Acute febrile exanthema caused by measles virus (MeV) characterized by (three Cs) cough, coryza, and conjunctivitis.
History:
History of measles virus infection and elimination programmes: Closely related to the recently eradicated cattle virus rinderpest, measles virus (MeV) probably evolved from an ancestral virus and emerged as a zoonotic infection in communities in which cattle and humans lived in close proximity. MeV most likely became established in humans about 5,000 years ago when human populations achieved sufficient size in Middle Eastern agrarian civilizations to maintain virus transmission. Measles did not always have a global distribution and probably first entered the Americas in the fifteenth century with the immigration of Europeans. MeV and smallpox infections probably facilitated the European conquest of Native American civilizations by causing large numbers of deaths among the fully susceptible Native Americans. The outbreak of measles in the US Army from 1917 to 1918 that resulted in >95,000 cases of measles and 3,000 deaths provided a striking example of the devastating effect of measles and associated bacterial co-infections that occurred before the introduction of antibiotics or measles vaccines. Increasing measles vaccine coverage prevented an estimated 17.1 million deaths between 2000 and 2014. | World Health Organization. Progress towards regional measles elimination, worldwide, 2000–2014. Wkly Epidemiol. Rec. 90, 623–631 (2015).
Microbiology
Measles virus (MeV):
Highly contagious negative strand RNA paramyxo virus that is transmitted via the respiratory route and causes systemic disease in previously unexposed humans and non-human primates.
Enveloped virus with a single strand, non-segmented negative sense RNA genome
Exclusively causes disease in old- and new-world non-human primates (NHPs) and humans
Genus: Morbillivirus (all morbilliviruses are highly contagious and is transmitted via the respiratory route)
Measles virus and the viral life cycle.: a) Structure of measles virus (MeV). The RNA genome of MeV is encapsulated by the N protein, forming a helical ribonucleoprotein (RNP) complex that is associated with viral RNA-dependent RNA polymerase (L protein) and polymerase cofactor (P). Two types of transmembrane glycoproteins, the H protein and the F protein, are incorporated into the lipid envelope that is derived from the host cell membrane. The H protein is responsible for receptor binding with the host cell, whereas the F protein mediates membrane fusion. The M protein interacts with both the RNP complex and the cytoplasmic tails of the glycoprotein spikes, and promotes virion assembly. The non-structural V protein and C protein are involved in the evasion of host innate immune responses in infected cells. b) MeV infection. Following the binding of the H protein to the host receptor, membrane fusion occurs, which releases the viral RNA into the host cytoplasm. Replication and transcription of the viral genome takes place entirely in the cytoplasm. De novo-synthesized RNP complexes are transported by RAS-related protein RAB11a-positive recycling endosomes that move along microtubules. The H protein and the F protein are transported to the plasma membrane using a different secretory pathway. The M protein interacts with RNP complexes, the cytoplasmic tails of the H protein and the F protein, the cell membrane and actin filaments in the host cells. These interactions promote virus assembly and regulate cell-to-cell fusion of MeV. | SLAM, signalling lymphocytic activation molecule. | Rota, P., Moss, W., Takeda, M. et al. Measles. Nat Rev Dis Primers 2, 16049 (2016). https://doi.org/10.1038/nrdp.2016.49
Epidemiology
No animal reservoir and occurs only in humans.
90% secondary attack rate
Global reported measles cases and estimated coverage with the first and second dose of measles-containing vaccine by year (1980–2014). | World Health Organization. WHO/UNICEF estimates of national immunization coverage. WHOhttp://www.who.int/immunization/monitoring_surveillance/data/en (2016). | World Health Organization. The number of global measles cases reported to WHO. WHOhttp://apps.who.int/immunization_monitoring/globalsummary/timeseries/tsincidencemeasles.html (2016).
Detection of the global distribution of measles virus genotypes and incidence in 2015: During 2014–2015, the most frequently reported measles virus (MeV) genotype was genotype H1, which is endemic in China, a country with a high reporting efficiency for molecular surveillance. The most widely distributed MeV genotypes globally were genotypes B3 and D8. In the past, genotype B3 viruses were only endemic in sub-Saharan Africa countries; but recently, genotype B3 viruses were associated with cases and outbreaks in all six WHO regions, including a large measles outbreak in the Philippines in 2014–2015. Likewise, genotype D8 had been primarily detected historically in South-East Asia, but more recently genotype D8 has caused reported outbreaks in all the WHO regions except the African region. The size of the pie sectors reflect the number of sequences reported for each genotype. | Mulders, M. et al. Global measles and rubella laboratory network support for elimination goals, 2010–2015. MMWR Morb. Mortal. Wkly Rep. 65, 438–442 (2016).
