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Year 5 Path Charis > Immuno 3 - Secondary immune deficiencies and HIV 1 infection > Flashcards

Immuno 3 - Secondary immune deficiencies and HIV 1 infection Flashcards

1
Q

o Commonest cause of secondary immune deficiency worldwide

A

• Malnutrition

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2
Q

B cell lymphoproliferative disorders associated with immune deficiency include

A 
MM 
CML
NHL
MGUS - monoclonal gammopathy of uncertain significance
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3
Q

Clinical features of immune deficiences

A
  • Infections – severe, persistent, recurrent, unusual
  • Autoimmune conditions (immune cytopaenias)
  • Allergic disease
  • Persistent inflammation
  • Cancer (particularly viral associated EBV, HHV-8)
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4
Q

First line ix if suspecting secondary immune deficiency/ immunodeficiency

A

FISH for an immunodeficiency

• FBC
o Hb
o Neutrophil/Lymphocyte/Platelet count

•	Immunoglobulins
o	IgG, IgA, IgM, IgE
o	Low gG: 
	Protein losing enteropathy
	Prednisolone >10mg/day
o	Low IgG + Low IgM:
	Monitor for B cell neoplasm
	Hx of exposure to rituximab
o	Low IgG + Low IgA
	Primary antibody deficiency

• Serum Complement
o C3, C4
o Screens for C1 inhibitory deficiency, Immune complex disease, Lupus

• HIV test
o 18-80 years

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5
Q

What is Goods’ syndrome?

A

Goods’ syndrome

  • Thymoma and antibody deficiency
  • Combined T and B cell (absent) defect
  • CMV PJP and muco-cutaneous candida
  • Autoimmune disease (Pure red cell aplasia, Myasthenia gravis, Lichen planus)
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6
Q

Other ix in secondary immunodeficiencies

A

U+Es

LFTs

Bone profile + Ca

Total protein + Albumin

Urine Protein: creatinine

Serum protein electrophoresis
o Separation of serum proteins by charge
o Detection of discrete bands
 Monoclonal identified by immunofixation with labelled IgG, IgM, IgA anti-sera
 Monoclonal protein associated with MM, WMG, NHL and MGUS
o SPE can miss free light chain disease

Serum free light chains
o Free light chain disease seen in 20% of MM cases
o Essential for work up of B cell lymphoproliferative disorders (SPE can miss free light chain disease)

WMG = Waldenstorm macroglobulinaemia

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7
Q

Secondary investigations for immune deficiencies

A

• Concentration of vaccine antibodies
o Tetanus toxin – protein antigen
o Pneumovax vaccine – carbohydrate antigen (all 23 serotypes or to individual pneumococcal serotypes)
o If reduced vaccine antibody levels:
 Offer test immunisation with Pneumovax II + tetanus to investigate immune function
 Looking at T cell independent activity
 Failure to respond to vaccination:
• Part of dx criteria for a number of primary antibody deficiency syndromes
• Criteria for receipt of IgG replacement therapy for secondary antibody deficiency syndromes

•	Analysis + quantification of lymphocyte subsets using flow cytometry 
o	CD3+CD4+ T cells
o	CD3+CD8+ T cells
o	CD3-CD56+CD16+ NK cells
o	CD19+ B cells
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8
Q

Third line investigations for secondary immunodeficiencies

A
  • Analysis of naïve + memory T and B cell subsets
  • Assessment of IgG subclasses
  • Determination of anti-cytokine and anti-complement antibodies

• Genetics
o Whole exome/Whole genome sequencing - ?primary or ?secondary immune defect

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9
Q

Which antibodies are responsible for the following conditions

SARS-CoV-2 infection
disseminated NTM (non-tuberculous mycobacteria) infection
cryptococcal infection
B cell lymphoproliferative disorders + SLE

