Pathogenesis of Measles Virus Infections

D. Pathogenesis

Measles first gains access to the body via the upper respiratory tract or the conjunctiva. The virus quickly spreads to the immediate lymph nodes. Destruction of the lymphoid tissues leads to a profound leucopenia. A primary viraemia ensues which is responsible for spreading the virus throughout the rest of the R-E system and the respiratory system. A secondary viraemia follows whereby the virus is further spread to involve the skin, the viscera, kidney and bladder. The Koplik's spots and the rash in measles are thought to result from a delayed hypersensitivity reaction, the virus antigen being absent from the lesion itself.

1. Acute measles panencephalitis - It is likely that CNS involvement, even in uncomplicated measles, is common. Transient EEG abnormalities are detected in 50% of patients. Measles virus is rarely isolated from the brain of a patient with acute measles panencephalitis. Therefore, current theories favour an autoimmune reaction as the possible cause of CNS damage.
2. Subacute measles encephalitis - arise only in patients with severe immune disorder. Therefore it is not usually accompanied by the formation of antibodies in the CSF. Infectious virus has not been isolated by conventional methods, suggesting defects in replication. Recently biological studies on brain tissue from a case of SME revealed that the envelope proteins were missing from the brain tissue and only the N and the P protein were consistently detected.
3. SSPE - in SSPE, the virus is first thought to gain entry to the CNS during the viraemia. Once there, it establishes a low-grade persistent infection. It is not known whether viral replication itself, or immunopathological mechanisms are responsible for the development of lesions. In SSPE, free infectious virus particles have never been isolated from the brain or the CSF, although some viral antigens may be found. Giant cells which are characteristic of acute measles infection are also absent. However, viral nucleocapsids are present in the cytoplasm. Therefore, some defect must exist in the virus replication process that prevents maturation. In the absence of free infectious particles, the infection may spread slowly by infectious nucleocapsids from cell to cell.

Antibodies in the CSF are oligoclonal as opposed to the polyclonal response seen in the sera. This suggests that antibody in the CSF is made locally by a much smaller population of lymphocytes which have invaded this compartment. The M-protein is not recognized by the antibodies present in the CSF. SSPE brain lesions have M, N and P proteins present in infected cells whereas the envelope proteins are missing. The measles mRNAs isolated from SSPE patients showed a high rate of mutations, the highest rate of mutation in the M gene, followed by the F, H, P and N genes. In some cases, infectious MV particles may be recovered if the brain cells are co-cultured with tissue culture cells susceptible to measles virus. In other cases though, the block is only partially overcome and the agent remains cell associated. In this case, although MV envelope mRNAs are present, the envelope proteins are not synthesized. Another hallmark of SSPE is the hyperimmune response to measles antigens that include neutralizing antibodies in the serum and the CSF. In spite of this, the infection cannot be controlled. CMI is much more important than the humoral response in clearing measles virus infection. There is no evidence to suggest that the CMI is impaired in patients who develop SSPE.

Natural immunity to measles is known to last at least 65 years. In 1781 measles disappeared from the Faroe islands following an epidemic and was not reintroduced until 1846. Individuals old enough to have experienced the disease 65 years previously were still protected. This unusual persistence of immunity suggests that measles virus may normally persist inside the body, possibly in lymphocytes so that immunity is restimulated from within.
 

E. Diagnosis

The symptoms of acute measles are so distinctive that laboratory diagnosis is seldom required. However, as the vaccination program progresses, atypical forms of measles have emerged and laboratory diagnosis may be required.

1. 1. Microscopy - production of multinucleate giant cells with inclusion bodies is pathognomonic for measles. During the prodrome phase, such cells are detectable in the NPS (nasopharyngeal secretions). This is more rapid and practical than virus isolation.
   
2. 2. Immunofluorescence - direct and indirect immunofluorescence have been used extensively to demonstrate MV antigens in cells from NPS specimens. This technique can also be applied to the urine as such cells may be present in the urine 2 to 5 days after the appearance of the rash. (Although like mumps, measles virus is also excreted in the urine, this route is unlikely to play a significant role in the spread of the virus infection.)
   
3. 3. Virus isolation - measles virus can be isolated form a variety of sources, e.g. throat or conjunctival washings, sputum, urinary sediment cells and lymphocytes. Primary human kidney (HEK) cells are the best, although primary monkey kidney can be used as well. Continuous cell lines such as vero cells can also be used although they are not as efficient as primary cell lines. A CPE develops between 2 to 15 days, and consist of either a broad syncytium or a stellate form with inclusion bodies visible. The presence of measles can be confirmed by haemadsorption. In acute measles, the isolation rate is difficult and the success rate is low. Isolation is most likely to be successful from material taken in the prodrome phase but not in the later stages after the rash has developed. Therefore isolation should only be attempted in complicated cases such as suspected SSPE where the lymphocytes may carry the virus, and in immunocompromised individuals developing pneumonia.
   
