ANTHONY OGNJAN DO FACPMetro Infectious Disease Consultants43134 Dequindere RdSterling Heights, Michigan, 48314Phone: 586 446-8688Fax: 586 446-9994

Clinical review and Up-dateA vaccine Preventable Disease

MEASLES

Michigan Osteopathic Association120th Annual Spring

Scientific ConventionSouthfield Michigan

May 16-19, 2019

MeaslesClinical review and Up-date: A vaccine Preventable Disease

SUMMARY

Epidemic Measles In the United States eliminated 2000 v Airport Measles

Sporadic Measles Still a threat among Groups of Unvaccinated / non-immune

Measles is a highly contagious disease among the susceptible : 90% attack rate

ComplicationsCan be Serious

v Immunosuppressionv Diarrheav Pneumonia

v Neurological

Symptomatic treatment: Fever control (No aspirin) : Hydration: NO ANTIVIRALS

Suspect v Incubation 5-21 days Febrile illness: Koplik Spots

v Out break with groups non-immune Morbilliform rash: Head- toe

Vaccinev Is safe and effective for protectionv 2 Shot series: Adults & Childrenv MMR® Is Preferred vaccine (MMR-V)

ENCOURAGE VACCINATIONS

Michigan Osteopathic Association120th Annual Spring

Scientific ConventionSouthfield Michigan

May 16-19, 2019

MeaslesMeasles Re-emerges5 things to remember

Measles Re-emerges: 5 things to remember

#1

Certain Patient Groups Are Most Vulnerablev Children < 5 years of agev Especially infantsv Adults older >20 yearsv Pregnant women

v Malnourished children

v People with severely compromised immune systems

- Cancer chemotherapy, leukemia- Organ transplantation- HIV infections- Immunosuppressive drugs

#2

People Who Think They Are Immune : May Not Be…v Born before 1957 v Are considered Immune

v Born 1957-1988 v Vaccinated: 1963-1963 Less effective vaccinev Vaccinated: 1962- 1989 Only single vaccine

v Check vaccine records for administration of 2 doses of vaccine as evidence of immunityv Alternatively, measuring measles IgG titers can demonstrate immunity v Proof of immunity should be documented for all people working in the healthcare field. v Proof of immunity is recommended for people living in or traveling to areas with ongoing

measles transmission.

Andrew T. Pavia, MD Never Seen Measles? 5 Things to Know May 02, 2019. Perspective/ Medscape/ Infectious Disease https://www.medscape.com/viewarticle/912500_

MeaslesMeasles Re-emerging5 things to remember

Measles Re-emerges: 5 things to remember

#3

The Most Important Diagnostic Tool Is Your H&P

Diagnose measles quickly

v Allows for quarantinev Important for contact tracingv vaccination of susceptible contactsv Other public health interventions

Historyv Patients vaccination statusv Possible exposure to measlesv Travel to areas of ongoing transmission.

PhysicalA careful history of disease progression & symptoms is critical.

v After an incubation period of 8-12 (“3Cs”)v Prodromal symptoms: Fever, Cough, Coryza, Conjunctivitis v During this period, Koplik spots

#4 LabsHighly contagious. (Aerosols). If patients need to go to a lab to have blood drawn, you should

notify the lab and infection control to help prevent exposing other patients.

Serum IGM v 1-2 day : after rashv Poor Specificity

PCR v Not generally availablev Throat and nasopharynx are the preferred

Andrew T. Pavia, MD Never Seen Measles? 5 Things to Know May 02, 2019. Perspective/ Medscape/ Infectious Disease https://www.medscape.com/viewarticle/912500_

Measles Re-emerges: 5 things to remember

#5

Infants an Children: MMR Vaccine Doses Can Be Given EarlierRoutine Childhood vaccinations v 1st 12-15 months

v 2nd dose before school entry at age 4-6 years.

During outbreaks or before travel v 2nd dose can be given 28 days after the first dose

High risk : 6-11 months

v MMR vaccine can be givenv Providing reasonable short-term protection. v However not considered a valid first dose:

Another dose must be given after the child's first birthday.

Outbreak situation:v Second dose aged 12 months or olderv An early dose to children aged 6-11 months living in

areas where transmission is ongoing or who will be traveling.

MeaslesMeasles Re-emerging5 things to remember

Andrew T. Pavia, MD Never Seen Measles? 5 Things to Know May 02, 2019. Perspective/ Medscape/ Infectious Disease https://www.medscape.com/viewarticle/912500_

Measles

EpidemiologyComparison Of Morbidity-Mortality

Historical Comparison Morbidity-Mortality For Vaccine Preventable Disease before 1980. (Measles-Mumps-Rubella)

Estimated Annual Cases (Average) PEAKDiseases Cases Deaths Cases Deaths

Measles 530,217 440 763,094 552

Years 1953-1962 1953-1962 1958 1958

Mumps 162,334 39 212,932 50

Years 1963-1968 1963-1968 1964 1964

Rubella 47,745 17 448,796 24

Years 1966-1968 1966-1968 1964 1968

JAMA, November, 14,2007. Vol.298, No 18 (2156)

EcologyMeaslesDefined: Epidemics Impact

• People born before 1957 lived through several years of epidemic measles before the first measles vaccine was licensed in 1963.

• Surveys suggest 95% - 98% of those born before 1957 are immune to measles.

US: How does being born before 1957 confer immunity to measles?

Therefore:Persons born before 1957 can be presumed to be immune.

ECOLOGY*

Measles …Defined

“Measles is one of the most important infectious diseases of humans….

Has caused millions of deaths since its emergence as a zoonotic disease thousands of years ago…..

For infectious disease epidemiologists…measles has served as a model of an acute infectious disease, particularly for understanding the nature of epidemics””

-Kenneth MaxcyJohns Hopkins University School of Public Health, 1948

*Ecology is the branch of biology which studies the interactions among organisms and their environment

EcologyMeaslesDefined: Clinical

“What is Measles?”

“Highly contagious” viral illness characterized by Fever, Malaise, Rash, Cough, Coryza, and Conjunctivitis

that occurs worldwide….

Natural measles infection is thought to confer lifelong immunity.

Immunity due to Measles vaccination is also highly protective against clinical infection.

Measles

Viral Human Ecology

Exposure

Prodrome*v FEVER 1040 f (400C)v COUGHv RHINORHEAv CONJUNCTIVITIS

VIRA

L LO

ADMeasles MorbidityHospitalized 1 : 4Encephalitis 1 :1,000 (0.1%)Death 1-2 :1,000

Contagious ~4 days before 4 days after the rash appears

TIMEPRODOROME*2-4 days

EXANTHEM~3-5 days After fever

Resolves 5-6 days

RECOVERYCough may persist

1-2 weeksKoplik Spots

INCUBATION5-21 days Median(Asymptomatic)

Immune Response

MeaslesClinical Exanthems

Development and distribution of measles rash. Reproduced from Perry RT and Halsey NA. The clinical significance of measles. J Infect Dis 2004;189(Suppl 1):S5

DiscreteMaculopapules

ConfluentMaculopapules

MeaslesFirst day Third day

of rash of rash

Koplik’s spotsOn Buccal mucosa

RashDiscrete

Search carefully for Koplik spots in patients with suspected measles, since they can improve the accuracy of clinical diagnosis …..However, this enanthem does not appear in all patients with measles.

Measles Exanthem:v Arises approximately 2- 4 days after onset of feverv Erythematous, Maculopapular, Blanching rash v Classically begins face

- And spreads cephalocaudally and centrifugally- To involve the neck, upper trunk, lower trunk, and extremities

v Early on, the lesions are blanching; v Later stages….they are not v May include petechiaev Severe cases, may appear hemorrhagic Children:

the extent of the rash and degree of confluence generallycorrelate with the severity of the illness.

v The palms and soles are rarely involved.

Respiratory Infections*v Otitis Mediav Mastoiditisv Bronchopneumoniav Laryngotracheobronchitis (croup)v Bronchiolitisv Giant cell pneumonia

CENTRAL NERVOUS SYSTEMv Febrile Convulsionsv Guillain-Bare syndromev Reye’s Syndromev Transverse myelitisv Encephalitisv Acute Disseminated Encephalomyelitisv Subacute Sclerosing Panencephalitis

S

Gastrointestinalv Diarrhea (Most common)v Mesenteric Enteritisv Appendicitisv Hepatitisv Pancreatitisv Stomatitisv Cancrun Oris)

MEASLESCOMPLICATIONS

*Bacterial Superinfections ~5%S. pneumoniaeS pyogenes

H influenzaeS. aureus

v Corneal Ulceration v Corneal Perforationsv Central Vein Occlusion

Symptomsv severity ranges from mild and less serious v First 4–6 wks. after an acute phase (and upon the immune functions are disturbance)v Complications are usually more severe in adults CASES v And malnourished and immune compromised individuals.

