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Year 5 -krish finess > IMMUNO: Secondary immune deficiencies and HIV infection > Flashcards

IMMUNO: Secondary immune deficiencies and HIV infection Flashcards

1
Q

What are the causes of immune deficiencies?

A
  1. Infections
  2. AI and allergic disease
  3. Persistent inflammation
  4. Cancer
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2
Q

Which childhood infection can cause secondary immune deficiency?

A

Measles - immune defect lasts from months to years

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3
Q

What are the common causes of secondary immune deficiencies?

A
  1. Malnutrition
  2. Measles
  3. TB
  4. HIV
  5. SARS-CoV-2
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4
Q

What are the drug causes of immune deficiencies?

A
  1. Small molecules e.g. steroids, methotrexate/azathioprine, phenytoin, tacrolimus, DMARD
  2. JAK inhibitors e.g. -tinibs
  3. Biologic and cellular therapies e.g. anti-CD20, CAR-T cell therapies
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5
Q

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?

A
  1. Biologics agents: anti-CD20/CD38/BCMA monoclonals, anti-TNF-α protein and receptor antagonists
  2. 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

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6
Q

Which B cell lymphoproliferative disorders are most associated with immune deficiency? (4)

A
  • MM
  • CLL
  • NHL
  • MGUS
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7
Q

What is the triad of Goods’ syndrome and what are the consequences of its immunodeficiency disorder?

A

TRIAD

  1. thymoma
  2. immunodeficiency
  3. hypogammaglobulinemia
  • B and T cells absent
  • CMV/ PJP / muco-cutaneous candida infections
  • AI disease e.g. pure red cell aplasia, MG, lichen planus
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8
Q

Which haematological cancers cause immunideficiency and how?

A

B and plasma cell cancers as well as their associated treatments.

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9
Q

How do you evaluate secondary immune deficiency?

A
  1. Infection history, unusual childhood complications of illness, reaction to vaccines, loss of schooling
  2. PMH of other illness e.g. lymphoma, bronchiectasis, lymphoma/cancers, TB, hep B/C.
  3. FH of infection/AI/cancer
  4. Medication history
  5. Vaccine history e.g childhood, pneumococcal, flu vaccines
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10
Q

How do you ‘FISH’ for immunodeficiency? What % of IDs will be picked up this way?

A
  1. FBC - Hb <10g/L, neutrophil, lymphocyte, platelet counts
  2. Immunoglobulins (IgG, IgA, IgM, IgE)
  3. Serum complement (C3, C4) - immune complex disease or lupus
  4. HIV test (18-80years)

This will pick up 85% of immune defects

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11
Q

What are the other first line investigations for immunodeficiency after FISH?

A

renal and liver

calcium and bone

total protein and albumin

urine protein/Cr ratio

serum protein electrophoresis

serum free light chains

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12
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

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13
Q

Which vaccine related tests can be used later in the testing process for immune deficiencies? What is the management if these are deranged?

A

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.

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14
Q

How is serum protein electrophoresis useful in immunodeficiency diagnosis? What can be missed on SPE?

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
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15
Q

What are monoclonal protein bands associated with on SPE?

A

If monoclonal proteins are found this can be associated with:

  1. MM,
  2. WMG (Waldenström Macroglobulinemia),
  3. NHL,
  4. MGUS
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16
Q

What is the virology of HIV?

A
  • 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
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17
Q

How can lymphocyte subsets be investigated in suspected immunodeficiency?

A

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.

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18
Q

Which complex tests can be used for diagnosis of immune deficiencies (third line)?

A

NTM = non-tuberculous myobaceria

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19
Q

What is the management of secondary immune deficiency?

A
  1. treat cause
  2. advise exposure reduction
  3. immunisation of patient and household contacts
  4. 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
  5. prophylactc antibiotics for confirmed recurrent bacterial infection
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20
Q

What are the indications for secondary antibody deficiency syndrome IgG replacement?

A

Unreversable hypogammaglobinaemia

OR

Hypogammaglobinaemia associated with treatment/post-treatmnet/cancer

AND

  1. Recurrent infections despite continuous abx for 6 months
  2. IgG <4g/L
  3. Failure of vaccine response to pneumococcal/other polysaccharice vaccine
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21
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
  • 78% virally suppressed in the UK
22
Q

What kind of virus is HIV?

A
  • Lentivirus - slow evolution of disease
  • Double stranded RNA virus
  • Retrovirus
23
Q

Describe infection of cells by HIV-1.

A
  • 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
24
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
25
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
  1. Acute
  2. Asymptomatic but progressive
  3. AIDS

Risk of transmission - greatest in acute phase, then in the AIDS phase

Viral diversity- greatest in the AIDS phase

26
Q

What drives viral diversity in HIV? What are the implications of this?

