Measles: A Review

Introduction

Measles is a febrile viral infection which can have devastating sequelae. Before availability of effective vaccine, measles was a universal childhood disease affecting 90% children below 15 years of age. The illness is on World Health Organization (WHO) list of diseases which are marked for eradication. Although on decline, cases of measles and its complications are still being seen.

In 2015, from South-east Asia region alone (of which India is a member country), 1,08,319 cases were reported and from Jan 2016 to 5 April 2016, 16,618 cases were reported from this region (WHO). The reported cases might represent only a fraction of actual number of cases because of variable surveillance and under reporting.

WHO data shows that in 2015 there were 81,739 cases reported from India with reported incidence rate of 62.38/1,000,000 total population.

The Measles Virus

The measles virus (MeV) is an enveloped negative sense single stranded RNA virus belonging to the genera Morbillivirus in the family Paramyxoviridae.

The virus is usually described as spherical but can be pleomorphic. The RNA genome consists of about 16000 nucleotides which code for eight proteins. H and F proteins are trans-membranous proteins which project outside the cell wall. These are important for attachment and subsequent entry of the virus in host cell. The wall is lined form inside by M (matrix) protein. N protein (nucleoprotein) envelops the RNA strand. The other proteins L and P are needed for viral replication. Remaining V and C proteins are responsible for interaction with host cell protein for regulation of viral replication and host response.¹

The C terminal of N protein is the most variable portion of the virus. According to the nucleotide coding of the N protein, various measles genotypes have been described.² WHO currently recognizes eight clades of measles virus (A,B,C,D,E,F,G,H), and within these eight clades, there are 23 recognized and one more provisional genotypes. These are 1, B2, B3,C1,C2, D1, D2, D3, D4, D5, D6, D7, D8, D9, D10, E, F, G1, G2, G3, E, F, G1, G2G3, H1, H2 and one provisional genotype D11.

These genotypes are important for measles surveillance. Specific genotypes are endemic to an area. In India, we have only limited epidemiological data. Predominant genotypes are D4 and D8; however, B3 and D7 are also reported.³ Appearance of a new genotype in an endemic suggests importation of the virus. The measles vaccine viruses are of ‘A’ genotype; additionally type A is not a naturally endemic genotype.⁴

Of the 11 measles virus genotypes detected globally during 2005-2010, five have not been detected since 2011 suggesting that they may have been eliminated. The decrease in the reported number of virus variants despite increasing quality of measles genotype surveillance indicates progress in the interruption of endemic virus transmission.⁵

This genotype variation does not mean antigenic variation. Infection from any genotype protects against all other genotypes. This is because neutralizing antibodies after infection or vaccination develop against H and F proteins. These proteins are relatively stable during evolution unlike similar RNA viruses like influenza.⁶ They do not vary across the genotypes or over time. Hence measles immunity after vaccination or natural infection is long lasting.

Historical aspect

MeV resembles a virus in cattle called Rinderpest virus. MeV is thought to have originated from close humancattle interaction. Earliest estimates of measles based on population size needed for sustained virus transmission was around 5000-10000 years ago in Eastern river valley civilizations.⁷ However, studies based on genetic diversity date the origin to as recent as 11th or 12th century.⁸

Transmission

Measles is highly transmissible. One infected person on an average infects 12-18 unvaccinated contacts. This is often called as reproductive number and denoted as R0. The transmission occurs through airborne route or by direct contact with respiratory secretions. The virus can remain suspended in aerosolized form for prolonged period, for even up to two hours.

Transmission can occur even during brief contacts such as in passengers’ in-transit in the same airport.⁹ However there is no evidence of human to human transmission with measles vaccine virus.¹⁰

Pathogenesis

There are four phases in measles - prodromal phase, incubation period, exanthematous period and recovery. Primary viremia causes the spread of virus to lymphoreticular system. A secondary viremia is responsible for the spread of the virus to body surface.

There have been new concepts about pathogenesis of measles.

It was thought that MeV infects respiratory epithelium and from there it spreads via monocytes. We now know that the wild type MeV specifically and exclusively binds receptors SLAM/CD150 and Nectin -4. These receptors are not present on epithelial cells or monocytes.¹¹

Studies done on animal model have elucidated the pathogenesis of MeV. After inhalation, the virus gets attached to either alveolar macrophage or dendritic cell through the Cd150+ receptors. Then it is taken up by T-lymphocytes which are CD150 positive including memory cells. This involvement of memory cells is the reason for virus induced immune suppression to other infections.

Viremia occurs through the infected lymphocytes. Infected lymphocytes and dendritic cells in the submucosa transmit the virus via Nectin 4 receptors to epithelial cells. These receptors are situated at the basolateral margins of the epithelial cells. The involvement of the epithelial and other cells of the body is responsible for clinical features and spread of infection.