IMMUNE SYSTEMReticuloendothelial or Macrophage system:

v Dysfunctionv Suppression

v TTPv DIC

v Myocarditisv Pericarditis

Measles

VirologyMeasles morbillivirusPathology IMMUNOSUPRESSION

Measles Virus:IMMUNOSUPRESSION Multiple organ systems

Targets v Epithelial tissuesv Reticuloendothelial tissues*

Mononuclear phagocytev Monocytesv Macrophagesv T-Lymphocytes

Pathological studies of children dying during acute measles

Multinucleated giant cells (typical of measles virus infection)

Throughoutv Respiratoryv Gastrointestinal tract

v Most Lymphoid tissues

In immunology, the mononuclear phagocyte system (also known as the reticuloendothelial system or macrophage system) is a part of the immune system that consists of the phagocytic cells located in reticular connective tissue.

Measles Mump Rubella VaccineVaccine OptionsIMPACT OF : “MMR VACCINE”

MEASLESVACCINATION INPACT United states

Post MMR VACCINE 1969:v Measles : Endemic Disease Elimination: 2000v Rubella : Endemic Disease Elimination: 2004v Mumps : 99% Endemic Disease Elimination

Measles

VirologyMeasles morbillivirus

Virus Classification

Unranked Virus

Realm Ribovira

Phylum Negarnaviricota

Class Monjivicetes

Order Mononegavirales

Family Paramyxoviridas

Genus Morbillivirus

Species Measles Morbillivirus

synonyms

Measles virus

Classic measles infection in immunocompetent patients

●Modified measles infection in patients with pre-existing but incompletely protective anti-measles antibody

●Atypical measles infection in patients immunized with the killed virus vaccine

●Neurologic syndromes following measles infection, including acute disseminated encephalomyelitis and subacute sclerosing panencephalitis

●Severe measles infection

●Complications of measles including secondary infection, giant cell pneumonia, and measles inclusion body encephalitis

Measles virus: v Single-strandedv Negative-sensev Envelopedv Non-segmented RNA virus

MEASLESVaccine : MMR(Measles, Mumps Rubella)Measles Immunosupression

Measles Vaccination

Long-term benefits of Measles Vaccination: By preventing measles-associated immune memory loss:

v Vaccination protects polymicrobial herd immunity:Measle Infections; Secondary Infection Complications

v There-by preventing all-cause infectious disease

MEASLES

Recovery and ComplicationsNeurological Complications : Encephalitis

EncephalitisAcute measles encephalitis may also occur in the absence of rash

CLINICALIncidence 1:1,000 Measles casesPresentation Appears within a few days of the rash typically day 5 (range 1 - 14 days)

Signs &Symptoms

v Feverv Headachev Vomitingv Stiff neck

v Meningeal irritation v Drowsinessv Convulsionsv Coma

CSFv Lymphocyte Pleocytosisv Protein Elevationv Glucose Normal

Pognisis v Neuro developmental sequelae v ~25% of casesv Rapidly progressive and fatal disease v ~15% of cases

MEASLES

Recovery and ComplicationsNeurological Complications : Acute Disseminated Encephalomyelitis

Acute Disseminated Encephalomyelitis DEMYELINATING NEUROPATHY

CLINICAL Symptoms: Thought to be a postinfectious autoimmune responseIncidence ~1 per 1,000 measles cases.

Presentation Develops during the Recovery phase of Acute Disease : typically within 2 weeks of the exanthem

Signs &Symptoms

GENERAL Mental status changes:

Neurological Myelitis

v Feverv Headachev Neck stiffnessv Seizures

v Confusionv Somnolencev Coma

v Ataxiav Myoclonusv Choreoathetosis

v Paraplegia / Quadriplegiav Sensory lossv Loss of bladder & Bowel

control

CSF v Lymphocytic pleocytosis Elevated protein concentration.

Prognisisv MORTALITY v 10-20%v Common Residual neurologic

abnormalities among survivorsv Behavior disordersv Mental retardationv Epilepsy

MEASLES

Recovery and ComplicationsNeurological Complications : Subacute Sclerosing Panencephalitis I

Subacute Sclerosing PanencephalitisProgressive Fatal degenerative disease of the Central Nervous System

Occurs 7 -10 years after natural measles virus infectionMay involve persistent infection with a genetic variant of measles virus within the CNS

CLINICAL Symptoms

Incidence Natural Measel Infection : 8.5 cases per million casesPost Vaccination : 0.06 cases per million (Decrease Cases)

Presentationv Age : onset : ≤20 yearsv Onset 7 -10 years after natural measles infection v ~50% had measles Infection before the age of 2 years

Stages

v Stage one v last fweeks - years

v Personality changesv Lethargy

v Strange behavior

v Stage twolasts 3 - 12 months

v Myoclonusv Worsening dementia

Stage three & fourv Further neurologic deteriorationv Flaccidity or decorticate rigidity

v Symptoms & signs of Autonomic dysfunction.

v Myoclonus is absent

v Stage four v Vegetative state. : Death

MEASLES

Recovery and ComplicationsNeurological Complications : Subacute Sclerosing Panencephalitis II

Subacute Sclerosing PanencephalitisProgressive Fatal degenerative disease of the Central Nervous System

DIAGNOSTIC STUDIES AND FINDINGSSERUM v Serum anti-measles antibody concentration is elevated

CSF v Detectable anti-measles antibodies v Elevated protein

EEGv EEG findings are characteristic of SSPE and may be pathognomonic

v Bursts of high-voltage complexes v Delta waves (slow waves) and sharp wavesv Each complex is followed by a relatively flat pattern

Brain Imaging v CT BRAIN v Demonstrate atrophy and scarring v MRI BRAIN v Brain may be normal.

The relentless and fatal course of SSPE underscores the importance of measles vaccination, not only for prevention of measles but also for

prevention of the severe neurologic sequelae that can ensue

1920’sThe Measles death rate in the

was around 30%

Pre-antibiotics : Post-antibioticsMeasles can lead to serious complications and death

even with modern medical care

Measles Morbidity Mortality has declined in developed countries

in association with economic development, improved nutritional status, and supportive care…. And Vaccines

Particularly antibiotic therapy to control secondary bacterial pneumonia….

VIRAL ECOLOGY:Measles has been targeted for eradicationgiven the favorable biologic characteristic that Humans are the only virus reservoir. …

Global Vaccine Action Plan*

Measles and rubella Targeted for elimination in five WHO Regions by 2020

However:Due to social and political factors

high transmissibility, Local, Regional, and Global elimination of measles has been achieved in very few areas of the world…

And…Measles remains “Endemic” in areas with low vaccination rates, particularly in the developing world…….

*Attack rate: is the biostatistical measure of frequency of morbidity, or speed of spread, in an at risk population. It is used in hypothetical predictions and during actual outbreaks of disease.

MeaslesAttack Rates*

90%Susceptible Non-immune

Individuals

Infectious droplets from the respiratory secretions of a patient with measles can remain airborne for up to two hours …

Therefore, the illness may be transmitted in public spaces, even in the absence of person-to-person contact.

AIRPORT MEASLES

MeaslesEpidemiology : Persons at risk

*PERSONS At RISK FOR MEASLESPerson RISK

v All Susceptible: Unvaccinated : And/or : No history of clinical disease

vInfants: Who lose passive antibody before the age of routine immunization

vChildren: Immunodeficiency due to HIV or AIDS, leukemia, or malnourished regardless of immunization status.

v SusceptibleIndividuals

Travelers v Areas where measles is endemic….v Contact with travelers infected…

from travel to endemic areas

*High risk person not vaccine eligible can be treated within six days of exposure withimmune globulin.

U.S. MEASLES : Since 2000*The majority of U.S measles cases v Occur among “unvaccinated” travelers including citizens and visitors who Acquire infections

while visiting endemic or epidemic outbreak areas of other countries

v Measles is more likely to spread and cause out breaks in U.S. communities where there are communities and groups of unvaccinated individuals

* The year 2000 Endemic Measles declared eliminated from the U.S ( “Endemic” end of endemic transmission for 12 months or more)

v College campuses (Dormitories)v Close-knit religious communities

Measles

Epidemic 2019U.S. Measles Statistics

2019 The states that have reported cases to CDC are Arizona, California, Colorado, Connecticut, Florida, Georgia, Illinois, Indiana, Kentucky, Maryland, Massachusetts, Michigan, Missouri, Nevada, New Hampshire, New Jersey, New York, Oregon, Texas, and Washington.