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Pathophysiology
The inhaled virus from the exposed droplets initially infects the respiratory tract’s lymphocytes, dendritic cells, and alveolar macrophages. It then spreads to the adjacent lymphoid tissue and disseminates throughout the bloodstream resulting in viremia and spread to distant organs. The virus residing in the dendritic cells and lymphocytes transfers itself to the epithelial cells of the respiratory tract which are shed and expelled as respiratory droplets during coughing and sneezing, infecting others and perpetuating the cycle.
Measles virus infection and transmission: Measles virus (MeV) is an airborne pathogen. MeV aspirated into the respiratory tract infects alveolar macrophages or dendritic cells (DCs) using signalling lymphocytic activation molecule (SLAM; also known as CD150) as a receptor. MeV infection is amplified in regional lymphoid tissues followed by a systemic infection throughout the body. MeV-infected lymphocytes and DCs migrate into the subepithelial cell layer and transmit MeV to epithelial cells of various organs or tissues using nectin 4 as a receptor. MeV infection is amplified in the epithelia, and a large amount of progeny viruses are released into the respiratory tract. | RNP, ribonucleoprotein. | Rota, P., Moss, W., Takeda, M. et al. Measles. Nat Rev Dis Primers 2, 16049 (2016). https://doi.org/10.1038/nrdp.2016.49
Clinical features
Incubation period:
MeV infection starts with an incubation period, during which the virus replicates primarily in myeloid and lymphoid cells and establishes a systemic infection.
Pathogenesis of measles: Schematic representation of the kinetics of measles virus (MeV) replication (part a) and measles-associated clinical signs (part b). | Rota, P., Moss, W., Takeda, M. et al. Measles. Nat Rev Dis Primers 2, 16049 (2016). https://doi.org/10.1038/nrdp.2016.49
Prodromal stage:
After 7–14 days, when MeV has spread to the peripheral lymphoid tissues, a prodromal phase starts with malaise, fever and cough. At that point, infected lymphocytes have disseminated the virus to peripheral tissues, including the skin and the submucosa of the respiratory tract, and have transmitted MeV to epithelial cells and keratinocytes.
Fever & malaise
Three Cs: Cough, coryza and conjunctivitis
Koplik’s spots (PATHOGNOMIC and appear 1-2 days before the rash): Small white papules on buccal mucosa (behind 2nd & 3rd molar)
Can occur in conjuncativa or vaginal mucosa
This patient presented on the third pre-eruptive day with “Koplik spots” indicative of the beginning onset of measles. In the prodromal or beginning stages, one of the signs of the onset of measles is the eruption of “Koplik spots” on the mucosa of the cheeks and tongue, which appear as irregularly-shaped, bright red spots often with a bluish-white central dot. | Wikimedia Commons, CDC (Public Domain)
Maculopapular rash:
The maculopapular skin rash appears 3–5 days after the prodromal phase and coincides with the appearance of MeV-specific humoral and cellular immune responses. The rash usually starts behind the ears or on the face and spreads to the trunk and extremities. Conjunctivitis appears around the same time and often results in photophobia. Both rash and conjunctivitis are caused by immune-mediated clearance of MeV-infected cells and may be absent in immunodeficient patients, making the disease difficult to recognize in this patient group
Rash appears on 4th day of fever, commonly the retroauricular space and spreads to the face, trunk and extremities
This child shows a classic day-4 rash with measles. |Centers for Disease Control and Prevention (Public Domain)
Complications
HALLMARK of measles is the transient immune suppression, leading to increased susceptibility to opportunistic infections. At the same time, the disease is paradoxically associated with induction of a robust virus-specific immune response, resulting in lifelong immunity to measles.
