Smallpox (3)

Smallpox : 

Smallpox Dr.G.Sreekanth Post graduate Dept of community medicine Guntur medical college, Guntur

: 

Smallpox is a serious, contagious and sometimes fatal disease. There is no specific treatment for smallpox, and the only prevention is vaccination. The name smallpox is derived from the latin word “spotted” and refers to the raised bumps that appear on the face and body of an infected person. Smallpox is in the Orthopoxvirus genus of viruses. Smallpox

Origin of Smallpox : 

Origin of Smallpox The name Variola was first used in the 6th century. Derived from the Latin word varius (spotted) or varus (pimple). Anglo-Saxons in the 10th century used the word poc or pocca (bag or pouch) to describe an exanthemous disease, possibly smallpox. In the 15th century, the English used the prefix small to distinguish variola the smallpox from syphilis, the great pox.

First Case of Smallpox : 

First Case of Smallpox There is no animal reservoir, and no human carriers. First certain evidence comes from the mummified remains of Ramses. (1157 B.C.) Written descriptions did not appear until the 10th century in Southwestern Asia.

Smallpox Travel : 

Smallpox Travel Smallpox was likely carried from Egyptian traders to India during the millennium B.C. where it became established as an endemic infection. Epidemics of the disease can be found in the bible, and in ancient Greek and Roman literature. From Asia and Africa smallpox spread with increasing frequency into less populous areas, and then into Europe.

Smallpox in the Ancient World : 

Smallpox in the Ancient World Peloponnesian Wars (430 B.C.) Thucydides recorded smallpox symptoms. A person aboard a ship from North Africa came to Athens infected with smallpox. Described as violent heats, unnatural, putrid odors, stomach distress, and the body covered with small pustules and ulcers. Also noted that those who survived became immune.

Smallpox in the New World : 

Smallpox in the New World In the early 16th century smallpox began to imported into the western hemisphere. The Spanish inadvertently owe success in conquering the Aztec and Incas in Mexico to smallpox. Smallpox arrived in North America via Canada, and Mexico.

Smallpox as Biological Warfare : 

Smallpox as Biological Warfare Lord Jeffrey Amherst, Commanding General of British Forces in North America during the French and Indian War. (1754-1763) Used blankets (smallpox blankets) coated with smallpox dust as germ warfare to wipe out the Native American population.

History of Variolation and Vaccine : 

History of Variolation and Vaccine Known that survivors became immune to the disease. As a result, physicians intentionally infected healthy persons with smallpox organisms. Variolation is the act of taking samples (pus from pustules or ground scabs) from patients whose disease had been benign, and introducing it into others through the nose or skin

Survival Rates with Variolation : 

Survival Rates with Variolation Two to Three percent of variolated persons died of smallpox, became the source of a new epidemic, or developed other illnesses from the lymph of the donor such as tuberculosis or syphilis. The case fatality rates were still ten times lower in those that were variolated compared to those with naturally occurring smallpox. Side effects of variolation were the appearance of smallpox itself, but it would disappear after a week or so.

Variolation in the New World : 

Variolation in the New World Reached the New World in 1721. Used to stop the epidemic in Boston. In 1766 American Soldiers under George Washington were unable to take Quebec from the English because of smallpox. Smallpox was apparently one of the main causes of the preservation of Canada in the British Empire. In 1777 Washington had all of his soldiers variolated beginning with new military operations.

Cows, Milkmaids, and the Pox : 

Cows, Milkmaids, and the Pox In rural areas of Europe it was known the milkmaids became immune to smallpox after developing smallpox 1774, farmer Benjamin Jesty was the first to vaccinate his wife and kids with material taken from the utters of cows. 1791, school teacher Peter Plett vaccinated his students with material from the utters of cows.

Edward Jenner : 

Edward Jenner

Edward Jenner : 

Edward Jenner Studied to become a physician in England. In May of 1776 dairymaid Sarah Nelmes consulted Jenner about a rash on her hand. He took this opportunity to test the protective properties of cowpox against smallpox. Determined that cowpox can be passed from person to person as well as from cow to person. The next step was to see if the cowpox would protect the patient from smallpox.