A

o Anti-type 1 IFN antibodies (IFN-α and IFN-ω)  SARS-CoV-2 infection

o Anti-type 2 IFN antibodies (IFN-γ)  disseminated NTM (non-tuberculous mycobacteria) infection

o Anti-GM-CSF antibodies  cryptococcal infection

o Anti-C1 inhibitor antibodies + acquired late onset angioedema  B cell lymphoproliferative disorders + SLE

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10
Q

Management of secondary immune deficiency

A
  • Treat underlying cause
  • Advise on measures to reduce exposure to infection

• Immunisation
o Against respiratory viruses + bacteria
o Offer vaccines to household contacts

• Education to treat bacterial infections promptly
o May require higher + longer therapies courses

• Prophylactic antibiotics
o For confirmed recurrent bacterial infection

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11
Q

criteria for

IgG replacement therapy for secondary antibody deficiency syndromes

A

• Underlying cause of hypogammaglobinaemia cannot be reversed or reversal is contraindicated
OR
• Hypogammaglobulinemia associated with
o Drugs
o Therapeutic monoclonal antibodies targeted at B cells and plasma cells
o Post-HSCT
o NHL, CLL, MM or other relevant B-cell malignancy

AND

  • Recurrent or severe bacterial infection despite continuous oral antibiotic therapy for 6 months
  • IgG <4.0g/L (excluding paraprotein/monoclonal protein)
  • Failure of vaccine response to unconjugated pneumococcal or other polysaccharide vaccine challenge
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12
Q

HIV

Time period between infection to symptomatic disease/AIDS
Highest risk of transmission

A

10 years

risk of transmission highest within the first 6 months

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13
Q

Mechanism of action of HIV

A
  • Targets CD4+ cells
  • Gp120 (initial binding) and gp41 (conformational change) binds to CD4+ T cells + HIV co-receptors
  • Binds to CD4 + then chemokine co-receptor CCR5 or CXCR4

• Replicates via a DNA intermediate using reverse transcriptase – converts RNA into DNA which can be integrated into host cell’s genes

  • Integrates into host genome
  • HIV DNA transcribed into viral mRNA  transcribed into viral proteins  package + release of mature virus

• Gag protein – intrastructural support for HIV

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14
Q

HIV1 lineages

A

HIV-1 consists of 4 distinct lineages M, N, O, and P

Each lineage arose from independent transmission from chimpanzees (Group M,N,O) and gorillas (O,P)

Group M virus is pandemic, consists of 9 subtypes and 40 recombinant forms

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15
Q 
What happens in HIV during
acute phase
chronic phase 
AIDS
to

CD4 T cell counts in the blood
Mucosal CD4 t cells
Immune activation

A

CD4 T cell counts in the blood
acute phase - drop
chronic phase - small rise
AIDS - dramatic decline

Mucosal CD4 t cells
drop in acute phase, never recover

Immune activation
significant increase

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16
Q

What predicts disease progression in HIV

A

Degree of immune activation
o Degree of immune activation can predict progression of infection (independent of CD4+) + response to ART

Initial viral burden (viral load set point)
• 3-6 months after initial infection a steady state HIV-1 viral concentration is observed in blood  viral load set point
• Progression to symptomatic HIV-1 infection stratified by VL set point
• Viral load set point correlated with long-term outcome
• Magnitude of VL set point influenced by
o Viral genotype
o CD8 T cell immune
o Host genetics (HLA, CCR5)
o Immune activation

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17
Q

Characteristic features of the immunology of HIV-1 infection

A

• CD4 T cell depletion

• Impairment of CD4 + CD8 T cell function – “exhaustion”
o Present but don’t work very well – don’t secrete antiviral inhibitory cytokines/chemokines, are not cytotoxic

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

• Loss of antigen-specific humoral immune responses
o Recurrent bacterial infections in sub-sacharan Africa are the main drivers of infection

• Chronic immune activation

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18
Q

How long does HIV need to integrate into T cells?

