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Pathogenesis of measles virus infection

Introduction

The development of the measles virus in earlier childhood is still relatively commonplace today in lower economic countries.A vaccination was developed approximately 40 years ago which reduced the incidence of the virus Worldwide.Unfortunately the virus has not been entirely eradicated, and a higher rate of infection still occurs more frequently in developing countries.

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In 2006 an invention of strategies were put into place by the World Health Organisation (WHO)/United Nations Children’s Fund (UNICEF)for the reduction of measles mortality rates1,2. Eradication of the measles virus encounters considerable imposing obstacles, including the growth in populations, demographic difficulties and the general population’s awareness to vaccination safety3. The WHO in 2012 plan to eradicate measles virus in the Western Pacific, a well designed sustainable plan is an necessity for this to ensure achievement, another decisive influence in the successfulness of the immunisation project is identifying the appropriate age at which immunisation should occur at. One of the main approaches to eradication of the measles virus infection is to immunise approximately 95% of the population, subsequently the majority of the population is acutely immunised against the measles virus infection which can cause astounding complications1.

Infection and Spread

Initial immunity for the neonate is maternal immunity transferred during pregnancy from mother to foetus. Younger women are being vaccinated in developing countries; consequently their own natural immunity is lower in comparison to non vaccinated women800. The measles virus is a contagious infection. The measles virus is caused by RNA viruses, which belongs to the genus Morbillivirus. Spread of the virus occurs due to coughing, sneezing, and personal contact with the infected. The measles virus can remain in an active state up to two hours once airborne or on contaminated surfaces. Prior to the characteristic rash associated more commonly with the measles virus, spread of the virus can develop from up to four days prior to first signs of infection and even up to four days after initial first signs of characteristic rash801. The initial symptoms of the virus display characteristics from 8-12 days following infection802. Measles virus spread is achievable through susceptible individuals whose immune system is in a state of compromised condition. Initial spread is initialised through the airways. Replication of the measles virus (MV) is acquired through numerous organs and tissues. Various types of cells and tissues are affected, which include dendritic cells (DC), and B and T lymphocytes. Generally the patient’s own immune system fights the infection and generates a life term of immunity against the infection and reoccurrence. The MV is characterised as an RNA envelope virus. Viral RNA continues to infect after initial 20 days after infection clearance. An indication of measles virus is a rash which manifests itself after approximately 10 days. Measles rash is an indication of the adaptive immune system responsiveness. At this stage CD4+ and CD8+ T cells infiltrate site for clearance. Both lymphocytes activate at same time, but CD8+ T cells is more severe, CD4+ response is longer. A diagnostic serum test for presence of IgM can be taken at this stage to evaluate the prognosis of measles. Antibody specific IgG is also produced at this interval. The immune system experiences prolonged immunosuppression. Differential amounts of cytokines and chemokines are produced at the varied stages of infection. After the initial infection levels of IL-8 increase, IFN-? and IL-2 are elevated by activation of CD4+ and CD8+ T cells during features of a rash. Following rash exposure CD4+ generates interleukin IL-4, IL-10, and IL-13. Failure to eliminate measles infection can contribute in the development of inclusion body encephalitis and pneumonia. Subacute sclerosing panencephalitis (SSPE) can also develop from persistent infection exposure in young children203.

Symptoms

The measles virus presents itself as a collaboration of symptoms, which are deemed characteristics of the virus and its associated effects on the patient’s body and immune- suppressed system. Measles virus is considered a highly infectious disease. If the measles virus is persistent in the body, the virus can affect the central nervous system (CNS). Initial symptoms of the measles virus include a state of fever, coughing and a rash with small bumps. One of the main complications of persistent measles virus is the influence on the CNS40. The virus conforms to a number of characteristics. These characteristics include such signs as a fever, redness of the eyes with the most common feature being a rash on the skin41.

Other symptoms of the virus include such features as coughing, muscle pain, runny nose, spots inside of mouth (Koplik’s spots), light sensitivity and eye irritation. The trade mark rash usually starts at the top of the body and moves down systematically41a.