Eradication : 

Eradication In 1801 Jenner said, “The annihilation of the smallpox, the most dreadful scourge of the human species, must be the final result of this practice.” Compulsory vaccinations began in the following years: 1807 in Bavaria 1810 in Denmark 1835 in Prussia 1853 in Britain

Eradication : 

Eradication 1940s: large scale preparations of a stable freeze dried vaccine was perfected by Collier. 1950: Pan American Sanitary Organization decided to undertake a hemisphere wide eradication program. 1958: Union of Soviet Socialist Republics proposed to the WHO that a global smallpox eradication program be undertaken.

Eradication : 

Eradication The campaign was based on a two fold strategy. 1) Mass vaccination campaigns in each country using a vaccine of ensured potency and stability that would reach at least 80% of the population. 2)Development of a system to detect and contain cases and outbreaks.

Eradication : 

Eradication 26 October 1977 the last naturally occurring case of smallpox was recorded in Merka Somalia. In 1978 two cases were reported. These were both from people working in labs with smallpox in England.

Eradication : 

Eradication 1980: WHO formally declared that smallpox was dead. The eradication of smallpox was one of the most important branches of modern medicine. Jenner has been acknowledged as the father of immunology,

Problem statement : 

Problem statement Known in ancient times Described by Ramses Natural disease eradicated Last U.S. case – 1949 (imported) Last international case – 1978 Most deaths of any infectious disease ~500 million deaths in 20th Century ~2 million deaths in 1967 Declared eradicated in 19

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TAXONOMY FAMILY: POXVIRIDAE SUBFAMILY: CHORDOPOXVIRINAE (infect vertebrates) GENERA: ORTHOPOXVIRUS (variola, vaccinia, cowpox, monkeypox) AVIPOXVIRUS (fowlpox) CAPRIPOXVIRUS (sheep-pox) LEPORIPOXVIRUS (myxoma) PARAPOXVIRUS (milker’s nodule) SULPOXVIRUS (swinepox) 2. SUBFAMILY: ENTOMOPOXVIRINAE (infect arthropods)

Slide 22: 

Variola virus – the agent of smallpox Orthopoxviridae family 2 strains of variola Variola major Variola minor Vaccinia Used for current vaccine Namesake of “vaccine” Cowpox – used by Jenner in first vaccine Monkeypox – rare but serious disease from monkeys in Africa

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Variola major Classic smallpox Predominant form in Asian epidemics Highest mVariola minor Same incubation period, mode of transmission, clinical presentation Causes milder disease Less severe prodrome and rash Mortality ~1% Discovered in 20th century

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Started in S. Africa Was most predominant form in N. America ortality (~30%) Environmental survival Longest (>24hr) in low temp/low humidity Inactive within few hours in hi temp/humidity Dispersed aerosol completely inactivated within 2 days of release

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http://books.nap.edu/html/variola_virus/ch2.html#TopOfPage

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CHARACTERISTICS SHARED BY SPECIES OF ORTHOPOXVIRUS : The largest and most complex viruses ight microscope double-stranded DNA They replicate in the cytoplasm of the host cell, therefore they must provide their own mRNA and DNA synthetic machinery (including DNA-dependent RNA polymerase) - Inclucison bodies: type B and type A Virions have a brick-like shape and are present in 2 forms, both are infectious: 1. EEV (Extracellular Enveloped Virus) 2. IMV (Intracellular Mature Virus) Serological cross-reactivity - Produce a hemagglutininin antigen (HA) - Vaccinia is the most intensively studied member of the poxvirus family

Slide 27: 

Fenner,F. et al. Smallpox and Its Eradiction. Genevea, Switzerland:WHO. 1998:1460

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Fenner,F. et al. Smallpox and Its Eradiction. Genevea, Switzerland:WHO. 1998:1460

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MORPHOLOGY OF THE VIRION - have an brick-like shape; dimensions 400x200nm - four major elements: 1. core ( 9 nm thick membrane, biconcave disk, a tightly compressed nucleoprotein) 2. lateral bodies ( unknown function) 3. outer membrane ( a protein shell 12nm thick, the surface consists of irregularly arranged tubules) 4. envelope ( an inconstant element, proteins are glycosylated and acylated) - Virons are present in two infectious forms: 1. EEV (Extracellular Enveloped Virus)- released from cells spontaneously, by exocytoses are enclosed within a lipoprotein envelope, which contains the haemagglutinin and other specific polypeptides - CEV (Cell Associated Enveloped Virus) 2. IMV (Intracellular Mature Virus) – released by cellular disruption, lacks envelope, “naked virus”

