Primary Immunodeficiency Flashcards
What presentations or histories should make you consider primary immunodeficiency?
Severe, recurrent invasive infections
Unusual organisms
Unusual sites of infection
Severe, recurrent or disproportionate inflammation
Unexplained lymphoproliferation
What is different about lymphocyte counts in children compared with adults
What would a lymphocyte count of <1 indicate?
Fivefold higher than adults
I.e. >7 at birth and >4 at 1 year
Higher proportion of B cells
Fewer CD8 cells at birth
Absolute counts are essential
<1= SCID until proven otherwise
What are the most likely immune deficiencies at these given age ranges?
- 0-52 weeks
- 1-4 yrs
- 4-16 yrs
- Adults
- SCID/ CID/ Severe neutropenia
- Antibody deficiency (XLA)/ Complement deficiency/ Innate defects
- CVID/ complement defects/ C1 inhibitor def (hereditary angioedema)
- CVID/ Secondary immunodeficiency/ Autoimmunity
What are the possible causes of severe combined immunodeficiency (SCID)?
Common gamma chain mutation
- X linked
- mutation for interleukin receptors on T + NK cells
JAC3 mutation
-TC specific loss of survival signals I.e. TC
RAG1/ARTEMIS/DNA ligase
-TCR/Ig receptor rearrangment failure i.e. TC + BC
ADA mutation
-mutation in adenosine deaminase (ADA) i.e. affects ALL lymphocyte cells (TC/BC/NK)
What is the pathophysiology behind ADA SCID?
Failure of ADA to metabolise adenosine which leads to build up of toxic metabolite
Toxic metabolite leads to death of common lyphoid precusor (CLP)
Lack of CLP means there is no BC/TC/NK precusors
I.e. deficiency of ALL lymphocytes
How might someone with SCID present clinically?
Early onset infections which fail to clear
- Bac= sinopulmonary/sepsis
- Viral= adenovirus/CMV/RSV/parainfluenza
- Fungal= persistant candida
- Opportunistic= PCP/aspergillus/MTB/BCG
- Vaccine related= BCG/rotavirus/polio i.e. becomes unwell after vaccinations
== persistent severe diarrhoea
Failure to thrive
Maternal-fetal engraftment
- erythrodermic rash
- eosinophilia
Lymphopenia
Omenn syndrome
Why might child with SCID present with GvDH erythrodermic rash?
Maternal lymphocytes cross the placenta and enter fetal circ
No fetal immune system leads to maternal lymphocytes expanding and attacking baby
What is Omenn syndrome?
What are the classical features?
Rare cause of SCID due to mutation in recombination-activating gene (RAG1 or RAG2)
Leads to deregulated T cells which attack tissues in fetus
Features:
- red, scaly dry rash i.e. erythroderma
- hair loss i.e. alopecia
- diarrhoea
- failure to thrive
- lymphadenopathy
- hepatosplenomegaly
When is SCID considered until proven otherwise?
When <6mon infaction has lymphocytes count <2x10^9
How is SCID managed?
Contact Immunologist
Prophylactic antifungal, antibiotics and antivirals
IVIG
Strict infection control
Nutritional support
No live vaccines i.e. rotavirus/BCG/MMR/LAIV
No breast feeding i.e. risk of CMV transfer
CMV negative and irradiated blood products
Ultimately will need BMT/gene therapy
I.e. other measures are to try and ensure child in best condition for transplant
How might a child with antibody deficiency present?
What pathogens are commonly responsible for infections in those with antibody deficiency?
What is a red flag sign in the history for Ig deficiency?
Characteristic infection:
-pneumonia/LRTI
-conjunctivits
-otitis media
-bronchiectasis
-sinusitis i.e. can present with constantly streaming nose
I.e. signs of bacterial infections due to Ig not being present to opsonise encapsulated bacteria
Streptococcal Haemophilus Staphlococcal Giardiasis Campylobacter Salmonella
1+ hospital admissions for chest infection
What is the function of Bruton’s tyrosine kinase? (BTK)
How is it involved with antibody deficiencies?
