Introduction
Measles virus is a single serotype paramyxovirus. Measles is one of the most contagious human viruses and has been largely contained by vaccination. Where vaccine has been effectively delivered, endemic measles virus transmission has been eliminated. However, difficulties in vaccine delivery, lack of health care support and objection to vaccination in some communities lead to over 300,000 deaths per year from measles. (Measles: Pathogenesis and Control, Dianne E Griffin, Michael B.A. Oldstone.) About 1 in 100,000 acutely infected individuals go on to develop CNS complications. One serious complication is Subacute Sclerosing Panencephalitis, a slow progressive disease that is often fatal, and can occur from 1 to 15 years following acute measles infection. Another more common complication associated with measles is Postinfectious Encephalomyelitis (PIE). Measles infection is typically acquired from inhalation of respiratory droplets as a consequence of exposure to individuals who are coughing and sneezing during the prodromal stage. Patients shed measles virus from the nasopharynx and are considered infectious from the beginning of the prodrome until about 4 days after the appearance of the rash. (Infectious Diseases, Peter Ball and James A. Gray). The prodromal phase is characterised by upper respiratory catarrh with Koplik's spots on the buccal mucosa accompanied by conjunctivitis, otitis media and rhinitis. About 24-48 hours later a dusky red maculopapular rash appears on the face and speads downwards. Uncomplicated measles lasts for 7-10 days, following which the fading rash leaves brown macules with fine desquamation, which can persist for up to 3 weeks.
Infection and spread
The term "pathogenesis" refers to the mechanisms associated with the origin and development of disease. (Viruses and Bone Marrow, Neal S.Young). In the context of viral infections this includes the entry of the virus into the host, the spread of the virus throughout the host, the host response to infection and the damage to tissue by the virus or by the host response.
Measles virus is acquired from inhalation of respiratory droplets from other infected individuals in the prodromal stage of measles. The measles virus enters the body via the nasopharynx and perhaps the conjunctiva. Spread to regional lymph nodes and primary viremia occurs by day 3. The virus multiplies in the respiratory epithelium at the site of infection as well as throughout the reticuloendothelial system during days 3 to 5. A secondary viremia occurs during days 5-7. This causes a generalized infection to be established. The secondary viraemia seeds virus to the epithelial surfaces of the body, where the growth of virus causes a rash and an enanthem. Measles is a virus which has the ability to replicate rather than be destroyed after being filtered out in the lymph node. The infected cells are generally macrophages or lymphocytes and if they are not seriously damaged, they can carry the virus to distant parts of the body in the course of their normal migratory movements. During the second week of infection, the infected leucocytes can carry the virus to organs such as the liver, spleen, skin and lung. During days 11 to 14 after exposure, the prodromal period of measles occurs. It appears that prodromal measles corresponds to a period of intense viral multiplication and dissemination during which tissue damage occurs, resulting in the clinical illness. During days 15 to 17, viremia diminishes as viral multiplication slows. During days 14 to 18 whenever the tissue viral content declines, the measles antibody appears. As serum antibody levels increase, the virus becomes undetectable in blood, urine and nasopharyngeal secretions. (Mucocutaneous manifestations of viral diseases, Steven Tyring, Angela Yen-Moore).
Antibodies are effective in mediating the destruction of virus-infected cells. This can occur by antibody-mediated activation of the complement system, leading to the assembly of the membrane attack complex and lysis of the infected cell. Most of the antibody response is T-dependent, requiring CD4+ T cells for affinity maturation and class switching. CD4+ T cells have at least three possible roles during viral infection. First, they are essential in providing help to B cells in the generation of an antibody response, a function particularly important for viral infections in which humoral immune responses are the primary mechanism of immunity. Second, CD4+ T cells can mediate delayed-type hypersensitivity responses (DTH). Generation of lymphokines by DTH T cells can draw macrophages into the site of infection in large numbers. These macrophages become activated and can mediate phagocytosis, release of toxic oxygen molecules and direct cytotoxicity against infected cells, viruses, tumour cells and bacteria. Third, CD4+ T cells can provide help to CD8+ T cells required for cytotoxic responses against virally infected cell.
T cells kill infected cells through the release of perforin and granezymes. In measles virus, CD4+ CTLs are generated which recognize and kill MHC class 11-positive cells infected with the virus. This suggests that the measles virus is generated by normal pathways of antigen presentation (i.e. following phagocytosis and degradation). However, other pathways have been implicated in which some measles proteins enter class 11 vesicles from the cytosol. (Immunology, David Male, Jonathan Brostoff, David B Roth, Ivan Roitt).
