Primary Immunodeficiency Disease

Question 1

describe factors of immune deficiency

Answer 1

SPUR;
Serious infection - unresponsive to oral antibiotics
Persistent infections - early structural damage, chronic infection
Unusual infection - usual organism and site
Recurrent infection - 2 major or 1 major and recurrent minor infections in 1 year (major hallmark). Usually due to - common bacteria (Staph. aureus), myobacteria (TB), fungi

other features;
weight loss 
severe skin rash (eczema)
chronic diarrhoea
mouth ulceration 
unusual autoimmune disease
lymphoproliferative disorders
cancer
family history

Question 2

describe the classification of immunodeficiency disorders

Answer 2

primary;
some children born with poor functioning immune system, some have flaws in B cell system and cannot produce antibodies
thymus is missing, small or abnormal means they may lack in T cells

secondary;
common
often subtle
often involves more than one component of immune system

Question 3

describe conditions associated with secondary immune deficiency

Answer 3

physiological imunne deficiency 
infection 
treatment interventions 
malignancy 
biochemical and nutritional disorders

Question 4

describe primary immunodeficiency disorders (PID)

Answer 4

respiratory disease - main and most common complication
recurrent respiratory infections are often first signs of warning and major cause of death
pulmonary complications (strep, pneumonia, haemophilis influenzae) cause significant morbidity and mortality in these patients
early diagnosis and appropriate treatment can prevent or at least slow the development of respiratory complications

Question 5

describe respiratory system complications of PIDs

Answer 5

upper;
sinusitis - primary antibody deficiency
otitis media - primary antibody deficiency
laryngeal angioedema - complement system disorder

lower;
malignancies 
interstitial lung disease (scarring)
pneumonia 
bronchitis, bronchiectasis

Question 6

describe primary antibody deficiency

Answer 6

PID
selective IgA deficiency 
common variable immunodeficiency (CVID)
specific antibody deficiency (SAD)
X-linked agammaglobulinemia (XLA)

Question 7

describe complement system disorders

Answer 7

hereditary angioedema (HAE)

Question 8

describe pneumonia as a PID

Answer 8

pneumonia is an inflammatory condition of the lung secondary to infection and one of the most frequent manifestations of PIDs;
primary antibody deficiency 
complement system disorder
congenital phagocytosis deficiency 
combined immunodeficiencies

Question 9

describe important PIDs associated with respiratory complications in children

Answer 9

congenital neutropenia;
kostmann syndrome
rare genetic disorder
type 1 is most common and inherited in autosomal dominant manner
clinical manifestations - severe chronic neutropenia from birth, accumulation of precursor cells in bone marrow, treatment with recombinant G-CSF (reduces infections)

Question 10

describe how to life cycle of a neutrophil can go wrong

Answer 10

1. defects in neutrophil development - severe congenital neutropenia (nopus formation)
2. defects in neutrophil trans-endothelial migration (rolling, adhesion, strengthening and spreading, intravascular crawling, docking structure formation, transmigration) - leukocyte adhesion deficiency
3. defects in neutrophil killing - chronic granulomatous disease

Question 11

describe the consequences if a patient’s phagocytes were unable to bind to endothelial adhesion molecules

Answer 11

failure to recognise activation markers expressed on endothelial cells
neutrophils are mobilised but cannot exit the bloodstream
clinical features - recurrent bacterial and fungal infections
blood count - very high neutrophil counts
site of infection - deep tissues (no pus formation)

Question 12

describe leukocyte adhesion deficiency

Answer 12

very rare autosomal recessive primary immunodeficiency
caused by genetic defect in CD18 integrin gene on leukocytes
results in failure of neutrophil adhesion and migration and reduced uptake and degradation of opsonised bacteria

Question 13

describe chronic granulomatous disease

Answer 13

deficiency of intracellular killing mechanism of phagocytes - absent respiratory burst
inability to generate oxygen/nitrogen free radicals (ROS/RNS)
impaired killing intracellular micro-organisms reuslting in excessive inflammation (failure to degrade chemoattractants and antigens, persistent accumulation of neutrophils, activated macrophages and lymphocytes leads to granuloma formation)

Question 14

describe clinical features of chronic granulomatous disease

Answer 14

recurrent deep bacterial infections (staphylococcus, aspergillus, pseudomonas cepacia, mycobacteria (TB))
recurrent fungal infections 
failure to thrive
lymphadenopathy and hepatosplenomegaly 
granuloma formation

Question 15

describe treatment of phagocyte deficiencies

Answer 15

immunoglobulin replacement therapy (IVIg)
aggressive management of infection - oral/IV antibiotics and anti-fungals, surgical draining of abscess
definitive therapy - haematopoietic stem cell transplantation, specific treatment (SCN - recombinant G-CSF), gene therapy

Question 16

describe severe combined immunodeficiency

Answer 16

failure of production of lymphocytes in the thymus

clinical features;
unwell by 3 months of age
persistent diarrhoea
failure to thrive
infections of all types (common (more severe than normal), unusual and vaccine associated disease)
unusual skin disease 
family history of early infant death

Question 17

describe the causes of severe combined immunodeficiency

Answer 17

>20 possible pathways identified;
deficiency of cytokine receptors 
deficiency of signalling molecules 
metabolic defects 
defective receptor rearrangements
presence of different lymphocyte subsets (T, B, NK) depend on exact mutation 

X-linked;
most common
mutation of a component of the IL-2 receptor - shared by many other cytokine receptors, results in inability to repsond to cytokines (failure of T cell and NK cell development, production of immature B cells)
clinical features - low/absent T cells (IL-2 important for development), normal or increased B cells, poorly developed lymphoid tissue and thymus

Question 18

describe treatment of severe combined immunodeficiency

Answer 18

prophylactic;
avoid infections - prophylactic antibodies and anti-fungals, no live attenuated vaccines
aggressive treatment of existing infections
antibody replacement - IV immunoglobulin

definitive;
stem cell transplant from HLA identical sibling
stem cell transplant from other sibling or parent or from matched unrelated donor

gene therapy;

Question 19

describe Bruton’s x-linked hypogammaglobulinaemia

Answer 19

no circulating B cells
no plasma cells
no circulating antibody after first 6 months
as the Bruton’s tyrosine kinase gene is essential for B cell development

Question 20

describe disorders of T cell effector function

Answer 20

cytokine production
cytotoxicity
T-B cell communication