The curse of the Scholarly Selective DR EDDIE CHAN VIDS REGISTRAR ROYAL MELBOURNE HOSPITAL

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Oswald Clarke
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1 The curse of the Scholarly Selective DR EDDIE CHAN VIDS REGISTRAR ROYAL MELBOURNE HOSPITAL

2 INTRODUCTION 30M Medical student Working in an immunology laboratory PDI

3 Used with patient s express permission

4 Used with patient s express permission

5 Used with patient s express permission

6 Systemically well Afebrile No response to keflex No topical steroids used Used with patient s express permission

7 Journey to medical school Past Hx Chickenpox in childhood Hypertension Candesartan Dry skin diprosone ointment previously Antibodies to: VZV, Measles, mumps, rubella Hep B (SAb)

9 Oh, yeah.. Inoculated with live vaccinia on 3/2/2015 R deltoid site healed over completely 5 weeks post vaccination Minor regional lymphadenopathy

11 INVESTIGATIONS Normal FBE HIV negative CXR (9/5/15): normal 3x indeterminant Interferon-gamma release assays Negative Mantoux in past T-cell function measured in Feb research collaborators OX40 assay: normal T-cell response to Staph enterotoxin B and tetanus toxoid CD38 upregulated following vaccination to vaccinia

12 The search for the virus Orthopoxvirus PCR negative Lesion base Scab EM on hold Skin swab for M/C/S: leucocytes negative culture: negative

13 HISTOLOGY H&E x40

15 Vaccinia the smallpox vaccine Like variola, belongs in the Orthopoxvirus genus dsdna virus, 200kb Vax = replication competent strain Scarification bifurcated needle Formation of an erythematous papule within 3 to 5 days. It becomes a vesicle, then a pustule reaching a maximum size of 1 to 2 cm in 8 to 12 days, then scabs and separates by 14 to 21 days Spread by direct contact through broken or abrasions to skin or mucosal membranes

16 The vaccinia vaccine ACAM2000 Live, replication-competent vaccinia virus Derived from a plaque-purified clone of the same strain that was used to manufacture Dryvax vaccine Grown in African green monkey kidney (Vero) cells Administered in a single dose in the upper arm over the deltoid muscle by the percutaneous route (scarification) using 15 jabs of a stainless steel bifurcated needle cutaneous reaction: the development of a vesicle or pustule at the site of inoculation Risk of adverse effects Imvamune 3 rd generation vaccine Highly-attenuated live vaccine replication-restricted to avian cells following >570 passages in primary chicken embryo fibroblast cells Injected subcutaneously in 2 doses at 0 and 4 weeks for primary vaccinees Does not produce a visible cutaneous reaction following administration Safer Efficacy unproven CDC MMWR (2015) 64 (2):1-26

17 Who to vaccinate? Lab staff using live pox virus in research Australian Immunisation Handbook 9 th edition (2008) CDC recommendation Laboratory workers who directly handle cultures contaminated or infected with vaccinia, recombinant vaccinia, or other orthopoxviruses (such as monkeypox, cowpox, and others) Laboratory workers who directly handle animals contaminated or infected with vaccinia, recombinant vaccinia, or other orthopoxviruses Public health and health care response team members Military personnel

18 Don t [knowingly] vaccinate Impaired immunity HIV/AIDS Leukaemia/lymphoma General malignancy Agammaglobulinaemia High steroid doses Chemotherapy Pregnant/trying to get pregnant/breastfeeding Children <1 Vaccinated within last 30 days with a live vaccine Prev Hx of cardiac disease AMI/angina CCF/cardiomyopathy Valvular disease Eczema diagnosis (even if mild, or not presently active) Anyone living in a household with a member who has any of the conditions as listed above

20 Vaccinia related AE Lane; J Infect Dis (1970); 122(4):

21 Vaccinia related AE Poland; Vaccine (2005):

Generalised vaccinia Generalized vaccinia is a disseminated macropapular or vesicular rash appearing anywhere on the body The skin lesions of generalized vaccinia are thought to contain virus spread