4. 4. Serology - diagnosis of measles infection can be made if the antibody titres rise by 4 fold between the acute and the convalescent phase or if measles-specific IgM is found. The methods that can be used include HAI, CF, neutralization and ELISA tests. Neutralization tests are the most sensitive but are not practical to perform. CFTs have a reduced sensitivity and thus are not useful for immune status screening.

Diagnosis of SSPE - the presence of measles specific antibodies in the CSF is the most reliable means of laboratory diagnosis of SSPE. Demonstration of MV-specific antibodies in the CSF may be sufficient with, if necessary, demonstration of MV-specific restricted heterogeneity by isoelectric focusing. Virus isolation from SSPE brain tissue is complicated. Alternately, brain biopsy material can be examined microscopically for inclusion bodies and virus antigen by immunofluorescence.

Syncytial formation caused by measles virus in cell culture (Courtesy of Linda Stannard, University of Capetown, S.A.)

F. Management

In the majority of patients, measles is an acute self-limiting disease that will run its course without the need for specific treatment. However, it is far more serious in the immunocompromised, the undernourished, and children with chronic debilitating diseases. Such patients can be protected by the administration of human anti-measles gammaglobulin if given within the first 3 days after exposure. Alternatively, the exposed individual can simply be vaccinated within 72 hours of exposure.

1. Pneumonia - antibiotics may be indicated in cases of secondary bacterial pneumonia or otitis media.
2. Encephalitis - treatment of acute measles encephalitis is only symptomatic and supportive. A wide variety of treatment has been tried for SSPE but no convincing effects have been demonstrated.

G. Prevention

With no animal reservoir, it must be possible to eradicate the virus through a controlled vaccination campaign. In the USA, where vaccination of all children is required before commencing school, case reports have fallen by over 99% but eradication has not been achieved. The following vaccines are available

1. Inactivated Vaccine - this vaccine was intended for use in young children less than 1 year of age who are most prone to severe complications. It was thought to be advisable to avoid the use of a live vaccine. It was found that at least 3 doses were needed to elicit a protective antibody response but the antibody levels soon waned. This leave the vaccinees open to attack by the natural virus. In some cases, the nature of the partial immunity led to serious hypersensitivity reactions to infection (Atypical measles). The exact mechanism is still uncertain but it was thought that the vaccine lacked an important antigen of the virus and thus immunity was not complete. In view of the above and the fact that antibody levels decline rapidly after administration of the killed vaccine, live vaccination is now generally recommended and individuals previously immunized with the killed vaccine should be reimmunized with the live vaccine. The killed vaccine has now been withdrawn.
   
2. Live vaccine - live vaccines are now usually used. The seroconversion rate is 95% and the immunity lasts for at least 10 years or more, possibly lifelong. The virulence of the attenuated strain now in use is so low that encephalitis has only been noted in 1 in 1 million recipients. SSPE has been reported in children given the live vaccine. However, the rate is lower than that following natural infection. Therefore the vaccine is safe for use in very young children. The live vaccine is now incorporated as part as the MMR vaccine. As vaccine-induced measles antibody develops more rapidly than following natural infection, MMR vaccine can be used to protect susceptible contacts during a measles outbreak. To be effective, the vaccine must be administered within three 3 days of exposure. If there is doubt about a child’s immunity, vaccine should be given since there are no ill effects from immunizing individuals who are already immune. Immunoglobulin should be given to those for whom the vaccine is contraindicated.

The vaccination programme has been most effective in the USA, where measles immunization is compulsory. The incidence rate has also declined dramatically in the UK but without the rigorously pursued vaccination as practiced in the US, it is not likely to be as effective as that in N. America. In the third world, malnutrition aggravates measles infection and there are 900,000 measles related deaths per year. Vaccination in these areas has failed to yield dramatic results. The problem is that the vaccine is usually given at 12 months of age (it should not be given in younger individuals because the presence of maternal antibodies may lead to a poor response.) but infection in these areas often occurs earlier in life. Vaccination should therefore be performed on younger children than in the developed world. However, this must be balanced with the fact that the success rate is lower in younger children (50-75% in 6-month-old-children as opposed to 95% for 12-month-old children.). Measles is highly infectious and has a very high attack rate and thus it would be extremely difficult to eradicate the virus altogether through vaccination.

Management of Outbreaks

Measles outbreaks are most deleterious in wards with immunocompromised children or adults e.g. children with leukaemia and bone marrow transplant recipients. Measles is definitely as dangerous as VZV in that setting. HNIG should be given to all severely immunocompromised children irrespective of their immunization status since it has been reported that severe measles infection can occur in those who had been immunized and had a documented low-level antibody response. Therefore, the routine screening of children for measles antibody before admission is probably unjustified since there would be no difference in the management. The same argument applies to the screening of patients for immunity before the administration of HNIG. The use of live-attenuated vaccine for postexposure prophylaxis is contraindicated. The same protocol applies to immunocompromised adults who come into contact with measles. Immunocompetent children under 12 months in whom there is a particular reason to avoid measles, such as a recent severe illness, can also be given immunoglobulin. MMR vaccine should then be given after an interval of at least 3 months, at around the usual age.