Herpes Simplex Virus Guidelines and areas for debate. Dr Catherine O Sullivan February 2016

Transcription

1 Herpes Simplex Virus Guidelines and areas for debate Dr Catherine O Sullivan February 2016

2 Neonatal disease 70% have disseminated and/or CNS infection often presents late (10 days - 4 weeks) mortality from local CNS disease 6%; morbidity 70% mortality from disseminated disease 30%; morbidity 17% poor outcomes may be attributed to delays between symptom onset and treatment Transmission: direct contact with infected maternal secretions in 10-25% a possible source of postnatal infection, usually a close relative; may be oro-labial HSV.

3 Why the debate? New UK guidelines for management of pregnant women & neonates Different management approaches UK vs. USA Rising incidence in UK adult population Variation in different UK regions? Limited evidence base

4 Evidence From USA with small numbers even the largest (Brown JAMA 2003) have only 10 neonatal cases (from 58,362 pregnancies) and historic need to extrapolate from US hospitals in to UK hospitals in 2016 practice changes e.g. suppressive aciclovir, increase of molecular testing

5 Number of selected STI diagnoses among females: England, Data from routine GUM clinic returns *First episode; ** Includes diagnoses of primary, secondary and early latent syphilis Chlamydia data from 2012 are not comparable to data from previous years. See Notes slide for more details Data type: service data 7 Public Health England: 2012 STI Slide Set

6 Guide line s

7 Type of delivery Rationale: Transmission: ~85% during delivery. Recommendation: C/S for all unless there have been no lesions or prodromal signs (US) C/S for primary/suspected primary if within 6/52 of delivery (UK) No C/S for recurrent (UK)

8 Type of delivery Evidence? ACOG acknowledge that C/S for recurrent is based on expert opinion/consensus C/S for primary/suspected primary: Brown. JAMA Primary: 2 maternal lesions at delivery: all LUSCS: no neonatal cases 7 no maternal lesions at delivery: all SVD: 4 neonatal cases Recurrent: 53 maternal lesions at delivery: 41 LUSCS: no neonatal cases; 12 SVD: no neonatal cases 98 no maternal lesions at delivery: 18 LUSCS: no neonatal cases; 80 SVD: 2 neonatal cases N.B. Are the risks the same: If received aciclovir suppressive therapy in pregnancy?

9 Asymptomatic neonates at risk Type of maternal lesions/delivery AAP guideline RCOG/BASHH guideline Recurrent / C-section Surface swabs & blood PCR Advice only Recurrent / Vaginal Surface swabs & blood PCR Advice only 1 st episode/ C-section Surface swabs, blood, & CSF PCR, ALT and start IV aciclovir immediately 1 st episode / Vaginal Surface swabs, blood, & CSF PCR, ALT and start IV aciclovir immediately Advice only Surface swabs & start IV aciclovir immediately

10 Neonates born to women with recurrent genital le s ions Prober et al vaginal deliveries to women with a history of genital HSV and HSV2 isolated from genital swab at delivery 19 women had active lesions at delivery 0 neonatal infections 33/33 neonates neutralizing antibody titres >1:5 Brown et al deliveries to women with culture/serology proven recurrent genital herpes 53 women had active lesions at delivery 12/53 had vaginal deliveries (all HSV2): 0 neonatal infections However 2 neonatal infections to the 8 women asymptomatically shedding HSV1

11 Neonates born by LUSCS to women with first episode ge nita l le s ions Brown et al deliveries to women with culture/serology proven 1 st episode genital HSV 3 maternal lesions at delivery: all C/S: no neonatal cases However 1 neonatal infection to the 6 women asymptomatically shedding in their 1 st episode and delivered by C/S Brown et al deliveries to women with culture/serology proven primary genital HSV in 3 rd trimester 2 women delivered by C/S: 1 neonatal infection

