Download ImmunzforWAO12_3_11

The History of Prevention of Epidemics:
Rinderpest 1713 AD to Smallpox 1796 AD to
Measles AD 1963-What to do or not to do and
if given, how to do it safely.
James M. Oleske, MD, MPH
François-Xavier Bagnoud Professor of Pediatrics
Director, Division of Pediatrics Allergy, Immunology & Infectious
Diseases
Peter Wenger MD FAAP, FIDSA
Department of Pediatrics, New Jersey Medical School, Newark, New
Jersey
Eradication of Rinderpest-95% Infection
fatality Rate in cloven-footed beasts

1713
• Pope Clement XI asked Dr. Giovanni Lancisi to stop outbreak in papal herds
 Charlatan cures banned
 Priests ordered to preach from their pulpits
• All herds with sick members slaughtered and buried in lime
• Isolate healthy herds
 Laymen found resistant or cheating
• Hanged and drawn and quartered
 Disobeying priests were imprisoned for life
• Within 9 months the outbreak ended in Papal states
 It persisted for 100 years with >200 million dead cattle in Protestant
sectors
Eradication of Rinderpest : A Costly Success
By the 1750’s crude “vaccine” used in England and
Netherlands: 50 years before Jenner !
 1761 first school of veterinary medicine founded
in Lyon, France
 1924 creation of the World Organization for
Animal Health in response to a devastating
European outbreak
 1950’s Rinderpest was eradicated in China
utilizing Lancisi’s measures: Uncooperative
farmers were “only” imprisoned !

Elephant RIDE – UNINTENDED CONSEQUENCES
Measles (Rubeola) Virology




Genus: Morbillivirus
Family: Paramyxoviridae
Canine distemper and rinderpest
viruses
Spherical, enveloped, single-stranded
RNA virus
• Six identified structural proteins:
3 complexed with RNA to form
nucleocapsid P, L, N protein and 3
complexed with viral envelope (F,
H, and M proteins)
http://biowiki.org/twiki/pub/Fall09/MeaslesVirus/Measles_virus.JPG
Measles Virology

Genetic variety
• WHO recognizes 23 genotypes
 phylogenetic analysis of the N gene
• Biologic significance unknown
• Allows monitoring transmission pathways
• Immune response generated through immunization protects
against all strains
 Molecular sequencing can distinguish between wild-type
and vaccine-virus
Measles Epidemiology 1


Humans are the only natural hosts
• No animal reservoirs
Highly contagious
• Attack rate in susceptible household contacts: 75%-90%
• Direct contact with infectious respiratory secretions
 Large respiratory droplets and droplet nuclei
• Lingers for at least 2 hours
• Requires airborne precautions
 Nasopharynx and conjunctiva
 Most infectious in prodromal period
• Before rash onset
Measles Epidemiology 2





Incubation period: 8-12 days
Contagious period: 1-2 days before symptom onset (3-5 days before rash) to 4 days
after rash appearance
• Immunocompromised patients may demonstrate prolonged excretion of virus
Peak incidence in temperate regions is late winter and spring
• Low relative humidity
Pre-vaccine era
• Pre-school and young school age children
• Few susceptible by 20 years of age
Immunity appears to be lifelong
• Wild-type infection or vaccine-induced
• Primary vaccine failure (≥12 months) ~5%
 Most infections in previously immunized children viewed as primary
vaccine failures
Measles Pathophysiology

Infects epithelial, reticuloendothelial, and white blood cells
• Multiple organ systems
 Multinucleated giant cells found throughout the respiratory and
GI tracts and in most lymphoid tissue on autopsy
 Onset of rash coincides with appearance of serum antibodies
• Skin and mucous membrane manifestations may represent a
hypersensitivity reaction to the virus*• Decline in CD4 cells
 Prior to rash onset and lasting up to 1 month
• Suppression of delayed-type hypersensitivity
Perry RT, Halsey NA. The clinical significance of measles: a review. JID. 189 (Suppl 1) S4-S16. May 1, 2004
Measles Clinical Presentation 1

