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Home , Eczema vaccinatum, Progressive vaccinia

The curse of the Scholarly Selective DR EDDIE CHAN VIDS REGISTRAR ROYAL MELBOURNE HOSPITAL INTRODUCTION .30M .Medical student .Working in an immunology laboratory PDI Used with patient’s express permission Used with patient’s express permission Used with patient’s express permission .Systemically well .Afebrile

.No response to keflex

.No topical steroids used

Used with patient’s express permission Journey to medical school .Past Hx • in childhood • Hypertension  Candesartan • Dry skin  diprosone ointment previously

.Antibodies to: • VZV, , mumps, • Hep B (SAb)

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

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 2015 - research collaborators • OX40 assay: normal T-cell response to Staph enterotoxin B and tetanus toxoid • CD38 upregulated following vaccination to vaccinia

The search for the . PCR negative .Lesion base .Scab

.EM on hold

.Skin swab for M/C/S: • leucocytes negative • culture: negative

HISTOLOGY

H&E x40

Vaccinia – the vaccine .Like variola, belongs in the Orthopoxvirus .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

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

Who to vaccinate? .Lab staff using live pox virus in research .Australian Immunisation Handbook 9th edition (2008) .CDC recommendation ◦ Laboratory workers who directly handle cultures contaminated or infected with vaccinia, recombinant vaccinia, or other (such as , , 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

Don’t [knowingly] vaccinate… .Impaired immunity .Pregnant/trying to get • HIV/AIDS pregnant/breastfeeding • Leukaemia/lymphoma .Children <1 • General malignancy .Vaccinated within last 30 days with a • Agammaglobulinaemia live vaccine • High steroid doses .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

Vaccinia related AE - 1968

Lane; J Infect Dis (1970); 122(4): 303-309 Vaccinia related AE – 2002-05

Poland; Vaccine (2005): 2078-81 Generalised vaccinia . is a disseminated macropapular or vesicular 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 .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 Generalised vaccinia Used with patient’s express permission .Predilection for areas currently or previously affected by atopic .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 .Mortality rate 5-30% .Children > adults .Mx: • VIG Eczema vaccinatum Used with patient’s express permission Eczema vaccinatum .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 • Bray; CID (2003); 36:766-74 • Antivirals () Vellozzi; CID (2005); 41:689-97

Progressive vaccinia Bray; CID (2003); 36:766-74

Treatment options .Vaccinia immunoglobulin .Methisazone • prepared as a ∼20-fold concentrate of g-globulin from • Antiviral pooled plasma samples obtained from recently vaccinated military recruits • Thiosemi-carbazone derivatives were found to inhibit the replication of vaccinia virus • A single inoculation of 0.6–1mL/kg of body weight was reported to produce prompt remission of generalized • Used in combo with VIg vaccinia and rapid improvement in many cases of eczema vaccinatum .Ribavirin • patients with progressive vaccinia often received multiple • Used in 1 case injections over the course of weeks to months

.Cidofovir .Others (human fibroblast interferon, adeninie • highly protective against rapidly lethal orthopoxvirus infection in laboratory animals arabinoside, idoxuridine, whole blood) • No effect .Immunomodulators • Mice work: Th1 cytokines IL-2 and IFN-g stimulate orthopoxvirus clearance Bray; CID (2003); 36:766-74 Lederman; JID (2012); 206: 1372-85

. 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 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 “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!!!” 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?)

Uncle Jack, what are they? Picked up bubonic plague last weekend… Don’t they hurt? These, no – they’re just buboes! Acknowledgements .A/Prof Damon Eisen

.Dr Justin Denholm & Dr Irani Thevarajan