What is CVID?
Common variable immune deficiency (CVID) is a disorder that impairs the immune system. People with CVID are highly susceptible to infection from foreign invaders such as bacteria, or more rarely, viruses and often develop recurrent infections, particularly in the lungs, sinuses, and ears.
Why is immunodeficiency an unmet clinical problem?
- There are a large spectrum of primary immunodeficiencies.
- Different clinical phenotypes
- Need to update knowledge in medical school / trianing
- Need for bettwe diagnostic criteria
- Failure to recognise and diagnose PIDs
- 8-12, 4 years from onset of symptoms
- Over 60% of patients will be 18 years or older when diagnosis is made
- 37% of them will have permanent tissue / organ damage
What is an immunocompromised host?
A state in which the immune system is unable to respond appropriately and effectively to infectious microorganisms
Due to a defect in one or more components of the immune system.
What can cause immunodeficiency?
Immunodeficiency is caused by defect one or more components of the immune system.
Why is a host “immunocompromised”?
Primary immunideficiencies are congenital
- Due to intrinsic gene defects (about 275 genes)
- Missing protein
- Missing cell
- Non-functional components
Secondary immunodeficiencies are aquired
- Due to an underlying disease / treatment
- Decreased production / function of immune components
- Increase loss or catabolism of immune components.
When should you suspect an immunodeficiency?
SPUR
S - Severe (Life threatening, IV antibiotics)
P - Persistant (longer treatment or different antibitics to treat it)
U - Unusual (Site of infection - deep, Type of microbe e.g. candida albicans -oppotunistic)
R - Recurrent (Keeps coming back)
What are the 10 warning signs of primary immunodeficiencies in childen?
Key = Family History! (25% have family history)
- Four or more new ear infections within a year
- Two or more serious sinus infections within a year
- Two or more months of antibiotics with little effect
- Two or more pneumonias within 1 year
- Failure of an infant to gain weight or grow abnormally
- Recurrent, deep skin or organ abscesses
- Persistant thrush in mouth or fungal infection on skin
- Need for IV antibiotics to clear infections
- Two or more deep seated infections including septicaemia
- A family history of PID
What are the 10 warning signs of primary immunodeficiency for adults?
- Two or more new ear infections within a year
- Two or more new sinus infectiosn within 1 year in the absence of allergy
- One pneumonia per year for more than a yeat
- Chronic diarrhoea or weight loss
- Recurrent viral infections (colds, herpes. warts and condyloma)
- Recurrent need for IV antibiotics to clear infections
- Recurrent, deep abscesses of the skin or internal organs
- Persistant thrush or fungal infection on skin or elsewhere
- Infection with normally harmless tuberculosis-like bacteria
- A family history of PID
What are the limitations of the 10 warning signs?
- General use: Lack of population-based evidence
- Family History
- Failure to thrive
- Diagnosis of sepsis treated with IV antibiotics
- PID patients with different defects / presentations
- T cells / B cells / Phagocytes / Complements
- Infections with subtle presentations (can present differently e.g. repeated infection in same area with same bacteria)
- PID patients with non-infectious manifestations
- Autoimmunity
- Malignancy
- Inflammatory responses
What PIDs are of clinical immportance?
- CVID - Common variable immunodeficiency - Predominantly antibody deficiency
- SCID - Severe combined immunodeficiency -Combined T and B cell deficiency
- Chronic Granulomatous Disease - Phagocytic defects
- DiGeorge syndrome - Cyclic neutropenia.
How does age of onset influence type of PID?
- Before 6 months - T-cell or phagocyte defect
- 6 months - 5 years - B cell / antibody or phagocyte defect
- Over 5 years or later in life - B cell / antibody / complement or secondary immunodeficiency
How do the type / site of microbe influence the type of PID?
Complement defects (Strep, Haemophilius influenzae and encapsulated bacteria)
- Pyogenic Infections (C3)
- Meningits / Sepsis / Arthritis (C5-C9)
- Angioedema (C1 inhibitor)
Phagocytic defects (Staph aureus, Pseudomonas, Non-TB mycobacteria, Candida, Aspergillus)
- Skin, mucour infections
- Deep seated infections
- Invasive fungal infections (aspergillosis)
Antibody deficiencies (strep, staph, haemophilius influenzae, enteroviruses, Giardia lamblia)
- Sinorespiratory Infections
- Arthropathies
- GI infections
- Malignancies
- Autoimmunity
T cell defects (Almost everything but most likely viral)
- Death if not treated
- Failure to thrive
- Deep skin and tissue abscesses
- Opportunistic infections
How do you manage primary immunodeficiency diseases?
