HIV infection

Question 1

common causes of secondary immune deficiency

Answer 1

malnutrition - commonest cause worldwide esp protein loss effects cell mediated immunity
measles
TB
HIV - residual immune dysfunction despite ART (immune inflammation or increased markers of cellular or solbule markers of immune activation) -> increased risk of heart, lung, liver disease
Covid

Question 2

how is measles a cause of secondary immune deficiency

Answer 2

immune defect lasts months to years,

implicated in increased morbidity and mortality due to secondary bacterial infection or diarrhoea.

Important in L or middle income countries.

Question 3

TB and secondary immune deficiency

Answer 3

associated with depressed cell mediated immune response
picked up by failure to detect +ve mantoux test, or failure of inf-gamma release on ag specific assay used
as treat TB - immune response can reconstitute (immune re-constitution) - immune response wakes up and see other infections that patient has - and mounts inflammatory response

Question 4

covid and secondary immune deficiencies

Answer 4

all things that make disease more severe
, virus, drugs and present of co-morbidities (renal disease and DM)

Question 5

drugs as a cause of immune deficiency

Answer 5

Glucocorticoids and mineralocorticoids

Cytotoxic agents: methotrexate, mycophenolate, cyclophosphamide
and azathioprine

Calcineurin inhibitors: cyclosporine and tacrolimus

Antiepileptic drugs (phenytoin, carbamazepine, levetiracetam

DMARD (sulphasalazine, leflunomide )

JAK inhibitors - Tofacitinib, upadacitinib, ruxolitinib

Question 6

steroids as a cause of secondary immune deficiency

Answer 6

Prednisolone - >10mg/day -> increased rate of Ab loss.

Higher dose -> increase susceptibility to infetcions

Question 7

cytotoxic drugs as a cause of secondary immune deficiency

Answer 7

kill rapidly turning over cells inc immune cells

methotrexate, mycophenolate -> antibody deficiency
cyclophosphamide and azathioprine -> antibody and cellular def

Question 8

calcineurin inhibitors and secondary immune deficiency

Answer 8

cellular immune deficiency
target dendritic cell, cd4 podicular dysfunction

will have knock on effect to respond to vaccine

Question 9

antiepileptic drugs and secondary immune deficiency

Answer 9

phenytoin, carbamazepine, levetiracetam

Ab deficiency

Question 10

DMARD and secondary immune deficiency

Answer 10

(sulphasalazine, leflunomide, methotrexate)

Ab immune deficiency

Question 11

Jak inhibitors and secondary immuen deficiency

Answer 11

Can cause Ab deficiency.

Involved on reactivation of herpes zoster

Question 12

biologic agents causing immune deficiency

Answer 12

anti-CD20/CD38/BCMA monoclonal antibodies
anti-TNF-α protein and receptor antagonists

Anti-CD20 – rituximab – increase the risk of Ab deficiency -> secondary bacterial and viral infection eg rhinovirus/norovirus where Ab are important in their control
B cells are APC to T cells – so risk of fungal infections for rituximab – so start on PCP prophylaxis

Agents targeting end stage of B cell maturation eg Anti-CD38 and anti-BCMA therapy will be found to be associated with increased risk of infection. Used in multiple myeloma rx

Question 13

cellular therapy effect on immune dysfunction

Answer 13

anti-CD19/BCMA CAR-T cell therapy

give rise to B cell aplasia -> sig increased risk of invasive bacterial infection
anti CD19 CAR T cell therapy - associated with sig infection

use preventative than Ig infusion

Question 14

rituximab and immune deficiency

Answer 14

Antibody deficiency and bacterial/viral/fungal infections are observed with anti-CD20 agents such as rituximab: ? Anti-CD38 and anti-BCMA therapy .

Risk of infection increased with repeated courses of rituximab and** in patient with a history of B cell malignancy (chemotherapy) and ANCA-related vasculitis (cyclophosphamide) .**

Question 15

anti-TNF agents and immune deficiency

Answer 15

risk of activation of latent TB
have to screen pts for latent TB - put on preventative anti-TB agents

Question 16

haematological cancers and immune deficiency

Answer 16

B and plasma cell cancers can present with immune deficiency
chemo, radio and biologic agents -> loss of immune cells and immune deficiency

Question 17

what are the B cell lymphoproliferative disorders associated with immune deficiency

Answer 17

Multiple myeloma

Chronic lymphocytic leukaemia

Non Hodgkin’s lymphoma

Monoclonal gammopathy of uncertain significance – benign condition that can progress to B cell cancer.