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Vaccinia Virus – Electron micrographs A. Non- enveloped virion (surface of outer membrane with tubular elements) C. Thin section of non-enveloped virion (biconcave core) B. Enveloped virion, found in extracellular medium D. Viral core, released after treatment of virions with Nonidet Fenner,F. et al. Smallpox and Its Eradiction. Genevea, Switzerland:WHO. 1998:1460

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Cytoplasmic inclusion bodies in infected cells B-type (Guarnieri bodies)- sites of viral replication produced by all orhopoxviruses A-type – strongly eosinophilic, found in cells infected with: cowpox,ectromelia and raccoonpox virus; appear late in the infection and are not associated with viral replication (may contain mature virions) Fenner,F. et al. Smallpox and Its Eradiction. Genevea, Switzerland:WHO. 1998:1460

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STRUCTURE OF THE VIRAL GENOME - Schemat of vaccinia virus DNA - Contains a single linear molecule of a double stranded DNA About 200 kbp long; guanine+cytosine content 36% - when denatured the two sister strands form a large single-stranded circular molecule, being attached at each end of the genome by covalent links - for the most part, the DNA sequences in the central part of the genome are unique, but the terminal fragments (inverted terminal repeats) cross-hybridize with each other and with the termini of other species of orthopoxvirus - The ITR’s include: an A+T-rich, incompletely base-paired, hairpin loop that connects the two DNA strands; set of short tandemly repeated sequences. The ITR’s are variable in length owing to deletions, repetitions, and transpositions - Inverted repeats in vaccinia are 10 kbp long in variola are 725 bp - Variola vs. Vaccinia: genomes are highly conserved with >95% nucleotide identity, however towards the termini the sequences diverge Poxviruses that have been inactivated that don’t damage their DNA can be reactivated

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Encodes about 200 proteins The central part of the genome encodes for structural and functional proteins; Virulence genes are found near the inverted repeats, -numerous virus-encoded enzymes,are packaged within the virus core, including: * multisubunit DNA-dependent RNA polymerase * RNA polymerase associated protein of 94kd (RAP94) * a transcription factor (VETF) * capping and methylating enzymes * poly(A) polymerase These components are used to synthesize translatable mRNA -Importatnt proteins for replication: * topoisomerase * thymidine kinase – allows the incorporation of Thymidine into DNA * thymidylate kinase – catalyzes the reversible phosphorylotransfer between ATP and TMP * ribonuceoside reductase – converts ribonucleoside diphosphates ( NDP’s ) into deoxyNDP’s * dUTPase – minimize the misincorporation of Uracil into DNA * Uracil-DNA gylclosylase – removes the RNA base (Uracil) from DNA * DNA ligase VIRAL PROTEINS

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non enzymatic -VIRAL PROTEINS Membrane proteins: A33R, A34R, A36R :*N-glycosylated, phosphorylated * fromation of actin tail and microvilli, which facilitate viral dissemination A36R : required for kinesin recruitment and is involved in microtubule-based motility of IEV’s A56R: Hemagglutinin, N- and O- glycosylated , promote cell fusion and cell to cell viral spread A27L: required for the formation of IEV, fusion protein, microtubule –dependent movment, normal sized plaques , has additional role in the viral assembly A28L: fusion protein; A28 deficient virions with normal amounts of A27 and A17 (binding partner) are unable to induce cell fusion 2. Core proteins: F17R, L4R, A3L, A10L : account for ~70% of the viral core by weight, bind DNA

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VIRAL IMMUNOMODULATORY STRATEGIES Poxviruses encode multiple classes of immunomodulatory proteins to inhibit diverse processes as: * apoptosis * the production of interferon * the production of chemokines and inflammatory cytokines * the activity of complement, NK, CTL’s, antibodies 2. The inhibitory proteins, produced by virus, fall into three main classes: - Virokines * resemble host cytokines * secreted from infected cells to block hosts receptors * vIL-10, vIL-18 - Viroreceptors * mimic host cellular receptors * altered cellular receptors that have lost their transmembrane sequnces and consequently are secreted from infected cells to sequester ligands * vINF-Rs, vTNFRs - Intracellular proteins * target host signal transduction pathways * inhibit inner antiviral pathways: apoptosis – vFLIP’s, serpins proinflammatory cascades - TNF

