Measles

  • Highly contagious disease resulting from infection with measles virus

  • First detailed clinical description of measles by Thomas Sydenham in 1676; Koplik sports described by Henry Koplik in 1896. First attenuated measles vaccine licensed in 1963. EPI started in 1974.

  • The first immunosuppressive infection to be described

Pathogen

  • Non-segmented, negative-sense RNA virus and a member of the Morbillivirus genus in the family of Paramyxoviridae

  • 24 known genotypes; 8 detected to be circulating since 2009. Genotyping can differentiate vaccine from wildtype virus

  • Antigenically monotypic, despite genotypic diversity and being an RNA virus (known to have higher mutation rates). Vaccines derived from a single measles genotype isolated in the 1950's remain protective worldwide. No need for new vaccines to be developed to counter evolving virus strains.

Transmission/epidemiology

  • Epidemiology determined by respiratory mode of transmission (respiratory droplets, small particle aerosol), high contagiousness (R0: 9-18 in different settings i.e. 1 person infects 9-18 other people, on average [one of the highest for a directly transmitted pathogen], and lifelong immunity following infection or vaccination

  • Contact patterns between susceptible and infectious individuals, affected by high birth rates (introducing new susceptible individuals), heterogeneities in vaccine coverage, and human mobility

  • Average incubation period from time of infection to onset of fever (10 days), onset of rash (14 days). Infectious period several days before and after onset of rash (=peak viraemia with cough and coryza most intense)

  • Spreads rapidly in susceptible populations and requires high levels of population immunity to interrupt transmission (e.g. 89-94% to achieve elimination)

  • Virus only maintained in human populations by unbroken chains of transmission (non-human primates can be infected but their population size is too small to sustain transmission), no latent or persistent states, no animal reservoir - elimination/eradication is therefore possible

  • Endemic transmission: temporal pattern, annual seasonal epidemics superimposed upon longer epidemic cycles of 2-5 years, resulting from accumulation of susceptible people over successive birth cohorts, and subsequent decline in susceptible individuals following an outbreak (i.e. accumulation & decline of susceptible individuals)

  • Measles outbreaks in the tropics have more variable seasonal patterns and, in regions with high birth rates, highly irregular, large measles outbreaks can occur

  • Outbreaks result in high costs related to case-based investigations, outbreak responses, and provision of health care. This risk will only be mitigated if measles is eradicated. Measles virus meets many of the biological criteria for disease eradication, including the absence of a non-human reservoir, accurate diagnosis, and the availability of a highly effective vaccine

  • Passively acquired, maternal anti-measles virus IgG antibodies protect young infants against measles in the first months of life but can also interfere with vaccine responses by neutralising vaccine virus.

  • Antibody levels generally higher in women with naturally acquired immunity

  • Infants born to women with vaccine-induced immunity become susceptible to measles at a younger age than those born to women with a history of wildtype measles virus infection.

  • The average age of measles cases is a function of the rate of decline of protective maternal antibodies, the age at which children acquire protective immunity from vaccination, and the rate of contact between susceptible and infectious individuals.

  • In densely populated urban settings with low measles vaccine coverage, the average age of infection is low and measles is a disease of infants and young children.

  • As measles vaccine coverage increases, or the rate of contact between susceptible and infectious individuals decreases, the age distribution shifts toward older children.

  • With increasing vaccination coverage and levels of population immunity, the age distribution of measles is further shifted into adolescence and adulthood. Following recent progress in increasing measles vaccine coverage, many countries now face a changing epidemiological profile in which a higher proportion of measles cases occur in adolescents and adults, albeit with a lower number of measles cases.

  • Outbreaks occurred in populations with immunity gaps, despite high overall vaccine coverage, including cases who received 2 doses of vaccine

Prevention

  • Measles vaccines introduced in the 1960's; coverage increased in the 1980's through EPI

  • Incidence & mortality declined (1) over the past century due to improved nutrition, socio-economic status, and healthcare; and (2) over the past few decades due to increased routine and mass vaccination campaigns

  • MCV1 at 6 months in some circumstances (during outbreaks, refugees/IDPs, HIV infected/exposed) but lower % develop protective immunity because of inhibitory effect of maternal antibodies and immaturity of immune system, 9 months in endemic settings (85% protective levels of antibody), 12-15 months where risk of measles is low (95% protection)

  • 2nd dose required to immunise children who failed to respond to 1st dose, through either routine EPI (MCV2 at 15-18 months, or later in low risk settings) or mass vaccination campaigns (supplemental immunisation activities [SIAs] targeting 9M - 5 or 15Y)

  • Primary goal of measles control/elimination programmes should be to get MCV coverage >85%. MCV2 remains suboptimal at only 61% in 2015.

