Presented by: irfan ahmed Final year pharm.D

introduction

• Measles is an acute, highly infectious disease characterizedby fever, respiratory symptoms, and a maculopapularrash. Complications are common and may be quite serious. • Measles has been recognized as a distinct clinical disease for morethan 10 centuries and in the developing world is associated withhigh mortality rates in early childhood. .

Pathogenesis and Pathology• Humans are the only natural host of the virus but other animals can be infected experimentaly• The virus gains access to the human body via the respiratory tract, where it

multiplies locally; the infection then spreads to the regional lymphoid tissue, where further multiplication occurs.

• Primary viremia disseminates the virus,which then replicates in the reticuloendothelial system. Finally, a secondary viremia seeds the epithelial surfaces of the body, including the skin, respiratory tract, and conjunctiva, where focal replication occurs.

• Measles can replicate in certain lymphocytes, which aids in dissemination throughout the body.

• The described events occur during the incubation period, which typically lasts 8–15 days but may last up to 3 weeks in adults.

• Patients are contagious during the prodromal phase (2–4 days) and the first 2–5 days of rash, when virus is present in tears, nasal and throat secretions, urine, and blood.

• The characteristic maculopapular rash appears about day 14 just as circulating antibodies become detectable, the viremia disappears, and the fever falls.

• The rash develops as a result of interaction of immune T cells with virus-infected cells in the small blood vessels and lasts about 1 week. (In patients with

• defective cell-mediated immunity, no rash develops.)

The epidemiology of

• measles is markedly affected by population size, density, movement and social behavior. In the absence of vaccination, the disease infects essentially everyone at some time during life except in

isolated populations. Beginning of vaccination in 1963.• Measles has not been endemic in the United States since1997.• Indigenous transmission of measles was interrupted in the

Americas in 2002.• Mathematical models suggest that transmission of measles to12–18 persons

Clinical characteristics• Fever( more then 40 degree)and malaise ranging from 8-16 days.• followed shortly thereafter by cough, coryza, and conjunctivitis.• An enanthem, characterized by small bluish white spots on a red

background (Koplik’s spots), may be seen on the buccal mucosa within the two days before

• and after the onset of rash. The characteristic maculopapular rash of measles usually appears an average of 14 days after infection begins .

Clinical characteristics• classically starts on the face and hairline and then spreads to the

trunk and extremities.• The patient’s temperature usually peaks 1–3 days following the

onset of rash. The rash, areas of which fade in order of appearance, typically lasts 5–7 days, and the illness is entirely gone

• by 10–14 days after the onset of symptoms. There are few clinically in apparent primary infections

Clinical characteristics• The infectious period is usually considered to stretch from four

days before to four days after the onset of rash.• Measles is usually transmitted in large respiratory droplets,

requiring close contact between patients and susceptible persons.

• measles virus can survive for at least two hours in fine droplets, and airborne spread has been documented.

• carrier state nor an animal reservoir is known

Other symptoms• runny nose, and red eyes

Complications

• The risk of complications and death is highest in young children and adults.

• In United states the most common complications are• 1) otitis media and pneumonia, which occur in 2–14% and in

2–9% of cases, respectively.

• In developing countries • Complications and case fatality rates may be higher. • Pneumonia, the most common cause of death, may be caused

by the measles virus itself or by secondary bacterial infection

• Secondary viral infections may play a prominent role in measles pneumonia-related deaths in the developing world.

• Severe diarrhea and malnutrition may result from measles infection, particularly in the developing world.