12 Maternal aciclovir suppressive therapy Braig et al pregnant women with genital HSV Randomly assigned to aciclovir or placebo from 36 weeks 0/167 aciclovir pts vs. 15/121 placebo had clinical recurrence at term Scott et al pregnant women with 1 st episode genital HSV - Randomly assigned to aciclovir or placebo from 36 weeks - 0/21 aciclovir pts vs. 9/25 placebo pts had clinical recurrence at term Post suppression papers: Case series: Pinninti et al 2012 describe 8 infants infected with HSV despite maternal aciclovir prophylaxis

13 Repeating CSF HSV PCR AAP asymptomatic neonates HSV guideline 2013 advises to repeat HSV CSF PCR if previously positive Assoc. British Neurologists/BPAIIG childhood encephalitis guideline 2012 Repeat LP considered particularly if there are concerns that the treatment is ineffective (severe disease, immune-compromise, previous relapse) (B, II) EU Concerted Action on Virus Meningitis Encephalitis 1996 At the end of treatment or as indicated by the individual clinical course, further paired CSF and serum samples for detection of HSV DNA and HSV specific antibodies must be obtained. Kimberlin et al neonatal HSE patients with CSF taken after 10/7 treatment Worse neurological outcome if CSF HSV PCR positive at end of treatment

14 Length & dose of post treatment prophylaxis Rudd et al 1994 Aim: to find dose of oral aciclovir syrup necessary to achieve theoretically therapeutic CSF concentration to prevent dermal/cns recurrence 8 infants post-hse and 1 with multiple recurrences of dermal & ocular disease Method: increasing oral doses from 600mg/m 2 /dose aiming for 2h post-administration plasma concentration of 2μg/ml and trough <1μg/ml Results: 1340mg/m 2 /dose 12h average dose required to achieve levels However renal & bone marrow function monitored but no results recorded Kimberlin et al 2011 Aim: to assess neurodevelopment outcome after HSV disease with and without aciclovir prophylaxis Method: 45 neonates post-hse & 29 post-sem disease randomly assigned to oral aciclovir 300mg/m 2 TDS for 6 months or placebo Bayley Scales at 12m performed in 62% of the post-hse group Results: Improved neurodevelopmental outcomes with aciclovir vs. placebo Infants suffering 2 cutaneous recurrences switched to aciclovir No significant difference in neutrophil counts However 31% infants in treatment group had 2 cutaneous recurrences, and 1/24 had a CNS recurrence

15 Sick neonate/infant maternal suppressive ACV treatment during pregnancy does not completely eliminate HSV asymptomatic shedding and MTCT of HSV infection BPSU : Diagnosis of maternal genital infection prior to delivery was extremely rare although most infected infants present within first two weeks of life, onset of disease symptoms and signs may occur during the first 24 hours and has been described beyond 30 days SEM disease may progress to CNS and disseminated disease if untreated

16 Sick neonate/infant At the time of presentation: absence of fever is common up to 40% of patients do not have skin vesicles (nor develop them) skin lesions may appear in areas of trauma and may not be frankly vesicular sepsis-like picture with respiratory and hepatic failure, severe coagulopathy (DIC) and marked elevation of ALT are typical findings of disseminated disease CNS disease can present with temperature instability, focal/generalised seizures, lethargy, irritability, tremors, poor feeding and bulging fontanelles, which can progress to hypotension, apnoea and shock & skin/mucosal lesions (~60-70%) Bacterial or fungal neonatal infections are more common than HSV Other viruses present in a similar way to HSV

17 Areas of debate Type of delivery Type of delivery if suppressive therapy received Suppressive therapy if recurrence Management if born to recurrent mothers +/- suppressive therapy Management if born to 1 st episode mothers +/- suppressive therapy +/- C-section Repeat CSF at end of treatment Length & dose of post treatment prophylaxis Threshold for starting/continuing aciclovir in the sick neonate/infant (with no known risk) -? At presentation? At presentation based on ALT/coag? If unresponsive to abx

18 Research priorities What is the current UK incidence? What are the current UK risk factors? Which mothers need LSCS? Which babies need tests +/- treatment? How long should prophylaxis be given for?