Questions from S Flashcards
You are on clinical review, and authorising a CMV/EBV DNA PCR run. Amongst results is patient with CMV DNA virus load of 10,135 IU/ml in haematology patient who had haematopoeitic stem cell transplant 3 months ago. Last samples was sent two weeks previously with level 1020IU/ml. Serial weekly samples prior to this were not detected.
What would you do next?
Gain further information:
- Check correct patient bled
- Check comparable assay used
- FBC/UE – suppression/ renal disease
- Stem cell transplant – matching CMV donor status
- Conditioning regimen
- Any blood products
You are on clinical review, and authorising a CMV/EBV DNA PCR run. Amongst results is patient with CMV DNA virus load of 10,135 IU/ml in haematology patient who had haematopoeitic stem stell transplant 3 months ago. Last samples was sent two weeks previously with level 1020IU/ml. Serial weekly samples prior to this were not detected.
Further information:
D+R-
6 weeks post-transplant
On Letermovir
No concerns regarding absorption
Why is patient on Letermovir?
What advice would you give?
- Letermorvir is licensed for CMV prophylaxis (not treatment). Less myelosuppressive and better for renal disease than alternatives
Steroids/ immunosuppression from GVHD
- Primary infection
- End organ disease either from CMV, or from GVHD – eyes/ lungs/ GI/ liver
- Consider other infections
- Send for CMV whole genome sequencing/ resistance testing
Why is this patient of Letermovir
- Less myelosuppressive/ nephrotoxic than ganciclovir/ foscarnet
- High risk D+/R-
Advice
- If no disease, consider observing, as undergoing primary infection - is this wrong?
- If no disease, switch to valganciclovir prophylaxis. As rising viral load on letermovir suggests failure, and likely viral load to rise further
- End-organ disease – IV ganciclovir treatment. Less myelosuppression as 3 months – should be engrafted
What are treatment options for CMV?
Valganciclovir
Ganciclovir
Foscarnet
Cidofovir
Brincidofovir
Maribavir
Letermovir only licensed as prophylaxis
What are mechanism of action of drugs for CMV?
Valganciclovir
Ganciclovir
Foscarnet
Cidofovir
Brincidofovir
Letermovir
Ganciclovir/ Valganciclovir - guanosine analogue, inhibits DNA polymerase
Foscarnet - pyrophosphate analogue, non-competitively inhibits DNA polymerase
Cidofovir/Brincidofovir - nucleotide analogue inhibits DNA polymerase
Letermovir- DNA termianse complex inhibitor
Post-stem cell transplant patient being treated for CMV infection.
rising viral load, and concerned about viral resistance.
Which genes are targeted during CMV resistance testing?
Mutations leading to CMV drug resistance have been described in
UL54 - DNA polymerase
UL 56 - viral terminase complex
UL97 - phosphotransferase encoding region
UL54 mutation - Ganciclovir resistance/ Cidofovir/ Foscarnet resistance
UL56 mutation - Letermovir resistance
UL97 mutation - Ganciclovir
Miller-Fisher variant GBS - virology FRCPath2 oral question
What is common presentation?
What auto-antibody is detected in 90% of cases?
What is treatment?
Miller Fisher Syndrome (MFS) is a variant of GBS.
Usually begins with the rapid development, over days, of 3 problems:
- ascending paralysis - leg weakness/ respiratory failure
- weak eye muscles, with double or blurred vision, and often drooping eyelids with facial weakness. Cranial nerve involvement is typical for Miller-Fischer
- loss of deep tendon reflexes, such as the knee and ankle jerk
Possible preceeding viral/ diarrhoeal illness few days before - Campylobacter/ HEV/ Influenza/ EBV/ CMV possible triggers
Associated with antibodies against ganglioside GQ1b - >90% patients
Treatment:
Steroids
IVIG
Plasma exchange
International Committee of Taxonomy of viruses (ICTV)
Explain their role in the classification of viruses
The objectives of the International Committee on Taxonomy of Viruses are
Agrees upon universal name, describe and classift each unique virus
Name must be stable and not confusing
GenBank sequences compiles list of nucleotide sequences which are not currently named.
What is required for PCR?
List all reagents/ equipment
Lysis
Extraction of DNA template
PCR -
Oligonucleotides
Primers
DNA Polymerase/ RT if required
Buffer - magnesium
Fluorescent probe
Thermal cycler
Analysis -
Analyser
What is meant by genetic barrier to resistance?