Measles encephalitis• occurs typically 4–7 days after the onset of rash (range generally 1–15

days), is reported approximately• once in every 1000 cases of measles.• Approximately 15% of patients with measles encephalitis die, and

another 25–35% have permanent neurologic residua.• Less common complications include bronchiolitis, sinusitis,

mastoiditis, myocarditis, keratoconjunctivitis,mesenteric adenitis, hepatitis, and thrombocytopenic purpura

• In United states the reported death to case ratio is 1-3 per 1000 cases

• And in developing countries it is 5-10% or even higher.• Atypical measles syndrome, characterized by high fever,

pneumonia, pleural effusions, edema of the hands and feet, hepatic abnormalities, and an unusual rash, is a rare manifestation of measles infection

• sometimes seen in persons who received killed measles vaccine in the past and who were subsequently exposed to measles virus

• Measles infection during pregnancy is associated with spontaneous abortion and with delivery of low birth weight infants.

• Although there have been rare reports of congenital malformations associated with measles infection during the first trimester,

• there is no good evidence for the existence of a congenital measles syndrome

sub acute sclerosing pan encephalitis (SSPE)• measles virus can cause a degenerative disorder of the central

nervous system known as) sub acute sclerosing pan encephalitis (SSPE. The reported risk of SSPE ranges from 1 case per 100,000 measles cases in persons infected after four years of age

• 18 cases per 100,000 measles cases in persons infected in infancy.

• A recent study in the U.S. noted a rate of 22 cases of SSPE per 100,000 reported measles cases.

• This illness begins insidiously an average of seven years following the initial infection and is characterized by progressively severe personality changes, myoclonic seizures, motor impairment,coma, and death over the course of several months to years

Epidemiology • Before the introduction and widespread use of measles vaccine,• measles infection was essentially universal in the United States.• Approximately 95% of persons living in urban areas were infected by

age 15 years.• The disease typically appeared in cycles with major peaks every 2–3

years. A marked seasonal pattern was apparent with peaks during the late spring months.

• The highest reported age-specific incidence rates were in children 5–9 years old.

• In the decade from 1950–1959, an annual average of more than 500,000 cases was reported.

• The true number of infections was estimated to be nearly 10 times as high.

• During the same period, nearly 500 measles deaths were recorded each year.

Etiology

• Measles is caused by a single-stranded RNA virus of the paramyxovirus group.

• It is very sensitive to acid conditions, drying, and light,but can survive in aerosolized droplets.

• Three membrane proteins appear to play critical roles in the pathogenesis.

• The hemagglutinin protein (H), which projects from the virion, attaches to cell surfaces.

• The fusion (F) protein allows cell-to-cell spread. • Finally, the matrix(M) protein, associated with the inner surface of the

viral envelope,• appears important for successful generation of intact viral particles.• Abnormalities in the synthesis of these proteins have been postulated

to play an important role in the pathogenesis of SSPE

• Measles virus infection with either wild type measles or live virus vaccine induces the production of a variety of antibodies.

• Immunoglobulin M (IgM) antibodies are detectable in approximately 80% of cases within the first 72 hours after rash onset and in nearly 100% of cases there after.

• IgM antibodies decline to undetectable levels within 1–2 months, they provide evidence of recent infection.

• Testing a single specimen for measles IgM antibody is the preferred method for evaluating suspected measles in most countries.

Diagnosis • IgG antibodies appear shortly after rash onset, and peak 2–4

weeks later and appear to last a lifetime. • Therefore single serum IgG antibody tests are typically used to

assess immunity to measles. • A significant rise in total antibody (IgG and IgM) in paired titers,

with acute serum drawn shortly after rash onset and convalescent serum two weeks later, provides laboratory confirmation of acute measles infection.

• Although testing of paired sera is less convenient and takes longer than IgM testing, it is more accurate and may help to validate IgM results in some situations.

• Serologic tests cannot distinguish between antibody produced by wild type infection and that resulting from live measles virus vaccination.

Diagnosis • Because of the widespread availability and ease of use, enzyme

linked immunosorbent assays (ELISA) tests are the most commonly used method to measure measles IgM and IgG antibodies.

• Several commercial ELISA kits have been shown to be sensitive and specific.

•Plaque reduction neutralization (PRN) assays are considered the gold standard for antibody testing because they provide a quantitative measure of the antibodies.

