Immunodefiency

• When should you suspect immunodeficiency?

  • Infections are Serious, Persistent, Unusual organism/site, Recurrent
  • Family History of known immunodeficiency, excess infections, unexplained deaths, history-associated features
  • HIV risk factors: Sexual history, Transfusions, IV drug use
• Signs to suspect immunodeficiency:

  • Failure to thrive (children) / Weight loss (adults)
  • Lymphopenia in infants (<2.8 x 10^9 /L)
  • Reactions to live vaccines
  • Associated congenital malformations
  • Lymphoid malignancies
• Classification of immunodeficiency:

  • Physiological: premature & elderly
  • Primary: Genetic, or no known cause
  • Secondary: Infections, malignancies, drugs, renal failure, malnutrition
  • Secondary to something we know about! – HIV & malnutrition
• Warning signs in adults to investigate if 2 or more present:

  • 4 or more infections requiring antibiotics within 1 year (otitis, bronchitis, sinusitis, pneumonia)
  • Recurring infections or infection requiring prolonged antibiotic therapy
  • Two or more severe bacterial infections (osteomyelitis, meningitis, septicaemia, cellulitis)
  • Two or more radiologically proven pneumonia within 3 years
  • Infection with unusual localization or unusual pathogen
  • PID (Primary Immunodeficiency) family history
• Defects of humoral immunity:

  • Primary ID: X-linked agammaglobulinaemia (XLA), Common variable immunodeficiency (CVID), IgA deficiency, IgG subclass deficiency, Defective antibody production
  • Secondary ID: B cell directed therapies (e.g. Rituximab), Thymoma, Lymphoma/B cell malignancy/Myeloma, Drug therapy, Post splenectomy (Immunoglobulin Loss)
• Common variable immunodeficiency (CVID):

  • Low IgG (>2 S.D. below mean for age)
  • Low IgA or IgM
  • Features: Onset 2-80 years old, poor response to vaccines, risk factor for granulomatous disease, autoimmune disease, malignancies, deficient T cell function, excessive suppressor T lymphocyte
• Causes of hyposplenism:

  • Post-splenectomy, Congenital asplenia, Sickle cell anaemia, Coeliac disease
  • Diagnosis based on detection of Howell-Jolly Bodies on blood film
• Overwhelming post-splenectomy infection (OPSI):

  • High risk of infection by encapsulated bacteria (e.g. Strep. pneumoniae, Haemophilus influenza, Neisseria meningitides)
  • Timing: 65% within 1-2 years, 30% ~5 years, some >20 years, 50 - 70% mortality
• Immunodeficiencies associated with neutrophil dysfunction:

  • Primary ID: Genetic (very rare): Chronic granulomatous disease (CGD), Leukocyte adhesion defect (LAD), Hyper-IgE syndrome, Kostmann’s syndrome
  • Secondary ID (Common): Drugs (e.g. steroids), Diabetes mellitus, Myelodysplasia
• T cell/combined immunodeficiencies:

  • Primary ID: Severe combined immunodeficiency (SCID), ADA deficiency, X-linked SCID & many more
  • Secondary ID: HIV, Chemotherapy, Radiotherapy, Transplant recipients, Treatment for severe autoimmune disease
• Clinical assessment of T cell function:

  • Clinical History, Lymphocyte counts, T cell numbers & subtypes, Expression of TCRs, cytokine receptors etc, ADA measurement, Delayed hypersensitivity skin tests, Vaccination with protein antigens, Proliferation assays
• Managing a patient with SCID – immediate concerns:

  • Ensure adequate therapy for infections, including unusual pathogens & mixed infection
  • Irradiate all blood products
  • No live vaccinations
  • Initiate immunological investigations – urgent
  • Consider immunoglobulin therapy
  • Early referral for haematopoetic stem cell (HSC) transplantation
• Improving the management of SCID patients:

  • Early diagnosis: Awareness, Rapid diagnostics
  • Early referral for transplant
  • Ideally: Pre-natal tissue-typing and diagnosis, Arrange neonatal bone marrow transplant, Excellent outcomes
• Emerging treatments for patients with T cell defects:

  • Gene therapy for SCID
  • Thymic transplants for DiGeorge Syndrome
• Management of patients with any ID – patient counselling:

  • Avoid all live vaccines
  • Consider genetic implications, Impact on careers, travel etc
  • MedicAlert & information for patient and healthcare professionals
• Management of patients with primary ID – infection management:

  • Cytostatic versus cytotoxic antibiotics?
  • Dosage and duration?
  • Consider co-infection
  • Investigate opportunistic pathogens
• Management of patients with primary ID – therapies:

  • Specific Therapies: Immunoglobulin, Bone marrow transplantation
• Overall perspectives:

  • Recognize possible PID early, at primary care level
  • Careful management will save lives and enable living
• Reference: Concise Clinical Immunology for Healthcare Professionals, Psychology Press, Mary Therese Keogan (2006)

  Basic immunology: functions and disorders of the immune system / Abul K. Abbas, Andrew H. Lichtman, Shiv Pillai; Illustrations by David L. Baker, Alexandra Baker. -- Fifth edition or any latest editions