Number of mutations required to evade neutralisation of by a drug
low barrier -
Lamivudine HIV - M184V
Lamivudine HBV- L180M/ M204I/ M204V
Efavirenz - K103 RT mutation
high barrier - entecavir - requires high number of mutations before becoming ineffective
RTA – orthopod has needlestick during surgery
IVDU is unlikely gain consciousness again
What is the process of consent for HIV testing?
Cannot consent – either await until awake, or have an external party consent in best interests.
When testing a source, make sure to word it in is in the best interests of both the source and the recipient to know the infection status
RTA – orthopod has needlestick during surgery
IVDU is unlikely gain consciousness again
Orthopod doesn’t want to take PEP.
What are the side-effects?
Advise not to stall, as it must be taken within 72 hours, as is more effective the sooner it is taken.
Raltegravir: loss of appetite, headache, difficulty in sleeping, abnormal dreams, depression, dizziness, vertigo, abdominal pain, bloating, flatulence, diarrhoea, nausea, vomiting, indigestion, rash, weakness, fatigue, fever, raised liver or pancreatic enzymes, and raised triglycerides.
emtricitabine/ tenofovir: The most common side-effects were fatigue (37% of PEP users), diarrhoea (25%), nausea (24%), flatulence (24%), abdominal cramps (21%), bloating (16%), headache (15%), vivid dreams (15%), depression (10%) and thirst (10%)
Check does not interact with any other medications
RTA – orthopod has needlestick during surgery
IVDU is unlikely gain consciousness again
What is the testing follow up for HCV, in the recipient?
6 weeks RNA
12 weeks RNA/Ab
24 weeks Ab
HCV incubation period is 2weeks - 6 months
Recipient - can check RNA on weeks 2 and 4 to help detect earlier.
Source - IVDU may be anti-HCV neg, but RNA pos, if had a very recent infection. Consider RNA testing if active IVDU
RTA – orthopod has needlestick during surgery
IVDU is unlikely gain consciousness again
HBV
Had HBV immunisation course previously. But last immunity check was 20iu/ml
What action would you take?
Clarify source infection status - consent issue
Give booster as it has been >12 months since last vaccine
HBV expouse NSI
unsure if been vaccinated before
Level checked >10 iu/ml
Booster given at same time
Does it need follow up testing for immunity?
As level >10 iu/ml - not classified as a non-responder
Therefore just needs booster, with no follow-up
RTA – orthopod has needlestick during surgery
IVDU is unlikely gain consciousness again
Concerned about HLTV
What would you do?
Consent issue - same as HIV.
Time sensitive - PEP occasionally offered if from known HTLV source. would be discussed with national HTLV centre
Clarify local population HTLV prevalence. And whether source is from high risk area -
HTLV 1 - Caribbean, West Africa, Japan
HTLV2 - Americas, and West Africa
Even if low risk, might still consider testing see note below
Testing includes Ab testing, and if positive proviral DNA testing
Incubation period is long - 6 months to years. So test initially, then likely re-test at 6 months.
Check PEP - UKAP suggest raltegravir, zidovudine, lamivudine for 6 weeks, as in vitro shows activity against HTLV1. But has not shown any clinical benefit
UKAP has noted that there is a gap in guidance on the investigation and management of HTLV-1 exposures for both patients and HCWs, and treatment recommendations. It would be beneficial for guidance to be developed by professional bodies in order to standardise clinical practice and improve reporting.
Testing for HTLV-1 infection in the event of a needlestick injury to HCWs may be one way of gathering such evidence for this cohort. Further research is required to better understand the prevalence of HTLV-1 infection in the general population and key risk groups including HCWs and those at risk of other BBVs for example, people who inject drugs or engage in other behaviours that are associated with BBV transmission risk. In particular, longitudinal studies into disease progression should be instigated to establish the risk of long-term morbidity and mortality.
https://www.gov.uk/government/publications/ukap-htlv-1-in-healthcare-workers-and-exposure-prone-procedures/ukap-statement-on-risk-of-htlv-1-transmission-from-healthcare-workers-to-patients-during-exposure-prone-procedures#:~:text=Recommendation%3A%20UKAP%20does%20not%20currently,1%20from%20HCWs%20to%20patients.
