HISTORY: - ((((1 Measles is considered to be an epidemic disease. It was earlier considered similar to smallpox and chickenpox but it was distinguished first time by a Persian Physician named Muhammad ibn Zakariya (32). In the year 1529, two-thirds of the people of Cuba had been found dead because of the measles outbreak. The population which died had a prior surveillance history of smallpox. At last in 1954, The virus has been recognised (causing measles) in a 11 year old boy called David Edmonston belonging to United States. This virus was then modified and transmitted into chick embryo tissue culture (38). ))))1
Concept of Measles: - (((2The scientific name for measles is "Rubeola". This disease is generally also known as Morbilli. The causative agent is Morbillivirus which causes a viral infection in the respiratory system. This virus has a spherical shape and it is non-segmented. It has a single stranded RNA. This species is also very narrowly correlated to Rinderpest and Canine Distemper. The following table describes the taxonomy of the measles virus.)))2
GROUP
ORDER
FAMILY
SUBFAMILY
GENUS
Negative sense ssRNA viruses
Mononegavirales
Paramyxoviridae
Paramyxovirinae
Morbilivirus
Molecular Biology:
(((3The virus consists of six structural proteins of which three are confined to RNA and the rest are related to Viral Membrane envelope. Amongst the membrane envelope two envelope proteins play a very vital role in the pathogenesis of its pathogenesis. The F protein as shown in the above diagram is liable for the fusion of virus with host cell membranes. It also helps the virus in viral penetration as well as Haemolysis. The H protein helps in the absorption of virus to cells.
Viral Zone - 2009. Swiss Institute of Bioinformatics
The genome of the virus is a Negative stranded RNA genome. It is linear in shape and is 15-16 kb in size. It encodes for seven proteins. Gene expression: - RNA polymerase (viral RNA dependant) fixes the encapsidated genome to the Leader part. Further it serially transcribes every gene by identifying Start and Stop genes. mRNAs gets capped as well as Polyadenylated during its production by L protein.)))3
Infection and spread:
(((2The impairment of Cell- mediated immunity is the initial step of infection. It has been studied that the measles vaccine supresses the tuberculin reaction temporarily. The magnitude of lymphocytes plays a vital role because in the case of severe disease, falling of total lymphocytes is directly related to narrow chance of recovery.
Mechanism: - The mechanism is regulated when the virus binds to CD46 surface protein of the Monocytes. This is considered to be the "Entry mediator" path. The binding process of virus to CD46 causes fall in the regulation of IL-12 synthesis. The diminished level of IL-12 supports the high response of Th2 like cells because IL-12 has been found as a vital stimulator for the Th1 clonal expansion. The main utility of IL-12 is to fuel the resting as well as activated T cells. The other functions also include the synthesis of IFN-gamma (by T cells), activation of NK cells as well as inhibition of IL-4 synthesis. Thus a decrease in the levels of IL-12 would weaken the adaptive immunity's achievement to measles as well as also lead to immunosuppression. The reason is found that IL-12 basically initiates the prompt stimulation of Ag-specific T cells in naïve host (7).)))2
(((4The recent investigations are around the CNS infection generated by measles virus and usually hamsters, rats as well as genetically altered mice are studied as model systems. Reduction of this infection would require an assembly of functional CD4+ and CD8+ along with IFN gamma. These studies have helped to discover new aspects like receptor-dependant spread of virus and virulent determinants by using recombinant measles virus as well as endogenous or transgenic receptors expressed by mice.)))4
(((5Modern studies of primate models explained that a wild variety of measles virus starts infecting the cells (immune cells) which has been found present in the respiratory system prior to its spread systemically. However, the identification of such cells is not clear. Thus in order to recognise the cells favouring the initial MV infection a very advantageous MV receptor in mice was used known as Human Signalling Lymphocyte Activation Molecule (SLAM, CD150) which had tissue specificity very similar to Humans. In order to do so mice were infected intra-nasally with measles virus (wild type) this had capability to express green fluorescent protein. The next procedure was to study the spread so the virus had to be isolated from different organs thus nasal-associated lymphoid tissue (NALT), the lungs, several lymph nodes (LNs), the spleen, and the thymus were examined by microscope and Flow cytometer.
