IMMUNO: Secondary immune deficiencies and HIV infection Flashcards
1
Q
What are some manifestations of immune deficiencies?
A
- Infections
- Autoimmune and allergic disease
- Persistent inflammation
- Cancer
2
Q
Which childhood infection can cause secondary immune deficiency?
A
Measles - immune defect lasts from months to years
3
Q
What are the common causes of secondary immune deficiencies?
A
- Malnutrition - most common worldwide
- Measles
- TB
- HIV
- SARS-CoV-2
4
Q
What are some drugs/therapies that can cause immunodeficiency?
A
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
5
Q
Which B cell lymphoproliferative disorders are most associated with immune deficiency?
A
- Multiple myeloma
- CLL
- NHL
- MGUS
6
Q
What is the 2 characteristics of Goods’ syndrome?
What are the consequences of its immunodeficiency disorder?
A
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
7
Q
Which haematological cancers cause immunodeficiency and how?
A
B and plasma cell cancers
- Antibody deficiency
- Leukopenia
- Treatment (cytotoxic chemotherapy)
8
Q
How do you evaluate secondary immune deficiency?
A
- 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
9
Q
How do you ‘FISH’ for immunodeficiency?
What % of immunodeficiencies will be picked up this way?
A
- 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
10
Q
What are the other first line investigations for immunodeficiency after FISH?
A
- Renal and liver profile
- Calcium and bone profile
- Total protein and albumin
- Urine protein/creatinine ratio
- Serum protein electrophoresis
- Serum free light chains
11
Q
What clinical situations can cause reduction in
- IgG only
- IgG and IgM
- IgG and IgA
A
IgG - Protein-losing enteropathy, prednisolone >10mg/day
IgG and IgM - B cell neoplasm, rituximab
IgG and IgA - Primary antibody deficiency
12
Q
Which vaccine-related tests can be used as a second line test for immune deficiencies?
What is the management if these are deranged?
A
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.
13
Q
How is serum protein electrophoresis useful in immunodeficiency diagnosis? What can be missed on SPE (electrophoresis)?
A
- 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
14
Q
What are monoclonal protein bands associated with on SPE (electrophoresis)?
A
If monoclonal proteins are found this can be associated with:
- MM
- WMG (Waldenström Macroglobulinemia - IgM)
- NHL
- MGUS
15
Q
How can lymphocyte subsets be investigated in suspected immunodeficiency?
A
Flow cytometry - quantifies subsets based on surface antigens
16
Q
What is the management of secondary immune deficiency?
A
- 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
17
Q
What are the indications for secondary antibody deficiency syndrome IgG replacement?
A
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
18
Q
Man with reduced IgG and IgM on predisolone 5mg and rituximab what is the cause of the deficiency
A
Rituximab
(predisolone <10mg should not have such an impact)
19
Q
How many people live with HIV in UK?
What % are virally suppressed in the UK?
A
- >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
20
Q
What kind of virus is HIV?
A
- Double-stranded RNA retrovirus
- Lentivirus (genus of retrovirus) - slow evolution of disease
21
Q
Describe the lifecycle of HIV-1.
A
- 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
22
Q
Where did HIV-1 originate?
A
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
23
Q
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?
A
- 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
24
Q
What drives viral diversity in HIV? What are the implications of this?
A
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
25
What is the life expectancy of those living with HIV and taking HAART?
80yrs = male
81yrs = female
26
How long does it take for HIV to infect cells?
HIV provirus integrates into memory CD4 T cells within **72 hours** of infection producing a long-lived reservoid of latent infection which is not responsive to ART
27
Does ART affect the latent HIV infection present in memory CD4 T cells?
No
- Latent cells infected with HIV do not respond to ART
- ART can prevent new cell from becoming infected but cannot eliminate infection once HIV-1 has integrated into host DNA
28
Describe the changes in these immune factors in the three phases of HIV infection:
1. CD4+ T cells in blood
2. Mucosal CD4+ T cells (including GIT)
3. Viraemia
4. Immune activation
29
What are the effects of HIV on the immune system?
1. CD4 T cell depletion
2. Impaired CD4 and CD8 T cell function
3. Loss of antigen-specific humoral response
4. Chronic immune activation
5. Disruption of lymph nodes and impaired ability to generate protective T/B cell immune responses
30
What types of test are used in the diagnosis of HIV infection? Compare their uses.
