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IMMUNO: Secondary immune deficiencies and HIV infection Flashcards

1
Q

What are some manifestations of immune deficiencies?

A
  1. Infections
  2. Autoimmune 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 - most common worldwide
  2. Measles
  3. TB
  4. HIV
  5. SARS-CoV-2
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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
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5
Q

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

A
  • Multiple myeloma
  • CLL
  • NHL
  • MGUS
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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
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7
Q

Which haematological cancers cause immunodeficiency and how?

A

B and plasma cell cancers

  • Antibody deficiency
  • Leukopenia
  • Treatment (cytotoxic chemotherapy)
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8
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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9
Q

How do you ‘FISH’ for immunodeficiency?
What % of immunodeficiencies 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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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
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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

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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 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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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
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14
Q

What are monoclonal protein bands associated with on SPE (electrophoresis)?

A

If monoclonal proteins are found this can be associated with:

  1. MM
  2. WMG (Waldenström Macroglobulinemia - IgM)
  3. NHL
  4. MGUS
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15
Q

How can lymphocyte subsets be investigated in suspected immunodeficiency?

A

Flow cytometry - quantifies subsets based on surface antigens

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16
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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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

  1. Recurrent infections despite continuous ABx for 6 months
  2. IgG <4g/L
  3. Failure of vaccine response to pneumococcal/other polysaccharide vaccine
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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)

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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
  • 78% virally suppressed in the UK
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20
Q

What kind of virus is HIV?

A
  • Lentivirus - slow evolution of disease
  • Double-stranded RNA virus
  • Retrovirus
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
  1. Acute
  2. Latent stage (asymptomatic but progessive)
  3. 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
Q

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

A

80yrs = male

81yrs = female

26
Q

How long does it take for HIV to infect cells?

A

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
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
28
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
29
Q

What are the effects of HIV on the immune system?

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
30
Q

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

A
  • 4th generation HIV-1 antigen/antibody tests
  • Assays to detect p24 antigen, gp41 from HIV-1 group O, gp160 envelope protein in HIV-1 and gp36 HIV-2
  • Rapid point of care tests - finger prick, 20 minutes but not sensitive
  • RNA PCR - used when serology negative or in children <18 months
31
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
32
Q

What some HIV-1 specific-tests ?

A
  1. Viral load
  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 and CD4:CD8 T cell ratio
33
Q

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

A

CCR5

34
Q

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

A

Risk of severe hypersensitivity to abacavir with this allele. Present in 8% of population in NW London.

35
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
36
Q

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

A
  • <800 - lymphadenopathy, thrombocytopenia
  • <500 - bacterial skin, herpes simplex/zoster, oral, fungal skin
  • <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
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 + lopinavir
  3. Integrase inhibitors - dolutegravir, raltegravir
  4. CCR5 antagonists - maraviroc (rarely) used
  5. Fusion inhibitors - T20 (not used)
38
Q

What are the 3 main uses 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 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
Q

What is the first line HIV therapy regimen?

A

2 NRTI and 1 NNRTI

OR

2 NRTI and 1 integrase inhibitor

40
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)

41
Q

Does ART reverse chronic inflammation?

A

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

42
Q

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

A

2-3 weeks later

43
Q

What should be monitored on ART for HIV-1?

A
  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

44
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

45
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
46
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

47
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

48
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

49
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

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