Enteroviral Chemotherapy

Transcription

1 Enteroviral Chemotherapy 1. Enviroxime & associated compounds Inhibit RNA replication Toxicity & bioavailability problems 2. 3C Protease Inhibitors Block protein synthesis Phase I trials 3. Capsid-binding compounds Prevent viral attachment & uncoating Pleconaril (Picovir )

2 Pleconaril in neonatal enteroviral sepsis Phase III open-label compassionate use trial 14 subjects with proven EV infection 12 treated with full 7 day course 10 survived

3 Cytomegalovirus

4 Cytomegalovirus Family: Herpesviridae Subfamily: Betaherpesvirinae Symmetry: icosahedral capsid Genome: dsdna Spherical lipid envelope Multinucleate giant cells Latent infection

5 Epidemiology Primary infection Recurrent infection - reactivation - reinfection No seasonal predilection

6 Transmission Saliva Urine Blood Semen (2%) Breastmilk Cervical secretions Transplacental Transplant tissue 10% shedding virus at any one time 90% of immunosuppressed patients

7 Seroepidemiology World-wide pathogen Dependent on: socioeconomic status cultural background geographic location sexual practices exposure to children age

8 Seroepidemiology 2 Increased rate during childhood, adolescence and child-bearing years Developed countries: 1 year 14% 2 years 26% 10 years 33% Adults 40-60%

9 Seroepidemiology 3 Developing countries: 3 years 80% adults >90%

10 Routes of Infection Transplacental - haematogenous Perinatal - genital secretions, breast milk, saliva Later - toddlers in day-care etc. Adults - sexual / non-sexual close contact

11 Congenital CMV 0.3-2% of all live births 1 o infection (3-6/1000 pregnancies) 10% symptomatic Mortality 10-30% Long-term sequelae Owl-eye viral inclusions Rash Hepatosplenomegaly

12 Fetal Infection Primary: Reactivation: 1-4% of women 20-50% fetal infection 10-30% of women 1-3% fetal infection

13 Neonatal disease Asymptomatic (90%): 10-15% long term sequelae Symptomatic (10%): % long term sequelae

14 Case - Mrs M.S. 30 years, school teacher Good general health G 4, P 2

15 Referred at 16/40 Persisting lethargy following flu-like illness at 6/40

16 Serology Toxoplasma IgG & IgM negative CMV IgG & IgM positive

17 Serology 9/40 12/40 15/40 CMV IgG 2.3 pos 2.5 pos 2.3 pos CMV IgM 0.79 pos 0.70 pos 0.41 pos

18 1. Was the maternal illness at 6/40 gestation a primary CMV infection?

19 Serology Previous pregnancy 9/40 12/40 15/40 CMV IgG 0.05 neg 2.3 pos 2.5 pos 2.3 pos CMV IgM 0.10 neg 0.79 pos 0.70 pos 0.41 pos

20 1. Illness at 6/40 Seroconversion between October & April IgM positive IgG avidity testing Clinical illness consistent with CMV CMV culture unhelpful

21 2. What risks are there to the fetus?

22 2. Risks to the fetus Fetal infection risk: 20-50% 90% chance of being normal at birth with 10-15% chance of later problems 10% chance of symptomatic congenital CMV at birth with high risk (>90%) of long term problems

23 3. How can we confirm fetal infection?

24 3. Confirming fetal infection Amniotic fluid - culture + PCR sensitivity dependent on timing >95% after 20/40 80% before 20/40 Fetal (cord) blood: IgM sensitivity 70-80%, specificity 97% CMV culture sensitivity 10% non-specific - anaemia, platelets, LFT Serial ultrasound

25 4. If the fetus is infected, what action should be taken?

26 4. Action if fetus infected 10-20% of infected fetuses have symptomatic CMV at birth Counselling for termination?? Serial ultrasound

27 Progress Amniocentesis 17/40: CMV viral culture negative CMV PCR negative Serial ultrasounds - NAD

28 Delivery 39/40, spontaneous NVD Female, 3760g, Apgar 6 1, 9 5 Active and generally well Bilateral clicky hips Urine CMV culture 1/52 - no growth

29 5. If the baby is normal at birth, what action should be taken?

30 5. Action if baby normal at birth Serial audiometry - deafness 5-15% (3% bilateral) delayed up to 5 years Serial visual assessment - chorioretinitis / optic atrophy (2%) Psychomotor assessment - microcephaly, dev. delay, behavioural Pneumonitis 1-4 months, rare

31 6. If the baby is symptomatic at birth, what action should be taken?

