2.1. Measles
Measles is one of the most contagious viruses, with a secondary attack rate among susceptible individuals higher than 90%. The virus can be transmitted in the air (aerosolized) in respiratory droplets, or by direct or indirect contact with the nasal and throat secretions of infected persons. Individuals with measles are considered infectious from four days before to four days after the onset of rash (11). Following exposure, the incubation period before onset of the first symptoms is usually 10–12 days. The rash usually appears 14 days after exposure (range 7–18 days) (11, 12)2.
Approximately 30% of reported cases of measles involve one or more complication. In developed countries these include otitis media (7–9%), pneumonia (1–6%), diarrhoea (6%), blindness and post-infectious encephalitis (1 per 1000 cases). The risk of serious measles complications is higher in infants and adults. A less common but very serious complication is subacute sclerosing panencephalitis (1 per 100 000 cases) (12).
Measles remains a leading cause of death globally among young children, despite the availability of safe and effective vaccines for over 40 years. An estimated 139 000 children died worldwide from measles in 2010, a 74% reduction compared with 2000 (14). The 2005 measles mortality reduction goal established by WHO and the United Nations Children's Fund (UNICEF), which was to reduce the number of measles deaths by 50% from 2000 levels, has now been achieved (15, 16). There is a new goal to achieve a 95% reduction worldwide by 2015, primarily by targeting children in the WHO regions with the highest number of measles deaths (Africa and South-East Asia) (3).
In settings where measles remains endemic, transmission of the virus shows a seasonal trend: in temperate areas, the most intense virus transmission usually occurs in late winter and spring. Before vaccination programmes, childhood infection was almost universal. Measles epidemics occurred in approximately four-year cycles, with periods of very high incidence alternating with low-incidence inter-epidemic periods. With the introduction and increased coverage of measles vaccination, the incidence of the disease during epidemic periods has fallen and the intervals between epidemics have lengthened. Very high levels of population immunity have led to the elimination of the disease in many countries, but if this level of population immunity is not maintained, the cyclical pattern of measles outbreaks will reappear.
In contrast to developing countries, the majority of cases in many European countries occur in adolescents and adults (17, 18). In most countries of the Region, measles vaccination coverage and population immunity among the general population are high and the cyclical pattern of measles is not seen. However, there are still susceptible groups in most countries. While some of these susceptible individuals live within communities with high levels of population immunity to measles and rubella, and are therefore at low risk of exposure to wild measles virus following an importation, others live in settings where the risk of exposure and further transmission between individuals is very high after the virus is introduced.
The case–fatality ratio for measles is highest in infants aged under 12 months. In developed countries, the case–fatality ratio is 0.05-0.1 per 1000 cases, much lower than in developing countries where it can be 3–6% (15, 19). Malnutrition and severe immunodeficiency (e.g. as a consequence of an advanced infection with human immunodeficiency virus) are risk factors for complications, including death.
2.1.1. Laboratory diagnosis of measles
In the European Region, where the incidence of measles is low, a clinical diagnosis of measles in the absence of a confirmed outbreak has a low positive predictive value, and clinical signs are unreliable as the sole criteria for diagnosis. A number of other infections can present with a rash resembling measles, therefore laboratory assessment is required for accurate diagnosis.
Measles-specific immunoglobulin M (IgM) and immunoglobulin G (IgG) are both produced during the primary immune response and can be detected in the serum within days of rash onset, using a sensitive enzyme-linked immunosorbent assay (ELISA). Approximately 70% of measles cases are IgM-positive at 0–2 days after the rash onset, and 90% are positive 3-5 days after rash onset. IgM antibody levels peak after 7–10 days and then decline, being rarely detectable after 6–8 weeks. IgG antibody levels peak within three weeks and persist long after the infection. Serum and secretory immunoglobulin A (IgA) antibodies are also produced. Re-exposure to measles induces a strong anamnestic immune response with a rapid boosting of IgG antibodies, preventing clinical disease. Measles virus can be isolated from conventional clinical specimens (nasopharyngeal swab, urine or peripheral blood mononuclear cells) up to five days following onset of the rash and may be detected using polymerase chain reaction (PCR) assays on specimens obtained up to seven days or more after onset of the rash. Recommendations for laboratory confirmation of the disease for surveillance have been described in the WHO Manual for the laboratory diagnosis of measles and rubella virus infection (20).
WHO recommends IgM antibody detection by ELISA as the standard test for routine measles surveillance
In addition to IgM antibody detection, measles can be diagnosed using other methods, including a minimum fourfold increase in IgG titre, antigen detection by immunofluorescence, reverse transcription (RT) PCR to detect measles virus ribonucleic acid (RNA), or isolation of measles virus. False-positive IgM test results may sometimes occur due to cross-reacting IgM antibodies to other agents (e.g. Epstein-Barr virus [EBV], human parvovirus B19), rheumatoid factor or other auto-antibodies, and polyclonal stimulation of IgM response by EBV.