Prodromal (2-4 days)
• Fever (39°C–40.5°C), cough, coryza, and conjunctivitis
 Symptoms intensify and usually peak on first day of
rash
• Appearance of Koplik spots appear 1 day prior to rash
onset and last 2-3 days
 Buccal mucosa opposite 1st molar
 Soft palate, conjunctiva, vaginal mucosa
Perry RT, Halsey NA. The clinical significance of measles: a review. JID. 189 (Suppl 1) S4-S16. May 1, 2004
Koplik Spots
http://www.pathguy.com/sol/24924.jpg
Koplik Spots
http://eso-cdn.bestpractice.bmj.com/best-practice/images/
bp/en-gb/217-4-tn_default.jpg
Measles Clinical Presentation 2




Rash first appears on face and neck
• Discrete erythematous patches (3-8 mm)
Lesions increase and spread downwards to trunk and extremities
(including palms in 25%-50%)
• Most intense over face and trunk
 Frequently become confluent
Rash persists for 3-7 days
• Desquamation may appear but not pronounced
• Severe desquamation seen in malnourished children
Immunocompromised patients may demonstrate an atypical
presentation
• Without rash
Perry RT, Halsey NA. The clinical significance of measles: a review. JID. 189 (Suppl 1) S4-S16. May 1, 2004
http://aapredbook.aappublications.org/week/iotw010504.dtl
http://www.cdc.gov/measles/about/photos.html
http://www.cdc.gov/measles/about/photos.html
Measles Clinical Presentation 3

Common associated signs and symptoms
• Photophobia secondary to iridocyclitis
• Sore throat
• Headache
• Abdominal pain
• Generalized mild lymphadenopathy
Measles Complication Risk Factors

At greatest risk
• <5 years and ≥20 years
• Immunocompromised
 T-cell suppression: Congenital or acquired T-cell deficiencies: 60% of all
measles-associated deaths in NJ in 1990-1991 occurred in HIV-infected
children*
• Chemotherapy for cancer or steroid therapy
• Bone marrow transplantation
• Malnourished
 Protein losing enteropathy, increased metabolic demand, decreased food
intake
 Vitamin A deficiencies: Measles infection lowers serum retinol levels
• Crowded living conditions
 Developing countries
*Palumbo P, Hoyt L, et al. Population-based
11:1008-14. 1992
study of measles and measles immunization in HIV-infected children. PIDJ.
Measles: Respiratory Complications




PNEUMONIA: Most common severe complication, responsible for most measlesassociated deaths due to:
Viral: Measles or Secondary infection with adenovirus or HSV,
Bacterial: Streptococcus pneumoniae, Staphylococcus aureus, H. influenzae
Immunocompromised Host: Diffuse Progressive Measles Pneumonitis (DPMP)
most common cause of death=Hecht’s giant cell pneumonia

OTITIS MEDIA: Most common complication in US 14% of children under 5 years of
age

LARYNGOTRACHEOBRONCHITIS: “measles croup” the cause of 9%-32% of US
children hospitalized and 2nd most common cause of death after pneumonia
Perry RT, Halsey NA. The clinical significance of measles: a review. JID. 189 (Suppl 1) S4-S16. May 1, 2004
Measles: Neurological Complications


Febrile Seizures: 0.3%-2.3% in hospitalized children in US and UK
(benign, with no long term residual damage)
Encephalitis: a. Post Infectious Encephalomyelitis (PIE); 1-3/1000
infections; onset 3-10 days post rash onset ; Highest incidence in
adolescents and adults;~25% case fatality rate &~33% have
neurological sequelae; b. Subacute Sclerosing Pan-Encephalitis (SSPE),
persistence of measles virus in CNS, slowly progressive infection and
demyelization to Vegetative state, 1/8.5 million US cases, onset 7-10
years post acute infection ( Disappeared in the US since advent of
measles immunization) c. Measles Inclusion Body Encephalitis (MIBE)
in Immunocompromised hosts with mental status changes, seizures
without fever.
Perry RT, Halsey NA. The clinical significance of measles: a review. JID. 189 (Suppl 1) S4-S16. 5/1/04
Measles Complications-GI and Ocular


