IMMUNO: Secondary immune deficiencies and HIV infection Pt.1 Flashcards
What are some manifestations of immune deficiencies?
- Infections
- Autoimmune and allergic disease
- Persistent inflammation
- Cancer
Which childhood infection can cause secondary immune deficiency?
Measles - immune defect lasts from months to years
What are the common causes of secondary immune deficiencies?
- Malnutrition - most common worldwide
- Measles
- TB
- HIV
- SARS-CoV-2
What are some drugs/therapies that can cause immunodeficiency?
Small molecules
- Steroids
- Cytoxic drugs - methotrexate/azathioprine,
- Antiepileptics - phenytoin/ carbamazepine/ levetiracetam
- Calcineurin inhibiors - tacrolimus,
- DMARD (sulphasalazine)
JAK inhibitors - ruxolitinib, tofacitinib
Biologic and cellular therapies
- Anti-CD20
- Anti-TNF (TB)
- CAR-T cell therapies
Which B cell lymphoproliferative disorders are most associated with immune deficiency?
- Multiple myeloma
- CLL
- NHL
- MGUS
What is the 2 characteristics of Goods’ syndrome?
What are the consequences of its immunodeficiency disorder?
Characteristics
- Thymoma
- Immunodeficiency due to hypogammaglobulinemia
Consequences
- B and T cells absent
- CMV/ PJP / muco-cutaneous candida infections
- Autoimmune disease disease e.g. pure red cell aplasia, myasthenia gravis, lichen planus
Which haematological cancers cause immunodeficiency and how?
B and plasma cell cancers
- Antibody deficiency
- Leukopenia
- Treatment (cytotoxic chemotherapy)
How do you evaluate secondary immune deficiency?
- Infection history, unusual childhood complications of illness, reaction to vaccines, loss of schooling
- PMH of other illness e.g. lymphoma, bronchiectasis, lymphoma/cancers, TB, hep B/C.
- FH of infection/AI/cancer
- Medication history
- Vaccine history e.g childhood, pneumococcal, flu vaccines
How do you ‘FISH’ for immunodeficiency?
What % of immunodeficiencies will be picked up this way?
- FBC - Hb <10g/L, neutrophil, lymphocyte, platelet counts
- Immunoglobulins (IgG, IgA, IgM, IgE)
- Serum complement (C3, C4) - immune complex disease or lupus
- HIV test (18-80years)
This will pick up 85% of immune defects
What are the other first line investigations for immunodeficiency after FISH?
- Renal and liver profile
- Calcium and bone profile
- Total protein and albumin
- Urine protein/creatinine ratio
- Serum protein electrophoresis
- Serum free light chains
What clinical situations can cause reduction in
- IgG only
- IgG and IgM
- IgG and IgA
IgG - Protein-losing enteropathy, prednisolone >10mg/day
IgG and IgM - B cell neoplasm, rituximab
IgG and IgA - Primary antibody deficiency
Which vaccine-related tests can be used as a second line test for immune deficiencies?
What is the management if these are deranged?
Measure concentration of vaccine antibodies (provided they were previously vaccinated)
- Tetanus toxoid- protein antigen detection
- Pneumovax vaccine - carbohydrate antigen detection (for all 23 serotypes or to individual pneumococcal serotypes).
If low… offer Pneumovax II and tetanus immunisation to test immune function.
Failure to respond to this is a criteria for receipt of IgG replacement therapy for secondary antibody deficiency syndromes.
How is serum protein electrophoresis useful in immunodeficiency diagnosis? What can be missed on SPE (electrophoresis)?
- Serum proteins are separated by charge. Discrete bands are formed for each immunoglobulin as they bind by immunofixation
- Monoclonal proteins can indicate MGUS, MM etc.
- SPE can miss free light chain disease (seen in 20% of MM) so must measure these separately
What are monoclonal protein bands associated with on SPE (electrophoresis)?
If monoclonal proteins are found this can be associated with:
- MM
- WMG (Waldenström Macroglobulinemia - IgM)
- NHL
- MGUS
How can lymphocyte subsets be investigated in suspected immunodeficiency?
Flow cytometry - quantifies subsets based on surface antigens
What is the management of secondary immune deficiency?
- Treat cause
- Advise exposure reduction
- Immunisation of patient and household contacts
- Education to treat bacterial infection promptly (excluded from antimicrobial stewardship rules) e.g. co-amoxiclav 625mg TDS for 10-14 days, rather than 375mg for 5-7 days
- Prophylactc antibiotics for confirmed recurrent bacterial infection
What are the indications for secondary antibody deficiency syndrome IgG replacement?
Unreversable hypogammaglobinaemia
OR
Hypogammaglobinaemia associated with treatment/post-treatment/cancer (e.g. cytoxic or biologic therapy, NHL/CLL/MM)
AND
- Recurrent infections despite continuous ABx for 6 months
- IgG <4g/L
- Failure of vaccine response to pneumococcal/other polysaccharide vaccine
Man with reduced IgG and IgM on predisolone 5mg and rituximab what is the cause of the deficiency
Rituximab
(predisolone <10mg should not have such an impact)
How many people live with HIV in UK?
What % are virally suppressed in the UK?
- >100,000 living with HIV in the UK
- Infections incidence fallen by 70% in the last 4-5 years
- ~70% those on ART have undetectable viral load
What kind of virus is HIV?
- Double-stranded RNA retrovirus
- Lentivirus (genus of retrovirus) - slow evolution of disease
Describe the lifecycle of HIV-1.
- Binds to CD4 and then to chemokine co-receptor CCR5 or CXCR4
- vRNA converting into DNA by reverse transcriptase
- vDNA integrated into host genome
- vDNA transcribed to viral mRNA
- vRNA translated to viral proteins
- Packaging and release of mature virus
Where did HIV-1 originate?
Chimpanzees
Lineages M, N, O and P present
- M lineage transmission occurred in Cameroon in 1910-1930 initially, spread along the Congo river into Kinshasa in 1960 and became pandemic
- M lineage consists of 9 subtypes and 40 recombinant forms
What is the natural history of HIV-1 infection as defined by viral replication?
What are the 3 phases?
When is risk of transmission greatest?
When is viral diversity greatest?
- Acute
- Latent stage (asymptomatic but progessive)
- AIDS
Risk of transmission - greatest in acute phase, then in the AIDS phase
Viral diversity greatest in the AIDS phase
What drives viral diversity in HIV? What are the implications of this?
Viral diversity due to
- Error-prone nature of HIV reverse transcriptase
- Short generation time of viral cycle
- Length of infection
Leads to…
- Emergence of drug resistance
- Evasion of immune system
Need to use combination therapies
What is the life expectancy of those living with HIV and taking HAART?
80yrs = male
81yrs = female
