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YR5 Immunology > Secondary immune deficiencies and HIV-1 infection > Flashcards

Secondary immune deficiencies and HIV-1 infection Flashcards

1
Q

What are 7 causes of secondary immune deficiencies?

A

Malnutrition (commonest globally)

Infectious Diseases e.g. HIV

Environmental stress

Age Extremes: Prematurity + old age

Surgery + trauma, splenectomy

Immunosuppressive drugs

Genetic + metabolic diseases

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2
Q

What are signs and symptoms of secondary immune deficiencies?

A

Infections: Severe, persistent, recurrent, unusual

Autoimmune conditions (cytopaenias) and allergic disease

Persistent inflammation

Cancer (viral associated EBV, HHV-8)

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3
Q

Which small molecules can cause immune deficiencies?

A
  • Glucocorticoids + mineralocorticoids
  • Cytotoxic agents: Methotrexate, mycophenolate, cyclophosphamide + azathioprine.
  • Calcineurin inhibitors: Cyclosporine + tacrolimus
  • Antiepileptic drugs (phenytoin, carbamazepine, levetiracetam)
  • DMARD (sulphasalazine, leflunomide)
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4
Q

Which JAK inhibitors can cause immune deficiencies?

A
  • Tofacitinib
  • Upadacitinib
  • Ruxolitinib

Being used in increasing no. diseases e.g. RA, GvHD

Can cause antibody deficiency

A/w increased risk of reactivation of herpes zoster

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5
Q

Which drug class can cause TB reoccurance?

A

Anti-TNF agents

Screen for latent TB

If detected give TB prophylaxis

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6
Q

Which cancers can present with secondary immune deficiencies?

A

B + plasma cell cancers (antibody deficiency syndromes are most common).

Chemotherapy, biological agents, + radiotherapy can leads to loss of immune cells + immune deficiency.

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7
Q

Which specific B-cell lymphoproliferative disorders are associated with secondary immune deficiency?

A

Multiple myeloma

Chronic lymphocytic leukaemia

Non Hodgkin’s lymphoma

Monoclonal gammopathy of uncertain significance

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8
Q

What is Good’s syndrome?

A

Thymoma + antibody deficiency

Combined T + B cell (absent) defect

Increased risk of CMV, PJP + muco-cutaneous candida

As thymus involved in control of central tolerance, increased risk of AI disease (Pure red cell aplasia, Myasthenia gravis, Lichen planus)

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9
Q

What are appropriate investigations for secondary immune deficiencies?

A

FISH

FBC: Hb < 10g/L, Neutrophil, Lymphocyte + Platelet count

Immunoglobulins: IgG, IgA, IgM, IgE

Serum complement: C3, C4

HIV test: 18-80y

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10
Q

What is serum protein electrophoresis?

A

Separation of serum proteins by charge

Detection of discrete bands: monoclonal identified by immunofixation with labelled IgG, IgA, IgM anti-sera

SPE can miss free light chain disease (seen in 20% multiple myeloma cases): hence measurement of free light chains is essential for work up of B cell LPD.

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11
Q

What are second line investigations for secondary immune deficiencies?

A

Measure concentration of vaccine antibodies:

  • Tetanus toxoid: Protein antigen
  • Pneumovax vaccine: Carbohydrate antigen (all 23 serotypes or to individual pneumococcal serotypes)
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12
Q

What are third line investigations for secondary immune deficiencies?

A

Analysis of naïve + memory T + B cell subsets

Assessment of IgG subclasses

Determination of anti-cytokine + complement antibodies

Genetics (whole exome or whole genome sequencing in cases where it is uncertain whether primary or secondary immune defect)

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13
Q

What is the management of secondary immune deficiencies?

A

Treat underlying cause

Advise on measures to reduce exposure to infection

Immunisation against respiratory viruses + bacteria + offer vaccines to household contacts

Education to treat bacterial infections promptly: May require higher doses + longer courses (co-amoxiclav 625mg TDS for 10-14d rather than 375mg for 5-7d)

Prophylactic abx for confirmed recurrent bacterial infection (>,2/y)

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14
Q

What type of immunodeficiency is more common?