Pathology

Measles infection causes lymphocytic infiltration and necrosis of epithelial cells. It causes small vessel vasculitis of the skin and mucous membrane. Histologically the lesions are characterized by intracellular edema and giant cell formation. Incubation period is 8-12 days. The patient is infective from three days before, up to 4-6 days after the onset of rash.

Clinical manifestations

Clinical manifestations start with onset of fever which increases after 2nd day of illness along with symptoms of coryza, cough and conjunctival congestion. Many patients experience gastro-intestinal symptoms such as vomiting and loose motions.

Enanthem usually appears on 3rd or 4th day of illness. These are greyish white pin-point spots which typically begin inside the cheek next to second molar. The enanthem, called as Koplik spots is transient, lasting for 1-3 days and is pathognomonic of measles. The Koplik spots can also be seen over conjunctiva and vaginal mucosa.

After four days of increasing fever, the exanthema appears, typically as erythematous maculo-papular rash beginning at the hair line of forehead and in occipital region spreading in cephalo-caudal distribution. Almost 50% patients have palmo-plantar rash.

After a day or two of onset of rash, the fever subsides. The rash often starts waning after seven days leaving behind coppery- brown pigmentation which is called as post measles staining and desquamation. The cough remains for 9-10 days.

Modified measles: Modified measles occur in partially immune patients such as those who have measles before six months of age or those who have been given immunoglobulins. Here the manifestations of measles are same but much less severe and incubation period may be more.

Atypical measles: Atypical measles is a distinct clinical entity which was commonly observed in patients who had received killed measles vaccine (Such a vaccine was available from 1962-1968 and was later withdrawn). The cases are however even described in recipients of live measles vaccine.

Incubation period remains same. Coryza is less distinct as compared to classical measles. Koplik spots have been described, but with rare incidence. The rash characteristically begins in extremities distally and then spreads proximally. There can be associated hepatosplenomegaly. The possible pathogenesis includes unbalanced activation of immune response to F and H viral proteins.

Black or hemorrhagic measles: Another type of measles which is potentially fatal with hemorrhagic rash. It is rarely described these days.

Laboratory diagnosis

Measles is often a clinical diagnosis. However, laboratory diagnosis may be needed in geographical areas where measles is rarely seen. It may also be needed in severe or complicated disease. Laboratory diagnosis of measles is by one of the three means such as, by isolation of measles virus from blood, saliva, or other body fluids, by demonstration of specific IgM antibodies or by demonstrating rising IgG titers.

a) Isolation of measles virus: Isolation of measles virus is rarely needed for clinical purpose. However, it is one of the most important investigations in outbreaks. Isolation of MeV and its genotyping helps to differentiate between endemic and imported measles. Maximum chances of positive isolation are within two days and not more than 10 days after the onset of rash.

b) IgM antibodies: IgM antibodies are detectable at the time of onset of rash and can persist up to 4-6 weeks. The initial test done within three days of onset of rash has 20% chance of being false negative. Repeat test is then advocated.

c) Rising titers of IgG: Estimation for IgG antibodies is done on the blood collected 2-4 weeks apart to show rising titers, and it can be used as a diagnostic test for measles. But both the tests need to be performed simultaneously using same method for antibody titer estimation.

Complications of measles

Measles is usually a self-limiting illness. One of the major effects of measles especially in developing countries is its effect in ushering the cycle of malnutrition-infectionmalnutrition. Because of its immune-suppressive effects, many children with measles suffer post-measles complications that include pneumonia, gastroenteritis and otitis media.

Measles and tuberculosis: Measles causes transient dysfunction of T lymphocytes, and it also causes temporary suppression of tuberculin hypersensitivity. Many textbooks and articles have mentioned about measles induced immune suppression as a risk factor for tuberculosis. But current studies from Korea have not proved the association between measles and tuberculosis.¹²

Pneumonia in measles: Pneumonia may develop in measles in three different ways. The commonest cause is bacterial or viral super infection. Adenovirus, Streptococcus pneumoniae, Staphylococcus are known to be associated with pneumonia. The second type of pneumonia is due to acute alveolitis which is characterized by diffuse radiological infiltrates.¹³ A third type of pneumonia, which is very rare, is associated with characteristic multinuclear giant cells. This type of pneumonia is very difficult to diagnose as it occurs in immune-compromised patients often without any rash or even serological evidence of measles. This is also often associated with acute encephalitis with inclusion bodies.¹⁴

CNS complications: Central nervous system may be affected in measles in four different ways, and causes illness such as Acute Measles Encephalitis (AME), Acute post infectious encephalitis (ADEM), Measles inclusion body encephalitis (MIBE) and Subacute sclerosing pan encephalitis (SSPE).¹⁵ A rare type of encephalitis occurring with transient changes in the splenium of Corpus callosum has also been reported.¹⁶

Acute measles encephalitis (AME): Occurs during the acute infection, usually while the exanthema is still persistent. It presents clinically with fever, rash, convulsions and change in sensorium. The CSF shows modest lymphocytic pleocytosis. Pathogenesis is due to direct CNS invasion and the course is monophasic.