32 6. Baby symptomatic at birth Confirm diagnosis with CMV culture in first 2 weeks Cranial ultrasound + other imaging Multidisciplinary approach to management - developmental paediatrician - early intervention program - physiotherapy, speech & O.T. - audiometry, visual assessment

33 Ganciclovir Treatment Limited studies - phase II Only administered to symptomatic neonates 12mg/Kg/day for 6/52 Reduced viraemia and shedding Long-term follow-up required Concerns about carcinogenicity and reproductive toxicity

34 CMV Vaccine Experimental live attenuated vaccine Reduces occurrence of severe illness in immunosuppressed subjects by % No effect on rate of infection Degree of fetal protection unknown Future: DNA, subunit, vector vaccines

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36 Rubella

37 Rubella Described in Germany Accepted as a distinct disease Viral aetiology confirmed Associated with congenital syndrome Isolated in tissue culture Commercial serological tests First vaccines Vaccination in Australia commenced (boys vaccinated from 1989)

38 Rubella Virus Family: Togavirus Genus: Rubivirus ssrna, enveloped Humans only reservoir Winter-Spring peak

39 Rubella 25-50% infections asymptomatic Nasopharyngeal secretions Highly infectious: 50-90% of susceptibles in an outbreak Infectious from -7 to +14 days IP days

40 Rubella Clinical Presentation Fever low-grade Lymphadenopathy (95%) occipital, postauricular, posterior cervical Exanthem maculopapular; face trunk limbs Polyarthralgia / arthritis

41 Congenital Rubella Syndrome Risk of damage <4/40 85% 4-8/40 20% 9-12/40 5% >16/40 Rare Gestational age influences defects >12/40 retinopathy and deafness only

42 Congenital Rubella Syndrome Outcome 1/3 1/3 1/3 lead normal life live with parents institutionalised

43 Congenital Rubella Syndrome Classical triad Ophthalmological cataracts, glaucoma, retinopathy Cardiac PDA, PA stenosis Auditory sensorineural deafness Cataracts Rubella pneumonitis

44 Congenital Rubella Syndrome Neurological meningoencephalitis, behavioural Others IUGR, blueberry muffin rash, HSM, thrombocytopenia, radiolucent bone disease Late endocrinopathies - IDDM (20%; 200x general population); thyroid dysfunction (5%) Long bone changes

45 Rubella APSU Surveillance cases Rate: 1.2 / 100,000 21/27 had defects (17 multiple)

46 Investigation of illness/contact Serological confirmation IgG seroconversion or rising titre IgM confirm with re-bleed or fractionation Fetal diagnostic testing AF, cord blood, CVS FetalIgM PCR

47 Rubella - Prevention Vaccine (live attenuated) 95% immunogenic 90% lifelong protection Seronegative women vaccinated postpartum Avoid vaccination during pregnancy Immunoglobulin Reduces clinical infection (87% to 18%) May use as pre-exposure prophylaxis May not influence foetal infection Use if termination not possible

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49 Neonatal Herpes Simplex Virus Sepsis

50 Herpes Simplex Virus 1 o infection during pregnancy Abortion, IUGR, preterm labour <1% 1 o infection near delivery SEM, encephalitis, disseminated Type-specific serology for clinically discordant couples Immunofluorescence

51 Case - Baby Nadia

52 History 38/40, uneventful pregnancy NVD, Apgar , 3420g Day 4 Reduced feeding with weak cry Coughing and cyanosis with feeds Febrile, 38.7 o C

53 Investigations CXR: RUL consolidation Hb 17.7, WCC 10.5, Plt 163 toxic granulation CSF: no cells, Prot 0.63 g/l, gluc 2.6 Ampicillin + gentamicin

54 Day 5 Day 5 - Babygram

55 Progress - Day 5 Abdominal distension + diarrhoea Barium swallow no evidence of TOF suggestive of malrotation Abdominal ultrasound whirlpool sign + metronidazole

56 Day 5 Day 5 - Barium Meal Barium Meal

57 Laparotomy

58 Progress Day 6-7 Day 8 + acyclovir decreased urine output generalised oedema oozing from venepuncture sites worsening LFT s and clotting

59 Results Coagulation APTT 95 INR 2.9 PT 35.2 Platelets 79

60 Diagnosis?

61 Additional Information 3mm crusted scalp lesion Mother: perineal burning and diarrhoea Father: recurrent cold sores

62 Progress Day 9 Rectal bleeding - 3 litres in 48 hours Oliguric renal failure Scalp lesion HSV IF positive (day 9) HSV PCR positive (day 9) HSV-1 isolated (day 11) Cerebrospinal fluid HSV + EV PCR negative

63 Scalp lesion: immunofluorescence HSV-1

64 Western Blot HSV-1 HSV-2 gg1 gc1 130K 130K 140K gg2 gg2 92K 140K 92K (HSV-2 ELISA)

65 Point-of-care HSV Assay

66 Further Progress Day 22 ascites, unsettled contrast study: no perforation peritoneal drain: PMN +++, E. coli vancomycin, gentamicin, metronidazole

67 Progress - Day 23 Febrile, tachycardia, increasing ventilation requirements, dopamine

68 Laparotomy - Day 23 Large sigmoid colon perforation Peritoneal contamination Sigmoid colectomy Proximal sigmoid end colostomy

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71 HSV PCR gel HSV PCR gel MWt Colon HSV-1 Water HSV-2