In the mouth, the wet surface means that the vesicles will break down and form ulcers earlier than on the dry skin. Hence in measles the foci in the mouth break down and form small visible ulcers (Koplik's spots) a day or so before the skin lesions have appeared. In measles circulating virus localises in sub-epithelial vessels in the respiratory tract, and after extravasation there is only a single layer of cells to grow through in the nearby epithelium before the discharge of virus to the exterior. Hence the secretions from the respiratory tract are infectious a few days before the skin rash appears and the disease becomes recognisable. Thus, a person could infect another person with measles before they are aware that they have the virus. Children usually go about thinking they have an ordinary cold. They then realise that they have measles but have already spread the disease far and wide. As far as is known measles is spread almost entirely by the droplet method from secretions of the nose and throat, just as are colds, but measles is, if anything, the more "catching". There is no evidence that measles is spread from the skin, and the scaling of measles, often regarded as very dangerous, probably never carries the disease. (Health and Disease: their determining factors, Roger Irving Lee).
Symptoms
The incubation period of measles is 10 to 12 days. The prodrome precedes the rash by 2 to 4 days and consists of fever to 40.6°C, hacking cough, coryza (symptoms of a head cold), conjunctivitis, photophobia (sensitivity to light), headache, myalgia (muscle pain), irritability, poor appetite and lethargy. The temperature may peak at 40.6°C for several days, then fall, but go up again when the rash appears. Posterior cervical adenopathy is common. Two days prior to the appearance of appearance of the rash, the pathognomonic Koplik's spots appear. These are small red macules, with a central bluish-white speck, which occur on the mucous membrane of the mouth opposite the molars, on the inner side of the lips and on the nasal and vaginal mucosa. Koplik's spots are usually no longer present after the second day of the exanthem. The rash begins on the face and neck, then spreads downward and progressively involves the chest, trunk and extremities. It is an erythematous maculopapular eruption which is discrete and blanches early, but after 2 to 4 days becomes confluent and develops a coppery appearance.
Measles can cause complications such as diarrhoea. It can also cause some more serious complications. Examination of the lung fields may reveal scattered rales which usually represent a viral pneumonitis. Immunocompromised and malnourished patients may develop a more severe Hecht's giant cell pneumonia. In few cases, severe bleeding into the skin, mucous membranes and other organs, associated with a decreased platelet count and prolonged bleeding time, results in the syndrome called black measles. The mortality of this syndrome is high.
Bacterial complications are usually due to group A streptococci, Haemophilus influenzae and Staphlococcus aureus. Otitis media and pneumonia are most common and should be suspected when fever persists beyond the third day of the rash, and when a leukocytosis develops. Encephalitis occurs in 1 in every 1000 patients. Fifty percent of measles patients have an abnormal EEG during the acute phase of the illness. Other complications include corneal ulceration, purulent cervical lymphadenitis and appendicitis. A positive tuberculin skin test may convert to negative during measles. A late complication of measles is subacute sclerosing pancephalitis. (Viruses and Bone Marrow, Neil S. Young).
Vaccination
A vaccine is a material originating from a microorganism or other parasite that induces an immunologically mediated resistance to disease. Material with similar structure can also be produced artificially rather than developed from the actual microorganism or parasite. (Mim's Pathogenesis of Infectious Disease, Cedric Mims, Nigel Dimmock, Anthony Nash, John Stephen). Measles vaccine is a live, attenuated (or weakened) strain of the measles virus grown in chick embryo tissue culture. This vaccine is a shot given subcutaneously (in the fatty layer of tissue under the skin).
Viral infections such as measles have receded when effective vaccines have been used. There are two types of prophylactic immunization. Passive immunization is where protection is conferred by introducing preformed antibodies or lymphocytes from another individual whose immune system was stimulated by the appropriate antigen. Active immunization, is where protection results from the administration of a vaccine, with dead or harmless living forms of an organism or with an inactivated toxin, that stimulates the immune system to produce lymphocytes and antibodies against that organism.