A

Secondary immune deficiency

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15
Q

Describe the secondary immune deficiency caused by measles

A

Immune defect lasts months-years

Increases morbidity + mortality esp. due to secondary bacterial infection/ unexplained diarrhoeal illness

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16
Q

Describe the secondary immune deficiency caused by TB

A

Depresses cell mediated immune response- detected as failed Mantoux test

In tx their immune system reconstitutes, sees infections the patient has experienced + mounts an inflammatory response

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17
Q

Describe the secondary immune deficiency caused by HIV

A

Residual immune dysfunction persists despite successful ART

Increased inflammation, cellular/ soluble markers of immune activation

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18
Q

Give an example of a glucocorticoid causing immune deficiency

A

>10mg/day prednisolone linked to increased rate of antibody loss

Affects cellular + humoral immunity

Increased susceptibility to bacterial + viral infections

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19
Q

How do calcineurin inhibitors cause immune deficiency?

A

Cause cellular immune deficiency

Target dendritic cells + CD4 follicular function

Impact on peoples ability to respond to vaccines

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20
Q

Name a biologic/ cellular therapy that can cause immune deficiency

A

Rituximab (anti-CD20 antibodies)

Increases risk of antibody deficiency

Increased risk of secondary infection

Increased risk of fungal infection e.g. PCP, so give PCP prophylaxis

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21
Q

What must be evaluated in history taking in a patient with suspected immune deficiency?

A

Clinical hx of infection + evidence: sputum cultures, response to abx

Alarm Sx for B cell malignancy

Hx for other illnesses: haematological malignancies, Hep B/C, TB

FH infection, AI, cancer

Medication hx

Vaccine hx

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22
Q

What are the front line chemical investigations for immune deficiency?

A

Renal + liver profile

Calcium + bone profile

Total protein + Albumin

Urine protein/ Cr ratio

Serum protein electrophoresis

Serum free light chains

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23
Q

What could cause isolated reduction in IgG?

A

Protein losing enteropathy

Prednisolone doses (cumulatively) >10mg/day

24
Q

What could cause a reduction in IgG and IgM?

A

B cell neoplasm

Hx of exposure to Rituximab

25
Q

What could cause a reduction in IgG and IgA?

A

Primary antibody deficiency

26
Q

What are monoclonal proteins associated with?

A

Multiple myeloma (IgG + IgA)

WMG (IgM)

NHL

MGUS

27
Q

How can SPE sometimes not detect multiple myeloma?

A

Some myeloma neoplasms just secrete light chains which are freely excreted into the urine so won’t be detected on SPE

SPE shows combination of heavy + light

Measurement of FLC in urine or serum essential

28
Q

If concentrations of vaccine antibodies are low, what should be done?

A

Offer test immunisation with Pneumovax II + tetanus

Failure to respond to vaccination is part of diagnostic criteria for numerous primary antibody deficiency syndromes + for receipt of IgG replacement therapy

29
Q

Why are vaccine antibody concentrations measured in the work up for immune deficiencies?

A

Tetanus: most of the UK have tetanus toxoid

Indirect marker of how well T cells speak to B cells to make antibodies

Pneumovax: T cell independent analysis of antibody production

30
Q

What is the criteria for IgG replacement therapy?

A

Underlying cause of hypogammaglobinaemia irreversible or CI

OR

Hypogammaglobinaemia a/w drugs, therapeutic monoclonal antibodies targeted at B cells + plasma cells, post-HSCT, NHL, CLL, MM

AND

Recurrent/ severe bacterial infection despite continuous oral prophylaxis for 6m

IgG <4

Failure of vaccine response to unconjugated pneumococcal vaccine challenge

31
Q

Give 4 features of HIV virology

A

4 lineages M, N, O, P (M most common)

Slow evolution

Double stranded RNA

Retrovirus

32
Q

Describe the replication of HIV virus

A

Binds to CD4 + 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 + release of mature virus

33
Q

Describe the natural history of HIV as defined by viral replication

A

Acute: Flu-like illness in 70%, viral load peaks then dips after 3-6m to a set point

Asymptomatic but progressive: Quiescent for 8-10y

AIDS: increase in viral replication as immune system collapses

34
Q

Describe the risk of transmission through the natural history of HIV

A

Directly proportional to amount of virus in blood

Lots of transmission often in acute phase

Risk of transmission declines in asymptomatic, though more people in this category

Risk increases again but when pt is v sick

35
Q

Why must combination therapy be used to treat HIV?

A

HIV not very good at replicating itself- huge no. of variants

Short generation time + long duration of infection

With progression of disease, get increased viral diversity so need to target different stages of the viral life cycle to reduce risk of drug resistance

36
Q

Why do patients with HIV need to take lifelong antivirals?