NUMBER OF MEASLES CASES REPORTED BY YEAR2010-2019 (January 1 - April 26, 2019)

MeaslesMeasles EpidemiologyAmerica’s biggest recent measles outbreaks: 2010-2109

v Orthodox Jewish Community: New Yorkv Amish Communities: Ohiov Somali American Community: Minnesota

2019v *Orthodox Jewish Community:

Metro-Detroit

*Under-vaccinated community

MICHIGANMEASLES 2019

Michigan is one of 17 states that allows parents to opt out of vaccinating their children for religious or philosophical reasons. Although as of 2014, parents are required to “receive education regarding the benefits of vaccination and the risks of disease” before claiming a nonmedical waiver for their child.

“Scientists had predicted that Oakland County Mi, would be at high risk for a measles outbreak...

Scientists from Baylor College of Medicine Found that Oakland County had the 5th largest number of vaccination exemptions in the country….

So this outbreak was, sadly, predicted.”- Abram Wagner

Professor Epidemiology University of Michigan

5

2017 Vaccination Ratesv Wayne County: 92.4% v Macomb County: 91.7%v Oakland County: 90.3%

MeaslesEpidemiologyMichigan Measles 2019

April 26, 2019 (Since March 13, 2019) 43 casesLocation CASES Demographics

Oakland County 40

Age 8 months - 63 yearsWayne County 1

Detroit 1

Washtenaw County 1

CDC has confirmed measles 704 Cases

v Arizonav Coloradov Connecticut v Georgiav Kentucky

v Michiganv Missouriv New Hampshirev New Jerseyv Oregon

2018: 17 measles outbreaks : TOTAL 349 cases2019 MEASLES OUTBREAKS319 CASES REPORTED NATIONWIDE 2018

Measles

Cracks in the Wall

Control of Vaccine Preventable Diseases

“Science and factsVs.

Superstition and Ignorance”*

*Ollie MaceCivil EngineerEuchre Master & Scotch aficionado

Vaccination

Is the societies' Admission price to prevent human suffering and death by controlling pestilence and disease…Vaccine preventable Disease… To be shared by all?

OrShould “some” be allowed free admission (No vaccines) …

placing the rest of society risk for vaccine preventable diseases?

Philosophically: Measles Attack rate 90%

Humans are social creaturesWhat is the admission charge to belong to

Society?

MeaslesVaccinesControl of Vaccine Preventable DiseasesVaccination Exemptions by State

VACCINATION EXEMPTIONS BY STATE ALL 50 STATES ALLOW FOR MEDICAL EXEMPTION FROM VACCINES. 3 STATES HAVE OTHER EXEMPTIONS

*Virginia an Missouri haveCertain specific Exemptions

Medical Exemption Only

Religious Exemptions

Religious and PersonBelief Exemptions

Measles

VaccinesControl of Vaccine Preventable DiseasesVaccination Exemptions by State

2017 Oakland county population1.251 million

PRE - VACCINE ERA Antiquity to 1963

Rhazes' book A Treatise on Smallpox and Measles

9th CenturyTwo forms of “Smallpox”:

v Variola major : Mortality rate ~30%v Variola minor : Mortality rate ~1%.

v Valuable information about diagnosis, therapy, and concepts of diseases during the Middle Ages.

Measles

HistoryTime Line : Landmark

Rhazes, Avicenna* (Ibn Sina, 980-1037)*

Modanlou HD A tribute to Zakariya Razi (865 - 925 AD), an Iranian pioneer scholar. Arch Iran Med. 2008 Nov; 11(6):673-7

*1970 His accurate description of measles was recognized by the World Health Organization is the first written account of the condition.

PRE - VACCINE ERA Antiquity to 1963

Francis Home Scottish physician

Measles

HistoryTime Line: Landmark

“1757… attempted to produce mild measles by mimicking the variolation process….

This process involved taking blood from an infected patient and inoculating it through the skin of an uninfected person….

In this way he was able to transfer measles to 10 of 12 patients….

This experiment clearly demonstrated the presence of measles virus in human blood”…Francis Home

1719 - 1813

Measles

HistoryTime Line: LandmarkKoplik Spots: 1896

“Koplik's spots“* 1896The spots, which are considered pathognomonic

for measles, occur in the mouth a few days before the skin rash appears, and before infectivity reaches its maximum.

This allows individuals incubating the disease to be isolated and helps to control epidemics.

Henry Koplik*1858 – 1927

*Some authors ascribe the first written description of these spots to Russian Nil Filatov (1847-1902) in 1895,who had observed equivalent phenomena. Koplik was aware of Filatov's work, thought his evidence insufficient and rejected his claim for priority.

Measles

Koplik Spots

“The first twenty-four to forty-eight hours of the invasion of measlesis marked by a suffusion, slight or marked, of the eyes, and the

conjunctiva at the nasal canthus is not only reddened but also slightly redundant. There is, at this stage, a slight febrile movement; there may be a cough or some little sneezing; the mother has noticed nothing except that the infant or child has a slight fever. At this period the eruption on the skin has not made its appearance. In the majority of cases there is no suspicion of any exanthema. In a few cases there is an indistinct spotting around the lips and alae nasi, but no eruption.

The mouth — If we look in the mouth at this period we see a redness of the faces; perhaps, not in all cases, a few spots on the soft palate. On the buccal mucous membrane and the inside of the lips, we invariably see a distinct eruption. It consists of small, irregular spots, of a bright red colour. In the centre of each spot, there is noted, in strong daylight, a minute bluish white speck. These red spots, with accompanying specks of a bluish colour, are absolutely pathognomonic of beginning measles, and when seen can be relied upon as the forerunner of the skin eruption”

- Dr Henry Koplik, MD

Koplik H. The diagnosis of the invasion of measles from a study of the exanthema as it appears on the buccal mucous membrane. Arch Pediatr 1896;13:918-22

Measles

HISTORY TIME LINE

Prior to the introduction of the measles vaccine in 1963, the CDC admits there was massive underreporting of

measles cases…

“because virtually all children acquired measles… The number of measles cases

probably approached 3.5 million per year”

An entire birth cohort!

MeaslesMeasles casesVaccine impact: Measles : MMR : Booster

Data are from the US Centers for Disease Control.

Measles cases in the United States: 1944-2007

MEASLES Vaccine 1963 MMR 1969

Second dose recommended

*2% - 5% of people do not develop measles immunity after the first dose of vaccine. The second dose is not a booster, but rather is intended to produce immunity in the small number of people who fail to respond to the first dose.

Measles

HistoryTimeline : Ecology Pre-vaccines

MEASLES HISTORICAL TIME LINE

PRE-VACCINE ERA Antiquity to 1963

1921 Measles became a nationally notifiable disease in the United States

First decade of reporting, an average of 6,000 measles-related deaths were reported each year.

.

Measles

HistoryTimeline : Ecology : Pre-vaccines

MEASLES HISTORICAL TIME LINE

Epidemiology

Before 1912 No accurate data

1920 United States

469,924 cases 7,575 deaths

1958- 1962 ANNUAL 503,282 cases 432 deaths1960 3 years before the first measles vaccine marketed 1960

442,000 cases Reported

1960380 Deaths

Likely 3.5 – 5 million infected

1969 Measles deaths were estimated at 1 in 10,000 cases.

PRE VACCINE ERA Antiquity to 1963John Enders &Thomas Peoples Edmonston “Measles” Virus

1954Thomas Peebles, following a measles outbreak at a local

school, succeeded in isolating a measles virus throat swab from an 11-year-old pupil,

David Edmonston.

Enders had been skeptical about Peebles’s work, but once the virus had been isolated he and other researchers set

about developing a vaccine.

v The virus continuously cultured until a live attenuated less virulent strain was isolated dubbed

Edmonston B vaccine virusv Licensed by the US Food & Drug Administration 1963.