**Screening Test:** Detects anti-HIV Ab via ELISA
**Confirmation Test:** Detects Ab via Western Blot
- A positive test requires patient to have SEROCONVERTED (i.e. started to produce Ab)
- This happens after ~10 weeks incubation period
**HIV-1 RNA tests:**
- When negative serology + high clinical suspicion
- In children <18m (serology not useful bc. passive transfer Abs from Mum)
**Rapid point of care tests:** Finger prick, 20 minutes but not sensitive
Assays to detect p24 antigen, gp41 from HIV-1 group O, gp160 envelope protein in HIV-1 and gp36 HIV-2
31
Which proteins are used in diagnostic assays for HIV-1 and HIV-2?
1. HIV-1 O group = gp41
2. HIV-1 M group = gp160
3. HIV-2 = gp36
32
What are some HIV-1 specific-tests used after diagnosis ?
1. **Viral load** - PCR used to detect viral RNA (very sensitive)
2. **Genotyping** for drug resistance
3. **Tropism** to confirm co-receptor (whether CCR5 positive - can use CCR5 antagonist)
4. **HLA-B*5701** blood test - abacavir
5. **T cell counts** - CD4 T cell count via FACS (flow cytometry), used to assess course of disease, onset of AIDS, and CD4:CD8 T cell ratio
33
Deficiency of which cell receptor renders a person resistant to HIV?
CCR5
34
Why do HIV patients need to be tested for HLA-B\*5701?
Risk of severe **hypersensitivity to abacavir** with this allele. Present in 8% of population in NW London.
35
What is the viral load set point significance? What factors affect the VL set point?
VL set point = the point to which, after 3-6 months of infection, the viral concentration plateaus
VL set point significance:
* Correlates with long term outcome
* Stratifies progression to symptomatic HIV-1 infection
VL set point is affected by:
1. Viral genotype
2. CD8 T cell immunity
3. Host genetics (HLA/CCR5)
4. Immune activation
36
As CD4 T cell count drops below 800 cells/mm^2, what infections are patients at risk of?
- <800 - lymphadenopathy, thrombocytopenia
- <500 - bacterial or fungal skin, oral, herpes simplex/zoster
- <400 - Kaposi's sarcoma
- <300 - hairy leukoplakia, tuberculosis
- <200 - PCP, cryptococcosis, toxoplasmosis
- <100 - CMV, lymphoma
MAC (*myobacterium avium complex)*
*(Other slide says CD4 thresholds for PCP, toxoplasma gondii and MAC are 200, 100 and 75 x10^9 cells/L respectively)*
37
What are the 5 classes of ART available in the UK? Give an example of each.
1. Reverse transcriptase inhibitors - NRTI, NNRTI
2. Boosted protease inhibitors - ritonavir + lopinavir
3. Integrase inhibitors - dolutegravir, raltegravir
4. CCR5 antagonists - maraviroc (rarely) used
5. Fusion inhibitors - T20 (not used)
38
What are the 3 main uses of ART?
**TEST AND TREAT**
- Those with active HIV-1, irrespective of CD4 T cell count
**TREAT TO PREVENT INFECTION**
- Prevent transmission to seronegative partner
- In pregnancy to prevent fetus infection
**PROPHYLAXIS**
- PReP to reduce risk of acquisition
- PEP after inadvertent exposure to HIV-1 infection following occupational exposure or after high risk sex
39
What is the first line HIV therapy regimen?
2 NRTI and 1 NNRTI
_OR_
2 NRTI and 1 integrase inhibitor
*Example regimen: Emtricitabine + Tenofovir + Efavirenz (Available as 1 pill: Atripla)*
40
What is the management of HIV in pregnany?
Zidovudine: Antepartum PO; For delivery IV
PO to newborn for 6/52 (reduces transmission from 26% to 8%)
41
What is the main reason for changes to HIV-1 therapy?
Drug toxicity rather than virological failure
## Footnote
*BUT it is safer to continue ART than to interrupt the anti-HIV treatment in almost all cases (SMART study)*
42
Does ART reverse chronic inflammation?
