Q5 LONG ANSWER 10M ★ High-yield

Classify immunodeficiency disorders. Describe the important primary immunodeficiencies and the causes of secondary immunodeficiency.

Pathology · 2nd Professional — Para-Clinical

Classification

Immunodeficiency is a failure of one or more components of the immune system, resulting in an increased susceptibility to infection.

Class	Nature	Onset
Primary	Genetically determined	Usually presents between 6 months and 2 years, as maternal IgG wanes
Secondary (acquired)	Consequence of another disease or its treatment	Far commoner than primary

Primary Immunodeficiencies

Disorder	Defect	Features
BRUTON agammaglobulinaemia	X-linked; BTK gene; B cells fail to mature	Recurrent pyogenic infection after 6 months; absent tonsils and lymph nodes; all immunoglobulins low; T cells normal
Selective IgA deficiency	Failure of IgA B cell maturation	The commonest primary immunodeficiency; often asymptomatic; sinopulmonary and gut infection; anaphylaxis to blood products containing IgA
Common variable immunodeficiency	Defective B cell differentiation	Presents in adults; recurrent infection, autoimmunity, raised lymphoma risk
DiGEORGE syndrome	22q11 deletion; failure of the third and fourth pharyngeal pouches	Absent thymus (T cell deficiency) and parathyroids (hypocalcaemic tetany); cardiac defects; abnormal facies
Severe combined immunodeficiency (SCID)	X-linked common gamma chain, or adenosine deaminase deficiency	Both T and B cell function absent; fatal in infancy without bone marrow transplantation; the "bubble boy" disease
Wiskott–Aldrich syndrome	X-linked was gene	Triad of eczema, thrombocytopenia and recurrent infection
Chronic granulomatous disease	NADPH oxidase deficiency	Phagocytes engulf but cannot kill; infection with catalase-positive organisms; diagnosed by the nitroblue tetrazolium test
Chediak–Higashi syndrome	Defective phagolysosome fusion	Giant granules in leucocytes; partial albinism; neuropathy
Complement deficiencies	C3, or the terminal components	C3 — severe pyogenic infection. C5–C9 — recurrent neisseria infection. C1 inhibitor — hereditary angio-oedema

CLINICAL PEARL

The pattern of infection tells you which arm has failed.
Antibody or complement defects give recurrent pyogenic bacterial infection.
T cell defects give viral, fungal and intracellular infection.
Phagocyte defects give staphylococcal and fungal abscesses with poor pus formation. The history narrows the diagnosis before any test is done.

Secondary Immunodeficiency — Far Commoner

Cause	Mechanism
Malnutrition	The commonest cause worldwide, and especially in India; impairs cell-mediated immunity and causes thymic atrophy
HIV infection	CD4 T cell depletion
Malignancy	Leukaemia, lymphoma, myeloma (functionally useless paraprotein)
Iatrogenic	Corticosteroids, cytotoxic chemotherapy, radiotherapy, immunosuppressants
Loss of protein	Nephrotic syndrome, protein-losing enteropathy, extensive burns
Splenectomy or hyposplenism	Loss of clearance of encapsulated organisms
Diabetes mellitus, chronic renal failure, cirrhosis	Multiple defects of phagocyte and lymphocyte function
Extremes of age	Immature or senescent immunity
Infections	Measles, tuberculosis, malaria

Approach to Investigation

Full blood count with differential — lymphocyte and neutrophil numbers → Serum immunoglobulins (IgG, IgA, IgM) and specific antibody responses → Lymphocyte subsets by flow cytometry — CD4, CD8, B and NK cells → Complement — C3, C4 and CH50 → Neutrophil function — nitroblue tetrazolium or dihydrorhodamine test → HIV serology in every case → Genetic testing where a specific primary disorder is suspected

Pattern of Infection BY Defect

Arm affected	Typical organisms	Example disorders
Antibody (B cell)	Encapsulated pyogenic bacteria — pneumococcus, Haemophilus, staphylococcus; enteroviruses; Giardia	Bruton, common variable immunodeficiency, IgA deficiency
T cell	Viruses, fungi, intracellular bacteria — Candida, Pneumocystis, cytomegalovirus, mycobacteria	DiGeorge, SCID, HIV
Phagocyte	Catalase-positive organisms — Staphylococcus aureus, Serratia, Nocardia, Aspergillus; abscesses with little pus	Chronic granulomatous disease, leucocyte adhesion deficiency
Complement	Early components — pyogenic and immune complex disease. Terminal components — neisseria	C3 deficiency; C5–C9 deficiency
Spleen	Encapsulated organisms; overwhelming sepsis	Splenectomy; sickle cell disease

Applied Aspects

Suspect immunodeficiency with recurrent, severe, persistent or unusual infections, infection with organisms of low virulence, failure to thrive, or a family history
Post-splenectomy sepsis from encapsulated organisms carries a high mortality; prevented by vaccination against pneumococcus, meningococcus and Haemophilus influenzae b, plus prophylactic penicillin
Live vaccines are contraindicated in T cell deficiency and in significant immunosuppression — BCG in an infant with SCID is fatal
Blood products must be irradiated for severely immunodeficient patients, to prevent transfusion-associated graft-versus-host disease
Immunoglobulin replacement transforms the outlook in antibody deficiencies; bone marrow transplantation is curative in SCID
In India, malnutrition and tuberculosis remain the dominant causes of acquired immunodeficiency, and are far more common than any inherited disorder
Maternal IgG protects the infant for the first 3 to 6 months, which is why most antibody deficiencies present only after that
Newborn screening for SCID by measuring T cell receptor excision circles allows transplantation before infection occurs, and transforms survival
Recurrent infection at a single site usually indicates a local anatomical problem rather than immunodeficiency — an obstruction, a foreign body or a fistula
Consanguinity raises the risk of autosomal recessive primary immunodeficiency, which is relevant in parts of India
The ten warning signs of primary immunodeficiency — including two or more pneumonias in a year, failure to thrive, recurrent deep abscesses and persistent thrush — are a practical screening tool for general practice
Antibody deficiency is treatable and often missed for years; the average delay to diagnosis of common variable immunodeficiency is measured in years, during which bronchiectasis develops irreversibly
Autoimmunity and malignancy accompany many primary immunodeficiencies, because immune regulation fails alongside immune defence
Genetic counselling is an essential part of management, since most primary immunodeficiencies are single-gene disorders with a defined recurrence risk
An HIV test is mandatory in every case of suspected immunodeficiency, whatever the age, before any inherited disorder is considered
Correcting malnutrition restores immune function, which makes it the single most effective immunological intervention available at population level
Vaccination of household contacts protects a patient who cannot be safely vaccinated themselves — a practical measure often forgotten
Antibiotic prophylaxis reduces infection in several primary immunodeficiencies, and is used lifelong after splenectomy in children

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