Measles

HistoryTime Line Landmark : Isolation Measles Vaccine Virus

John Enders* 1897 - 1985

Thomas Peoples**1921 - 2010

*Children’s Medical Center at Boston. In this laboratory much outstanding work on the viral diseases of man has been done under his direction and it was here that the work was done on the cultivation of the poliomyelitis viruses for which Enders was awarded, together with T. H. Weller and F. C. Robbins, the Nobel Prize for Physiology or Medicine in 1954

** Early Dr Peoples 1950’s, worked at the side of Dr John Enders whose “breakout” work on virus andtissue cultures led to the development of polio vaccines and a Nobel Prize in 1954

Measles

HistoryTime Line: Hallmark Vaccine Development : 1963-1967

MEASLES HISTORICAL TIME LINE 1963 - 1967

VACCINE DEVELOPMENT 1953 - 2005

1963To1967

Two Vaccines MarketedMerck

Rubeovax®Attenuated (“Live”) vaccine

Pfizer

Pfizer-Vax Measles-K®Inactivated (“killed”) virus vaccine

v 95% effective at preventing measlesv Protection ~ 3 years

However:v 30-40%:children: fever of +1030 f:

~6th day (Lasting 2- 5 days)v 30-60%: developed “modified measles rash”

v Due to the high number of side effectsv recommended co-administration measles

immune globulin

v No detectable levels of measles antibodies one year later

v 1965: new and abnormal measles-like illnessv Among children previously vaccinated with

inactivated measles virus vaccine and exposed to measles.

v Pfizer’s inactivated vaccine was taken off the market in 1968

.

Measles

HistoryTime Line: Hall mark: Vaccine Development

MEASLES HISTORICAL TIME LINE

VACCINE DEVELOPMENT 1953 - 2005

1967Live attenuated measles vaccine introduced in the United States in 1967

Attenuvax®Merck further attenuated

Edmonston B strain

PRESENTLY

Edmonston-Enders Measles Virus (Formerly Moraten Vaccine Strain)

Approved for Vaccine use in 1969 Edmonston – Ender Measles strain

1969 Incorporated: Measles; Mump; Rubella (MMR®) Vaccine

2018 Incorporated: Measles; Mumps; Rubella & Varicella Vaccine (Proquad®)

.

Vaccine ControversyCan Vaccines Cause Autism?

Science and Facts Vs. Superstition and Ignorance

VaccinesMyths and perceptions What is Autism

Autism, or autism spectrum disorder (ASD):Refers to a broad range of conditions characterized by

challenges with social skills, repetitive behaviors, speech and nonverbal communication.

We now know that there is not one autism :but many subtypes,

and each person with autism can have unique strengths and challenges….

What is Autism. There is no one type of Autism, but many. https://www.autismspeaks.org/what-autism

Autism

Vaccines

Myths and perceptions perceptionsAndrew Jeremy Wakesfield 1998

Andrew Jeremy Wakefield• Discredited former British doctor who became an anti-vaccine activist. • Gastroenterologist until he was struck off the UK medical register for

unethical behaviour, misconduct and fraud.

1998 Authored a fraudulent “research paper” claiming that there was a link between the measles, mumps and rubella (MMR) vaccine, and autism and bowel disease.

- "Profile: Dr Andrew Wakefield". BBC. 27 January 2010.- Smith, Rebecca (29 January 2010). "Andrew Wakefield – the man behind the MMR controversy". The Daily Telegraph. London.- Godlee F, Smith J, Marcovitch H (2011). "Wakefield's article linking MMR vaccine and autism was fraudulent". BMJ. 342: c7452. doi:10.1136/bmj.c7452.- Fang FC; Steen RG; Casadevall A (October 2012). "Misconduct accounts for the majority of retracted scientific publications". Proceedings of the National Academy of

Sciences. 109: 17028–17033. doi:10.1073/pnas.1212247109. PMC 3479492. PMID 23027971.-- "Great Science Frauds". Time Magazine, 13 January 2012- *Robin Birch, (Australia )· Andrew Wakefield Is Not A Fraud April 12, 2017. Vax Info Start Here For researching alternative information about vaccines.

http://vaxinfostarthere.com/wakefield-not-fraud/

AUTISMLack of evidence Vaccination

for association:

No causal association between MMR vaccine and ASD is established

v Drutz JE, Duryea TK, Torchia MM. Autism spectrum disorder and chronic disease: No evidence for vaccines or thimerosal as a contributing factor. UpToDate® March 20,2019

v DeStefano F, Bodenstab HM, Offit PA . Principal Controversies in Vaccine Safety in the United States. Clin Infect Dis. 2019;

v Immunization Safety Review: Vaccines and Autism. A report of the Institute of Medicine, National Academies Press, Washington, DC 2004

Unlike most other medical interventions, vaccines are given to healthy people, and people are far less willing to tolerate vaccines adverse effects ….….than adverse effects of other treatments.

Random thoughts

VACCINES WORK

SAFTETY FIRST

Measles Mump Rubella VaccineVaccine Options

MEASLESVACCINATION

Post MMR VACCINE 1969:v Measles : Endemic Disease Elimination: 2000v Rubella : Endemic Disease Elimination: 2004v Mumps : 99% Endemic Disease Elimination

Measles Mump Rubella VaccineVaccine Options

MMR®)MMRV* (Proquad®): with Varicella: “Chicken Pox”)Live Vaccines

Unless the parent expresses a preference for MMRV vaccine:

Centers for Disease Control and Prevention recommends

MMR® vaccine and varicella vaccine should be administered as separate injections for the first

dose in children 12-47 months of age.

Measles Mump Rubella VaccineHistorically: Vaccine availability

MMRVACCINE Characteristics : Available

IndividualVaccines

Year Vaccine1963 Measles1967 Mump1969 Rubella

IncorporatedVaccines

1969 Measles; Mump; Rubella (MMR) 1985 Measles; Mumps; Rubella & Varicella (MMRV)

Measles Mump Rubella Vaccine

Immune Response

MMRVACINATION:

Immune response

Induces both humoral and cellular immune responses……v Induces measles virus-specific T lymphocytesv Antibodies First appear between 12 -15 days v Antibodies Peak at 21 to 28 days.

• IgM antibodies appear transiently in blood • IgA antibodies are predominant in mucosal secretions• IgG antibodies persist in blood for years

Both humoral and cellular responses can be induced by measles vaccine, Lower magnitude and shorted duration compared to those following wild-type

measles virus infection.

MEASLESVaccine : MMRVaccine Effectivness I

MMR Vaccine Effectiveness and Duration of Protection

MMR U.S. vaccination schedule: considered protected for life against Measles & Rubella. Mumps immunity may decrease over time: and may not be protected later in life.

v MEASLES v Both serologic / epidemiologic evidence indicate : vaccine-induced measles immunity appears to be long-term and probably lifelong in most persons.

v MUMPS v A third dose of MMR can provide added short term protection to a close contact with a mumps patient during an outbreak.

v RUBELLA v Studies indicate one dose of confers long-term, probably lifelong, protection against rubella

MEASLESVaccine : MMRVaccine Effectivness II

MMR Vaccine Effectiveness and Duration of Protection

One Dose

Virus Effective RangeMeasles 93% (39-100%)Mumps 78% (49-92%)Rubella 97% (94-100%)

Two Doses

Measles 97% (67-100%)Mumps 88% (31%-95%)

MEASLESVaccine : MMR(Measles, Mumps Rubella)Indications Children

MMR VACCINES: 2 Vaccinations

Childrenv Starting with the first dose at 12 - 15 months of agev Second dose at 4 through 6 years of age.

v At least 1 month should elapse between a dose of a measles-containing vaccine such as M-M-R® and a dose of ProQuad®

v At least 3 months should elapse between a dose of varicella-containing vaccine and ProQuad®

VACCINE Birth 1month

2month

4month

6month

12Month

15month

18month

19-23month

2-3years

4-6years

Hepatitis B 1st 2nd 3rd

Rotovirus 1st 2nd 3rd

Diphtheria, Tetanus,Pertussis

1st 2nd 3rd 4th

Haemophilus Influenza B

1st 2nd At risk 3rd or 4th

PneumococcusConjugate PCV 13

1st 2nd 3rd 4th PPSV 23Inactivated Polio 1st 2nd 3rd 4th

Influenza Influenza Yearly : (Killed virus : IM Vaccine Live Attenuated Virus : Intranasal

Measles, MumpsRubella

1st 2nd

Varicella 1st 3rd

Hepatitis A HEP A 2 doses HepA seriesMeningococcal CERTAIN HIGH RISK GROUPS

Range of Recommended ages

Certain High Risk Groups

Measles Vaccine ScheduleRecommended Immunization Schedule for Persons Age 0 through 18 years, United States, 2014 Immunization Schedules, Centers for Disease Control and Prevention http://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html (Accessed 5/15/2014)

1st live (VIRAL) Vaccine *2nd Dose MMR / MMRV

*2% - 5% of people do not develop measles immunity after the first dose of vaccine. The second dose is not a booster, but rather is intended to produce immunity in the small number of people who fail to respond to the first dose.