Immune suppression:
In uncomplicated measles cases, clinical signs usually start to fade a few days after the onset of rash and patients recover in approximately 1 week. By contrast, measles-associated immune suppression, which coincides with widespread epithelial damage, increases susceptibility to secondary bacterial infections that can result in complications, such as diarrhoea, pneumonia or otitis media
Hecht giant cell pneumonia (due to measles itself)
Warthin-Finkeldey cells (multinucleated giant cells/syncytia) (PATHOGNOMIC): Fused B-cells found in lymphoid tissues in the upper respiratory tract
Secondary bacterial infection:
Diarrhoea
Pneumonia: M/C cause of death
Otitis media: M/C complication
Images collected from experimentally infected NHPs, illustration mechanisms underlying MV entry (A,B), dissemination (C,D), transmission (E,F) and immune suppression (G,H). MV-infected cells were detected by immunohistochemical staining (A,C,D,F) or by immunofluorescent double-staining (B,E,G). (A) infection of a single cell (arrow, likely an alveolar macrophage) in the alveolar lumen 3 DPI; (B) infection of epithelial cells in the trachea 5 DPI (arrow in insert points at green cilia), green = GFP, red = cytokeratin, blue = DAPI; (C) infection of myeloid and lymphoid cells in BALT (arrow) 4 DPI, BL = bronchial lumen; (D) low-magnification image of a lymph node 9 DPI, with many B-cell follicles containing large concentrations of MV-infected lymphocytes; (E) MV-infected epithelial cells in the trachea 9 DPI (green = GFP, red = cytokeratin, blue = DAPI, TL = tracheal lumen); (F) Disruption of the epithelium (arrow) of an adenoid containing many MV-infected lymphocytes 9 DPI; (G) MV-infected B-lymphocytes (including Warthin-Finkeldey syncytia, arrows) in a B-cell follicle 9 DPI (green = GFP, red = CD20, blue = DAPI); (H) follicular exhaustion of B-cell follicles 11 DPI (brown = CD20). | Laksono, B. M., de Vries, R. D., McQuaid, S., Duprex, W. P., & de Swart, R. L. (2016). Measles Virus Host Invasion and Pathogenesis. Viruses, 8(8), 210. https://doi.org/10.3390/v8080210
Long-term CNS complications:
Recovery is followed by lifelong immunity to measles. In rare cases, severe measles-associated central nervous system (CNS) complications may develop:
Acute disseminated encephalomyelitis (ADEM): Autoimmune demyelinating disease that occurs within days to weeks
Measles inclusion body encephalitis (MIBE): Progressive brain infection in patients with impaired cellular immunity occurring within months of the initial infection.
Subacute sclerosing panencephalitis (SSPE): Progressive neurological disease that presents 5-10 years after the acute illness and thought to be caused by an abnormal host response to the production of mutated virions
Measles during pregnancy:
MeV infection during pregnancy increases the risk of maternal, fetal and neonatal complications; it can damage the placenta and/or fetus and lead to spontaneous termination, stillborn birth or live birth of infants with congenital measles
Maternal death
Spontaneous abortion
Intrauterine fetal death
Low birth-weight infant
Diagnosis
The diagnosis of measles hinges on a high clinical suspicion, especially when evaluating children with febrile illness and a maculopapular rash.
Reverse transcription PCR (RT-PCR)
Detection of anti-MeV IgM antibodies or MeV RNA
Plaque reduction neutralization assay:
gold standard test with the highest sensitivity.
Differential diagnosis:
Other viral illnesses associated with rash
Chicken pox: Appears on 1st day of fever, with centripetal distribution and pleomorphic appearance like dewdrops on a rose petal.
Erythema infectiosum: Rash on cheeks (slapped cheek appearance), and moves to trunk and extremities
Erythema subitum: Macules/maculopapular rash
Infectious mononucleosis: Associated with maculopapular rash
Rubella (German measles)
Roseola
Management
Treatment of uncomplicated measles cases typically involves supportive care, including antipyretics, antitussives, hydration and/or environmental controls (for example, humidification).
Trivalent measles-mumps-rubella (MMR) vaccine:
Administered in 2 doses with children most often receiving the first dose around 1 year of age and the second dose typically given between the ages of 4 to 6
Live attenuated vaccine
Edmonston-Zagreb stain
Summary:
Measles is caused by a highly infectious, airborne pathogen: measles virus. | Measles. Nat Rev Dis Primers 2, 16050 (2016). https://doi.org/10.1038/nrdp.2016.50
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