What would Ig levels be in those with this Ig deficiency?
Signal molecule involved in switching from pro to pre B cells in the bone marrow ready for it to leave the bone marrow and enter the blood and secondary lymphoid tissue to continue its maturation process
Mutation in this function leads to disruption in maturation pathway of the BC leading to there being fewer mature B cells and therefore lack of Ig being produced
I.e. called X-linked agammaglobulaemia (XLA)
XLA= all Ig would be low
When are antibody deficiencies most likely to present?
After 6 months due to this being the time which maternal Ig has decayed away meaning there is a loss of protection
How can XLA be managed?
Prophylactic antibiotics
IVIG or SCIG
Refer to respiratory team to help manage recurrent chest infections and bronchiectasis
What causes hyper IgM syndrome?
How might someone with hyper IgM present?
Deficiency of CD40L on TH cells resulting in inability to generate signals for class switchitng to occur from IgM to the appropriate Ig. Leads to raised levels of IgM disproportionate the other Ig.
Recurrent bacterial infections
Liver problems i.e. cryptospiridiosis
What are the 3 main reasons for neutrophil defects?
Defects in absolute number
- severe congenitial neutropenia
- cyclical neutropenia I.e. mutation in ELANE
- secondary neutropenia i.e. drugs/chemotherapy
Defections in neutrophil chemotaxis
-Leukocyte adhesion deficiency i.e. CD18 def
Defects in neutrophil killing
- X-linked chronic granulomatous i.e. problem with ROS production
- autosomal recessive CGD
How might someone with neutropenia present?
How can they be managed?
Mouth ulcers
Stomatitis
Neutropenic sepsis
Recurrent fever
Treat with GCSF to stimulation neutrophils from BM
How might someone with a defect in neutrophil chemotaxis present?
Large LN Delayed umbilical cord detachment No pus or inflammatory change at infection site Skin infections Perianal fistulas
How might someone with defects in neutrophil killing ability present?
Early onset deep seated infections which are catalase positive organisms (i.e. organisms which cause problems with hydrogen peroxide)
Perianal abscess
IBD like disease
How do oxygen radicals kill bacteria?
What is the pathogenesis behind chronic granulomatous disease?
How might someone with this condition present?
How is it treated?
Radical (O2-) causes endocytic vacuole to be charged causing a potential difference
Leads to K+ influx which activates antimicrobial peptides which kill the ingested bacteria
Failure of subunit of NADPH complex leading to inability to produce oxygen radicals
Deep seated infection with catalase positive organisms i.e. staph, aspergillus, norcardia, serratia)
TX:
- prophylactic Abx
- antifungals
- alloBMT
- gene therapy
What conditions are those with complement deficiencies at greatest risk of developing?
Haemophilius influenza B Streptococcus pneumonia Neisseria meningitis I.e. encapsulated organisms ->tends to present with recurrent infections with these organisms
Why are complement deficiencies associated with SLE?
Incomplete complement cascade leads to immune complexes building up and being deposited in the tissues which results in chronic inflammation
What is Mannose-Binding Lectin (MBL) deficiency?
Relatively common deficiency in the population which leads to inhibition of the alernative pathway
Generally doesn’t cause any problems in the general population but can in those already suspectible to infection i.e CF-> leads to more severe variant of disease
What is the normal action of C1 esterase?
What happens in C1 esterase deficiency?
How can it be treated?
What should be tested for it C1 esterase deficiency is suspected?
Normally inhibits bradykinin which acts to promotes blood vessel dilatation and increased vessel permeability i.e angiodema
Without inhibition of bradykinin, intermittent angioedema occurs (Hereditary angioedema) in response to minor triggers (infections or stress)
-swelling occurs in face, airways and GIT
Prophylaxtic C1 esterase inhibitor
Check C4= will be low in this condition