MMR VACCINES: 2 Vaccinations

Adults*v No Evidence of Immunity* v One Dose

v High Risk

High-risk people need 2 dosesv Healthcare personnelv International travelers v Students at post-high school educational institutions, v people exposed to measles in an outbreak setting

* Previously vaccinated with killed measles vaccine or th an unknown type of measles vaccineduring 1963 – 1967*.

** The killed vaccine was found to be not effective and people who received it should be revaccinated with live vaccine

*No evidence of immunity: “Defined”:- Having Historically documented receipt of 1 dose [ or 2 doses: 4 weeks apart if high risk] of live measles virus- containing vaccine,

- OR laboratory evidence of immunity or laboratory confirmation of disease,- OR No Evidence of immunity having been born birth before 1957

MEASLESVaccine : MMR(Measles, Mumps Rubella)

MEASLESVaccine : MMR(Measles, Mumps Rubella)

VACCINE SAFETYv The MMRV vaccine is very safe, and it is effective at preventing measles,

mumps, rubella, and varicella.

Vaccines, like any medicine, can have side effects.

v Most people who get MMRV vaccine do not have any serious problemsGetting MMR or MMR-V vaccine is much safer than getting measles, mumps,

rubella, or varicella

MEASLESVaccine : MMR(Measles, Mumps RubellaMMR Vs MMR(V)

MMR Vs. MMRV Varicella

MMR®MMRV (Proquad®) First dose 12 months to 23 Month

Fewer Vaccine Injections

Fever* v Higher risks of fever within the 42 days after vaccinationv Highest risk occurs during the 5-12 days after vaccinationv Febrile seizures during the 5-12 days after vaccination.

v * Important to discuss febrile seizure risk with parents when considering using MMRV vaccine for the first dose in a child aged 12-47 months.

v A personal history of febrile seizures or a family history of either febrile seizures or epilepsy increases a child’s risk of having a febrile seizure.

v These children should generally be vaccinated with MMR and varicella vaccines instead of MMRV vaccine

MEASLESVaccine : MMR(Measles, Mumps RubellaVaccine Side effects)

Three systems used to monitor vaccine safety

VARES Vaccine Adverse Event Reporting System v An early warning system that helps CDC and FDA monitor problems following

vaccination. Anyone can report possible vaccine side effects to VAERS.

VSD Vaccine Safety Datalinkv Collaboration between CDC and nine health care organizations which allows

ongoing monitoring and proactive searches of vaccine-related data.

CISA The Clinical Immunization Safety Assessment Project:v Partnership between CDC and several medical centers that conducts clinical

research on vaccine-associated health risks

Post Exposureprophylaxis

MEASLES

MEASLESPOST EXPOSURENon-immune Exposure2013 MMR ACIP post-exposure IG prophylaxis for measles.

2013 MMR ACIP post-exposure IG prophylaxis for measles.

Is there anything that can be done for unvaccinated people who have already been exposed to measles, mumps, or rubella?

v MMR v Measles vaccine, given as MMR, may be effective if given within the first 3 days (72 hours) after exposure to measles

v Immune Globulin v May be effective for as long as 6 days after exposure.

v Postexposure prophylaxis with MMR vaccine does not prevent or alter the clinical severity of mumps or rubella.

v If the exposed person does not have evidence of mumps or rubella immunity they should be vaccinated since not all exposures result in infection

Ask the experts: Measles mumps Rubella. Immunization Action Coalition. http://www.immunize.org/askexperts/experts_mmr.asp

MEASLESPOST EXPOSURENon-immune Exposure2013 MMR ACIP post-exposure IG prophylaxis for measles.

Ask the experts: Measles mumps Rubella. Immunization Action Coalition. http://www.immunize.org/askexperts/experts_mmr.asp

2013 MMR ACIP post-exposure IG prophylaxis for measles. NON Immune

Age Recommendations

All infants <12 months: v IGIM : 0.5 mL/kg of body weight: the maximum dose is 15 mL.

Infants age 6 -11 months:Alternatively:v MMR vaccine (instead of IGIM) if it can be given within 72 hours

of exposure.

>12 monthsPost 1 dose MMR:

v IG is NOT indicated for these individualsv UNLESS they are severely immunocompromised.

Pregnant (Non-immune) v Intravenous IGIV) dose of 400 mg/kg of body weight.

Severe Immunosuppressed v Intaveneous IGIV dose of 400 mg/kg of body weight.

Immune Globulin should not be used to control measles outbreaks

Vaccines:Staying current with vaccines

Admittedly, some physicians aren’t well versed in the science or technology of vaccines….

This opens the attacks, and fuels the controversy upon vaccine medicine by opponents of vaccinations…

“Celebrity scientists”, “Free choice advocates”, Alternate Medical, and certain Religious groups…

But Vaccine technology does not function in a vacuum…

Vaccine science has come a long way since Edward Jenner and others first immunized people with the Cowpox virus to protect against Smallpox…

Random thoughts

Vaccines:Staying current with vaccines

Today‘s vaccines are created using modern technology, and involve many scientific disciplines including : Microbiology, Microbial Genetics, Biochemistry, Pharmacology, Pathophysiology, Computer Science, Epidemiology, Immunology Statistics and on and on….

AND…..The safety and effectiveness of vaccines are “time tested” and “clinically” validated by the Millions of vaccine recipients….Vaccinations are scrutinized on a continuous basis (“VAERS”*) … and, I might add… by the most modern and most sophisticated system of statistical analysis ever developed….

*Vaccine Adverse Event Reporting System

Random thoughts

Vaccines:Staying current with vaccines

Our patients and their families should feel confident that the“How to, and Wherefores” of vaccine administration is greatly understood….

...And the techniques involved, for safe and effectivevaccination delivery, have been simplified for the average physician by consensus, of multiple, and an incredibly large, and diverse groups of Scientists, Physicians and Clinical Practitioners

- Anthony F. Ognjan, D.O., FACPYou are in good hands

Random thoughts

Measles

Lecture Bibliography

Measles

Bibliography I SIX RASHES OF CHILDHOOD• Bialecki C, Feder HM, Grant-Kels JM (November 1989). "The six classic childhood exanthems: a review and

update". J Am Acad Dermatol. 21 (5 Pt 1): 891–903• Chamberlain N. Skin Rashes: Diseases 1-6* A. T. Still University of Health Sciences/Kirksville College of Osteopathic

Medicin © 1996-2013• Morens DM, Katz AR. The "fourth disease" of childhood: reevaluation of a nonexistent disease. Am J Epidemiol.

1991 Sep 15;134(6):628-40.• Powell KR. Filatow-Dukes' disease. Epidermolytic toxin-producing staphylococci as the etiologic agent of the

fourth childhood exanthem. Am J Dis Child. 1979 Jan;133(1):88-911• Weisse ME. The fourth disease, 1900-2000. Lancet. 2001 Jan 27;357(9252):299-301.

MEASLES• Maldonad YA, Kaplan SL, Sullivan M. Measles: Clinical manifestations, diagnosis, treatment, and prevention.

UpToDate® Feb 2019.updated: Oct 26, 2018• Orenstein WA, Robert T. Perry RT, Neal A. Halsey NA. The Clinical Significance of Measles: A ReviewThe Journal

of Infectious Diseases, Volume 189, Issue Supplement_1, 1 May 2004, Pages S4–S16, https://doi.org/10.1086/377712

• Maldonad YA, Kaplan SL, Sullivan M. Measles: Clinical manifestations, diagnosis, treatment, and prevention. UpToDate® Feb 2019.updated: Oct 26, 2018

Measles

Bibliography II

TRANSMISSION• SIMPSON RE. Infectiousness of communicable diseases in the household (measles, chickenpox, and mumps).

Lancet. 1952;2(6734):549.• Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases, 12th

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pediatric practice: airborne transmission in an office setting. Pediatrics. 1985;75(4):676• Notes from the field: Multiple cases of measles after exposure during air travel--Australia and New Zealand,

January 2011.Centers for Disease Control and Prevention (CDC) MMWR Morb Mortal Wkly Rep. 2011;60(25):851• Vega JS, Escobedo M, Schulte CR, Rosen JB, Schauer S, Wiseman R, Lippold SA, Regan JJ, Notes from the field:

measles transmission at a domestic terminal gate in an international airport - United States, January 2014.Centers for Disease Control and Prevention (CDC) MMWR Morb Mortal Wkly Rep. 2014;63(50):1211.

