Immunodeficiency

Primary immunodeficiencies are genetic/congenital abnormalities of the immune system whilst secondary immunodeficiencies are acquired.

Background

  • There are many primary immunodeficiency disorders- most are inherited genetic disorders and are very rare (symptomatic cases: 1/10000).  Most present in childhood and most present in males (X-linked).

Classification

  • Can be classified as disorders of immune systems:
    • B-cell and Immunoglobulin system- Mainly antibody deficiencies which account for the majority (50%) of cases
      • e.g. Common variable immunodeficiency, Selective IgA deficiency, Bruton’s/X-linked agammaglobulinaemia; Transient hypogammaglobulinaemia of the newborn; IgG deficiency
    • T-cell and cell-mediated immune system- accounts for 30% of cases
      • NB Many of these disorders span both T- and B-cells e.g. Severe combined immunodeficiency; DiGeorge syndrome; Wiskott-Aldrich syndrome; Ataxia-telangiectasia; X-linked hyper-IgM
    • Phagocytic (Polymorphic/mononuclear) system (including macrophage dysfunction)
      • e.g. Chronic granulomatous disease
    • Complement system (mainly complement deficiencies)
  • NB Many disorders span more than one system e.g. Severe combined immunodeficiency (T- and B-cells); DiGeorge syndrome; Wiskott-Aldrich syndrome; Ataxia-telangiectasia; X-linked hyper-IgM

Disorders

Disorders of Humoral Immunity

  • Often present >6 months of age (loss of maternal antibodies), but can present late (into adulthood- see below)
  • Classically present with infections of encapsulated bacteria (tend to fight of viral and fungal infections with an intact innate immune system)
    • Chronic sinusitis / Recurrent acute sinusitis; other recurrent infections e.g. Strep pneumoniae pneumonia; unusual infections e.g. mycobacterial/fungal infections
  1. Common Variable Immunodeficiency
    • Not that common (1/75000); technically group of different disorders (a ‘heterogeneous syndrome’) with variable presentation and outcome
      • e.g. can present in infancy or into adulthood; can present in males and females (although females tend to have a better phenotype)
      • CVID is a diagnosis of exclusion (i.e. other causes of Ig deficiency should be ruled out)
    • Commonly associated with autoimmunity and family history
      • e.g. idiopathic thrombocytopenic purpura; haemolytic anaemia; thyroid disease; vitiligo; diabetes (insulin-dependent); rheumatoid arthritis; SLE; psoriasis; uveitis; IBD (mainly UC)
    • Characterised by failure of B cell differentiation into plasma cells and defective interaction between T- and B-cells
      • Causing reduced levels of immunoglobulin (IgG and IgA > IgM > IgE)
      • Up to half of patients also have associated T-cell dysfunction
  2. Selective IgA Deficiency
    • Most common (1/300-700) but often asymptomatic/undiagnosed (incidence based on blood samples)
    • IgA is found mainly in mucosal membranes and is thought to prevent bacteria from attaching to mucosal surfaces
    • Patients are at increased risk of allergies and autoimmune disease (atopy is common)
    • Patients commonly present with recurrent URTIs, including sinusitis, as well as GI infections
    • Although IgA < 5mg/dl; IgG can be normal and patients can often respond normally to vaccinations.  However, patients can respond abnormally (e.g. anaphylaxis) to blood/blood product transfusions due to the presence of IgA
  • Bruton’s/X-linked Agammaglobulinaemia
    • Caused by mutation/absence of Bruton’s tyrosine kinase (Btk) gene- important in cell signalling pathways involved in B-cell maturation (rare: 1/350000-400000)
      • X-linked (male)
      • Failure of maturation and absence (/minimal levels) of all immunoglobulin (IgG, IgA and IgM)
    • Often present in the first year of life with recurrent otitis media; pneumonia; and sinusitis BUT 20% of children can present later (3-5 years)