  • Burden of disease decreased from >2 million deaths/year prior to the increase in global vaccine coverage in the 1980's, reduced pneuminia, blindness, chronic neurological conditions

  • This progress has had the perverse effect of diminishing the perceived public health importance of measles and the value of measles vaccination. Antivaccine sentiments are increasingly voiced, in part because of successful measles control

  • However, measles remains an important VPD, cause of morbidity/mortality (>100,000 deaths/year)

  • Interest in regional elimination and global eradication. Global vaccine Action Plan for 2012-20 to eliminate measles and rubella in 5 WHO regions by 2020. Measles elimination goal for the Western Pacific region set for 2012.

  • Precise measurements of measles incidence and mortality are lacking, however, because most cases and deaths occur in countries with poor vital registration and disease surveillance systems. Estimates based on imperfect reporting and models. Case-based surveillance and standardised testing through WHO Global Measles and Rubella Lab network. WHO mortality estimates based on model including number/age distribution of reported cases, vaccine coverage, age/country-specific case fatality ratios.

  • Therefore....

  • Deaths decreased from 651,600 in 2000 to 134,200 in 2015 (vaccination estimated to have prevented 20.3 million deaths during this period)

  • Steady decline in measles cases (853,479 in 2000 to 254,928 in 2015), but increases in 2018 & 2019

  • 2016:

  • 2017:

  • 2018:

  • 2019: several countries declared outbreak

  • 2018-19 measles outbreak in the Western pacific region, /predominantly affected (most cases) in the Philippines

  • 2016:

  • 2017:

  • 2018:

  • 2019:

Philippines:

  • 2010: 6,361 confirmed cases

  • 2011: 6,520 confirmed cases

  • 2012: 1,509 confirmed cases

  • 2013: 4,855 confirmed cases

  • 2014: 53,906 confirmed cases (measles outbreak, measles-rubella SIA conducted)

  • 2015: MCV1 (82%), MCV2 (67%), 2,021 confirmed cases

  • 2016: MCV1 (80%), MCV2 (66%), 647 confirmed cases (6.2/million) (87 at SLH=13%)

  • 2017: MCV1 (89%), MCV2 (80%), 2,407 confirmed cases (23.1/million) (114 at SLH=4.7%), dengavaxia controversy towards end of 2017 severely affected the immunisation programme in the country. Start of measles clustering in BARMM (Sept 2017)

  • 2018: MCV1 (67%), MCV2 (59%), 22,794 confirmed cases (195/million) (DOH: 20,827 cases, 199 deaths=1.32%CFR) (2,049 at SLH=9%). Outbreak in Mindanao (March 2018). Measles-rubella SIA campaign Phase 1 (NCR & Mandanao) and Phase 2 (Visayas/Luzon except NCR) challenging because of dengavaxia issue.

  • 2019: MCV1 (73%), MCV2 (68%), 48,375 confirmed cases (449/million). (DOH: 48,525 cases, 642 deaths=0.96%CFR; NCR Jan 1-May 16 8,102 cases, 142 deaths, CFR 1.8%) (3,189 at SLH=6.6%). Outbreak in Luzon, Visayas and some parts of Mindanao (Feb 2019). Peak in the first few months of 2019 led to conduct of nationwide (all regions) outbreak response immunisation with selective strategy for unvaccinated and undervaccinated children/adolescents. Vaccination status of measles cases by age group (see DOH data).

  • 2020: 3,462 confirmed cases (incomplete) (DOH: 3,408 cases, 35 deaths by May)

* different vaccination coverage estimates (DOH presentation, WHO etc...); breakdown by age groups (DOH) data; majority in NCR are in the 6-59 month age group. 10% <6 months.

  • Total in PH 2016-19=647+2,407+22,794+48,375 = 74,223

  • Total in SLH 2016-19=87+114+2,049+3,189=5,439 (7.3% of the total)

  • Issues: HR to manage and supervise the program (immunisation/surveillance), vaccine management (limited storage capacity), financing

  • Susceptible adult population, e.g. young adults 15-30, no immunisation policy to cover this group

  • COVID-19: immunisation service seriously affected, some LGUs suspended immunisation as focus shift to COVID response. MCV1 and 2 coverage decreased in 2020, campaign in late 2020??

