Measles virus: Structure, Pathogenesis, Lab Diagnosis

The name measles is derived from the Latin, misellus, meaning miserable. Measles (also called Rubeola-(from rubeolus, Latin for reddish) ) is usually a disease of childhood (aged 3-10 years) and is followed by life-long immunity. 

Measles is a highly contagious and sometimes deadly disease that spreads through coughing and sneezing. It can spread like wildfire in naive populations. Measles is an important cause of childhood mortality in developing countries. Human is the natural host of this pathogen.

Structure of Measles Virus

• Measles virus is a member of the genus Morbillivirus of the family Paramyxoviridae. Paramyxoviruses are so-called because they have an affinity for mucous membranes (Greek: myxa = mucus).
• Measles virus is a typical paramyxovirus (spherical enveloped particles that contain a non-segmented negative-strand RNA genome with a linear arrangement of genes).
• Measles virus has two glycoproteins  spikes that are important in pathogenesis:
  • F (fusion) protein, which is responsible for the fusion of virus and host cell membranes, viral penetration, and hemolysis, and the
  • H (haemagglutinin) protein, which is responsible for the binding of the virus to cells

• Measles virus has only one serotype i.e. Life long immunity occurs in individuals who have had the disease.
• Hemagglutinin is the antigen against which neutralizing antibody is formed.
• Infants are protected during the first six months of life ( they get maternal antibody as it passes the placenta)

Replication cycle of Measles Virus

• Adsorption to the cell surface: via Hemagglutinin. The cellular receptor of the measles virus is CD46 molecule.
• Penetrates the cell surface and uncoats
• Virion RNA polymerase transcribes the negative-strand genome to mRNA
• Specific viral proteins are formed
• Assembly to helical nucleocapsid
• Release of the virus by budding

Transmission and Epidemiology of Measles

• Worldwide distribution, outbreaks in 2-3 years
• Measles virus is extremely infectious, most children contract the clinical disease on exposure
• Transmitted via respiratory droplets produced by sneezing or coughing during the prodromal period or direct contact with nasal or throat secretions from an infected person,  which continues up to a few days after the rash appears.
• Less commonly, it is spread by airborne aerosolized droplet nuclei or by indirect contact with freshly contaminated articles.
• More serious outcomes in malnourished children, and people with deficient cell-mediated immunity.

Pathogenesis

• Measles virus invades the cells lining the upper respiratory tracts i.e respiratory epithelium of the nasopharynx and spreads to the regional lymph nodes
• After 2-3 days of replication in these sites, a primary viremia widens the infection to the reticuloendothelial system where further replication takes place.
• Secondary viremia occurs and the virus enters skin, conjunctivae, respiratory tract and other organs, including the spleen, thymus, lung, liver, and kidney and further replication occurs.
• Appearances of rash (cytotoxic T cells attack measles virus-infected vascular endothelial cells in the skin).
• Formation of Multinucleated giant cells.

Clinical features of Measles

• Incubation period: 10-14 days
• Prodromal phase: Characterized by fever, conjunctivitis (causing photophobia), running nose, and coughing.

• The appearance of Koplik’s spot (bright red lesions with the white, central dot) # Diagnostic feature

• The appearance of Maculopapular rashes, common features of which includes:

• Occurs 5‐7 days after symptoms    
• Lasts 3 or more days
• Brownish hue
• Progresses from face to body to extremities
• The rash becomes confluent as it progresses
• Rash affects palms and soles
• Soon after the rash appears, the patient is no longer infectious.

Complications  because of Measles infections

• Encephalitis: 1 per 1000 cases
• Subacute sclerosing panencephalitis (SSPE): Fatal disease of the nervous system that can develop after several years after measles.
• Giant cell pneumonia
• Co-infections:
  • Secondary bacterial pneumonia
  • Bacterial otitis media

• Increased risk of stillbirth in pregnant women infected with measles.
• Measles virus infection of a fetus causes fetal death
• Atypical measles develops in some people who were given killed vaccine and subsequently infected with the measles virus.

Laboratory diagnosis of measles

• Most diagnoses are made on clinical grounds; the presence of koplik’s spot provides a definitive diagnosis.
• If laboratory diagnosis is necessary, it can be done by
  • Isolation of virus in a cell culture
  • A positive serologic test for measles IgM
  • Demonstrating a rise in antiviral antibody titer of greater than four-fold.
  • Identification of measles virus RNA from a clinical specimen by PCR

Isolation and Identification of the virus

Nasopharyngeal and conjunctival swabs, blood samples, respiratory secretions, and urine collected from a patient during the febrile period are appropriate sources for viral isolation. Monkey or human kidney cells or a lymphoblastoid cell line (B95-a) are optimal for isolation attempts. Measles virus grows slowly; typical cytopathic effects (multinucleated giant cells containing both intranuclear and intracytoplasmic inclusion bodies) take 7-10 days to develop. Shell vial culture tests are completed in 2-3 days using fluorescent antibody staining to detect measles antigens in the inoculated cultures.  

However, virus isolation is technically difficult. It is not routinely performed for diagnosis as sensitivity is lower than serologic techniques.

Serology

Serologic confirmation of measles infection depends on a fourfold rise in antibody titer between acute-phase and convalescent-phase sera (where the second serum sample is collected at least 10 days after the first, acute sample) or on the demonstration of measles specific IgM antibody in a single serum specimen drawn between 1 and 2 weeks after the onset of rash. IgM antibody levels peak after about 7-10 days and then decline rapidly, and are rarely detected after 6-8 weeks.  

ELISA, HI, and neutralization tests all may be used to measure measles antibodies, though ELISA is the most practical method.  IgG antibody levels peak within about 4 weeks and persist long after infection.  

The major part of the immune response is directed against the viral nucleoprotein. Patients with subacute sclerosing panencephalitis (SSPE) display an exaggerated antibody response, with titers 10 to 100 fold higher than those seen in typical convalescent sera.  

Haemagglutination–inhibition tests or ELISA antibody assays are the most practical, but plaque reduction neutralization tests are the most sensitive and specific. The virus has been isolated from respiratory tract secretions and rarely from urine or circulating lymphocytes during the prodromal phase of illness or within a few days after the rash onset.  

Immunofluorescence staining of nasal or throat secretions or urine has been successful but is not widely available. SSPE is confirmed based on characteristic EEG patterns and demonstration of measles antibody in the cerebrospinal fluid (CSF) with an increased CSF to serum measles antibody ratio, or by the demonstration of virus in brain tissue.  

Very high measles antibody titers aside from acute infection and SSPE are regularly seen in autoimmune chronic active hepatitis and occasionally in systemic lupus erythematosus.

Prevention of Measles

Measles can be prevented with MMR vaccine. The vaccine protects against three diseases: measles, mumps, and rubella.
The MMR vaccine is very safe and effective. Two doses of MMR vaccine are about 97% effective at preventing measles; one dose is about 93% effective.
CDC recommends children get two doses of MMR vaccine,

1. the first dose at 12 through 15 months of age, and
2. the second dose at 4 through 6 years of age.
   Teens and adults should also be up to date on their MMR vaccination.