• However, PRN testing is laborious and generally confined to research settings. In addition to the humoral immunity represented by the antibodies,

Diagnosis • Measles virus can be cultured from respiratory secretions,

urine or whole blood or detected by reverse transcriptase polymerase chain reaction (RT-PCR) in these specimens.

• These tests can support the laboratory diagnosis of measles but they do not currently serve as frontline diagnostic tools because they take too much time to provide results and the sensitivity of the tests is highly dependent on the timing and quality of the specimen collection and on proper shipping.

• However, testing of viral specimens by culture and RT-PCR allows determination of the genotype of the virus, which enhances the ability to identify sources of infection and track chains of transmission.

Limitations

• Both serologic and virologic specimens require a cold chain for storage and transport.

• Methods are currently being developed to allow both serologic and virologic testing from a single specimen and to limit the invasiveness of the collection method and the need for a cold chain. The two most promising are oral fluid collection and filter paper blood spots.

• Oral fluids specimens have been used successfully without cold chain in the United Kingdom for measles surveillance.

• since the mid-1990s, initially with a radioimmunoassay and more recently with ELISA tests with reasonably high sensitivity and specificity. However, these tests are not currently commercially available.

Treatment

• There is no specific treatment for measles. Most people with uncomplicated measles will recover with rest and supportive treatment.

• Symptomatic treatment,• Vitamin A on recommendation of WHO to reduce blindness.• A specific drug treatment for measles ERDRP-0519 has shown promising

results in animal studies, but has not yet been tested in humans.

• In May 2015, the journal Science, published a report in which researchers found that the measles infection can leave a population at increased risk for mortality from other diseases for 2 to 3 years.

Immunization

•Passive immunity• Passive immunity against measles disease can be induced by the

administration of commercially prepared immune globulin (IG) (formerly called immune serum globulin [ISG]).

• Administration of 0.25 mL of IG per kilogram (maximum dose 15 mL) can modify or prevent the development of measles in the exposed person.

• The IG preparation is most effective if administered within six days of exposure, preferably as soon after the exposure as possible.

• IG is particularly indicated for susceptible household contacts, especially those who are immunocompromised.

Immunity

• Almost all infants acquire passive immunity against measles from the transfer of maternal antibodies across the placenta. Such infants are usually immune to measles for at least the first six months of life. Immunity

• gradually wanes thereafter, and by 12–15 months essentially 100% of infants are susceptible. Children born to mothers who have vaccine induced antibodies tend to become seronegative earlier than infants born to mothers who have had measles disease.

• Measles disease induces higher levels of antibodies than measles vaccination.

• “Modified” measles is a mild form of illness occasionally seen in persons with passively acquired antibody.

• The incubation period may be prolonged up to 20 days.

Active Immunity.• In 1963, two types of measles vaccine were licensed in the

United States. One was a vaccine prepared from live attenuated virus grown in chick embryo tissue culture (Edmonston B strain).

• Because there was a high rate of reactions to this vaccine, including fever, rash, and catarrhal symptoms, the concomitant administration of IG was recommended.

• A second vaccine used the same virus, but the virus had been inactivated (killed) by formaldehyde.

• Immunity to the killed measles virus vaccine (KMV), or to KMV followed by live measles vaccine within three months, was short lived and induced hypersensitivity to measles virus in some persons, resulting in atypical measles syndrome

Vaccination history• Beginning in 1965, vaccines prepared from further-attenuated

strains of measles virus and not requiring the concomitant administration of IG became available and quickly became the most common vaccines

• The use in the United States (Schwarz strain licensed in 1965 and Moraten strain licensed in 1968).

• From 1965–1989, when one dose of measles vaccine was recommended, more than 172 million doses of measles containing vaccines were distributed in the United States.

• Following the recommendation of a routine two-dose schedule in late 1989.

History • more than 213 million doses were distributed from 1990 to

2005.• The age at which measles vaccine is administered represents a

balance between the ability of the vaccinee to respond to vaccination and the risk of measles.

