Secondary immune deficiencies and HIV-1 infection Flashcards
What are 7 causes of secondary immune deficiencies?
Malnutrition (commonest globally)
Infectious Diseases e.g. HIV
Environmental stress
Age Extremes: Prematurity + old age
Surgery + trauma, splenectomy
Immunosuppressive drugs
Genetic + metabolic diseases
What are signs and symptoms of secondary immune deficiencies?
Infections: Severe, persistent, recurrent, unusual
Autoimmune conditions (cytopaenias) and allergic disease
Persistent inflammation
Cancer (viral associated EBV, HHV-8)
Which small molecules can cause immune deficiencies?
- Glucocorticoids + mineralocorticoids
- Cytotoxic agents: Methotrexate, mycophenolate, cyclophosphamide + azathioprine.
- Calcineurin inhibitors: Cyclosporine + tacrolimus
- Antiepileptic drugs (phenytoin, carbamazepine, levetiracetam)
- DMARD (sulphasalazine, leflunomide)
Which JAK inhibitors can cause immune deficiencies?
- 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
Which drug class can cause TB reoccurance?
Anti-TNF agents
Screen for latent TB
If detected give TB prophylaxis
Which cancers can present with secondary immune deficiencies?
B + plasma cell cancers (antibody deficiency syndromes are most common).
Chemotherapy, biological agents, + radiotherapy can leads to loss of immune cells + immune deficiency.
Which specific B-cell lymphoproliferative disorders are associated with secondary immune deficiency?
Multiple myeloma
Chronic lymphocytic leukaemia
Non Hodgkin’s lymphoma
Monoclonal gammopathy of uncertain significance
What is Good’s syndrome?
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)
What are appropriate investigations for secondary immune deficiencies?
FISH
FBC: Hb < 10g/L, Neutrophil, Lymphocyte + Platelet count
Immunoglobulins: IgG, IgA, IgM, IgE
Serum complement: C3, C4
HIV test: 18-80y
What is serum protein electrophoresis?
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.
What are second line investigations for secondary immune deficiencies?
Measure concentration of vaccine antibodies:
- Tetanus toxoid: Protein antigen
- Pneumovax vaccine: Carbohydrate antigen (all 23 serotypes or to individual pneumococcal serotypes)
What are third line investigations for secondary immune deficiencies?
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)
What is the management of secondary immune deficiencies?
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)
What type of immunodeficiency is more common?
Secondary immune deficiency
Describe the secondary immune deficiency caused by measles
Immune defect lasts months-years
Increases morbidity + mortality esp. due to secondary bacterial infection/ unexplained diarrhoeal illness
Describe the secondary immune deficiency caused by TB
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
Describe the secondary immune deficiency caused by HIV
Residual immune dysfunction persists despite successful ART
Increased inflammation, cellular/ soluble markers of immune activation
Give an example of a glucocorticoid causing immune deficiency
>10mg/day prednisolone linked to increased rate of antibody loss
Affects cellular + humoral immunity
Increased susceptibility to bacterial + viral infections
How do calcineurin inhibitors cause immune deficiency?
Cause cellular immune deficiency
Target dendritic cells + CD4 follicular function
Impact on peoples ability to respond to vaccines
Name a biologic/ cellular therapy that can cause immune deficiency
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
What must be evaluated in history taking in a patient with suspected immune deficiency?
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
What are the front line chemical investigations for immune deficiency?
Renal + liver profile
Calcium + bone profile
Total protein + Albumin
Urine protein/ Cr ratio
Serum protein electrophoresis
Serum free light chains
What could cause isolated reduction in IgG?
Protein losing enteropathy
Prednisolone doses (cumulatively) >10mg/day
What could cause a reduction in IgG and IgM?
B cell neoplasm
Hx of exposure to Rituximab
What could cause a reduction in IgG and IgA?
Primary antibody deficiency
What are monoclonal proteins associated with?
Multiple myeloma (IgG + IgA)
WMG (IgM)
NHL
MGUS
How can SPE sometimes not detect multiple myeloma?
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
If concentrations of vaccine antibodies are low, what should be done?
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
Why are vaccine antibody concentrations measured in the work up for immune deficiencies?
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
What is the criteria for IgG replacement therapy?
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
Give 4 features of HIV virology
4 lineages M, N, O, P (M most common)
Slow evolution
Double stranded RNA
Retrovirus
Describe the replication of HIV virus
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
Describe the natural history of HIV as defined by viral replication
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
Describe the risk of transmission through the natural history of HIV
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
Why must combination therapy be used to treat HIV?
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
Why do patients with HIV need to take lifelong antivirals?
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
Describe the T cell immunology in natural HIV infection
Dip in CD4 T cells in blood
Some partially recover
Slow decline 8-10y
Rapid decline when in AIDS phase
Describe the CD4 T cell count in the mucosa in HIV infection
Profound depletion of CD4 T cells
Dont really receover
Dissociation between counts in blood vs tissues
What is the immune deficiency often linked to in HIV?
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
Describe the humoral immunology in HIV infection
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
Describe how viral load differs depending on humoral response to HIV infection
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
List 5 features of untreated HIV immunology
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
What happens to the immune system in acute HIV?
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
What tests can be used to diagnose HIV?
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
What baseline investigations should be performed in HIV?
FBC
Renal, liver, bone, lipid profile, HbA1c
Sexual health screen
Screen for latent TB using IGRA
CXR + ECG
Toxoplasma serology
Which HIV specific tests need to be performed?
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
What is viral load set point correlated with? What is the magnitude influenced by?
Long term outcome
Viral genotype
CD8 T cell immune response
Host genetics (HLA + CCR5)
Immune activation
Give examples of infections seen at different cell counts in HIV
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)
How does kaposi and TB infection differ depending ono cell count?
Good: Pulmonary TB
~400: Cutaneous Kaposi sarcoma
Low: Miliary TB
~50: Kaposi affecting lungs + GIT
Which drugs can be used as part of antiretroviral therapy?
NRTI
NNRTI
Protease inhibitors
Integrase inhibitors
How does ART work in HIV?
Prevents new cells being infected but can’t eliminate infection once HIV has integrated into hist DNA
What happens if ART is stopped?
HIV replication re-commences + will be detectable in blood 2-3w later
Does ART change chronic immune inflammation?
No, does not reverse chronic immune inflammation
This is a RF for cardiovascular, liver, bone + CNS disease
What needs to be monitored in patients with HIV?
Compliance with drug therapy + any SEs
Viral load every 6m
Potential liver, renal, bone + lipid toxicity
Cardiovascular + osteoporosis risk
Sexual health + vaccine uptake
What is the concept of the shock and kill strategy?
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
What are broadly neutralising antibodies?
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