• Banerjee E, Hickman C, Engels K, Kenyon C Notes from the Field: Measles Transmission in an International Airport at a Domestic Terminal Gate--April-May 2014. Centers for Disease Control and Prevention (CDC) MMWR Morb Mortal Wkly Rep. 2015;64(24):679.

Measles

Bibliography IIIMEASLES HISTORICAL TIME LINE

• What is the History of Measles in America and Other Countries? National Vaccine Information Center. https://www.nvic.org/vaccines-and-diseases/measles/measles-history-in-america.aspx#_edn2

• Lois N Manger The Medical Influence of Rhazes Overview. Science and it’s times. Understanting Social Significance of Scientific Discovery. Gale group inc. Copyright 201. Encyclopedia.comhttps://www.encyclopedia.com/science/encyclopedias-almanacs-transcripts-and-maps/medical-influence-rhaze

• Measles Pre vaccine History. Center for Disease Control and Prevention (CDC) Atlanta, Georgia. https://www.cdc.gov/measles/about/history.htm

• Measles Vaccine Development. Center for Disease Control and Prevention. CDC Atlanta, Georgia https://www.cdc.gov/measles/about/history.htm

• Measles Elimination. Center for Disease Control and Prevention. CDC Atlanta, Georgia https://www.cdc.gov/measles/about/history.htm

• Immunization, Vaccines and Biologicals: Measles World Health Organizaion. (WHO) https://www.who.int/immunization/diseases/measles/en/

THOMAS PEOPLES & JOHN ENDERS• Douglas Martin Dr. Thomas C Peoples, who Identified measles Virus, dies at 89. New York Times Aug 4 2010.

https://www.nytimes.com/2010/08/05/health/05peebles.html• Thomas Peoples The telegraphhttps://www.telegraph.co.uk/news/obituaries/medicine-obituaries/7937398/Thomas-Peebles.html

10 August 2010

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Francis Home:• Plotkin SA. Vaccination against measles in the 18th century. Clin Pediatr (Phila). 1967 May;6(5):312-5

EPIDEMIOLOGY• CDC: Achievements in Public Health, 1900-1999 Impact of Vaccines Universally Recommended for Children -- United States, 1990-

1998 MMWR April 02, 1999 / 48(12);243-248• CDC. Measles, Mumps and Rubella – Vaccine Use and Strategies for Elimination of Measles, Rubella and Congenital Rubella

Syndrome and Control of Mumps: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR May 22, 1998; 47(RR-8): 1-57.

• CDC SUPPLEMENT – Collected Recommendations of the Public Health Service Advisory Committee on Immunization Practices MMWR Oct. 25, 1969; 18(43) : 1-31

• Durrheim DN, Crowcroft NS, Strebel PM Measles - The epidemiology of elimination Vaccine. 2014;32(51):6880. Epub 2014 Nov 4• Global Vaccine Action Plan. Decade of vaccine collaboration. Vaccine. 2013;31 Suppl 2:B5

Measles

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MEASLES IMMUNOSUPRESSION• C. L. Karp, M. Wysocka, L. M. Wahl, J. M. Ahearn, P. J. Cuomo, B. Sherry, G. Trinchieri, D. E. Griffin Mechanism of

suppression of cell-mediated immunity by measles virus. Science 273, 228–231 (1996). doi:10.1126/science.273.5272.228 pmid:8662504

• B. Hahm, Hostile communication of measles virus with host innate immunity and dendritic cells. Curr. Top. Microbiol. Immunol. 330, 271–287 (2009). doi:10.1007/978-3-540-70617-5_13 pmid:19203114

• . Schneider-Schaulies, J. Schneider-Schaulies, Measles virus-induced immunosuppression. Curr. Top. Microbiol. Immunol. 330, 243–269 (2009). doi:10.1007/978-3-540-70617-5_12 pmid:1920311

• R. D. de Vries, S. McQuaid, G. van Amerongen, S. Yüksel, R. J. Verburgh, A. D. Osterhaus, W. P. Duprex, R. L. de Swart, Measles immune suppression: Lessons from the macaque model. PLOS Pathog. 8, e1002885 (2012). doi:10.1371/journal.ppat.1002885 pmid:22952446

• Laksono BM, de Vries RD, McQuaid S, Duprex WP Measles Virus Host Invasion and Pathogenesis Viruses. 2016 Aug; 8(8): 210. Published online 2016 Jul 28. doi: 10.3390/v8080210 PMCID: PMC4997572PMID: 27483301

• Mina M.J., Metcalf C.J., de Swart R.L., Osterhaus A.D., Grenfell B.T. Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality. Science. 2015;348:694–699. doi: 10.1126/science.aaa3662.

Measles

Bibliography VComplications

PNEUMONIA

• Maldonad YA, Kaplan SL, Sullivan M. Measles: Clinical manifestations, diagnosis, treatment, and prevention. UpToDate® Feb 2019.updated: Oct 26, 2018

• Rupp ME, Schwartz ML, Bechard DE. Measles Pneumonia: Treatment of a Near-Fatal Case With Corticosteroids and Vitamin A. https://doi.org/10.1378/chest.103.5.1625

• Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book), 12th ed, Atkinson W, Wolfe C, Hamborsky J (Eds), The Public Health Foundation, Washington, DC 2011.

• Bernstein DI, Schiff GM. Measles. In: Infectious Diseases, Gorbach SL, Bartlett JG, Blacklow NR (Eds), WB Saunders, Philadelphia 1998. p.1296.

• Beckford AP, Kaschula RO, Stephen C Factors associated with fatal cases of measles. A retrospective autopsy study. S Afr Med J. 1985;68(12):858

• Quiambao BP, Gatchalian SR, Halonen P, Lucero M, Sombrero L, Paladin FJ, Meurman O, Merin J, Ruutu P. Coinfection is common in measles-associated pneumonia. Pediatr Infect Dis J. 1998;17(2):89

• Olson RW. Hodge GR. Measles Pneumonia Bacterial Suprainfection as a Complicating Factor JAMA. 1975;232(4):363-365.doi:10.1001/jama.1975.03250040017018

NEUROLOGIC COMPLICATIONSENCEPHALITIS• Maldonad YA, Kaplan SL, Sullivan M. Measles: Clinical manifestations, diagnosis, treatment, and prevention.

UpToDate® Feb 2019.updated: Oct 26, 2018• Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book), 12th ed, Atkinson W, Wolfe C,

Hamborsky J (Eds), The Public Health Foundation, Washington, DC 2011.• Zeng SZ, Zhang B, Zhang Y, Xie LY, Xiong J, Yu T, Xie ZP, Gao HC, Duan ZJ Identification of 12 Cases of Acute Measles

Encephalitis Without Rash. Clin Infect Dis. 2016;63(12):1630

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Bibliography VIComplications

NEUROLOGIC COMPLICATIONSENCEPHALITIS• Maldonad YA, Kaplan SL, Sullivan M. Measles: Clinical manifestations, diagnosis, treatment, and prevention.

UpToDate® Feb 2019.updated: Oct 26, 2018• Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book), 12th ed, Atkinson W, Wolfe C,

Hamborsky J (Eds), The Public Health Foundation, Washington, DC 2011.• Zeng SZ, Zhang B, Zhang Y, Xie LY, Xiong J, Yu T, Xie ZP, Gao HC, Duan ZJ Identification of 12 Cases of Acute Measles

Encephalitis Without Rash. Clin Infect Dis. 2016;63(12):1630• Cherry JD. Measles virus. In: Textbook of Pediatric Infectious Diseases, 6th ed, Feigin RD, Cherry JD, Demmler-Harrison

GJ, et al (Eds), Saunders, Philadelphia 2009. p.242

ACUTE DISSEMINATED ENCEPHALOMYELITIS• Maldonad YA, Kaplan SL, Sullivan M. Measles: Clinical manifestations, diagnosis, treatment, and prevention.

UpToDate® Feb 2019.updated: Oct 26, 2018• Bernstein DI, Schiff GM. Measles. In: Infectious Diseases, Gorbach SL, Bartlett JG, Blacklow NR (Eds), WB Saunders,

Philadelphia 1998. p.1296• Johnson RT, Griffin DE, Hirsch RL, Wolinsky JS, Roedenbeck S, Lindo de Soriano I, Vaisberg A. Measles

encephalomyelitis--clinical and immunologic studies. N Engl J Med. 1984;310(3):137• Tenembaum S, Chamoles N, Fejerman N Acute disseminated encephalomyelitis: a long-term follow-up study of 84

pediatric patients. Neurology. 2002;59(8):1224

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Bibliography VIIComplications

NEUROLOGIC COMPLICATIONS

SUBUBACUTE SCLEROSING PANENCEPHALITIS • Maldonad YA, Kaplan SL, Sullivan M. Measles: Clinical manifestations, diagnosis, treatment, and prevention.

