IMMUNO: Secondary immune deficiencies and HIV infection 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
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
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
Describe the changes in these immune factors in the three phases of HIV infection:
- CD4+ T cells in blood
- Mucosal CD4+ T cells (including GIT)
- Viraemia
- Immune activation
What are the effects of HIV on the immune system?
- CD4 T cell depletion
- Impaired CD4 and CD8 T cell function
- Loss of antigen-specific humoral response
- Chronic immune activation
- Disruption of lymph nodes and impaired ability to generate protective T/B cell immune responses
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
Which proteins are used in diagnostic assays for HIV-1 and HIV-2?
- HIV-1 O group = gp41
- HIV-1 M group = gp160
- HIV-2 = gp36
What are some HIV-1 specific-tests used after diagnosis ?
- Viral load - PCR used to detect viral RNA (very sensitive)
- Genotyping for drug resistance
- Tropism to confirm co-receptor (whether CCR5 positive - can use CCR5 antagonist)
- HLA-B*5701 blood test - abacavir
- 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
Deficiency of which cell receptor renders a person resistant to HIV?
CCR5
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.
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:
- Viral genotype
- CD8 T cell immunity
- Host genetics (HLA/CCR5)
- Immune activation
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)
What are the 5 classes of ART available in the UK? Give an example of each.
- Reverse transcriptase inhibitors - NRTI, NNRTI
- Boosted protease inhibitors - ritonavir + lopinavir
- Integrase inhibitors - dolutegravir, raltegravir
- CCR5 antagonists - maraviroc (rarely) used
- Fusion inhibitors - T20 (not used)
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
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)
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%)
What is the main reason for changes to HIV-1 therapy?
Drug toxicity rather than virological failure
BUT it is safer to continue ART than to interrupt the anti-HIV treatment in almost all cases (SMART study)
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
How soon after stopping ART does HIV-1 become detectable in blood?
2-3 weeks later
What should be monitored on ART for HIV-1?
- Compliance and side-effects
- Regular viral load
- Liver, renal, bone and lipid toxicity
- CD4 T cells (only if <350 cells/ul)
- CVD and osteoporosis risk
- Monitor sexual health and vaccine uptake
Should be undetectable within 3 months of starting ART
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
What are the main strategies proposed/used for HIV-1 cure?
- Allogeneic stem cell transpants from CCR-delta32 HLA matched donors (used in Berlin and London patients)
- Shock and Kill strategy
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
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
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
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