Diagnosis of acute measles include serum based specific IgM EIAs42. In 2000 a uniformed quality assured system was introduced by the World Health Organisation (WHO). The WHO established LabNet to create a homologous system to ensure diagnosis of measles and rubella. Laboratory Network (LabNet) is available in over a hundred countries. One major hurdle in the successfulness of diagnosis; is the collecting of the serum samples. Newly devised methods of sampling specimen included dried blood spots (DBS) and oral fluid (OF). Serum sampling is considered to quintessential standard for diagnosis but successful alternatives are being sought, which include the promising DBS and OF. These DBS and OF diagnostic tests offer viable potential in diagnostics for measles. Transport considerations would be less tedious when not using serum samples and the issues surrounding the safety and necessity of using needles would be eliminated. Great number of research is being implemented into more effective and conclusive methods for the diagnosis of measles43. As the WHO has implemented plans to eliminate measles, greater attentiveness to the diagnostics of measles is essential and required for the WHO to be successful in their plan for reduced mortality rates44.

Complications of the measles virus have been attributed to autism in children after they have received the mumps, measles, and rubella vaccine (MMR). Studies conducted suggest that the cases of autism did not increase at the period of administration of the MMR vaccine.

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Variation in different types of autism is being studied in comparison to administration of the MMR vaccine45. The link between MMR vaccination and autism is unauthenticated but cases could exist if the child was genetically predisposed after receiving the vaccination. The vaccine is significant, as without it mortality rates would prevail46.

Vaccination

The implementation of vaccinations against the measles virus has been one of the most successful vaccinations worldwide. The measles vaccine has saved millions of lives around the world. It has been estimated that approximately 30-40 million people of cases of the virus each year still occur with approximately 800,000 deaths a year being contributed to the virus.

The susceptibility to the measles virus is directed towards numerous influential contributory factors. The efficacy of the vaccine is dependent of a number of influential factors. Transfer of maternal antibodies occurs through the placenta. The rate of maternal antibodies in less developed countries has been shown to be lower than transferred maternal antibodies in developed countries. One contributory factor is malaria placenta infection. It has been documented that maternal antibodies still are transferred, but these antibodies tend to diminish at a greater rate. An implementation plan of action was the introduction of malaria netting which may improve the outcome.

Low birth weights are more vulnerable to measles virus than normal healthy weight births. Suggestions put forward mitigate plans to vaccinate the more susceptible at an earlier age. Due to near elimination of naturally occurring measles, most immunity is due to vaccination, fewer antibodies get passed through placenta to the foetus, therefore the foetus immunity to measles is lower. Another suggestion to improve vaccination rate success is to vaccinate pre- adolescence to increase antibody levels.

Finding a suitable age of vaccination is paramount and difficult, as vaccinated mothers pass on fewer antibodies than mother who naturally incurred the measles virus. An established immunisation programme has to be introduced which embraces all age groups and range of immunity. Due to lower antibody levels being transferred from the mother, the measles virus susceptibility could be as low as 4-5 months for the child. Due to such a young age of susceptibility, new regimes will have to be adapted to incorporate capturing of the earlier infected age group.

The number of doses required and the efficacy of the doses is also of concern. Some countries have adopted a two dose strategy and other countries have a one dose strategy. The World Health Organisation (WHO) recommends a two dose strategy200. The different strains of the vaccines allows for different groups to be immunized.

Non-injectable vaccine for the measles virus is being studied. Aerosol vaccine is displaying promising results. A study is presently on going to determine the sufficiency of aerosol vaccine in comparison to the injectable vaccine. Aerosol vaccine promises great expectations, allowing greater immune response for children 9 months or older. Aerosol vaccine allows for self administration, are less audacious to use than the injectable vaccine201. A needle-free approach is being investigated, which would prove to be cost effective and an alternative to the injectable vaccine202. A needle- free approach may be one of the better options going forward as there are numerous constraints of the live attenuated vaccines (LAVs), which include qualified administrators of vaccinations, sterile needles, and correct storage of vaccines. Non needle vaccines could allow for lower costs for administrating, easily administrated, little maintenance, one dose vaccine, safe and globally effective and available.203

