox, live attenuated influenza, BCG, live oral typhoid, yellow fever, MMR, MMRV and dengue (DEN4CYD) are contraindicated. ^[4] Most other live vaccines appear to be safe in less severe antibody deficiency, and varicella vaccine in particular can be given to patients with pure humoral defects. ^[4]
• Complete and most partial T-cell defects and syndromic defects (SCID, complete DiGeorge, Wiskott-Aldrich, ataxia-telangiectasia, many hyper-IgM variants): all live vaccines are avoided. ^[4] Interferon-gamma and interferon-alpha defects also avoid all live vaccines; defects of the interferon-gamma/interleukin-12 axis avoid live bacterial vaccines. ^[4]
• Phagocyte defects: chronic granulomatous disease avoids live bacterial vaccines only but takes live viral vaccines; undefined phagocyte defects or those with associated T/NK impairment (Chediak-Higashi, leukocyte adhesion deficiency, myeloperoxidase deficiency) avoid all live vaccines. ^[4]
• Complement defects: no live vaccine is contraindicated; all routine vaccines are effective and recommended. ^[4]
• Suspected or undiagnosed severe immunodeficiency in a relative is itself a contraindication: MMR, varicella and MMRV should not be given to someone with a family history of congenital immunodeficiency until immune competence is established. ^[5]
• Rotavirus vaccine is specifically contraindicated in SCID. ^[5]

Inactivated, recombinant and subunit vaccines are given according to national schedules, and household contacts should also be immunised to protect the patient (with the exception of smallpox). ^[4] Patients receiving immune globulin probably will not respond to live vaccines while on replacement, so live vaccines are avoided anyway and inactivated vaccines are timed around infusions. ^[4]

Outcome depends on the disorder. Most patients with an immunoglobulin or complement deficiency have near-normal life expectancy if diagnosed early and treated, so long as there is no chronic lung disease. ^[2] SCID and untreated severe T-cell defects are lethal in infancy; early diagnosis and transplantation change this. ^[3] Primary immunodeficiency carries increased risks of cancer (lymphoma, leukaemia, gastric carcinoma in CVID) and of autoimmune disease, which become part of long-term follow-up. ^{[1] [2]}

The 2022 IUIS classification and newborn screening programmes have changed the natural history of SCID. ^{[1] [3]} Every child with SCID found before infection begins can be transplanted in the first months of life with excellent survival. ^[3] Prenatal testing and carrier advice are offered once the family mutation is known. ^[2] All other prevention is individual: genetic counselling, early vaccination and prompt treatment. ^[2]

• Infants. Immaturity of the immune system is normal and not “primary immunodeficiency,” but it makes infants vulnerable. Many warning signs of SCID (failure to thrive, thrush, diarrhoea) are easily mistaken for common problems, which is why newborn TREC screening is so important. ^{[2] [3]}
• Children at day care and school. Repeated exposure makes up to 10 respiratory infections a year expected; this must not be over-interpreted as immunodeficiency. ^[2]
• Adolescents and adults. CVID and selective IgA deficiency dominate. Unexplained bronchiectasis, cytopenia, splenomegaly, granulomatous lung disease or malabsorption in a young adult warrants Ig measurement. ^{[1] [2]}
• Pregnancy. Genetic counselling and prenatal diagnosis are offered where the mutation is known; routine maternal antenatal immunisation decisions should take the neonate's immune status into account, and infants born to high-risk families may need isolation and early TREC testing. ^[2]
• Families. X-linked defects invite screening of male relatives and maternal carrier testing. ^{[1] [2]}

• A full blood count with differential and a quantitative immunoglobulin panel are the most informative cheap tests and can be performed in most district hospitals. ^[2]
• Delayed umbilical cord separation, absent tonsils, early serious infection and absent thymic shadow on chest radiograph are clinical signs that cost nothing and guide referral. ^[2]
• Opportunistic infection (thrush, severe varicella, atypical mycobacterial disease) in an infant should raise the same suspicion as in a well-resourced setting. ^[2]
• If flow cytometry and gene sequencing are unavailable, send the clinical story and a basic lymphocyte differential to the nearest referral centre; do not delay treatment while waiting. ^[2]
• Stem cell transplantation and immune globulin are expensive; prophylactic antibiotics (trimethoprim and sulfamethoxazole), good hygiene, prompt antibiotics and avoidance of live vaccines remain the accessible core of care. ^[2]
• Complement assay (CH50) is inexpensive relative to component analysis and should be ordered when neisserial infection recurs before advanced investigations are available. ^[6]

• Primary immunodeficiency (inborn error of immunity) is a genetically determined defect of a single immune component, present from birth, often presenting in infancy or childhood but sometimes in adulthood.
• Antibody (B-cell) defects are the largest group (50 to 60%) and present after 6 months with recurrent sino-pulmonary bacterial infection and with low immunoglobulin. ^[1]
• T-cell defects are rarer (5 to 10%) but more dangerous, with opportunistic, viral, fungal and mycobacterial infection; suspicious clues include live-vaccine infection and transfusion-associated graft versus host disease. ^{[1] [2]}
• Combined defects (about 20%) present in the first year with failure to thrive and serious infection; SCID is uniformly fatal in infancy without diagnosis and early stem cell transplantation. ^{[1] [3]}
• Phagocyte defects (10 to 15%) cause staphylococcal and gram-negative abscesses; chronic granulomatous disease is diagnosed by a respiratory burst test. ^{[1] [2]}
• Complement defects (2% or fewer) have a distinctive infection pattern: encapsulated bacteria with early components, Neisseria with terminal components. ^{[1] [6]}
• Recurrent infection is common and usually not immunodeficiency; investigate when infections are severe, complicated, in multiple sites, refractory, unusual or familial. ^[2]
• Age at onset locates the defect: under 6 months T-cell; 6 to 12 months combined or antibody; over 12 months usually antibody or secondary. ^[2]
• Initial investigations are full blood count, immunoglobulins, vaccine responses, delayed hypersensitivity and CH50/AH50; advanced tests follow. ^[2]
• Live vaccine avoidance depends on compartment: all live vaccines in severe T-cell disease; live bacterial vaccines only in chronic granulomatous disease; none in complement defects. ^[4]
• Antibody replacement is usually 400 mg/kg intravenous immune globulin monthly (800 mg/kg if needed), with trough IgG above 600 mg/dL; subcutaneous 100 to 150 mg/kg weekly is an alternative. ^[2]
• Stem cell transplantation is curative for severe T-cell and combined defects, with at least 80% survival and 96% if SCID is diagnosed by 3 months of age. ^{[2] [3]}
• Newborn TREC screening and early transplantation have changed SCID from a fatal disease to a curable one. ^{[2] [3]}

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