Diarrhea
• Most common in people <5 years and >30 years
• 30%-70% of hospitalized patients with measles in US
• Typical onset just before rash
• Dehydration common
Blindness
• Keratitis (inflammation of the cornea)
 Common
 Secondary infections with viruses (adenovirus, HSV) and bacteria
(Pseudomonas spp. and staph)
 Scarring and blindness
• Vitamin A deficiency
• Cortical damage secondary to encephalitis
Perry RT, Halsey NA. The clinical significance of measles: a review. JID. 189 (Suppl 1) S4-S16. May 1, 2004
Global Situation*


In 2008, ~83% of the world’s children received one dose of measlescontaining vaccine (MCV) by their first birthday
• Up from 72% in 2000
In 2008 there were an estimated 164,000 deaths due to measles
• A 78% decrease (733,000 deaths) since 2000
• >95% of deaths in low-income countries with weak health
infrastructures
• Mainly seen in children <5 years of age
*WHO estimates. See http://www.who.int
United States- Stable Misery
• Pre-vaccine era ( befor1963 Licensure)
 ~500,000 cases annually
• In reality, ~4 million infected/year
 ~500 deaths
 ~150,000 with respiratory complications
 ~48,000 hospitalizations
 7,000 seizure episodes
 4,000 cases of encephalitis
 Up to 25% of people with measles-associated
encephalitis were permanently brain damaged or deaf
United States …Going…Going..
• Since 1963 (vaccine licensure)
 99% decrease in measles incidence
• Most pronounced decrease seen with enactment of laws requiring
vaccination for school entry in early 1980’s
 From 1985 – 1992
• Children with exemptions were 35x more likely to contract measles
than nonexempt children*
• 1989-1991 resurgence
• Estimated 55,000 measles cases with >130 deaths
• Controlled by:
 Increased rate of immunization
 Institution of 2-dose regimen in children
*Omer SB, Salmon DA, Orenstein WA, et al. Vaccine refusal, mandatory immunization, and the risks
of vaccine-preventable diseases. NEJM2009;360:1981-88
United States …Going…Going..…Gone??
• Measles elimination (i.e., interruption of endemic measles
transmission) was declared in the US in 2000 !
 No sustained transmission for ≥1 year
• Median of 56 cases from 2001 – 2008*
 Range: 37 - 140
 Associated with imported infection
• January – June 17, 2011*
 156 cases reported
• More than reported for 2010
• Highest number reported for this period since 1996
*http://emergency.cdc.gov/HAN/han00323.asp; Accessed June 23, 2011
Measles
Prevention-Immunization of Children

Two dose schedule
• All children
 First dose : 12-15 months of age
 Second dose: 4-6 years of age
 May get 2nd dose ≥28 days after 1st dose
• If traveling abroad
 6-12 months of age, prior to travel
 Then follow standard schedule (see
above)
Measles: Prevention-Post Exposure Prophylaxis (PEP)

Intramuscular immune globulin (IG) can be given up to 6 days postexposure
• Delay giving children MMR 5-6 months after receiving IG depending
on the dose

IVIG preparations usually contain adequate amount of measles
antibodies
• For those receiving IVIG regularly, 400mg/kg should be adequate
for prophylaxis for exposures occurring within 3 weeks of receiving
IVIG
The Dilemma




Measles remains endemic in many parts of the world
• The world is a village
Measles is highly contagious
• Airborne transmission
• Most contagious prior to presentation of rash
 Resembles upper respiratory tract infection
Low index of suspicion in regions where control has been most successful
• Diagnosis and institution of infection control interventions commonly
delayed
On reintroduction into regions of low endemicity or where elimination has
been achieved
• Serious consequences of disease especially in vulnerable populations
• Great expense in time and money to public health and medical entities as
well as to society as a whole
In 1736 I lost one of my Sons, a fine Boy of 4 Years
old, by the Smallpox taken in the common way. I
long regretted bitterly and still regret that I had not
given it to him by Inoculation. This I mention for the
Sake of Parents who omit that Operation on the
Supposition that they should never forgive
themselves if a Child died under it; my Example
showing that the Regret may be the same either
way, and that therefore the safer should be chosen.
Benjamin Franklin
Autobiography
[Part III, p. 83]
SMALLPOX
SMALLPOX