A positive IgM antibody test in recently vaccinated individuals must be interpreted according to the clinical signs and the local epidemiology of disease. Mild rash and low-grade fever, usually without other symptoms of measles (cough, coryza or conjunctivitis), can be observed 1-2 weeks after measles vaccination in some vaccine recipients (10, 13, 21).
In countries with low measles incidence, the use of IgM alone to diagnose a single case of measles without evidence of other cases in the community may not be sufficient, and efforts should be made to confirm the diagnosis using other laboratory methods in addition to the IgM test, and/or to rule out other diseases with similar clinical presentation.
2.2. Rubella
Rubella is an acute viral illness, characterized by mild maculopapular rash often with postauricular or suboccipital adenopathy. Usually mild in children, rubella in adults may be accompanied by low-grade fever, headache and arthralgias. Less common complications are thrombocytopenia and encephalitis (1 per 6000 cases), which may be fatal. Up to 50% of infections with the rubella virus can be asymptomatic. Like measles virus, rubella virus is also transmitted by respiratory droplets and by direct or indirect contact with the nasal and throat secretions of infected persons, but is less contagious. Individuals are most infectious when the rash is erupting, but they may shed virus from seven days before to 14 days after the onset of rash. Following exposure, the incubation period before onset of symptoms is usually 14–18 days (range 12–23 days). The outcome of rubella is most serious when infection occurs during early pregnancy, as it can result in spontaneous abortion, stillbirth or an infant born with a combination of birth defects, known as CRS (22, 23, 24).
In the pre-vaccine era, the epidemiology of rubella was similar to the epidemiology of measles, with seasonal variation and regular epidemic peaks alternating with low-incidence periods. In temperate climates, regular seasonal increases of rubella occurred in spring, with small epidemics every three to four years, and larger epidemics every six to nine years (22, 23).
Rubella vaccination programmes have been highly effective in modifying the epidemiology of rubella, and a number of countries have eliminated the disease, with a similar effect to that of measles vaccination programmes on measles (22, 25). However, in many countries of the Region, rubella vaccination has been introduced in different ways and often much later than measles vaccination. This has resulted in marked differences in rubella susceptibility profiles and rubella epidemiology across these countries. In addition, rubella surveillance is not well established in many countries, making estimates of the true burden in Europe difficult.
2.2.1. Laboratory diagnosis of rubella
A number of infections can present with signs and symptoms compatible with rubella. In addition, up to 50% of infected persons may have minimal or no clinical symptoms. Therefore, a laboratory assessment is critical for confirmation of a clinical rubella diagnosis.
Humoral and cell-mediated immunity develop following natural infection and with immunization. With natural infection, IgM antibodies become detectable within 3–4 days and IgG antibodies within one week of the onset of rash. Rubella-specific IgM can often be detected in individuals up to two months after illness and, in a decreasing percentage of individuals, up to six or seven months after natural infection, vaccination and reinfection (26). In addition, false-positive IgM test results may occur because of cross-reacting IgM antibodies (e.g. to EBV, human parvovirus B19, etc.), rheumatoid factor or other autoantibodies, and polyclonal immune stimulation by EBV.
Following infection, the virus can be isolated from nasopharyngeal secretions from a few days before to up to seven days after the onset of rash. The detection of viral RNA by RT-PCR may be possible for 3–4 days longer. However, the optimal time to collect specimens is within four days of the onset of symptoms (20, 22, 26).
WHO recommends IgM antibody detection by ELISA as the standard test for routine rubella surveillance
In countries with low incidence of rubella, a positive rubella IgM result in a person without known exposure to other cases in the community or through travel to endemic countries should be assessed using other laboratory methods in order to distinguish a primary rubella infection from a false-positive result. Recommendations for testing are described in the WHO Manual for the laboratory diagnosis of measles and rubella virus infection (20).
2.2.2. Rubella infections in pregnant women
Cases of rubella in pregnant woman should be reported like any other rubella case and have pregnancy status noted on the report form. A single positive IgM test result is sufficient for classifying a case as laboratory-confirmed for surveillance purposes. However, for clinical management and medical decision-making, additional testing (detection of a significant rise of IgG antibodies, avidity testing, rubella immunoblot, virus detection or virus isolation) may be needed. A consultation with a medical expert is strongly recommended. Although not included in this document, detailed procedures should be in place in all Member States for appropriate screening and follow-up of pregnant women exposed to rubella, given the serious consequences of rubella infection during pregnancy (27).
Pregnant women known to have been exposed to rubella should be assessed for rubella-specific IgG antibody and those found to be negative should be monitored for IgM and IgG seroconversion and for the outcome of their pregnancies. Pregnant women found to be susceptible should be vaccinated after delivery.
A registry of pregnant women with rubella can be used for recording pregnancy outcomes (e.g. abortion, stillbirth, defects associated with congenital rubella) and for laboratory follow-up of infants (See Chapter 6).
