Primary Immunodeficiency Disease Flashcards
describe factors of immune deficiency
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
describe the classification of immunodeficiency disorders
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
describe conditions associated with secondary immune deficiency
physiological imunne deficiency infection treatment interventions malignancy biochemical and nutritional disorders
describe primary immunodeficiency disorders (PID)
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
describe respiratory system complications of PIDs
upper;
sinusitis - primary antibody deficiency
otitis media - primary antibody deficiency
laryngeal angioedema - complement system disorder
lower; malignancies interstitial lung disease (scarring) pneumonia bronchitis, bronchiectasis
describe primary antibody deficiency
PID selective IgA deficiency common variable immunodeficiency (CVID) specific antibody deficiency (SAD) X-linked agammaglobulinemia (XLA)
describe complement system disorders
hereditary angioedema (HAE)
describe pneumonia as a PID
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
describe important PIDs associated with respiratory complications in children
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)
describe how to life cycle of a neutrophil can go wrong
- defects in neutrophil development - severe congenital neutropenia (nopus formation)
- defects in neutrophil trans-endothelial migration (rolling, adhesion, strengthening and spreading, intravascular crawling, docking structure formation, transmigration) - leukocyte adhesion deficiency
- defects in neutrophil killing - chronic granulomatous disease
describe the consequences if a patient’s phagocytes were unable to bind to endothelial adhesion molecules
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)
describe leukocyte adhesion deficiency
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
describe chronic granulomatous disease
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)
describe clinical features of chronic granulomatous disease
recurrent deep bacterial infections (staphylococcus, aspergillus, pseudomonas cepacia, mycobacteria (TB)) recurrent fungal infections failure to thrive lymphadenopathy and hepatosplenomegaly granuloma formation
describe treatment of phagocyte deficiencies
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
describe severe combined immunodeficiency
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
describe the causes of severe combined immunodeficiency
>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
describe treatment of severe combined immunodeficiency
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;
describe Bruton’s x-linked hypogammaglobulinaemia
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
describe disorders of T cell effector function
cytokine production
cytotoxicity
T-B cell communication