EPIDEMIOLOGY
• Once worldwide in distribution ; Eradicated in 1977 in
Somalia driven by vaccine campaign
• 2 principal forms Variola major >30% case-fatality and
Variola minor <1% case-fatality rate
TRANSMISSION
• Person to person by Droplet nuclei
• Fomite Contaminated clothing/bed linens
• No known animal or insect reservoirs/vectors
SMALLPOX AS A BIO-WEAPON
High infectivity, high secondary attack rate of10-20 2ed
generation cases and Susceptible population (wide spread
civilian vaccination ceased around 1980), no known cure
VACCINIA
Length of Protection



Primary Vaccination
• > 95% primary vaccines have neutralizing antibody at titer
>1:10 within 1-2 weeks
 7 days after revaccination
• Evidence of cell-mediated response by day 8
• High level immunity
 3 to 5 years
 Decreasing afterwards
Revaccination
• Some level of immunity – 30 years or longer?
Efficacy in prevention – 95%
CONTRAINDICATIONS TO SMALLPOX
IMMUNIZATION


In Vaccines and Household Contacts
• History of eczema, atopic dermatitis, Darier’s disease irrespective of disease
severity or activity and other acute or chronic exfoliative skin conditions (burns,
impetigo, zoster, herpes, severe acne, or psoriasis) should not receive vaccine
until the condition resolves
• Immunodeficiency; HIV-infection, cancer, autoimmune diseases, transplant,
humeral or cell-mediated deficiencies, immunosuppressive therapy
• Pregnancy or women trying to become pregnant (4 weeks post-vac.)
In Vaccines only
• Breastfeeding mothers
• All children < 1 year of age, ACIP advises against non-emergency use of
smallpox vaccine in children < 18 years of age, Concurrent moderate or severe
short-term illness
• Severe allergic reaction to past smallpox vaccination or to one of the vaccine
components
(Polymyxin B sulfate, Streptomycin sulfate, Chlortetracyline hydrochloride,
Neomycin sulfate, phenol
VACCINIA COMPLICATIONS








Incidence*
• 164.6 per million primary vaccinations
• 10.0 per million revaccinations
Erythema Multiforme
Stevens Johnson Syndrome
Eczema Vaccinatum
Generalized Vaccinia
Vaccinia Necrosum (Progressive Vaccinia)
Postvaccinial Encephalopathy and Encephalomyelitis
Treatment
• Supportive care
• Antipruritics
• Vaccinia immune globulin (VIG) : Used only in severe progressive cases
*Lane, M.L., et al. Complications of Smallpox Vaccination, 1968: Results of Ten Statewide Surveys. JID.
122;4:303-309. October 1970
VACCINIA IMMUNE GLOBULIN (VIG)




Obtained from previously vaccinated individuals
VIGIM
• Intramuscular injection
• 0.01% thiomersal
Two new IV preparations (VIGIV)
• No thiomersal
Available as IND products from CDC and DoD
VACCINIA ERYTHEMA MULTIFORME
Vaccinia immune globulin not indicated
VACCINIA PERIOCULAR AUTOINOCULATION
Consider VIG In More Serious Cases
GENERALIZED VACCINIA
Consider VIG In More Serious Cases
ECZEMA VACCINATUM
* Early treatment with VIG * Treatment of secondary bacterial / fungal infections
* Lesions contain virus mandating * Infection control precautions
VACCINIA NECROSUM (PROGRESSIVE VACCINIA)



•
•

Occurs in people with compromised immune systems; Poorer
prognosis especially in CMI deficits
Vaccinia lesion fails to heal, secondary lesions may appear and
gradually spread
Mortality rate ~ 25-33%
Management includes ; Aggressive VIG therapy, Surgical
debridement, Treatment of secondary bacterial or fungal
infection
Second line treatment Cidofovir ; No studied in humans, only
available under Investigational New Drug (IND) protocol from
CDC and Department of Defense
Lesions contain virus, and needs strict Infection control precautions
VACCINIA
Vaccinia Necrosum
Fatal in patient with an immunodeficiency
“Future generations will know by history only that the loathsome
smallpox has existed.” Thomas Jefferson to Edward Jenner1806
Ali Maow Maalin
Thank You
Questions??