• The proportion of vaccine recipients who developed antibodies to measles virus increases with increasing age at administration up to 12–15 months of age

History • When measles vaccine was first introduced in the United

States, it was administered at nine months of age because of the high risk of measles,

• even though seroconversion rates were not optimal.• As the risk of measles declined, the age at administration was

raised to 12 months (1965) and 15 months (1976) to assure maximal seroconversion rates.

Vaccination schdule • Recent studies, performed when an increasing proportion of infants

are born to mothers with vaccine-induced immunity, indicate seroconversion rates at 12 months are comparable to rates at 15 months.

• Thus,in 1994 the Advisory Committee for Immunization Practices (ACIP) recommended that the first dose of measles vaccine as part of measlesmumps- rubella (MMR) vaccine could be administered any time between 12 and 15 months of age.

• Administration of further-attenuated live measles vaccine to children at 12–15 months of age or older can be expected to produce measurable circulating antibodies in 95% or more of recipients.

• During measles outbreaks, vaccine can be given to children as young as six months of age with subsequent revaccination.

• The vast majority of persons with seroconversion have long-term, probably lifelong immunity.

Vaccination schdule• Because measles transmission had been documented among

the 2–5% of persons who did not respond to a first dose of measles vaccine,

• in 1989, both the Committee on Infectious Diseases of the American Academy of Pediatrics (AAP) and the ACIP recommended

• a change from a one-dose schedule to a routine two-dose schedule for measles vaccination.

• The second dose recommendation focused on school children. States and localities generally implemented second dose vaccination for one school grade cohort at a time

Risk of infections• In addition to school age children, other groups of people are at• increased risk of exposure to measles including persons who

work in health-care facilities, students in post high school institutions and international travelers.

• Persons in these groups should receive two doses of measles vaccine if they do not have other evidence of measles immunity

• Because almost half of imported measles cases occur in United States residents returning from overseas trips, infants 6–11 months of age traveling internationally should receive a dose of measles vaccine before departure

• and persons over 13 months of age should receive the second dose of measles vaccine before departure,given at least 28 days after the first dose.

ADR risk

• Fever higher than 103°F (39.4°C) and fleeting rash are reported in 5–15% of recipients of measles vaccine.

• Encephalitis has been reported after the use of measles vaccine Comparing the number of cases reported to have occurred within the 30 days after immunization to the number of doses distributed in the United States yields an estimate of approximately one case of encephalitis per million doses of vaccine distributed.

• This rate is similar to that of reported encephalitis of unknown cause seen in a comparable period in the general population in the same age group.

• The Institute of Medicine has concluded that available evidence is not sufficient to prove that vaccination causes encephalopathy or encephalitis.

ADR risk• Some have raised concerns that MMR vaccine can cause

autism.• However, an exhaustive review by the Institute of Medicine of

at least 13 studies that addressed the question concluded that the evidence favors rejection of a causal relationship between MMR and autism.

Contraindications • Measles vaccine is contraindicated in persons with

immunodeficiency or immunosuppression. • However, it should be administered to persons with

asymptomatic human immunodeficiency virus (HIV) infection since measles disease may be severe or fatal in such persons

Contraindications • MMR vaccination causes clinically evident thrombocytopenia

in• 1:30,000 to 1:40,000 vaccinations.• Because persons with a history of idiopathic

thrombocytopenic purpura (ITP) may be at increased risk for thrombocytopenia following measles vaccination.

• a history of ITP is a contraindication to measles vaccination.

Contraindications • Vaccination of persons who received IG, whole blood, or other

antibody-containing blood products should be postponed for 3–7 months or longer depending on the product and dose received to avoid potential interference with seroconversion.

• Vaccination should be postponed in persons with severe febrile illnesses.

• Persons with mild illnesses such as upper respiratory tract infections may be vaccinated.

Impact of Vaccination on Disease