2.3. Congenital rubella syndrome
The most serious consequence of rubella virus infection can develop when a woman becomes infected during pregnancy. Infants infected with rubella virus in utero may have a variety of physical defects, known collectively as congenital rubella syndrome (CRS). This is most likely to develop with maternal infection during the first 12 weeks of pregnancy, although isolated birth defects, particularly sensorineural hearing impairment, can be found in infants with maternal infection at up to 20 weeks of pregnancy (22). CRS is seen in 0.6–2.2 children per 1000 live births during epidemics in countries without rubella immunization programmes (28).
The clinical features associated with CRS are: ophthalmic (e.g. cataracts, microphthalmia, glaucoma, pigmentary retinopathy and chorioretinitis); auditory (e.g. sensorineural hearing impairment); cardiac (e.g. patent ductus arteriosus, peripheral pulmonary artery stenosis, or ventricular septal defects); and craniofacial (e.g. microcephaly). CRS can also present with neonatal manifestations that include meningoencephalitis, hepatosplenomegaly, hepatitis, thrombocytopenia and radiolucencies in the long bones (a characteristic radiological pattern of CRS). Thrombocytopenia can be fatal. Interstitial pneumonitis is also a complication of CRS in infancy (29).
Infants with CRS who survive the neonatal period may face serious disabilities (such as visual and hearing impairment) and have an increased risk of developmental delays, type I diabetes mellitus and thyroiditis. A progressive rubella panencephalitis, resembling subacute sclerosing panencephalitis, has been observed in a few individuals with CRS (22, 30-32).
Infants with congenital rubella infection will have a positive rubella-specific IgM test at or shortly after birth, at least through the first three months of life. Because some infants do not test positive at birth, a second IgM test should be done shortly after an initial negative result if there is clinical suspicion. Most infants with CRS will be IgM-positive between three and six months of life; however, the laboratory confirmation of a possible congenital rubella case in an infant aged over six months should not rely on the IgM test alone. In the absence of vaccination or postnatal rubella, congenital rubella can also be confirmed by serial IgG testing for the sustained presence of IgG over several months.3 All congenitally infected infants, including those without clinical manifestations of CRS, may shed virus for up to at least one year of age and can transmit rubella to others (27).
2.4. Rationale for disease elimination and an integrated approach to measles and rubella surveillance in the European Region
Measles and rubella infections have many similarities. Both are viral diseases caused by pathogens that infect only humans. In the absence of prevention, both can have a serious impact on a population's morbidity and mortality. Both are also preventable with safe and widely used vaccines, which are often given as a combined vaccine. These characteristics make elimination of both diseases feasible.
Strategies recommended for elimination of these diseases depend on local epidemiology, historical vaccination coverage and the ability of the health system to deliver vaccine with high coverage to susceptible groups of people. All Member States currently have routine two-dose measles and rubella vaccination programmes using combined vaccines (usually measles/mumps/rubella (MMR) vaccine). Many countries that have recently introduced rubella vaccine have also undertaken supplementary immunization activities using combined measles and rubella (MR) vaccine with a strategy targeting susceptible children, adolescents and women of childbearing age, or in some cases adults of both sexes.
Integrating rubella and measles surveillance is cost-effective, given that the symptoms of the diseases are similar and both diseases commonly affect the same age groups. Thus, testing of specimens of suspected measles or rubella cases (at least IgM-negative ones) for the other disease is clinically and epidemiologically sound as it allows to confirm or rule out each of two diseases.
As the incidence of measles and rubella declines, Member States will need to ensure that their surveillance systems remain sensitive to the detection of sporadic cases. Based on the experience of countries that have eliminated measles, the principal benchmark for assessing the quality of surveillance in the absence of, or at low incidence of, measles and/or rubella is the rate of suspected cases which have been investigated and discarded. The rate of discarded cases should be at least 2 per 100 000 population per year at the national level, and in >80% subnational administrative units (additional details are given in Chapter 5).
Achieving this benchmark requires that all sporadic illnesses clinically consistent with measles or rubella be thoroughly investigated and adequate specimens obtained for laboratory confirmation and, if possible, virus isolation. If serum specimens have not been obtained, or were collected outside the time period optimal for IgM detection, other tests or types of specimens should be used to determine etiology. In the absence of laboratory results, cases clinically consistent with measles or rubella which cannot be epidemiologically linked to other confirmed cases should be classified as clinically compatible cases and reported to the surveillance system. In countries with an annual incidence of measles or rubella of <1 per 1 000 000 population, all cases should be either laboratory-confirmed or epidemiologically linked to a laboratory-confirmed case.
- 2
The incubation period from exposure to the onset of rash is with a range of 7–18 days, but rarely, as long as 19–21 days. Use of immunoglobulins in the early stage of infection can prolong incubation. Some countries use 21 days as the longest incubation period (11, 12, 13).
- 3
Maternal IgG will be declining or absent after six months of age.