Acute post-infectious encephalitis (ADEM): ADEM is monophasic immune-mediated encephalitis which occurs within 2-4 weeks after measles infection. Virus antigen or RNA can only rarely be demonstrated in these patients and the pathogenesis is due to immuneinteraction rather than direct CNS invasion.

Measles inclusion body encephalitis (MIBE): MIBE occurs after weeks to months of measles virus infection, typically in childhood. It is noted most commonly in immune-compromised patients. The diagnosis is extremely difficult as patients do not have history of typical measles rash. EEG and MRI findings are nonspecific and measles serology is often negative or positive in low titers. Brain biopsy shows eosinophilic inclusion bodies like those seen in SSPE. They are positive for measles virus RNA. The prognosis is dismal, survival has been reported in only one case so far.

Subacute sclerosing pan encephalitis (SSPE): As against inclusion body encephalitis, SSPE typically occurs 1-10 years after measles infection in immunecompetent children. Those who have suffered from measles at younger age (less than one year) are more at risk. The average age of SSPE has come down from 13 years to 7.6 years, possibly due to early age of measles illness. Recent studies have shown that all SSPE is associated with only wild virus infection and not with vaccine virus. The cases of SSPE in measles vaccinated patients have been attributed to either subclinical measles prior to vaccination or to primary vaccine failure.¹⁷

Mortality associated with measles

In 2014, there were 1,14,900 deaths globally due to measles. Children under five years of age and adults over 20 years of age are more at risk.

Measles mortality is expressed in terms of case fatality rate (CFR). The measles related death has been used as one of the indicators for progress of any nation in terms of measles control. In 2013, there have been 0.14 million deaths and India contributed to nearly 50% of them.¹⁸ The CFR is more in girls (as against most infectious diseases) and is more in rural population. Measles contributes significantly to under-five mortality and measles control alone can decrease the mortality by 27%.

Estimates from India

Death from measles was reported to be 0.2% cases from 1985 to 1992. Pneumonia was the cause for 60% of deaths. Common cause of death in children was pneumonia and encephalitis in adults.

Disease associations

Multiple sclerosis and inflammatory bowel disease are thought to be due to measles but not yet proven.

Treatment of measles

Measles is most often a self-limiting viral disease and the treatment is mainly symptomatic. Treatment of associated fever, cough and loose motions according to severity of symptoms is indicated.

Continuing and encouraging nutrition and being watchful about potential complications such as pneumonia, otitis media and dysentery would be vital in monitoring a child with measles.

WHO recommends two doses of vitamin A (Vit A) on consecutive days (2,00,000 IU each for a child above 1 year and 1, 00,000 IU for infants) in areas with coexisting Vit A deficiency. There are anecdotal reports of role of intravenous Ribavirin in the treatment of measles.

Vitamin A

Vitamin A given to a child suffering from measles has been proved to reduce mortality, especially in hospitalized patients in areas where case fatality rate is high.¹⁹ This benefit has been seen with of 200,000 IU/day for two days and not with one day therapy. It has also shown benefit in reducing morbidity associated with measles, pneumonia, otitis media and diarrhoea. Whether such benefit is also seen in developed countries is not known. But one study from Japan has shown morbidity benefit with reduced doses of Vit A.¹⁹

There is plausible biological explanation for the beneficial role of Vit A in measles. Vit A is vital for integrity of epithelial cells. Epithelial cells are main targets for virus induced destruction.

Vit A levels are depressed in patients suffering from measles. This can be due to exhaustion of storage and/or due to blockage of release of hepatic stores of Vit A. This effect of measles causing hyporetinemia is also reported from industrialized countries such as US.¹⁹

Antibiotic prophylaxis in measles

Prophylactic administration of antibiotics mainly sulfamethaxazole-pyrimethamine combination is associated with reduced mortality and morbidity in randomized trials done in Africa.²⁰ However more such trials validating the results are needed before any recommendation to use antibiotics prophylactically can be made.

Measles prevention

Vitamin A and immunization, either active or passive can prevent measles. Active immunization, i.e. vaccination is the cornerstone for measles prevention at individual and community level.

Vaccine

Measles vaccine was made from attenuated strain called Edmonston B in 1963. This was further attenuated by Shwartz and has been used worldwide since 1965. In US, a further attenuated strain called Morat (for more attenuation) is used.²¹

The effectiveness of the vaccine depends on the age at vaccination. When given before one year of age, its effectivity is 85% whereas after one year of age the effectivity rises to 95%. Outbreaks tend to occur when there is clustering of susceptible population.