A
  1. Error prone nature of HIV reverse transcriptase
  2. Short generation time of viral cycle
  3. Length of infection

Viral diversity –> evasion of cytotoxic T lymphocytes and emergence of drug resistant virus when drug therapy is inadequate

27
Q

What is the life expectancy of those living with HIV and taking HAART?

A

80yrs = male

81yrs = female

28
Q

How many virions are produced each day in HIV? What is their source? How long does it take for HIV to infect cells?

A

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

29
Q

Does ART affect the latent HIV infection present in memory CD4 T cells?

A

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

30
Q

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
A

Acute:

  1. steep decline then slow increase
  2. steep decline
  3. peaks then drops
  4. peaks then plateaus

Chronic

  1. slow increase then slow decline
  2. slow increase then slow decline
  3. slow increase
  4. slow increase

AIDS

  1. steep decline
  2. decline
  3. peaks then drops
  4. steady
31
Q

How does regenerative capacity and target cell selectivity change in HIV-1 natural course of infection?

A

Regenerative capacity - decreases in acute, chronic and AIDS phases

Target cell selectivity - peaks in the initial stages of chronic infection then decreases

32
Q

Name 5 distinctive features of immunology of HIV-1 infection.

A
  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
33
Q

What types of test are used in the diagnosis of HIV infection? Compare their uses.

A
  1. 4th generation combined HIV-1 antigen/antibody tests
  2. Assays to detect p2 antigen, gp41 from HIV-1 group O, gp160 envelope protein in HIV-1 M and gp36 HIV-2
  3. Rapid point of care tests
  4. 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
34
Q

Which proteins are used in diagnostic assays for HIV-1 and HIV-2?

A
  1. HIV-1 O group = gp41
  2. HIV-1 M group = gp160
  3. HIV-2 = gp36
35
Q

What HIV-1 specific-tests are used to monitor HIV-1 infection?

A
  1. Viral load
  2. Genotyping for ART drug resistance
  3. Tropism to confirm co-receptor (whether CCR5 positive)
  4. HLA-B*5701 blood test
  5. T cell counts including CD4 T cell count and %, CD4:CD8 T cell ratio
36
Q

Deficiency of which cell receptor renders a person resistant to HIV?

A

CCR5

37
Q

Why do HIV patients need to be tested for HLA-B*5701?

A

Risk of severe sensitivity to Abacavir with this allele. Present in 8% of population in NW London.

38
Q

What is the viral load set point significance? What factors affect the VL set point?

A
  • 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
39
Q

As CD4 T cell count drops below 800 cells/mm^2, what infections are patients at risk of?

A
  1. <800 - lymphadenopathy, thrombocytopenia
  2. <500 - bacterial skin, herpes simplex/zoster, oral, fungal skin
  3. <400 - Kaposi’s sarcoma
  4. <300 - hairy leukoplakia, tuberculosis
  5. <200 - PCP, cryptococcis, toxoplasmosis
  6. <100 - CMV, lymphoma
  7. 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)

40
Q

What are the 5 classes of ART available in the UK? Give an example of each.

A
  1. Reverse transcriptase inhibitors - NRTI, NNRTI
  2. Boosted protease inhibitors - ritonavir + PI
  3. Integrase inhibitors - DTG, RTG EVG
  4. CCR5 antagonists - Maraviroc
  5. Fusion inhibitors - T20 (rarely used)
41
Q

What are the 3 patient groups who benefit from use of ART?

A

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

42
Q

What is the first line HIV therapy regimen?

A

2 NRTI and 1 NRTI

OR

2 NRTI and 1 integrase inhibitor

43
Q

What is the main reason for changes to HIV-1 therapy?

A

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)

44
Q

Does ART reverse chronic inflammation?

A

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

45
Q

How soon after stopping ART does HIV-1 become detectable in blood?

A

2-3 weeks later

46
Q

What should be monitored on ART for HIV-1?

A
  1. Compliance and SE
  2. Viral load
  3. Liver, renal, bone and lipid toxicity
  4. CD4 T cells (only if <350 cells/ul)
  5. CVD and osteoporosis risk
47
Q

What are vaccine trials for HIV-1 focusing on?

A

Development of neutralising and non-neutralising antibodies

Use of CMV vectors, TLR adjuvants, checkpoint inhibitors to stimulate CD8 T cell immune responses

48
Q

What are the main strategies proposed/used for HIV-1 cure?

A
  1. Allogeneic stem cell transpants from CCR-delta32 HLA matched donors (used in Berlin and London patients)
  2. Shock and Kill strategy
49
Q

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
A

Rituximab

50
Q

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
A

Thymoma with antibody deficiency/Goods’ syndrome

51
Q

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
A

Herpes zoster, Pulmonary Tuberculosis, Pneumococcal pneumonia

52
Q

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
A

Residual immune activation is commonly seen in patients on suppressive ART regimens

Year 5 -krish finess (55 decks)

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