22 Generalised vaccinia Generalized vaccinia is a disseminated macropapular or vesicular rash appearing anywhere on the body The skin lesions of generalized vaccinia are thought to contain virus spread by the haematogenous route 5-9 days after smallpox vaccination May be accompanied by fever Can also appear as a regional form that is characterized by extensive vesiculation around the vaccination site or as an eruption localized to a single body region Usually self limiting Vellozzi; CID (2005); 41:689-97

23 Generalised vaccinia

24 Used with patient s express permission

Eczema vaccinatum Predilection for areas currently or previously affected by atopic dermatitis Disrupted skin in patients with atopic dermatitis permits viral implantation Local rash

25 Eczema vaccinatum Predilection for areas currently or previously affected by atopic dermatitis Disrupted skin in patients with atopic dermatitis permits viral implantation Local rash generalised, pox like eruption papular, vesicular, pustular, or erosive rash syndrome 5-19 days after exposure Lesions become necrotic + secondary infection Mortality rate 5-30% Children > adults Mx: VIG

26 Eczema vaccinatum

27 Used with patient s express permission

28 Eczema vaccinatum

Progressive vaccinia Due to continued vaccinia virus replication Enlargement of the primary inoculation site spreading to other parts of the body initial vaccination lesion continues to progress

29 Progressive vaccinia Due to continued vaccinia virus replication Enlargement of the primary inoculation site spreading to other parts of the body initial vaccination lesion continues to progress without apparent healing >15 days after smallpox vaccination Initial vesicles have no surrounding erythema & oedema Spread of virus in deep tissue necrosis & osteomyelitis Slower pace of development Results from defects in cell mediated immunity Mx: VIG Antivirals (cidofovir) Bray; CID (2003); 36: Vellozzi; CID (2005); 41:689-97

30 Progressive vaccinia

31 Bray; CID (2003); 36:766-74

32 Treatment options Vaccinia immunoglobulin prepared as a 20-fold concentrate of g-globulin from pooled plasma samples obtained from recently vaccinated military recruits A single inoculation of 0.6 1mL/kg of body weight was reported to produce prompt remission of generalized vaccinia and rapid improvement in many cases of eczema vaccinatum patients with progressive vaccinia often received multiple injections over the course of weeks to months Cidofovir highly protective against rapidly lethal orthopoxvirus infection in laboratory animals Immunomodulators Mice work: Th1 cytokines IL-2 and IFN-g stimulate orthopoxvirus clearance Methisazone Antiviral Thiosemi-carbazone derivatives were found to inhibit the replication of vaccinia virus Used in combo with VIg Ribavirin Used in 1 case Others (human fibroblast interferon, adeninie arabinoside, idoxuridine, whole blood) No effect Bray; CID (2003); 36:766-74

US marine vaccinated with vaccinia, then developed AML req induction chemo Diagnosed as progressive vaccinia (blood), complicated by superimposed bacterial infection Mx with: VIg o 341

33 US marine vaccinated with vaccinia, then developed AML req induction chemo Diagnosed as progressive vaccinia (blood), complicated by superimposed bacterial infection Mx with: VIg o 341 vials used ST-246 (oral, topical) o 73 days oral, 68 days topical CMX-001 (prodrug of cidofovir) o 6x weekly doses Immune reconstitution important factor Lederman; JID (2012); 206:

34 Is this vaccinia 1. Temporal pattern is inconsistent 2. Patient is completely well 3. Lesion swabs PCR negative for orthopoxvirus 4. Histopathology doesn t show vaccinia

35 Of course it s discoid eczema! It can t be anything else! Its not related to the vaccine if that s what you re thinking!!!

36 Further Questions Why now, post vaccination? How common is discoid eczema post vaccination? Could it still be Vaccinia (ie. how sensitive is the PCR for picking up poxvirus in a human case?)

37 Uncle Jack, what are they? Picked up bubonic plague last weekend Don t they hurt? These, no they re just buboes!

38 Acknowledgements A/Prof Damon Eisen Dr Justin Denholm & Dr Irani Thevarajan

Smallpox Recognition and Vaccination

Smallpox Recognition and Vaccination Daniel R. Lucey, MD, MPH Georgetown University Medical and Law Centers Senior Scholar, O Neill Law Institute for Global Health Hong Kong Centre for Health Protection