The duration of resistance to disease depends to some extent on the type of infection. In the case of systemic infections with an incubation period of a week or two, a low residual level of immunity gives resistance to disease, because even if re-infection does occur, the immune response is boosted during the incubation period and the infection is terminated before the onset of the disease. Repeated subclinical booster infections may be important in maintaining immunity to diseases such as measles. Active immunization such as attenuated vaccine gives 97% seroconversion and long-term immunity. Mild febrile reactions occur in 3% of vaccinated individuals. In the UK universal immunization, using combined measles, mumps, rubella (MMR) vaccine, is given between 12-18 months. The first dose of the MMR vaccine is likely to give 90 percent of those receiving it protection against measles. The second dose is usually given when the child is 4-6 years old. Ninety-nine out of 100 people will be protected against measles after the second dose. Measles has become rare as a result. In passive immunization, human normal immunoglobulin protects if given within 72 hours of exposure. This is useful in immunocompromised non-immune children.
The MMR vaccine contains weakened versions of live measles, mumps and rubella viruses. Since the viruses are weakened, individuals who have recently had the vaccine cannot infect other people. The MMR vaccine works by triggering the immune system to produce antibodies against measles, mumps and rubella, as though the body has been infected with them. Antibodies are produced by the body to neutralise or destroy disease-carrying organisms and toxins. An individual's immune system also learns how to produce the appropriate antibodies quickly. If the individual then comes into contact with measles, the immune system will recognise it and immediately produce the antibodies needed to fight it. Prior to the use of the live attenuated measles vaccine, an inactivated vaccine was used. Five percent of persons immunized with the vaccine develop an atypical measles syndrome when exposed to natural measles. This syndrome consists of a rash which begins on the distal extremities and moves towards the head, pneumonia, oedema of the lips and feet, fever and prostration. The rash may be maculopapular, vesicular, urticarial, petechial or purpuric. This syndrome rarely occurs in recipients of the live attenuated measles vaccine. Live attenuated vaccines have the advantages of establishing long-lasting protection, safety and low-cost, thus allowing widespread vaccination. However, live viruses occasionally cause disease, and they also cannot be used in immunocompromised individuals.
Subacute sclerosing panencephalitis (SSPE)
A late complication of measles, usually occurring three to ten years after the initial infection is subacute sclerosing panencephalitis (SSPE). This is a progressive degenerative disease of the central nervous system characterised by progressive dementia, spasticity and coma. (Infectious Diseases, Haragopal Thadepalli). SSPE is fatal in over 95% of cases. The duration of illness may be as short as 6 weeks or longer than 10 years, with 80% of individuals succumbing between 9 months and 3 years. Death usually ensues in one year. CSF examination reveals elevated gamma globulin and high measles antibody titres. At least one case has been reported following live attenuated measles virus vaccination.
Pathologically, SSPE is characterised by a mild to moderate inflammatory response with perivascular cuffs and tissue infiltration by macrophages and lymphocytes. Initial clinical manifestations of SSPE are insidious, consisting of such changes as shortened attention span, poor scholastic performance, and subtle behavioural problems. More overt signs appear within a few weeks or months of the onset of clinical symptoms (e.g. mental deterioration, myoclonic jerking and ataxia). The disease culminates in stupor, dementia, decorticate rigidity, and finally, death.
The histopathologic findings of SSPE are more varied than with many of the other slow virus diseases. They consist of the following degenerative and inflammatory components: perivascular mononuclear cell infiltrates, astocytic hyperplasia, diffuse destruction of myelin, and prominent acidophilic inclusion bodies in neuronal and glial cells, which exhibit varying degrees of cellular injury and degeneration. (The Biologic and Clinical Basis of Infectious Disease, Youmans, Paterson and Sommers).
The pathogenesis of SSPE is not understood since it is not known why the measles virus persists in the central nervous system (CNS) in affected children. One plausible hypothesis is that a defect in the normal immune mechanisms underlies the continuing infection. Some support for this is provided by the fact that SSPE occurs more frequently in children who have had measles before the age of two years, when the virus may have been introduced into the body at a time when the immune system was immature. (Viral disease, P.J. Vinkin, G.W. Bruyn, Harold L. Klawans, Robert R. McKendall).
The diagnosis of SSPE is based upon characteristic clinical manifestations, the presence of characteristic periodic EEG discharges, and demonstration of raised antibody titre against measles in the plasma and cerebrospinal fluid. (Neurology Update, Huw Morris).
Treatment for SSPE is still undetermined. A combination of oral Isoprinosine and intraventricular interferon alfa appears to be the most effective treatment. Patients responding to treatment need to receive it lifelong. At present, effective immunisation against measles is the only solution available to prevent SSPE.