ART does not usually reverse chronic immune inflammation which is still a risk factor for **cardiovascular, liver and bone and CNS disease**
BUT if they start ART before significant immune damage, they will have a similar life expectancy to seronegative controls
43
How soon after stopping ART does HIV-1 become detectable in blood?
2-3 weeks later
44
What should be monitored on ART for HIV-1?
1. Compliance and side-effects
2. Regular viral load
3. Liver, renal, bone and lipid toxicity
4. CD4 T cells (only if \<350 cells/ul)
5. CVD and osteoporosis risk
6. Monitor sexual health and vaccine uptake
Should be undetectable within 3 months of starting ART
45
What are vaccine trials for HIV-1 focusing on?
Development of neutralising and non-neutralising antibodies
Use of CMV vectors, TLR adjuvants, checkpoint inhibitors to stimulate CD8 T cell immune responses
46
What are the main strategies proposed/used for HIV-1 cure?
1. Allogeneic stem cell transpants from CCR-delta32 HLA matched donors (used in Berlin and London patients)
2. Shock and Kill strategy
47
A 65 year-old male with a history of steroid dependent asthma, hypertension, Type 2 Diabetes Mellitus and osteoporosis presents with recurrent chest, sinus, and skin infections. Past medical history of chemotherapy for follicular lymphoma and he has recently completed a 2 year maintenance therapy of 3 monthly rituximab. Current oral medication includes Prednisolone 5mg OD, Losartan 50mg OD, metformin500mg BD, alendronic acid 70mg weekly.
Serum immunoglobulins are as follows
* IgG – 3.9g/L (ref interval 6.4-16.0g/L)
* IgA – 0.9g/L (ref interval 0.8-3.4g/L)
* IgM – 0.1g/L (ref interval 0.5-2.0g/L)
* IgE 200IU/ml (reference interval 3-120IU/ml)
Which of the following medication are most likely to have cause antibody deficiency
* A) Metformin
* B) Losartan
* C) Prednisolone
* D) Alendronic Acid
* E) Rituximab
Rituximab
48
A 57-year-old male is referred to the Chest clinic with recurrent chest infections, requiring antibiotic therapy. Past medical history reveal lichen planus and a history of surgery for an anterior mediastinal mass 4 year previously. Physical examination show nail candidiasis, sternotomy scar and bi-basal crepitations. A HRCT chest scan shows extensive bronchiectasis.
Immune investigation are as follows
* IgG – 3.1g/L (ref interval 6.4-16.0g/L)
* IgA – 0.4g/L (ref interval 0.8-3.4g/L)
* IgM – 0.2g/L (ref interval 0.5-2.0g/L)
* IgE 500IU/ml (reference interval 3-120IU/ml)
* B cell count 10cell/ul ( ref interval 100-500)
What is the most likely diagnosis?
* A) Partial antibody deficiency syndrome
* B) Common variable immune deficiency
* C) High grade B cell Mediastinal Lymphoma
* D) Thymoma with antibody deficiency/Good’s syndrome
* E) Hyper IgE syndrome
Thymoma with antibody deficiency/Goods' syndrome
49
Which of the following condition are more likely to present in patients with a CD4 T cell counts of more than 350cells/ul
* A) CMV retinitis, Toxoplasma encephalitis, visceral Kaposi sarcoma
* B) Herpes zoster, Pulmonary Tuberculosis, Pneumococcal pneumonia
* C) Pneumocystis jirovecci pneumonia, disseminated MAC, ITP
* D) EBV CNS lymphoma, oral candida, cryptococcal meningitis
* E) Cutaneous Kaposi sarcoma, disseminated MAC, HSV infection
Herpes zoster, Pulmonary Tuberculosis, Pneumococcal pneumonia
50
Which of the following statements are true about HIV-1 infection
* A) Reverse transcription is associated with few errors in copying HIV-1 RNA template
* B) Preferred option to commence ART in the UK is dual combination therapy containing an integrase inhibitor and NRTI
* C) HLA-B\*5701 blood test is used to prevent hypersensitivity reaction with protease inhibitors
* D) Residual immune activation is commonly seen in patients on suppressive ART regimens
* E) HIV-1 serology point care tests have similar diagnostic performance to 4th generation combined p24antigen/antibody tests
Residual immune activation is commonly seen in patients on suppressive ART regimens