Should HCWs be screened for HTLV?
Recommendation: UKAP does not currently recommend routine occupational health monitoring of HCWs infected with HTLV-1. Rationale: As above, there is a lack of evidence around risk of transmission of HTLV-1 from HCWs to patients.
https://www.gov.uk/government/publications/ukap-htlv-1-in-healthcare-workers-and-exposure-prone-procedures/ukap-statement-on-risk-of-htlv-1-transmission-from-healthcare-workers-to-patients-during-exposure-prone-procedures#:~:text=Recommendation%3A%20UKAP%20does%20not%20currently,1%20from%20HCWs%20to%20patients.
HCW has HTLV infection.
Are they allowed to perform EPPs?
Risk assessment completed by OH
currently there is a lack of evidence that restriction of EPP practice would improve patient safety and there is an unknown risk of transmission from HCWs to patients. Therefore, it would not be appropriate to restrict HCWs practice at this time.
Restriction to EPP practice for HCWs with HTLV-1 could have significant implications for individual HCW careers, without there being sufficient evidence that this is necessary on patient safety grounds, it is unlikely that it could be successfully embedded into practice or accepted by HCW groups.
Pro-viral load will have an impact on the risk of transmission and seroconversion, however there is insufficient evidence available to be able to infer the likelihood of healthcare workers having a high viral load, and therefore a subsequent higher risk of transmission. The variable risk of transmission associated with different viral loads in this context has not been quantified and so no ‘cut off’ level can be determined, below which a HCW living with HTLV-1 could be allowed to perform EPPs.
https://www.gov.uk/government/publications/ukap-htlv-1-in-healthcare-workers-and-exposure-prone-procedures/ukap-statement-on-risk-of-htlv-1-transmission-from-healthcare-workers-to-patients-during-exposure-prone-procedures#:~:text=Recommendation%3A%20UKAP%20does%20not%20currently,1%20from%20HCWs%20to%20patients.
Patient with recurrent HSV infection
What actions would you take to prevent further recurrence?
Check swab to confirm diagnosis - may have had HSV1, and now HSV2. So not a recurrence, but a new infection
Consider intensifying treatment to max dose, and increase duration. For example, increase to 800mg 5x/day for a week. To ensure that we have best attempt at trying to clear the virus.
If <6 episodes per year, then give episodic treatment
Supply pack, so can take as soon as symptoms recur
If >6 episodes per year, then consider suppressive therapy
Stop suppressive treatment after a maximum of one year, to reassess the frequency of recurrences. The minimum assessment period should include at least 2 further recurrent episodes. Consider restarting suppressive treatment if a person has a high rate of recurrence off treatment
If having multiple courses aciclovir, then check renal function
All cases of recurrence should be screened for HIV
Patient with recurrent HSV infection
Has breakthrough infection whilst on long-term suppressive therapy
What actions would you take
Check no systemic symptoms - fever/ pneumonitis/ encephalitis
Increase aciclovir dose and duration
consider swabbing if anti-viral resistance suspected
consider pregnancy test
What is difference in disease between HSV1 and HSV2
HSV2 disease is likely to be mores severe - this includes skin/ genital infection, or encephalitis
What are the Westgard Rules?
1 2s
One measurement exceeds 2 standard deviations either above or below the mean of the reference range.
1 3s
One measurement exceeds 3 standard deviations either above or below the mean of the reference range.
2 2s
2 consecutive measurements exceed 2 standard deviations of the reference range, and on the same side of the mean.
R 4s
Two measurements in the same run have a 4 standard deviation difference (such as one exceeding 2 standard deviations above the mean, and another exceeding 2 standard deviations below the mean).
4 1s
4 consecutive measurements exceed 1 standard deviation on the same side of the mean.
10x 10 consecutive measurements are on the same side of the mean.
What would you do if test fails Westgard rules?
The Westgard rules are a set of statistical patterns, each being unlikely to occur by random variability, thereby raising a suspicion of faulty accuracy or precision of the measurement system.
12s (top of table) - serves as warning pattern, and recommends careful inspection of data
The recommended consequences when any of the belowpatterns occur is to reject the run and investigate the cause
13s
22s
R4s
41S
10x
Viral load testing assay
How many controls do we need to accurate viral load quantification?
minimum 5 testing reference points
For examples
100 copies
1000 copies
10000 copies
100000 copies
1000000 copies
May need to interpret a viral load graph with fluorescence points
UK cervical screening program
UK HPV immunisation program - introduced 2008 girls, extended to boys 2019
Who is tested?