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VIRAL IMMUNOMODULATORY PROTEINS Complement Regulatory Proteins - VCP – Vaccinia virus Complement control Protein, consists of short consensus repeats found in hosts’ complement regulatory proteins. Inhibits the classic and alternative pathways of complement through binding and inactivating both C4b and C3b SPICE- the smallpox inhibitor of complement enzymes molecularly engineered homologue of VCP (Rosengrad et al;.Univ. of Penn.) Demostrated: the functional advantage of variola complement regulatory protein Over the vaccinia homologue - More human complement specific than VCP 100-fold more potent at inactivating C4b&C3b; SPICE serves to inhibit the formation of the C3/C5 convertases necessary for Complement-mediated viral clearance SPICE- provides the first evidence that variola proteins are particulary adept at overcoming human immunity, and the decreased function of VCP suggests one reason why the vaccinia virus vaccine was associated with relatively low mortality. Disabling SPICE may be useful therapeuticaly

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All ages and genders affected Incubation period From infection to onset of prodrome Range 7-17 days Typical 12-14 days Epidemiology Humans are the only natural host of smallpox

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Transmission Airborne route known effective mode Initially via aerosol in BT attack Then person-to-person Hospital outbreaks from coughing patients Highly infectious <10 virions sufficient to cause infection Aerosol exposure <15 minutes sufficient

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Person-to-person transmission Secondary Attack Rate (SAR) 25-40% in unvaccinated contacts Relatively slow spread in populations (compared to measles, etc.) Higher during cool, dry conditions Historically 3-4 contacts infected May be 10-20 in unvaccinated population Very high potential for nosocomial spread Usually requires face-to-face contact

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Transmission via fomites Contaminated hospital linens/laundry May have been successfully used as weapon in French-Indian war Infectiousness – Rash is marker Onset approx one day before rash Peaks during first week of rash ? Carrier state possible Some data show virus detectable in saliva of contacts who never become infected Unclear if they can transmit infection, but theoretically possib

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Infectious Materials Saliva Vesicular fluid Scabs Urine Conjunctival fluid Possibly blood

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Role of index case severity Does not predict transmissibility Does not predict severity of 2° cases Role of prior vaccination Immunity wanes with time Maintain partial immunity for many years Partial immunity reduces disease severity Reduces transmissibility (less virus shed

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Mortality 25-30% overall in unvaccinated population Infants, elderly greatest risk (>40%) Higher in immunocompromised May be dependent on ICU facilities Dependent on virus strain Dependent on disease variant

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Factors that allowed smallpox eradication Slow spread Effective, relatively safe vaccine No animal/insect vectors No sig. carrier state (infected die or recover) Infectious only with symptoms Prior infection gives lifelong immunity International cooperation

Smallpox : 

Smallpox Clinical Presentations, Transmission, Treatment, Vaccination

Pathogenesis of Smallpox : 

Pathogenesis of Smallpox Virus lands on respiratory/oral mucosa Macrophages carry to regional nodes Primary viremia on Day 3 Invades reticuloendothelial organs Secondary viremia on Day 8 White Blood Cells infected WBCs migrate capillaries, invade dermis Infects dermal cells Influx of WBCs, mediators cause vesicle Systemic inflammatory response Triggered by viremia Sepsis, multiorgan failure, often DIC

Pathogenesis of Smallpox : 

Pathogenesis of Smallpox Severity of disease Not influenced by severity of source case Probably related to degree of viremia Inoculation dose Longer exposure, higher concentration at release Virulence of variola strain, engineered resistance Host immune status Type of rash predictive of outcome More severe rashes = poorer outcomes

Pathogenesis of Smallpox : 

Pathogenesis of Smallpox Three stages of disease Incubation Asymptomatic Prodromal Nonspecific febrile illness, flu-like Eruptive Characteristic rash After introduction of smallpox into the oropharyngeal cavities it spreads to the regional lymph nodes

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Incubation Stage From time of infection to onset of symptoms Average 12-14 days (range 7-17) Important for epidemiologic investigation Considered non-infectious during this stage Virus sometimes culturable

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Variola Major has 4 clinical presentations based on the nature and evolution of the lesions; those 4 types are: Ordinary: most frequent (more than 90% of cases in both vaccinated and unvaccinated persons); corresponds to classical description of smallpox Modified: milder and may occur in previously vaccinated people; rarely fatal Flat and Hemorrhagic: very severe but uncommon

Stages of Smallpox : 