Disorders of Innate (+/- Humoral) Immunity

  • Usually more severe than isolated Ig/B-cell disorders, presenting earlier in life with failure to thrive and severe infections
  1. DiGeorge Syndrome
  2. Severe Combined Immunodeficiency 
    • Another syndrome which can manifest from several, usually genetic, disorders- characterised by recurrent, severe and opportunistic infections, failure to thrive and chronic diarrhoea presenting in the young infant (usually a few months after birth).
      • Other signs include rashes, hepatopathy, chest infections (interstitial pneumonia (cf lobar pneumonia), fungal infections
    • Fairly rare at 1/75-100,000.  Almost half of cases are x-linked (far more common in males) and others are autosomal recessive (with Jak3 and ADA deficiency)
      • Most commonly caused by a defect in the γ-chain of the interleukin receptors (X-linked)
    • Can encompass a range of white cell abnormalities
      • Most cause a T-cell defect- usually completely absent.  Many also affect B-cell and NK cell production.  A severe lymphopenia is seen on FBC.
      • Patients often do not mount any immune response to vaccinations and so can get symptoms with certain vaccinations
    • Patients will require IVIg and should be considered for an emergency bone marrow transplant
      • Without treatment, infections will usually kill the patient before they are 2 years old.
  3. Wiskott-Aldrich Syndrome
    • X-linked recessive condition characterised by
      • Recurrent bacterial infections of the sinuses/lungs
      • Eczema (resembles atopic dermatitis)
      • Bleeding tendency due to thrombocytopenia and platelet dysfunction.  This can be of the form of bloody diarrhoea, purpuric rash or excessive bruising.
        • NB These patients are also at risk of autoimmune conditions e.g. autoimmune haemolytic anaemia, vasculitides (inc glomerulonephritis); IBD etc as well as non-Hodgkins lymphoma
    • Typically presents in infants/toddlers
    • Caused by a defect of the WAS-protein gene, normal function of which is required for normal antibody, T-cell and platelet function
      • As a result, patients often have low IgG (often normal B-cells- IgM may be affected but this may be a sign of CVID or other syndrome- IgA and IgE may be elevated); low T cell count (particularly CD8+) and low/small platelets
    • Management should involve vaccinations and active management of any infections; may involve transfusions and/or stem cell transplant
      • Most patients survive well into their 20s/30s if treated conservatively.  Stem cell transplant can almost cure this condition and lengthen life span to normal.

Disorders of Phagocytic immunity

  1. Chronic Granulomatous Disease
    • CGD is a group of genetic syndromes in which phagocytes are unable to kill bacteria/fungi that have been ingested.
      • Usually caused by a defective gene encoding NADPH oxidase enzyme responsible for oxygen radical formation
      • Most commonly X-linked or autosomal recessive
    • Usually presents <2 with recurrent bacterial/fungal infections e.g. fungal pneumonia, skin abscesses/infections, lymphadenitis, diarrhoea
      • commonly with Aspergillus fumigatus; Candida albicans and Candida glabrata
    • Granulomas of the skin and GI tract can also be seen
    • Investigations include a phagocytic oxidase activity (Nitroblue tetrazolium- NBT- microscopy stain) test and genetic test
    • Management is usually prophylactic antibiotics and antifungals
      • Co-trimoxazole (Trimethoprim + Sulfamethoxazole- 5mg/kg/day based on trimethoprim) is often used because is reduces bacterial infection without increasing the risk of fungal infections
      • Itraconazole is also used
      • Interferon gamma may also be used to enhance immune function
      • Prednisolone may be used in moderate-severe granulomatous disease, particularly if causing GI symptoms
    • Acute infections should be managed as per case

Disorders of the Complement System

  • Variety of complement deficiencies- each with specific features.  Patients may be at risk of immune complex deposition disorders e.g. SLE, as well as recurrent bacterial infection

When to suspect immunodeficiency

  • Warning History
    • ≥8 ear infections in a year
    • ≥2 serious sinus infections in one year
    • ≥2 episodes of pneumonia in one year
    • ≥2 deep-seated or unusually located infections
    • Recurrent deep skin or organ abscesses
    • Need for IV antibiotics to clear infections
    • Infections with unusual or opportunistic organisms
    • Family History
  • Warning Signs
    • Poor growth/Failure to thrive
    • Absent lymph nodes/tonsils
    • Skin lesions: telangiectasias, petechiae, dermatomyositis, lupus-like rash
    • Ataxia
    • Oral thrush (>1 year old)
    • Oral ulcers
  • If a patient has any one or more of the bold warning signs, and an immunodeficiency is suspected, IgG/IgM/IgA and a FBC can be measured to screen for a primary immunodeficiency

Management

  • Most require high dose and IV antibiotics for treatment of acute infections.  Many will require prophylactic antibiotics too
  • Where appropriate, vaccines should be given
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    • Patients with T-cell deficiencies should receive cytomegalovirus-negative irradiated blood products
  • IVIg should be used to replace immunoglobulin
  • Stem cell/bone marrow transplants can be curative for cellular immunodeficiency
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