A

Integration of HIV provirus into memory CD4 T cells within 72h of infection leads to formation of long lived reservoir of latent infection which doesn’t respond to current ART

37
Q

Describe the T cell immunology in natural HIV infection

A

Dip in CD4 T cells in blood

Some partially recover

Slow decline 8-10y

Rapid decline when in AIDS phase

38
Q

Describe the CD4 T cell count in the mucosa in HIV infection

A

Profound depletion of CD4 T cells

Dont really receover

Dissociation between counts in blood vs tissues

39
Q

What is the immune deficiency often linked to in HIV?

A

Immune system not responding properly to immune activation

With acute infection get increase in immune activation- generating a pro-inflammatory response

Capacity to make new CD4 T cells reduces with progressive infection

40
Q

Describe the humoral immunology in HIV infection

A

Acute: IgM to envelope protein gp41 + Gag

Later ~12w: neutralising antibodies with capacity to prevent viral infection of that strain- but virus will have mutated

41
Q

Describe how viral load differs depending on humoral response to HIV infection

A

Good B cell response: antibodies inhibiting replication by phagocytosis, fixation of complement. Bring down viral load

Poor/ ineffective antibodies: have high viral load set point, doesn’t vary over asymptomatic phase. Make antibodies targeting conserved parts of the HIV envelope- broadly neutralising antibodies

42
Q

List 5 features of untreated HIV immunology

A

CD4 T cell depletion

Chronic immune activation

Impairment of CD4 + CD8 T cell function

Disruption of lymph node architecture + impaired ability to generate protective T + B cell immune responses

Loss of antigen-specific humoral immune responses: tetanus vaccine + alloimmune responses

43
Q

What happens to the immune system in acute HIV?

A

Significant increase in HIV viral load in blood

Significant risk of viral transmission

Transient reduction in blood CD4 T cells

Increase in CD8 T cell immune response coinciding with drop in VL

CD8 T cell activation

Induction of HIV specific antibodies

44
Q

What tests can be used to diagnose HIV?

A

4th gen combined antigen/ antibody tests: 1m post acquisition

Rapid POC: results in <20mins less sensitive

RNA tests when serological tests are -ve but high clinical suspicion of acute infection

RNA/ DNA tests for kids <18m

45
Q

What baseline investigations should be performed in HIV?

A

FBC

Renal, liver, bone, lipid profile, HbA1c

Sexual health screen

Screen for latent TB using IGRA

CXR + ECG
Toxoplasma serology

46
Q

Which HIV specific tests need to be performed?

A

HIV viral load

HIV genotype for ART drug resistance

HIV tropism test to confirm co-receptor use (potential for CCR5 antagonists)

HLA-B*5701 to avoid Abacavir + risk of hypersensitivity reaction SJS/TEN

CD4 T cell count + %

CD4: CD8 T cell ratio

47
Q

What is viral load set point correlated with? What is the magnitude influenced by?

A

Long term outcome

Viral genotype

CD8 T cell immune response

Host genetics (HLA + CCR5)

Immune activation

48
Q

Give examples of infections seen at different cell counts in HIV

A

500: bacterial/ fungal skin infection, HSV, HZV
400: Kaposi sarcoma
300: TB
200: PCP
100: Toxoplasmosis, CMV, EBV brain lymphoma
75: Mycobacterium avium complex (MAC)

49
Q

How does kaposi and TB infection differ depending ono cell count?

A

Good: Pulmonary TB

~400: Cutaneous Kaposi sarcoma

Low: Miliary TB

~50: Kaposi affecting lungs + GIT

50
Q

Which drugs can be used as part of antiretroviral therapy?

A

NRTI

NNRTI

Protease inhibitors

Integrase inhibitors

51
Q

How does ART work in HIV?

A

Prevents new cells being infected but can’t eliminate infection once HIV has integrated into hist DNA

52
Q

What happens if ART is stopped?

A

HIV replication re-commences + will be detectable in blood 2-3w later

53
Q

Does ART change chronic immune inflammation?

A

No, does not reverse chronic immune inflammation

This is a RF for cardiovascular, liver, bone + CNS disease

54
Q

What needs to be monitored in patients with HIV?

A

Compliance with drug therapy + any SEs

Viral load every 6m

Potential liver, renal, bone + lipid toxicity

Cardiovascular + osteoporosis risk

Sexual health + vaccine uptake

55
Q

What is the concept of the shock and kill strategy?

A

Shock: drugs reactivate latent HIV in CD4 infected T cells

Kill: activated NK or CD8 T cells eliminate HIV infected cells

Continue ART to prevent infection of new cells

56
Q

What are broadly neutralising antibodies?

A

Neutralise multiple strains: bind to conserved envelope epitopes

In 1-30% of patients

May also activate other immune cells to help destroy HIV infected cells

YR5 Immunology (14 decks)

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