Subacute sclerosing panencephalitis

Subacute sclerosing panencephalitis (SSPE) is contributed to the association of the measles virus. SSPE is a fatal neurological infection affecting the central nervous system (CNS), which mainly affects children. As the disease progresses, oligodendroctyes, astrocytes and endothelial cells become affected, this ultimately accumulates to death of the patient. The occurrence of SSPE was once considered to occurs in approximately 1:300,000, but more recent research would suggest cases of 1:10,00055. The direct cause of SSPE is still unidentified56

Thepathogenesis of Subacute sclerosing panencephalitis is still undefined but the incidence is considered to be mainly an adaptive immune response which involves cell- mediated responses and antibody- mediated responses, but some research suggests that both the innate and adaptive immune response is involved57,58. SSPE can linger for a number of years while causing neurological damage. Signs of SSPE become evident 6 years post measles infection. It has been documented that 95% of patients with Subacute sclerosing panencephalitis will die within 5 years of initial determination of the disease, and with only 5% of patients going into remission. The treatment Subacute sclerosing panencephalitis includes the controlling of seizures. Diagnoses of Subacute sclerosing panencephalitis are associated with electroencephalography. Demyelination and the prevalence of the measles virus are involved with SSPE. Some treatment trials are ongoing and include such drugs as isoprinosine57.

Symptoms of Subacute sclerosing panencephalitis include changes in behaviour, reduction in mental capacity and involuntary twitching. Symptoms can also be represented by non conforming characteristics, which can cause SSPE to be a missed diagnosis59. Subacute sclerosing panencephalitis has also been documented to be more prevalent in males60.

Future treatments for Subacute sclerosing panencephalitis include optimising the use of antivirals and molecule inhibitors61. The administration of alpha-interferon could increase the rate of mortality among patients of SSPE62. Combination therapy has been utilised in hoping to achieve the best treatment approach available, IFN-alpha and ribavirin has been optimised but with minute improved outcome63. Other research has been conducted based on apoptosis (programmed cell death) and Subacute sclerosing panencephalitis, again combination drug therapy optimising flupirtine and antiviral drugs has been acknowledged64.

The aetiology of Subacute sclerosing panencephalitis is unknown, but is contributed to the relentless measles virus65. The measles virus is attributed to an array of neurological diseases66. With advancing new methodologies being discovered, advancing research and improvements directed towards disease diagnosis into SSPE, new treatments and preventative measures a viable cure may one day may become notably and genuinely palpable67.

Conclusion

Measles virus is contagious and affects impoverished countries more readily than developed countries. Alternative therapies focus on the influential factors which may determine susceptibility, such as deficiency in vitamin A. Measles virus in children with vitamin A deficiency may prove more harmful. The World Health Organisation set a recommendation of the required dosage of vitamin A for children with the measles virus living in impoverished surroundings30.

Treatments for the contagious measles virus include vaccinations. Newly improved methods of vaccine administration are being developed, enhancing the cost- effectiveness and ease of use. The consequences of MV include Subacute sclerosing panencephalitis (SSPE), pneumonia and inclusion body encephalitis. Preventable measure and characteristic features of the virus should be dispensed to the public to educate the people on the importance of vaccination against measles virus. Reduction of two-thirds of deaths of the under-five is planned by the World Health Organisation, in its plan referred to as the Fourth Millennium Development Goal (MDG 4) by 2015. Elimination of the virus is being benchmarked against getting pre-puberty women vaccinated and aiming to vaccinate children at a younger age. Global recognition around the world on the severe consequences of the virus is essential for the eradication of this preventable infection. Countries around the World must be capable of alerting their appropriate agencies if a measles outbreak is thought to have occurred, failure of recognition could be detrimental to the more suscepitable31. A global uniformed approach to dosage to the young should be widely implemented around the World, and the consequences of a measles outbreak should be made clear to leading government agencies to cascade to their appropriate teams of experts.

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