Stages of Smallpox Prodromal Stage Common symptoms High fever, prostration, low back myalgias, HA Occasional symptoms Vomiting, abdominal pain, delirium Duration typically 3-5 days End of stage heralded by mucosal lesions Mucosal lesions onset of infectiousness

Stages of Smallpox: Rash Phase : 

Stages of Smallpox: Rash Phase ClassEruptive Stage (Rash) May start with transient defervescence Characteristic rash Centrifugal (in order of appearance & severity) Initially oral mucosa– borders pre-eruptive stage Head, face Forearms, hands, palms Legs, soles, +/- trunk ic Centrifugal Rash of Smallpox Involving Face and Extremities, Including the Soles.

Stages of Smallpox: Rash Phase : 

Stages of Smallpox: Rash Phase

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Classic Smallpox RasClassic Smallpox Rash, Demonstrating Same Development Stage (Pustular) of All

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Rash stages of development All lesions in one region at same stage Starts macular, then papular Deep, tense vesicles by Day 2 of rash Turns to round, tense, deep pustules Pustules dry to scabs by Day 9 Scabs separate

Stages of Smallpox: Rash Phase : 

Stages of Smallpox: Rash Phase Scarring From separated scabs Fibrosis, granulation in sebaceous glands Pink, depressed pock marks Prominent on face, usually >5 lesions permanent Rash variations Sine eruptione variant Prodrome without rash Clinically less severe

That was “ordinary” smallpox, now for the 3 other types : 

That was “ordinary” smallpox, now for the 3 other types Modified variant Previously vaccinated with partial immunity Milder rash, better outcome, faster resolution prodromal illness Rash variations Ordinary (Classic presentation) variant >90% all cases Subdivided based on confluence of lesions Discrete (<10% mortality) Semiconfluent (25-50% mortality), most common Confluent (50-75% mortality Flat (or

Discrete Type of Classical Smallpox Rash : 

Discrete Type of Classical Smallpox Rash

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Rash variations Flat (Malignant) variant Uncommon Prodrome more sudden, severe More likely severe abdominal pain Rash never forms pustules/scabs Leathery in appearance Sometimes hemorrhagic or exfoliating DDX – acute abdomen, hemorrhagic varicella >90% mortality

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Rash variations Hemorrhagic Rare Prodrome more acute and severe Bleeding diathesis before onset of rash Rash is also hemorrhagic Pregnant women at highest risk (?immune state) Higher risk of transmission (more fluid shedding) DDX – meningococcemia, DIC Mortality 100%

complications : 

complications Sepsis/toxemia Usual cause of death Associated with multiorgan failure Usually occurs during 2nd week of illness Encephalitis Occasional Similar to demylination of measles, varicella Secondary bacterial infections uncommon Staphylococcus aureus cellulitis Responds to appropriate antibiotics Corneal ulcers A leading cause of blindness before 20th Century Conjunctivitis rare During 1st week of illness

When is a person contagious? : 

When is a person contagious? A person with smallpox is sometimes contagious with the onset of fever (the prodrome phase) but a person is most contagious with the onset of the rash Luckily, by the time a person gets the rash they are so sick they can’t likely move around the community An infected person is contagious until the last smallpox scab falls off

Clinical Diagnosis : 

Clinical Diagnosis Clinical diagnosis Sufficient in outbreak setting >90% have classical syndrome Prodrome followed by rash Rarely, variants can be difficult to recognize Hemorrhagic – mimics meningococcemia Malignant – more rapidly fatal Sine eruptione – prodrome without rash Partially immune – milder, often atypical Traditional confirmatory methods Electron microscopy of vesicle fluid Rapidly confirms if orthopoxvirus Culture on chick membrane or cell culture Slow, specific for variola

Newer rapid tests : 

Newer rapid tests Available only at reference labs (e.g. CDC) PCR, RFLP Specimen procurement/handling By recently successfully immunized person Open vesicle with blunt end of blade Collect with cotton swab Place swab into sealed vacuum blood tube Place tube in larger jar, tape lid

Common conditions confused with Smallpox: differential : 

Common conditions confused with Smallpox: differential Varicella (primary infection with varicella zoster virus) Disseminated herpes zoster Impetigo Drug eruptions Contact dermatitis Erythema multiforme minor Eyrthema multiforme (includes Steven Johnsons Syndrome) Enteroviral infection esp. Hand, foot and mouth disease Disseminated herpes simplex Scabies and insect bites Molluscum contagrosum