Supportive treatment
- Infection prevention (prophylactic antimicrobials)
- Treat infections promptly and aggressively (passive immunisation)
- Nutritional support (Vitamins A, D)
- Use UV-irradiated CMV (cytomegaly viris) neg blood products only
- Avoid live attenuated vaccines in patients with severe PIDs (SCID)
Specific treatment
- Regular immunoglobulin therapy (IVIG or SCIG)
- SCID: Hematopoietic Stem Cell therapy (HSCT, 90% success)
Co-morbidites
- Autoimmune and malignancies
- Organ damages (lung function assessment)
- Avoid non essential exposure to radiation
What is immunoglubulin replacement therapy?
Goal - Get serum IgG above 8g/L
Life long treatment.
There are different formulations - IvIg, ScIg (young patients)
Used in conditions such as:
- CVID
- XLA (Bruton’s disease)
- Hyper-IgM syndrome
What are some causes of secondary immune deficiencies?
Decreased production of immune components
- Malnutrition (KEY!)
- Infection (HIV)
- Liver diseases
- Lymphoproliferative diseases
- Spenectomy
- Causes: Infarction, (sickle cell), trauma, autoimmune haemolytic disease, infiltration (tumour), coeliac disease, congenital
Why is the spleen important?
- Because without it, you are suseptible to blood borne infections - Encapsulated bacteria!.
- The spleen produces antibodies Acute (IgM) and long term (IgG)
- Splenic macrophages
- Removal of opsonised microbes
- Removal of immune complexes
*
Give examples of some encapsulated bacteria
- Hemophilus influenzae type b (Hib)
- Streptococcus pneumoniae (pneumococcus)
- Neisseria meningitidis (meningococcus)
- Group B streptococcus (GBS)
- Klebsiella pneumoniae
- Salmonella typhi
A popular mnemonic to remember most of the encapsulated bacteria is the SHiNE SKiS bacteria (S. pneumoniae, Hib, N. meningitidis, E. Coli, Salmonella, Klebsiella, Group B streptococci).
How do they present and how do you treat an aplenic or splenectomised patient?
Presentation:
- Increased suseptibility to encapsulated bacteria
- OPSI (overwhelming post-splenectomy infection) -Sepsis and meningitis (1-2% risk of death over 15 years)
Management:
- Penecillin prophylaxis (life-long)
- Immunisation against encapsulated bacteria
- Medic alert bracelet
Patient with haematological malignancy
Increases suseptibility to infections
- Chemotherapy-induced neutropenia
- Chemotherapy-induced damage to mucosal barriers
- Vascular catheters
Treat suspected neutropenic sepsis as an ACUTE MEDICAL EMERGENCY and offer empiric antibiotic therapy immediately.
Assess patient’s risk of septic complications.
What other things can increase loss of or result in catabolism of immune components?
Protein-losing conditions
- Nephropathy
- Enteropathy
Burns - Breach innate barrier
What factors do you look at to diagnose IDs?
The pattern and type of infections always reflect the nature of immunological defect
- Age
- Sex
- Sites and frequency of infections
- Type of organisms
- Viruses and fungi - T cell deficiency
- Bacteria and fungi - B cell / Granulocytes deficiency
- Sensitivity and type of treatment (surgery)
- Family history
What lab investigations get conducted for immunideficiency?
- General
- FBC and differential
- Tests of humoral (antibody) immunity
- IgG, IgA, IgM (+/- IgE)
- IgG1-4 subclasses
- IgG levels specific to previous vaccines
- Tetnus, HiB, Pneumococcus, measles, mumps, rubella
- Measure antibody in response to “test” immunisation
- Test for cell mediated immunity
- Lymphocyte count (FBC)
- Lymphocyte subset analysis
- In vitro tests of T cell function
- Tests for phagocytic cells
- Neutrophil count (FBC)
- Neutrophil function tests (eg oxidative burst for CGD)
- Adhesion molecule expression (for LAD)
- Tests for complement
- Individual components
- Tests of complement function
- Definitive tests
- Moleculat testing and gene mutations.
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Introduction13
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An Infection Model11
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Microbes19
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Innate Immune System31
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Antimicrobials28
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Antimicrobial Resistnce16
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Healthcare Infections15
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Adaptive Immunity26
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Infection On Surfaces29
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Streptococci14
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Infection Prevention21
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HIV20
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Immunocompromised22
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Viral Hepatitis17
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Travel Related Infections20