UpToDate® Feb 2019.updated: Oct 26, 2018• Dyken PR. Viral diseases of the central nervous system. In: Pediatric Neurology: Principles and Practice, Mosby, St.

Louis 1994. p.670• Subacute sclerosing panencephalitis surveillance - United States. Centers for Disease Control (CDC) MMWR Morb

Mortal Wkly Rep. 1982;31(43):585• Bellini WJ, Rota JS, Lowe LE, Katz RS, Dyken PR, Zaki SR, Shieh WJ, Rota PA Subacute sclerosing panencephalitis: more

cases of this fatal disease are prevented by measles immunization than was previously recognized. J Infect Dis. 2005;192(10):1686.

• Bernstein DI, Reuman PD, Schiff GM. Rubeola (measles) and subacute sclerosing panencephalitis virus. In: Infectious Diseases, Gorbach SL, Bartlett JG, Blacklow NR (Eds), WB Saunders, Philadelphia 1998. p.2135

• Garg RK Subacute sclerosing panencephalitis. J Neurol. 2008;255(12):1861. Epub 2008 Oct 14• Adams RD, Victor M, Ropper AH. Viral infections of the central nervous system. In: Principles of Neurology, McGraw-

Hill, New York City 1997. p.767.• Seo YS, Kim HS, Jung DE 18F-FDG PET and MRS of the early stages of subacute sclerosing panencephalitis in a child

with a normal initial MRI. Pediatr Radiol. 2010 Nov;40(11):1822-5. Epub 2010 Mar 1

Measles

Bibliography VIIIEpidemiology§ Naim Y. Measles virus A pathogen, vaccine, and a vector. Hum Vaccin Immunother. 2015 Jan; 11(1): 21–26. Published

online 2014 Aug 5. doi: 10.4161/hv.34298PMCID: PMC4514292PMID: 25483511§ Measles, World Health Organization Fact sheet Updated February 2014 § Millennium Development Goals. United Nations. 18 March 2013§ Briefed V, Hashed Y, Sherman FE, Odagiri K, Yunis EJ. Fatal measles infection in children with leukemia. Lab Invest 1973;

28:279 - 91; PMID: 4348408 [PubMed] [Google Scholar]§ Polonsky JA, Ronsse A, Ciglenecki I, Rull M, Porten K.High levels of mortality, malnutrition, and measles, among recently-

displaced Somali refugees in Dagahaley camp, Dadaab refugee camp complex, Kenya, 2011. Confl Health 2013; 7:1; http://dx.doi.org/10.1186/1752-1505-7-1; PMID: 23339463

§ Clements CJ, Cutts FT. The epidemiology of measles: thirty years of vaccination. Curr Top Microbiol Immunol 1995; 191:13 - 33; http://dx.doi.org/10.1007/978-3-642-78621-1_2; PMID: 7789156

§ Ask the experts: Measles mumps Rubella. Immunization Action Coalition. http://www.immunize.org/askexperts/experts_mmr.asp

MEALSES OUTBREAKS§ Cultural Perspectives on Vaccination. History of Vaccines: History and Society: Vaccine Science. The History of Vaccines.

https://www.historyofvaccines.org/index.php/content/articles/cultural-perspectives-vaccination§ Julia Belluz New York’s Orthodox Jewish community is battling measles outbreaks. Vaccine deniers are to blame. March 27, 2019.

Vox Media. https://www.vox.com/science-and-health/2018/11/9/18068036/measles-new-york-orthodox-jewish-community-vaccines• Measles outbreak sickens dozens of Minnesota Somalis. ASSOCIATED PRESS. SC Times. Published 2:12 p.m. CT May 3,

2017. https://www.sctimes.com/story/news/local/minnesota/2017/05/03/measles-outbreak-sickens-dozens-minnesota-somalis/101252532/

• Melissa Jenco. Study: Low vaccination rate in Amish children linked to hospitalization. AAP news August 2, 2017. AAP news and Journals, Gateway https://www.aappublications.org/news/2017/08/02/AmishVaccines080217

• Williamson G, Ahmed B,Kumar PS, et.al. Vaccine-Preventable Diseases Requiring Hospitalization. Pediatrics. September 2017 Vol 130/issue 3

Measles

Bibliography IX EpidemiologyMICHIGAN MEASLES § 2019 Michigan Measles Outbreak Information. Michigan Department of Health & Human Services.

https://www.michigan.gov/mdhhs/0,5885,7-339-73971_4911_4914_68359-492981--,00.html§ Mike Martindale and Shawn D. Lewis With 5th most vaccine exemptions, Oakland measles outbreak 'sadly, predicted’, The Detroit

News. Published 10:31 p.m. ET April 3, 2019 | Updated 10:19 a.m. ET April 4, 2019 https://www.detroitnews.com/story/news/local/oakland-county/2019/04/04/measles-outbreak-puts-detroit-area-high-alert/3304068002/

§ Tracy Samilton & Kate Wells. Orthodox Jewish community in Oakland County gets word out on measles case. March 14, 2019. Michigan Radio (“NPR”) https://www.michiganradio.org/post/orthodox-jewish-community-oakland-county-gets-word-out-measles-case

§ CDC: Michigan Vaccination Among the Worst in Country, Preventable Illnesses Poised To Make Comeback. https://forum.facepunch.com/f/pd/beapr/CDC-Michigan-Vaccination-Among-the-Worst-in-Country-Preventable-Illnesses-Poised-To-Make-Comeback/1/

§ Kristen Jordan Shamus. How Oakland Co.'s Orthodox Jewish enclave became the epicenter for Michigan measles outbreak, Detroit Free Press. Published 6:01 a.m. ET April 14, 2019 | Updated 2:12 p.m. ET April 29, 2019. https://www.freep.com/story/news/local/michigan/2019/04/14/michigan-measles-outbreak-orthodox-jewish-community-oakland-county/3411582002/

§ (Michigan) School Immunization Data MDHHS Adult & Children's Services Children & Families Immunization Info for Families & Providers. https://www.michigan.gov/mdhhs/0,5885,7-339-73971_4911_4914_68361-335711--,00.html

§ Julie Mack The 49 Michigan schools with vaccine waiver rates of 30 percent or more. jmack1@mlive.com | Posted February 10, 2019 at 08:45 AM | Updated March 10, 2019 at 12:58 PM https://expo.mlive.com/news/g66l-2019/02/0a8a2145747498/the-49-michigan-schools-with-vaccine-waiver-rates-of-30-percent-or-more.html

Measles

Bibliography X

VIROLOGY

• Enders JF, Peebles TC.Propagation in tissue cultures of cytopathogenic agents from patients with measles. Proc Soc Exp Biol Med 1954; 86:277 - 86; http://dx.doi.org/10.3181/00379727-86-21073; PMID: 13177653

• Naim Y. Measles virus A pathogen, vaccine, and a vector. Hum Vaccin Immunother. 2015 Jan; 11(1): 21–26. Published online 2014 Aug 5. doi: 10.4161/hv.34298PMCID: PMC4514292PMID: 25483511

• Katz SL John F. Enders and measles virus vaccine--a reminiscence. Curr Top Microbiol Immunol. 2009;329:3-11. https://www.ncbi.nlm.nih.gov/pubmed/19198559

Measles

Bibliography XIClinical Disease• Measles (Rubeola) Measles: It Isn’t Just a Little Rash Infographic. Center for Disease Control and Prevention, Atlanta Georgia.

https://www.cdc.gov/measles/parent-infographic.html• Measles home: About Measles: Transmission of Measles. Centers For Disease Control and prevention.(CDC) Atlanta,

Georgiahttps://www.cdc.gov/measles/about/transmission.html• Maldonad YA, Kaplan SL, Sullivan M. Measles: Clinical manifestations, diagnosis, treatment, and prevention. UpToDate® Feb

2019.updated: Oct 26, 2018

KOPLIK SPOTS• Koplik's spots: Related people Henry Koplik, Nikolaj Flindt, Nil Feodorovich Filatov. Whonamedit? A dictionary of

medical eponyms. http://www.whonamedit.com/synd.cfm/1437.html• Henry Koplik From Wikipedia, the free encyclopedia. https://en.wikipedia.org/wiki/Henry_Koplik• Koplik spots © 2019 UpToDate, Inc. and/or its affiliates. All Rights Reserved (Photo)• Koplik H. The diagnosis of the invasion of measles from a study of the exanthema as it appears on the buccal

mucous membrane. Arch Pediatr 1896;13:918-22• Bixby, Derrick (July 1997). "Classic Paper: The diagnosis of the invasion of measles from a study of the exanthema

as it appears on the buccal mucous membrane". Reviews in Medical Virology. 7 (2): 71–74. doi:10.1002/(SICI)1099-1654(199707)7:2<71::AID-RMV185>3.0.CO;2-S. PMID 10398471.