Treatment of Smallpox : 

Treatment of Smallpox Management of cases Supportive Post-exposure prophylaxis Vaccine Vaccinia immunoglobulin Primary prophylaxis Vaccine Vaccine is administered up to 4 days after exposure to the virus and before the rash appears, provides protective immunity and can prevent infection or ameliorate the severity of the disease There is really no effective treatment, other than the management of the symptoms Adequate fluid intake (difficult) Alleviation of pain and fever Keeping skin lesions clean to prevent bacterial infection Some compounds, such as Cidofovir, are under investigation as chemotherapeutic agents

Vaccination : 

Vaccination In 1796, Edward Jenner demonstrated that immunity to smallpox could be produced by inoculating a human with material from a lesion on the udder of a cow (cowpox); Jenner called this material vaccine from vacca which is Latin for cow At some time during the nineteenth century, the virus used for smallpox ceased to be cowpox and was changed to vaccinia Vaccinia is in the same family has cowpox and smallpox but genetically different In the early 1950s (150 years after Jenner’s vaccination came out) an estimated 50 million cases of smallpox occurred in the world each year, which feel to around 10-15 million by 1967 b/c of vaccination

Vaccination Post-Exposure Prophylaxis : 

Vaccination Post-Exposure Prophylaxis Vaccine administration Jet gun Rapid High maintenance Bifurcated needle High efficacy, sterilizable, simple, rapid (1500/day) Uses less vaccine Mainstay for the WHO eradication campaign The smallpox vaccine is actual live vaccinia virus, unlike other superficial layer of the skin

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Vaccine Protective if given within 3-4 days exposure Reduces incidence 2-3 fold Decreases mortality by ~50% Vaccinia immune globulin (VIG) 3 fold decrease in incidence and mortality Passive immunity for 2 weeks Very limited supply (at CDC a brisk cell-mediated immune response

prevention : 

prevention Vaccination policies Last mandated in U.S. in 1972 World travelers until 1979 Laboratory workers Stability Freeze-dried lasts decades Current stock probably still potent Supply 7-15 million doses in U.S. as of 1999 >20 years old Stock controlled by CDC Production No current active production New vaccine production scheduled for 2004

Vaccination : 

Vaccination Vaccine efficacy Nearly complete protection for responders Effective for all ages except neonates Reduces secondary attack rate 10 fold Highest efficacy Those who are vaccinated 3-4 times Successful vaccination in previous 3 years Also protects from monkeypox Duration of efficacy – single dose Probably 5-10 years Some immunity >20 years Lower morbidity & mortality (3 fold) Revaccination leads to >30 years protection Neutralizing antibody used as marker

Vaccine adverse effects : 

Vaccine adverse effects Successful vaccination reaction (“take”) Pruritic hyperemic papule Day 3-4 “Jennerian” vesicle by Day 7-9 Dries by Day 14 Marks immunity If no vesicle, revaccinate from different lot Vaccine adverse effects Pregnancy Rare fetal vaccinia No known malformations Mild symptoms nearly universal 1º “take” reaction in all successful vaccinations Mild tender axillary lymphadenopathy common 70% infants have prolonged

Serious complications : 

Serious complications Occur in 74-250 per million (1/10,000) 3-4 fold higher risk in infants <1 y.o. Highest risk in primary vaccinees Types of reactions Severe cutaneous Most common Associated with vaccinia viremia Encephalitis 1 in 300,000 25% mortality, survivors usually neuro sequelae Similar to measles, varicella Fever, headache, lethargy, paralysis, meningitis, coma No effective treatment

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Types of reactions Vaccinia gangrenosum/necrosum Original lesion spreads and does not heal Mortality 100% in untreated, 20-36% treated Highest risk in immunocompromised Treatment Vaccinia immunoglobulin (VIG) Thiosemicarbazone Eczema vaccinatum Vaccinees or their contacts with h/o eczema Vaccinial lesions away from inoculation site Mortality 30-40% in children <2yo Treatment - VIG reduces

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Generalized vaccinia Distant vaccinial lesions 6-9 days after vaccine Usually mild, self-limited Autoinoculation TouchiVaccinia immunoglobulin Limited stock available via CDC Uses Post-exposure prophylaxis Vaccine adverse effects – very effective Pre-vaccine prophylaxis Very effective for hi-risk vaccinees For all severe adverse effects except encephalitis Doesn’t alter vaccine efficacy ng vesicle then others or self (eyes

