IMMUNO: Secondary immune deficiencies and HIV infection Flashcards
What are the causes of immune deficiencies?
- Infections
- AI 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
- Measles
- TB
- HIV
- SARS-CoV-2
What are the drug causes of immune deficiencies?
- Small molecules e.g. steroids, methotrexate/azathioprine, phenytoin, tacrolimus, DMARD
- JAK inhibitors e.g. -tinibs
- Biologic and cellular therapies e.g. anti-CD20, CAR-T cell therapies
Give two examples of biologic agents/cellular therapies. When is risk of immunodeficiency from these greatest? What are anti-TNF agents linkes to in terms of infection?
- Biologics agents: anti-CD20/CD38/BCMA monoclonals, anti-TNF-α protein and receptor antagonists
- Cellular therapy: anti-CD19/BCMA CAR-T cell therapy
Risk: increases with repeated courses AND in patients with B cell malignancy and vasculitis
Anti-TNF: liked to TB reactivation
Which B cell lymphoproliferative disorders are most associated with immune deficiency? (4)
- MM
- CLL
- NHL
- MGUS
What is the triad of Goods’ syndrome and what are the consequences of its immunodeficiency disorder?
TRIAD
- thymoma
- immunodeficiency
- hypogammaglobulinemia
- B and T cells absent
- CMV/ PJP / muco-cutaneous candida infections
- AI disease e.g. pure red cell aplasia, MG, lichen planus
Which haematological cancers cause immunideficiency and how?
B and plasma cell cancers as well as their associated treatments.
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 IDs 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
calcium and bone
total protein and albumin
urine protein/Cr 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 later in the testing process for immune deficiencies? What is the management if these are deranged?
Tetanus toxoid- protein antigen detection
Pneumovax vaccine - carbohydrate antigen detection (for all 23 serotypes of 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?
- 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?
If monoclonal proteins are found this can be associated with:
- MM,
- WMG (Waldenström Macroglobulinemia),
- NHL,
- MGUS
What is the virology of HIV?
- Binds to CD4 and then cheomokine co-receptor CCR5 or CXCR4
- Replicates via DNA intermediate
- Integrates into host genome
- HIV DN Atranscribed to viral mRNA
- Viral RNA translates to viral proteins
- Packaging and release of mature virus
How can lymphocyte subsets be investigated in suspected immunodeficiency?
Flow cytometry
Gate for specific surface antigens e.g. CD3+CD4+ T cells, CD3+CD8+ T cells, CD3-CD56+CD16+ NK cells, CD19+ B cells.
Which complex tests can be used for diagnosis of immune deficiencies (third line)?
NTM = non-tuberculous myobaceria
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-treatmnet/cancer
AND
- Recurrent infections despite continuous abx for 6 months
- IgG <4g/L
- Failure of vaccine response to pneumococcal/other polysaccharice vaccine
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
- 78% virally suppressed in the UK
What kind of virus is HIV?
- Lentivirus - slow evolution of disease
- Double stranded RNA virus
- Retrovirus
Describe infection of cells by HIV-1.
- Binds to CD4 and then to chemokine co-receptor CCR5 or CXCR4
- Replicates via a DNA intermediate
- Integrates into host genome
- HIV DNA transcribed to viral mRNA
- Viral RNA 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
- Asymptomatic but progressive
- 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?
- Error prone nature of HIV reverse transcriptase
- Short generation time of viral cycle
- Length of infection
Viral diversity –> evasion of cytotoxic T lymphocytes and emergence of drug resistant virus when drug therapy is inadequate
What is the life expectancy of those living with HIV and taking HAART?
80yrs = male
81yrs = female
How many virions are produced each day in HIV? What is their source? How long does it take for HIV to infect cells?
10^10 virions produce each day from recently infected CD4 T 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
Acute:
- steep decline then slow increase
- steep decline
- peaks then drops
- peaks then plateaus
Chronic
- slow increase then slow decline
- slow increase then slow decline
- slow increase
- slow increase
AIDS
- steep decline
- decline
- peaks then drops
- steady
How does regenerative capacity and target cell selectivity change in HIV-1 natural course of infection?
Regenerative capacity - decreases in acute, chronic and AIDS phases
Target cell selectivity - peaks in the initial stages of chronic infection then decreases
Name 5 distinctive features of immunology of HIV-1 infection.
- 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.
- 4th generation combined HIV-1 antigen/antibody tests
- Assays to detect p2 antigen, gp41 from HIV-1 group O, gp160 envelope protein in HIV-1 M and gp36 HIV-2
- Rapid point of care tests
- RNA and DNA HIV-1 tests
Pros/cons:
- Antigen/antibody tests will detect infection 1 month post acquisition
- Rapid point of care test results available within 20min but less sensitive
- RNA/DNA tests only used where serological tests are negative but HIV-1 suspectedm or in children <18months to diagnose infecion
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 HIV-1 specific-tests are used to monitor HIV-1 infection?
- Viral load
- Genotyping for ART drug resistance
- Tropism to confirm co-receptor (whether CCR5 positive)
- HLA-B*5701 blood test
- T cell counts including CD4 T cell count 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 sensitivity 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 skin, herpes simplex/zoster, oral, fungal skin
- <400 - Kaposi’s sarcoma
- <300 - hairy leukoplakia, tuberculosis
- <200 - PCP, cryptococcis, 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 + PI
- Integrase inhibitors - DTG, RTG EVG
- CCR5 antagonists - Maraviroc
- Fusion inhibitors - T20 (rarely used)
What are the 3 patient groups who benefit from use of ART?
TEST AND TREAT - those with active HIV-1, irrespective of CD4 T cell count
TREAT TO PREVENT INFECTION - prevent transmission to seronegative partners, in pregnancy to prevent fetus infection
PROPHYLAXIS - PreP to reduce risk of acquisition, post-exposure prophylaxis 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 NRTI
OR
2 NRTI and 1 integrase inhibitor
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 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 SE
- Viral load
- Liver, renal, bone and lipid toxicity
- CD4 T cells (only if <350 cells/ul)
- CVD and osteoporosis risk
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