Clinical

  • Virus spreads first to local lymphoid tissue, then disseminated throughout the blood stream through infected lymphocytes, infecting cells in almost all organ systems

Disease course

An acute febrile illness associated with a characteristic erythematous maculopapular rash. Begins with a fever and typically one of the 3 "Cs", then ?Koplik's spots, then rash 3-4 days after the fever. Recovery usually within 1 week of rash onset

  • Incubation (); prodromal phase (day 1-3), rash phase (day 4-9), convalescent phase (day 9+)

  • Fever: day 1-10 (peak day 4): first on the face/behind the ears, then spreads to trunk/extremities. Deeply pigmented rash that desquamates during recovery in malnourished children. Rash may be absent if HIV+ (as represents perivascular lymphocytic infiltration)

  • Rash (day 4-9)

  • Koplik's spots (day 3-6)

  • Cough (day 2-10)

  • Coryza (day 1-7)

  • Conjunctivitis (day 1-7)

Measles case definition: generalised maculopapular rash, fever (>38.3C), and either CCC has high sensitivity (75-90%) but low PPV when incidence is low (indicating need for serological confirmation)

Vaccine-modified measles (children with previous immunity following vaccination): rash may be minimal, may not have 3 "Cs"

Complications

Can affect most organ systems (respiratory tract common), most common in young infants, adults >20 years, pregnant, immunocompromised/undernourished, particularly children with Vit A deficiency.

  • Respiratory tract is a frequent site of complications: (1) Pneumonia: accounts for most measles-associated morbidity/mortality (primary [Hecht's giant cell pneumonia] or secondary viral/bacterial); (2) Laryngotracheobronchitis (croup); (3) Otitis media

  • GI: (1) Diarrhoea due to secondary bacterial/protozoal infection can result in considerable mortality/morbidity; (2) stomatitis

  • Keratoconjunctivitis (blindness) was a frequent cause of blindness before widespread use of measles vaccine and Vit A supplementation

  • Measles in pregnancy associated with adverse pregnancy outcomes (LBW, spontaneous abortion, intrauterine fetal death, maternal death)

  • Neurological (rare): (1) acute demyelinating encephalomyelitis (ADEM): demyelinating autoimmune disease triggered by the virus, occurring within days/weeks (1/1,000); (2) measles inclusion body encephalitis (MIBE), progressive measles virus brain infection resulting in neuro deterioration and death in individuals with impaired cellular immunity within months of acute illness (3) subacute sclerosing panencephalitis (SSPE): delayed complication 5-10 years after acute illness caused by host response to production of mutated virons with defected assembly and budding (1:10,000 - 1:100,000, more common if infected <2 years, and reduced incidence if vaccinated)

  • Post-measles immune suppression: Deficiencies of both innate and adaptive immune responses, increased susceptibility to secondary baterial/viral infections for several weeks/months (?years) after infection

  • **Death: case fatality ratios range from <1:1,000 to 5% in endemic areas of SSA and Asia, to 20-30% in refugees/IDPs. Variation determined by average age of infection, nutritional/immunological status of the population, vaccine coverage, access to health care

Diagnosis

  • Clinical (differentials could include rubella, HHV type 6, parvovirus B19, dengue). Clinical diagnosis more challenging if unfamiliar, prior to rash, immunocompromised/HIV and less rash, maternal antibodies/prior vaccination (can have longer incubation, mild prodrome, less apparent rash)

  • Serology: measles-specific IgM (detectable 4 days after rash in almost all cases), peak within 1-3 weeks, undetectable within 4-8 weeks; or ≥ x4 increase in IgG (acute vs. convalescent sera)

  • RT-PCR using throat, NPS, urine samples before IgM detectable

Management

  • Isolate (airborne precautions)

  • Supportive: prevent dehydration / nutritional deficiencies (Identify those at high risk: nutritional (particularly Vit A)/immune (HIV) deficiency)

  • Assess & treat complications: secondary bacterial infections e.g. pneumonia or OM (limited evidence for prophylactic antibiotics)

  • Vitamin A: once-daily doses for 2 consecutive days (third dose if clinical evidence of deficiency): reduces mortality if <2 years (RR 0.18[95% CI 0.03-0.61] and risk of pneumonia-specific mortality (0.33 [0.08-0.92])

  • No specific antiviral therapies (ribavirin, interferon and others have been used)