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Progressive Vaccinia Generalized Vaccinia Eczema Vaccinia

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Contact Vaccinia Developed Erythema Multiforme 1 mo. After vaccine Progressive Vaccinia Secondary herpes infection

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No absolute contraindications to vaccinate Relative contraindications (Hi Risk Groups) History of eczema or chronic skin disorder Age <1 y.o. Pregnant Immunosuppressed (HIV, malignancy) Use VIG if hi-risk must be vaccinated

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Summary of vaccine strategy in outbreak (unless vaccinated in last 3-5 years) All confirmed or suspected cases All contacts of confirmed/suspected cases All hospital personnel of hospitalized cases All other patients in hospital with cases Home care-givers Mortuary workers handling deceased cases Prophylactic VIG for hi-risk groups

Infection Control : 

Infection Control Vital component of outbreak management Transmission is key No animal/arthropod vectors No known asymptomatic reservoirs carrier state hypothetical but not confirmed Higher rate in cool, dry conditions Transmission Overall secondary attack rate 25-40% Historically 3-4 cases per index patient Outbreak in mostly nonimmune population Anticipate 10-20 cases per contact All body fluids infectious Respiratory secretions main culprit Cough dramatically increases transmission

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Period of infectiousness Onset usually 1 day before rash associated with mucosal lesions sometimes transient defervescense at end of prodromal stage Lasts until all lesions scabbed over Longer duration with more severe casIsolation of Cases Home isolation is preferable Avoids nosocomial spread Droplet and inoculation protection Contact precautions – glove, gown, face shield Aerosol protection Negative pressure room, HEPA filter Assign immune persons for care

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Management of Case Contacts Carefully identify true contacts Exposure to a case patient after fever onset Contact with secretions OR Face-to-face contact OR In nosocomial setting with a case Includes ALL hospital patients and staff Except for nosocomial, large group exposure unlikely – usually bedridden by fever onset Vaccination Proven benefit given within 3-4 days of exposure Observation for 17 days Twice daily temperature check Isolation if fever > 38.0º

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Handling of specimens BSL4 laboratory containment only Disposal of linens/laundry Dispose in biohazard containers Autoclave before laundering Launder in hot water & bleach Cremation recommended for corpses

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Surveillance and containment critical Correct identification of those at risk Conservation of vaccine Target only those with true risk Limited national supply Components Aggressive case-seeking Aggressive contact-seeking & observation

decontamination : 

decontamination Original aerosol release setting Likely no decontamination applicable Rapid dispersion of virus <6 hours in higher heat, humidity Most gone by 24 hours even under ideal conditions Completely dissipated by 2 days Delayed onset of symptoms (at least 1 week) Virus long gone by time of index case recognition in covert release If known recent release HEPA filtration Sterilization of surfaces Standard disinfectants such as bleach

Smallpox Essential Pearls : 

Smallpox Essential Pearls Smallpox has been weaponized Case fatality will likely approach 30% Clinical diagnosis Asymptomatic incubation period 7-17 days Prodrome with high fever 3-5 days Eruptive phase with typical rash Highly infectious Not infectious prior to fever onset Infectiousness starts one day before rash Lasts until all lesions scabbed over

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Secondary attack rate 25-40% Expect 10-20 2º cases per index case No specific treatment, only supportive Case identification & isolation essential Droplets / secretions (contact isolation) Aerosols (negative pressure isolation) Isolate at home if possible (quarantine) Post-exposure prophylaxis for contacts Vaccine (with VIG for hi-risk groups) Fever observation x 17days, isolate if

bioweapon : 

bioweapon Features making smallpox a likely agent Can be produced in large quantities Stable for storage and transportation Known to produce stable aerosol High mortality Highly infectious Person-to-person spread Most of the world has little or no immun

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Prior attempted use as bioweapon French and Indian Wars (1754-1767) British gave Native Americans infected blankets Outbreaks ensued, some tribes lost 50% Allegations of use in U.S. Civil War Alleged use by Japanese in China in WWII

Certain unanswered questions : 

Certain unanswered questions Any unknown animal reservior Transformation of any other orthopoxvirus to SP Absolute containment of lab sample Will monkeypox able to replace the eradicated SP Bioweapon—waged in the future