Two doses increase the protectiveness and decrease the chances of outbreaks.

WHO recommends two doses, first at 9 months and 2^nd dose at 15 months of age. Many countries with low incidence rate of measles give first measles containing vaccine at 15 months of age and repeat dose at an age of four years.

The vaccination is safe with minor side effects which include some respiratory symptoms and occasionally mild rash (0.2% vaccines).

The vaccine also leads to transient suppression of tuberculin reactivity for up to six weeks.

Vaccine needs to be administered subcutaneously or intramuscularly. Commercial preparations of measles vaccine combined with mumps, rubella (MMR) and varicella vaccine (MMR-V) are available.

Immunoglobulin Immunoglobulins are effective in preventing measles and mortality from measles when given to a susceptible contact.²²

Vit A for measles prophylaxis

Multiple studies have found that routine Vit A supplementation reduces the incidence of measles. Cochrane meta-analysis in 2010 found that routine Vit A supplementation reduces incidence of measles by 50% (RR 0.50 (CI0.37-0.67).²³

Measles eradication/elimination program

Measles virus does not cause persistent infection except in SSPE. It has no non-human reservoir and the vaccine is very safe and effective. These three criteria make measles a possible target for elimination / eradication. Although the SSPE is a persistent viral infection, the virus is defective and cannot transmit.

Initial aim of measles vaccination program is measles mortality reduction. Then it should focus on outbreak control, and finally measles elimination. In 2010, WHO expert committee decided that measles eradication is indeed biologically, programmatically possible.

One challenge about measles elimination is highly infectious nature of the illness. R0 (reproduction number) denotes number of cases one case generates over its entire infective period in an otherwise nonimmune population. R0 for measles is highest at 12-18 cases suggesting that it is one of the most infectious illnesses.

Elimination of measles is defined as no endemic measles transmission in a geographical area for a period of more than 12 months. To achieve this, we must have more that 95% population coverage for two dose measles vaccine. We must also have a strong surveillance system to diagnose measles cases rapidly. Also, we must have the facility to do genotyping study and categorize cases as imported or endemic. This will ascertain presence or otherwise of endemic transmission.

What is being planned

In 2008, India was the only member state of WHO which had only one dose for measles vaccination. In 2010, Government of India (GoI) committed itself to measles elimination in a phased manner. In the first phase, there would be strengthening of routine immunization including introduction of two dose measles vaccine program. The goal is to eliminate measles by 2020.

The strategies include achieving high coverage with the first dose of the measles vaccine (i.e. first-dose coverage for the measles vaccine must be ≥90% at the national level and ≥80% for each district); intensive surveillance activities supported by adequate laboratory support (outbreak and case-based surveillance assisted by laboratories to ensure serological/virological categorization); appropriate case management (including administration of vitamin A); and implementation of catch-up measles vaccination campaigns for children aged 9 months to 10 years in states with <80% evaluated coverage with the first dose of measles vaccine. Measlescontaining-vaccine (MCV) 2 (2nd dose of measles vaccine) is being introduced in states with coverage >80%.

Along with measles, there is initiation of congenital rubella syndrome surveillance and planned introduction of Measles-Rubella vaccine, initially in a campaign mode and then as routine immunization at 9 and 15 months.

What has been achieved

Before widespread vaccination, measles caused estimated 2.6 million deaths every year. During 2000– 2014, the number of annually reported measles cases worldwide decreased by 69%, from 853 479 to 267 482, and measles incidence decreased by 73%, from 146 to 40 cases per million population.

WHO has developed a model to estimate measles mortality by using numbers and age distribution of reported cases, routine and Supplemental Immunization Activities Measles-containing-vaccine (SIA MCV ) coverage, and age- specific, country-specific case-fatality rates. During 2000-2014, estimated measles deaths decreased by 79%, from 546 800 to 114 900, and all regions had substantial reductions in estimated measles mortality. Compared with no measles vaccination, an estimated 17.1 million deaths were prevented by measles vaccination during 2000–2014.

Difficulties ahead

Measles being a highly communicable disease even with a vaccine of high effectiveness, number of susceptible people increase over a period of time. Additionally, waning of immunity and secondary vaccine failure is reported to occur in 15-20% cases, but the figure may go down with increasing vaccination coverage.

Such unprotected population would be highly susceptible to any ‘imported’ measles and outbreaks of various proportions would ensue. Outbreaks indicate deficiencies and hence need to strengthen routine immunization program.

A good surveillance system which differentiates outbreaks as due to imported virus as against endemic virus would need genotypic information of the circulating virus. Similarly, real time responses to outbreaks for containment are needed.

There are also other concerns about specificity of serological diagnosis of measles (IgM) in the later stages of measles elimination.²⁴

Conflicts of interest

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Financial support

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