• Enders, J.F.; Peebles, T.C. (1954). "Propagation in tissue culture of cytopathogenic agents from patients with measles". Proc. Soc. Exp. Biol. Med. 86 (2): 277–86. doi:10.3181/00379727-86-21073. PMID 13177653.

• Koplik, H (1896). "The diagnosis of the invasion of measles from a study of the exanthema as it appears on the buccal mucous membrane". Arch Pediatr. 13: 918–22.

• Koplik, Henry (1899). "the new diagnostic spots of measles on the buccal and labial mucous membranes". Med. News, (NY). 74: 673–6.

• Anon (1903). "Review; The Diseases of Infancy and Childhood, by Henry Koplik". Lancet. 162 (4171): 389–390.

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Bibliography XIIClinical DiseaseKOPLIK SPOTS Continued• Zenner D, Nakul L .Predictive power of Koplik's spots for the diagnosis of measles.J Infect Dev Ctries. 2012;6(3):271. Epub 2012 Mar 12• Falkener, L (1901). "Fitalow's spots in morbilli". Lancet. 157 (4040): 315–7.

EXANTHAMS• Hudson JB, Weinstein L. Chang TW. Thrombocytopenic purpura in measles. J Pediatr. 1956;48(1):48• Abramson O, Dagan R, Tal A, Sofer S. Severe complications of measles requiring intensive care in infants and young children. Arch

Pediatr Adolesc Med. 1995;149(11):1237• Suringa DW, Bank LJ, Ackerman AB .Role of measles virus in skin lesions and Koplik's spots. N Engl J Med. 1970;283(21):1139.• Bernstein DI, Schiff GM. Measles. In: Infectious Diseases, Gorbach SL, Bartlett JG, Blacklow NR (Eds), WB Saunders, Philadelphia 1998.

p.1296• Koplik, Henry (1899). "the new diagnostic spots of measles on the buccal and labial mucous membranes". Med. News, (NY). 74: 673–6

DIFFEIRENTAL DIAGNOSIS• Measles Rash Differential. Epocrates on line. https://online.epocrates.com/diseases/21735/Measles-infection/Differential-Diagnosis• Maldonad YA, Kaplan SL, Sullivan M. Measles: Clinical manifestations, diagnosis, treatment, and prevention. UpToDate® Feb

2019.updated: Oct 26, 2018

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Bibliography XIII

MMR VACCINE CONTROVERSY

• Brian Deer. Huge sums paid to Andrew Wakefield :MMR doctor given legal aid thousands. The Sunday Times, December 31 2006. http://briandeer.com/mmr/st-dec-2006.htm

• Lisa A. Rickard. The Anti-Vaccine Movement And A Trial Lawyer-Funded Climate Of Fear. Forbeshttps://www.forbes.com/sites/theapothecary/2014/04/28/the-anti-vaccine-movement-and-a-trial-lawyer-funded-climate-of-fear/#307fd76762bd

• Andrew Wakefield’s Harmful Myth of Vaccine-induced “Autistic Entercolitis”: How the MMR Vaccine Scare Began. GI Society: The Canadian Society of Intestional research. https://www.badgut.org/information-centre/a-z-digestive-topics/andrew-wakefield-vaccine-myth/

• Alice Park. Doctor behind vaccine-autism link loses license. TIME MAGAZINE May 24, 2010. http://healthland.time.com/2010/05/24/doctor-behind-vaccine-autism-link-loses-license

• Burgess DC1, Burgess MA, Leask J The MMR vaccination and autism controversy in United Kingdom 1998-2005: inevitable community outrage or a failure of risk communication? Vaccine. 2006 May 1;24(18):3921-8. Epub 2006 Mar 3.

• Do Vaccines Cause Autism?. Common Questions. The History of Vaccines. An educational resource by the College of Physicians of Philadelphia. https://www.historyofvaccines.org/content/articles/do-vaccines-cause-autism

• Vaccines Do Not Cause Autism. Common concerns. Vaccine Safety. Centers of Disease Control and Prevention, Atlanta Georgia. https://www.cdc.gov/vaccinesafety/concerns/autism.html

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Bibliography XIVVACCINES

VACCINE• Polio and Swimming Pools: Historical Connections. History of Vaccines June 28, 2012 Project Direction. History of Vaccines

https://www.historyofvaccines.org/content/blog/polio-and-swimming-pools-historical-connections• John Enders: the Father of Modern Vaccines. Tag Achives: David Edmonston. Virology Molecular Biology and Pathogenesis

August 4, 2016. https://norkinvirology.wordpress.com/tag/david-edmonston/• ProQuad® (MMR) Mark Vaccines.com. Product Information https://www.merckvaccines.com/products/proquad• CDC. Use of Combination Measles, Mumps, Rubella, and Varicella Vaccine: Recommendations of the Advisory Committee on

Immunization Practices (ACIP). MMWR. 2010 May 07;59(RR03):1-12.• Hornig M, Briese T, Buie T, Bauman ML, Lauwers G, et al. Lack of association between measles virus vaccine and autism with

enteropathy: A case-control study. PLoS One. 2008 Sep 4;3(9):e3140.• Klein NP, Fireman B, Yih WK, Lewis E, Kulldorff M. Measles-mumps-rubella-varicella combination vaccine and the risk of

febrile seizures. Pediatrics. 2010 Jul;126(1):e1-8.• Klein NP, Lewis E, Baxter R, et al. Measles-containing vaccines and febrile seizures in children age 4 to 6 years Pediatrics. 2012

May;129(5):809 -814.• Rowhani-Rahbar A, Fireman B, Lewis E, Nordin J, Naleway A, et al. Effect of age on the risk of Fever and seizures following

immunization with measles-containing vaccines in children JAMA Pediatr. 2013 Dec;167(12):1111-7.• Low vaccination rates a big factor in ongoing measles outbreak. By ABC Radio | @ABCRadioJanuary 27, 2019 6:22 pm

https://wtop.com/health-fitness/2019/01/low-vaccination-rates-a-big-factor-in-ongoing-measles-outbreak/• Mike Martindale and Shawn D. Lewis With 5th most vaccine exemptions, Oakland measles outbreak 'sadly, predicted’, The

Detroit News. Published 10:31 p.m. ET April 3, 2019 | Updated 10:19 a.m. ET April 4, 2019 https://www.detroitnews.com/story/news/local/oakland-county/2019/04/04/measles-outbreak-puts-detroit-area-high-alert/3304068002/

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Bibliography XV VACCINESHISTORY• What is the History of Measles Vaccine in America and Other Countries? National Vaccine Infeormation Center: Your

Health, Your Family. Your Choice. https://www.nvic.org/vaccines-and-diseases/measles/history-measles-vaccine.aspx• Hendriks J, Blume S Measles Vaccination Before the Measles-Mumps-Rubella Vaccine Am J Public Health. 2013

Aug;103(8):1393-401• Institute of Medicine Committee to Review Adverse Effects of Vaccines. Adverse Events Associated with Childhood

Vaccines (Evidence Bearing on Causality). Washington, DC: The National Academies Press. 1994 Chap. 6. P. 118• FDA Measles, Mumps, Rubella and Varicella Virus Vaccine Live. Oct 23, 2018

VACCINE EFFECTIVNESS & DURATION• One of the Recommended Vaccines: MMR and MMRV Vaccine Composition and Dosage: About the vaccine. Vaccine and

Preventable Disease. Centers for Disease Control and prevention (CDC) Atlanta, Georgia. MMR and MMRV Vaccine Composition and Dosage. MMR and MMRV Vaccine Composition and Dosage

VACCINE SAFETY• Vaccine Adverse Event Reporting System: Vaccine Safety Monitoring – VAER. Centers for Disease Control and Prevention. Atlanta Georga.

https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vaers/index.html• Vaccine Safety Datalink (VSD) Vaccine Safety Monitoring – VSD. Centers for Disease Control and Prevention. Atlanta Georga.

https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/index.html• Clinical Immunization Safety Assessment (CISA) Project. Vaccine Safety Monitoring – CISA. Centers for Disease Control and Prevention. Atlanta

Georga. https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/cisa/index.htm