A

• Integration of HIV provirus in memory T cells within 72 hours of infection  formation of long-lived reservoir of latent infection  does not respond to current ART

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19
Q

How does HIV survive?

A

• Error prone nature of HIV RT  short generation time of viral cycle + length of infection  driving force for viral diversity

• Viral mutation
o Evasion of the CTL (cytotoxic T lymphocyte) immune responses
o Emergence of drug resistant virus in patients with inadequate drug treatment

20
Q

What happens during the acute phase of HIV infection?

A

• Significant increase in HIV-1 viral load in blood

• Flu like symptoms in 70% of cases
o Infectious mononucleosis type picture

  • Transient reduction in blood CD4+ T cells
  • C8 T cell activation (CD38+ and HLA-DR+)
  • Increase in CD8 T cell immune response coincides with drop in VL
  • Induction of HIV-1 specific antibodies
21
Q

How does HIV damage the immune system?

A
  • HIV remains infectious even when Ab coated
  • Activated infected CD4+ helper T cells –> killed by CD8+ T cells and are anergised (disabled)
  • CD4 T-cell memory lost & failure to activate memory CTL
  • Monocytes and dendritic cells –> not activated by the CD4+ T cells –> cannot prime naïve CD8+ CTL (due to impaired antigen presenting functions)
  • Infected monocytes dendritic cells –> killed by virus or CTL
  • Quasispecies are produced due to error-prone reverse transcriptase = these escape from immune response
  • Effective immunity requires antibodies to prevent infection and neutralize virus, and sufficient CTL to eliminate latently infected cells
22
Q

Diagnosis of HIV infection (7)

A

• 4th generation combined HIV-1 antigen/antibody tests
o Will detect infection 1 month post acquisition

• rapid point of care HIV-1 tests
o Results available within 20 mins
o Less sensitive than 4th generation test

•	Assay detect 
o	p24 antigen – part of nuclear capsid
o	gp41 – from HIV-1 Group O 
o	gp160 – envelop protein on HIV-`
o	gp36 – HIV 2

• HIV-1 RNA tests
o In cases where HIV-1 serological tests are negative but there is high clinical suspicion of acute HIV-1 infection

• HIV-1 RNA and/or DNA tests
o Used to diagnose infection in children <18 months

• Screening test – detects anti-HIV ab via ELISA
• Confirmation test – detects ab via Western Blot
o A positive test requires the patient to have seroconverted (i.e. started to produce ab)
o This happens after around 10 weeks incubation

23
Q

HIV specific tests

A

• HIV-1
o Viral load
o Genotype (for ART drug resistance)
o Tropism test to confirm co-receptor use in HIV-1 in patients who may be candidates for treatment with CCR5 antagonists

• HLA-B*5701 blood test
o To avoid prescribing Abacavir
o Risk of severe hypersensitivity in those with this allele (can die from it)
o to prevent hypersensitivity reaction with protease inhibitors

• Analysis of T cell counts
o CD4 T cell count + percentage – to stratify risk of infection
o CD4: CD8 t cell ratio

24
Q

Infections + CD4 count

500 cells/mm3

400 cells/mm3

300 cells/mm3

200 cells/mm3

100 cells/mm3

50 cells/mm3

A

> 500
Community acquired organisms - HSV, zoster, pneumonia, bacterial skin infections, oral, skin fungal infections

400 cells/mm3
Kaposi’s sarcoma
Cutanous kaposis

300
Hairy leukoplakia
TB

<200
PCP
Cryptosporidium
Candida
Fungal pneumonia

<100
Toxoplasmosis
Cryptococcus
Candida, HSV, CMV oesophagitis

<50
CMV
Cryptococcus
Lymphoma
MAC (mycobacterium avium complex)
Toxoplasmosis 
Visceral Kaposis
25
Q

At which CD4 levels do the following present + how do you treat?