25-49 every 3 years
50-65 every 5 years
UK cervical screening program
What is tested?
Sample first tested for high risks types of HPV - those associated with development of cervical cancer (14 oncogenic HPV types in total)
If positive, cytology assessment performed on same sample
If HPV pos, cytology neg, will be invited back for repeat screen in 12 months, instead of back to routine schedule
If HPV pos, cytology pos - to have colposcopy and biopsy
UK HPV screening program
What and when are vaccines given?
2-dose schedule
First approx age 10, and second approx 14
MSMaged <45
HIV+ wants to breastfeed
What criteria need to be met for this to be recommended?
https://www.bhiva.org/file/5bfd308d5e189/BF-Leaflet-2.pdf
BHIVA information on infant feeding for parents living with HIV
Explain one last time that there is risk of transmission. Formula milk has zero risk transmission. BHIVA recommend formula feeding because of this
HIV Viral load undetectable
Willingness to engage with MDT
Willingness to have monthly blood tests
Blood tests for baby/ parent at birth
Blood tests for baby/ parents every 4 weeks
Blood tests for baby at 4 weeks + 8 weeks after stopping feeding
Blood test for baby at 22-24 months to confirm loss of HIV Ab from mother
Good adherence with ART
No evidence of painful nipples/ mastitis
HIV+ wants to breastfeed
What testing is required for mother/ baby?
Blood tests for baby/ parent at birth
Blood tests for baby/ parent every 4 weeks
Blood tests for baby at 4 weeks + 8 weeks after stopping feeding
Blood test for baby at 22-24 months to confirm loss of HIV Ab from mother
HIV+ wants to breastfeed
What is approximate risk of transmission to baby?
PROMISE Trial - Africa/ India
In this study, over time, the number of infants who got HIV, according to how long they were breastfed was:
After 6 months of breastfeeding: 3 in 1000 infants
After 9 months of breastfeeding: 6 in 1000 infants
After 12 months of breastfeeding: 7 in 1000 infants
After 18 months of breastfeeding: 7 in 1000 infants
After 24 months of breastfeeding: 7 in 1000 infants
HIV+ breastfed baby
Mother wants to introduce solids before 6 months of age, and have a “mixed feeding” diet.
What are the risks of this?
‘Mixed feeding’ is where babies receive formula milk and/or solid foods as well as breast/chest milk.
Giving solid foods before 6 months of age, in addition to breast/chest milk, at least doubles the risk of babies getting HIV.
Therefore this is NOT recommended. The lining of the baby’s intestines is not ready to take solid foods before 6 months of age, and this may cause inflammation of the gut which can increase the risk of HIV passing to the baby.
International Committee of Taxonomy Viruses (ICTV)
Explain their role in the classification of enteroviruses
Serologic studies have distinguished 71 human enterovirus serotypes on the basis of antibody neutralization tests. On the basis of their pathogenesis in humans and animals, the enteroviruses were originally classified into four groups, polioviruses, Coxsackie A viruses (CA), Coxsackie B viruses (CB), and echoviruses, but it was quickly realized that there were significant overlaps in the biological properties of viruses in the different groups.
Enteroviruses isolated more recently are named with a system of consecutive numbers: EV-D68, EV-B69, EV-D70, EV-A71, etc., where genotyping is based on the VP1 capsid region.[2]
New staff member tests positive for HBV
HBsAg detected
Anti-HBc detected
HBeAg not detected
Anti-HBe detected
What document gives guidance on how to manage?
UKAP 2023 -
Integrated guidance on health clearance of healthcare workers and the management of healthcare workers living with bloodborne viruses
UK Advisory Panel for Healthcare Workers Living with Bloodborne Viruses (UKAP)
New staff member tests positive for HBV
HBsAg detected
Anti-HBc detected
HBeAg not detected
Anti-HBe detected
What advice would you give?
Repeat sample to confirm patient details
Refer to hepatology for further assessment
HIV / HCV screening
Cease EPPS until HBV DNA level known
<200 - can do EPPs
>200 - stop EPPs
Viral loads every 6 months