Question 18

what is Good’s syndrome

Answer 18

thymoma and ab deficiency :

Combined T and B cell (absent) defect
sinus, chest and GI infection
CMV PJP and muco-cutaneous candida
Autoimmune disease because thymus involved in central tolerance (Pure red cell aplasia, Myasthenia gravis, Lichen planus)

Question 19

hx for secondary immune deficiency

Answer 19

clinical hx of infection
alarm sx for B cell cancers
hx of other illnesses - autoimmune cytopenia, bronchiectasis, rx for lymphoma/cancer/TB/hep B/C
Fx of infection/autoimmune disease/cancer
meds
vaccine hx - childhood, pneumococcal, influenza (household contacts should get flu vaccine)

Question 20

how do you Ix for immune deficiency

Answer 20

FISH:
Full Blood count
* Hb < 10g/L
* neutrophil count
* lymphocyte count
* platelet count

Immunoglobulins (IgG, IgA, IgM, IgE )

Serum complement (C3, C4) - see whether unexplained lupus or complement deficiency

HIV test (18-80 years)

Question 21

chemistry for immune deficiency

Answer 21

UE
LFT
Ca and bone profile
total protein and albumin - determine whether protein losing state
urine protein/creatine ratio - make sure not nephrotic syndrome
serum protein electrophoresis
serum free light chains
faecal calprotectin - make sure not IBD

Question 22

serum immunoglublin test for immune deficiency

Answer 22

immunoglobulin profile may be helpful in dx:
Isolated reduction in IgG -> Protein loosing enteropathy or cumulative Prednisolone >10mg/day

Reduction in IgG and IgM -> Monitor for B cell neoplasm or History of exposure to rituximab

Reduction in IgG and IgA -> ? Primary antibody deficiency

Question 23

serum protein electrophoresis for immune deficiency

Answer 23

separation of serum proteins by charge
Detection of discrete bands: monoclonal identified by immunofixation with labelled IgG, IgA, IgM anti-sera.

Monoclonal protein associated with multiple myeloma (IgG and IgA), WMG (IgM), NHL (IgM) and MGUS (IgM)

can miss free light chain disease - so need to measure them in B cell cancer work up

Question 24

second line test to ix immune deficiency

Answer 24

1. measure conc of vaccine ab - if Ig are low then want to know what the functional sig is

Tetanus vaccine – marker for protein Ag – how well T cell talk to B cell

Pneumovax – carb ag - T cell independent analysis of Ab production

if ab levels low - offer test immunisation with Pneumovax II and tetanus - ix immune function

failure to respond is part of diagnostic criteria for many primary immune deficiencies, and for IgG replacement for secondary ab def syndromes

2. analysis of lymphocyte subset using flow cytometry - quantify lymphocyte subsets

Question 25

third line investigation for immune deficiencies

Answer 25

Analysis of naïve and memory T and B cell subsets

Assessment of IgG subclasses

Determination of anti-cytokine and complement antibodies

Anti-Type 1 interferon antibodies (IFN-α and IFN-ω) in SARS-CoV-2 infection - Male predominance as opposed to female – more in elderly male

Anti Type 2 interferon antibodies (IFN-γ) in disseminated NTM infection

Anti-GM-CSF antibodies disseminated in cryptococcal infection

Anti-C1 inhibitor antibodies and acquired late onset angioedema ( B cell LPD and SLE)

Genetics (whole exome or whole genome sequencing in cases where it is difficult to work if you are dealing with primary or secondary immune defect

Question 26

mx of secondary immune deficiency

Answer 26

treat cause
advise measures to reduce infection
immunisation against virus and bacteria - and for househiold contacts
education to treat bacterial infections promptly - may need higher and longer therapies
prophylactic abx for recurrent bacterial infection (>2/yr)

Question 27

IgG replacement for secindary ab deficiency syndrome

Answer 27

when underlying cause of hypogammaglobinaemia cannot be reversed, or is CI
OR - Hypogammaglobinaemia associated with drugs, therapeutic monoclonal antibodies targeted at B cells and plasma cells, post-HSCT, NHL, CLL, MM or other relevant B-cell malignancy
AND
recurrent/severe bacterial infection despite prophylaxis
IgG <4 - excluding paraprotein/monoclonal protein
failure response to unconjugated pneumococcal/other polysaccharide vaccine challenge