PCP
Toxoplasma
MAC (mycobacterium avium complex)

A

PCP
<200 cells/mm3
Co-trimoxazole

Toxoplasma
<100 cells/mm3
Co-trimoxazole

MAC
<75 cells/mm3
Azithromycin

26
Q

At which CD4 count should ART be considered

A

All HIV-1 infected individuals should consider ART irrespective of CD4 T cell count

27
Q

Life cycle of HIV

A 
Attachment + entry
Reverse transcription + DNA synthesis
Integration to host DNA
Viral transcription
Viral protein + synthesis
Assembly + budding
28
Q

Give an example of an attachment inhibitor

A

Maraviroc

CCR5 antagonist

29
Q

Give an example of a fusion inhibitor + state 2 side effects

A

Enfuvirtide

Local reaction to injection
Hypersensitivity (0.1-1%)

30
Q

Give 5 limitations of HAART

A

o Doesn’t eradicate latent HIV-1
o Fails to restore HIV-specific T cell responses
o Toxicities
o Cannot eliminate infection once HIV-1 has integrated into host DNA
o Does not reverse chronic immune inflammation – RF for CV, liver, bone, CNS disease

but
o Can prevent new cells from becoming infected

31
Q

Give a few examples of NRTIs

A

Nucleoside reverse transcriptase inhibitor

Zidovudine (can also be given to pregnant women)
Lamivudine
Didanosine 
Stavudine 
Zalcitabine 
Emtricitabine

Abacavir
Combivir
Trizivir

Epzicom

32
Q

NRTIs SE

A

rare

fever
headache
GI disturbance

33
Q

NtRTI + SE

A

Nucleotide reverse transcriptase inhibitor

Tenofovir

Bone and renal toxicity

34
Q

NNRTI + SE

A

Non nucleoside transcriptase inhibitors

Nevirapine (heaptitis + rash)

Delaviridine (rash)

Efavirenz (CNS effects)

35
Q

Integrase inhibitors

A

Raltegravir

lvitegravir

Dolutegravir

36
Q

Protease inhibitors

SE

A 
Ritonavir
Darunavir
Indinavir
Nelfinavir
Amprenavir 
Fosamprenavir
Lopinavir
Atazanavir
Saquinavir

SE
Hyperlipidaemias
Fat redistribution
T2DM

37
Q

main reason why HIV-1 patients change HIV therapy

A

Drug toxicity rather than virological failure

38
Q

ART in the UK consists of

A

2 NRTI (backbone regimen) and 1 NRTI or

2NRTI (backbone regimen) and 1 Integrase inhibitor

39
Q

Give examples of drugs used in the backbone regimen

A

Abacavir + lamivudine

Emtricitabine + tenofovir

40
Q

Give examples of drugs used for the third drug of choice in ART

A

Integrase inhibitors
 Raltegravir
 Dolutegravir

41
Q

Life expectancy of HIV +ve individuals

A

If ART started before significant immune damage – similar life expectancy to age + sex matched to seronegative controls

42
Q

After how long is the viral load detectable in blood once someone stops ART?

A

o If stopped, HIV-1 replication re-commences + will be readily detectible in blood 2-3 weeks later

43
Q

Monitoring individuals on ART (5)

A

• Check for compliance with drug therapy + adverse SE
• Regular HIV-1 viral load
• Monitor liver, renal, bone, lipid toxicity
• CD4 T cell monitoring not needed fir counts >350 cells/ul
• Assess CV + osteoporosis RF – HIV drugs can increase bone loss
•

44
Q

Describe the shock and kill strategy for treatment of HIV

A

SHOCK

drugs to reactivate HIV-1 virus

KILL
agents to eliminate HIV-1 infected cells

ART
prevent infection of new cells

45
Q

Which immunoglobulin does prednisolone affect and at which doses

A

Prednisolone – selective depression in IgG, seen with higher doses >10mg/day

Year 5 Path Charis (44 decks)

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