Polyoma Flashcards
Name other Polyomaviruses than BK/JC
Ki and Wu (respiratory), Merkel cell polyomavirus, Trichodysplasia spinulosa virus
What is the name of the polyomavirus antigen involved in infection?
Large T
What is the receptor for JC virus?
Alpha-2,6 sialic acid
In which tissues is JC latent?
Tonsillar, renal tubular cells, bone marrow, brain
What does JC virus isolated from PML look like?
Highly variable genomic rearragnements of noncoding control region (JC architype is shed in urine and doesn’t cause disease)
How does primary JC/BK infection present and what is seroprevelence?
Mild respiratory symptoms, or asympotmatic, most infections during childhood and JC 50% seroprevelance by teen years, Bk 80%
What groups are at risk of reactivation of JC?
Reactivation is common in all people, and 30% shed in urine asymptomaticlaly but immunosuppressed patients are at risk of reactivation and disease. AIDS (80%), Haematological malignancies (13%), SOT/BMT (5%), chronic inflammatory disease (2%)
Clinical featres of JC virus
Asymptomatic, PML, other nuerologies: JC-granule cell neuropathy, JCV encephalopathy, JCV meningitis. JC associated nephropathy in kidney transplant, ?implicated in colorectal carcinoma
Clinical features of PML
Insidous onset and steady progression. Progressive demyelination of white matter. Cognitiive deterioration, gait and coordination abnormalities, limb paresis and seizures
In PML what does CT/MRI show
White matter lesions
What are the three states of PML?
1) PML due to immune suppression 2) PML/IRIS at the same time upon immunereconstitution 3)PML-IRIS - worsening of existing PML due to IRIS
PML-IRIS, who is at risk? Symptoms? Treatment?
Can occur on initiation of ART or during plasma exchange in MS patients on natalizumab. Acute onset, odema, mass effect. Treated with corticosteroids, or maraviroc
What groups are at risk of PML?
BMT, SOT, AIDS, leucaemia, inflammatory malignancies, CD4 lymphocytopaenia, mAbs
Which mAbs increase the risk of reactivation of BK/JC and could lead to PML?
Natalizumab (MS). Efalizumab (psoriasis) rituximab, JAK inhibitors
What are the risk factors for PML in patients using natalizumab?
1) JC virus antibody (>1.5) 2) Prior immunosuppression 3) Treatment duration (>2 years)
What is the wash out period of natalizumab?
3 months
What test is used for the antibody index of JC?
STRATIFY JC assay (Focus diagnostics)
When is MRI used in natalizumab use?
At baseline and then 1) annually if low risk 2) 6 monthly if intermediate risk 3) 3 monthly if high risk
In patients with JC AI >1.5 what is their risk of PML after 2 years?
1 in 113
When is JC anitbody index tested in natalizumab use?
At baseline, then no testing for 12 m. Then 1) if <1.5 test 6 monthly 2) if >1.5 no further testing
Kidney transplant patient with nephropathy - BK virus negative in urine and blood, but SV40 staining positiive in biopsy. What are the next steps?
Test JC virus in urine (high VL) and blood (often low level or undetectable). Reduction of immunosuppression and IVIG if no resolution of symptoms
What would you see in a brain biopsy in a patient with PML
Intranuclear inclusions, bizarre astrocytes, lipid laden macrophages, SV40 positive
When and how would you use quantitiative PCR for JCV?
Monitoring JCV VL in CSF in patients on ART/removal of mAbs. NIBSC have WHO 1st international standard
What is sens/spec for PML in CSF/blood/biopsy?
CSF = 72-92% sens, 92-100% specific. Blood 40% sesitivity, 92% specificity. Brain bx = 64-96% sensitvity 100% specificity
What treatment is available for PML?
Reduction of immunosuppression or ART. Reconstitution of CD4/CD8 T cells are crititcal for halting progression of PML.
Name four novel therapys for PML
1) JC /BK specific T cell therapy 2) Checkpoint inhibitors (PD-1 mAb) 3) hrIL-7 4) Mirtazipine (5HT2AR)
Where does BK remain latent?
Renal tubular epithelial cells
What are risk factors for BK disease?
Immunosuppression plus high BK virus IgG titre pre trasnplant, older age
Clinical features of BK infection?
BK associated nephropathy (renal tx patients), haemorrhagic cystitis (BMT patients) other rare presentations - pneumonitis, retinitis, liver disease, meningoencephalitis, PML
What is the risk of BKVAN casuing allograft failure in renal tx patients and when is this most likely to occur?
1-10% risk of allograft failure, 3% chance of ureteral stenosis = average diagnosis at 44 weeks
What % of renal transplant patients have BK viruria and how many of these will go on to develop BKVAN?
80% with viruria and 5-10% will develop BKVAN
Does BKV screening in urine have a good PPV/NPV?
Excellent NPV but poor PPV, can be useful for early detection
What is the policy for screening for BKVAN in renal tx patients?
VL in plasma monthly until 9 m post transnplant and then 3 monthly for 2 years.
New guidance says annually from year 3-5
At what level of BKV in plamsa in renal tx pateints would you intervene?
If VL 1000-10000 copies/ml then repeat and confirm at 2-3 weeks , if sustained at >1000 then continue to monitor at 2-4 weeks. If >10000 then reduce IS
When would you perform a renal biopsy in BK virus?
Never without evidence of renal function disorder. E.g. altered renal function, increase in serum creatinine, haematuria or proteinuria)
What would you observe in a biopsy of BKVAN?
Severe tubular damage, interstitial inflammation, tubulitis, interstitial fibrosis. SV40 positiive (but false neg do occur in early infection) Use Banff ci-score for pathology
How do you monitor BKVAN post reduction of immunosuppression?
Plasma viral load negativity can be used to show resolution of nephropathy
Differential diagnosis of BKVAN
Allograft rejection, JC, adenovirus, CMV, HSV
If resolution of BKVAN does not occur after reducation of immunosuppression what are the next steps?
Addition of IVIG and finally re-transplantation
What is the risk of haemorrhagic cystitis due to BK in BMT patients?
10-25%
What are symptoms of BK virus in BMT patients
Haematuria, dysuria, urgency and frequency, suprapubic pain
When is BK haemorrhagic cystitis most likely to occur in BMT patients?
2-8 weeks post tx - can be 1 week to 8 months
What are the differential diagnosis for haemorrhagic cystitis in BMT patients?
BK, direct toxicity, CMV, adenovirus, JC and HSV are rare causes
What is the diagnostic triad of BKV haemorrhagic cystitis in HSCT?
1) Cystitis 2) Grade 2+ haematuria 3) viruria >log 7
What screening is implemented for BK virus in HSCT?
No asymptomatic screening
What are the VL cut offs associated with highest risk/specificity for BK haemorrhagic cystitis?
Plasma VL 3-4 log copies/ml, and >log 7 viruria
Treatment options for BK associated haemorrhagic cystitis
It generally resolves on its own, so only supportive management - hyperhydration, bladder irrigation, platelet transfusion and pain treatment. Cidofovir (with probenecid) could be considered but data not great. Reduction of immunosuppression is not routine due to risk of rejection, can be considered if benefit outweighs risk
What are decoy cells?
BK infected renal tubular epithelial cells shed in urine, show basophilic inclusions with pap stain. 100% sensitivity but only 20% specificity as seen in JC and adeno infection
What is NPV/PPV in plasma for BKVAN?
100% NPV and 50% PPV
When can monthly/weekly screening stop and patients be back to routine screening after having pos BK in plasma?
After 3x negative viral loads
Then test at 3,6,12 m post clearance