Observations:
DAY
LOCATION
PERCENTAGE
CONCLUSION
1
Alveolar macrophages.
Dendritic cells.
B and T lymphocytes.
2.5%
0.5%
The cells were found to be expressed Human SLAM and also concluded that this infection momentarily increases expression of SLAM.
2
Lymphatic tissues.
Mediastinal lymph node.
A very high proportion of infection was observed.
3
Mediastinal LN cells
8%
A very high proportion of infection was observed.
.)))5
How it spreads?
The spreading process of measles basically starts due to the droplet spread from Nose, throat and mouth of the patient infected with measles. These (droplets) are found to spread out by the patient while coughing or sneezing. The infection has very high proximity for four days prior to appearance of rash and four days later on to the rash. It has been examined that the virus has the ability to spread the infection until two hours once the patient has moved out from the room.
It has also been estimated that the prior infection is not dependant on receptor's function and CD150 positive cells in epithelium has been seen to be initial targets. In order to proceed for the next step of infection virus has been found to release from the host, it is then examined that an unknown receptor is needed on epithelial cells in order to overpass the barrier internally. In the way to transmit the infection to the organs and the skin, it's necessary for the receptor to pass the barrier from the apical side to the basolateral side of the endothelial cell. Howsoever, many functions like transmigration through endothelial cells diminish the infected leucocytes. The infection also has the chance to spread either by cell contact-mediated infection of endothelial cells and basolateral virus release or by passage of infected leucocytes.
http://www.brown.edu/Courses/Bio_160/Projects2000/MMR/MeaslesPathogenesis.htm
Symptoms:
The measles has been recognised with the basic symptoms like fever which stays for four days as well as three Cs (cough, coryza and conjunctivitis). The fever is determined to be very high which can be upto 1040 F. After few days many white spots enclosed with red appears randomly on the inner side of the cheeks known as KOPLIK SPOTS.
View of Koplik Spots
http://www.righthealth.com/topic/Measles_Picture/Overview/adam_images
These spots are very rarely been seen because of their location and they are found to disappear soon just after a day of its appearance. As the disease progresses, it appears in the form of rashes. These rashes basically are found to be seen after one or two days of the Koplik spots. The ears or the face are been recognised as a starting point of the rashes and randomly it spreads out down towards the body.
View of Rashes on back
http://www.righthealth.com/topic/Measles_Picture/Overview/adam_images
Characteristics of Rashes: - Rashes can be explained as a Maculopapular, Erythematous rash which can be noticed generally due after many days of fever begins. Rashes frequently cause itching and it also possesses the property of staining from red to brown (dark) prior to get disappear. These rashes are said to begin approximately four days later to the onset of the first symptom and goes upto eight days.)))wiki(4)
(((6The symptoms are then found to appear in the abdomen including Nausea and Vomiting. In some cases diarrhoea and abdominal pain are also been found. The symptoms generally end in around 14 days of time. In some cases infection may get fatal upon some conditions like Otitis media, pneumonia, hepatitis and encephalitis. There are very cases wherein there has been seen a impediment in the nervous system, which results in hazardous effects. In the rarest of the cases, brain inflammation may occur after some days of appearance of rash and this impediment leads to the damage of the brain. However in extreme cases, a very upsetting Subacute Sclerosing Panencephalitis may occur after several years of measles attack. Although the condition being measured very rare (1 in 1, 00,000) but the its progression may lead to death. )))6
Vaccination:
The historical discovery of vaccination for the measles vaccines started in the year 1954 when Enders and Peebles developed a live attenuated vaccine against measles virus. They started their study by isolating the causing agent from the blood of the patient who had claimed of appearance of the rashes. Edmonston B strain of live attenuated measles (vaccine) has been developed by Enders and his co-workers and this work was basically been done in 1950s and this agent was tested in different cell cultures including in primary renal (24 passages), primary amnion (28 passages) as well as in chick embryo (six serials) and finally they adjusted the virus into embryo (chick) fibroblasts. Later on, the 14th passage in chick embryo fibroblasts has made the confirmation of the attenuation and immunogenicity of the viral vaccine related to cynomolgus monkeys. Later after a period of five and half months these animals were targeted with the infectious virus to check their resistance. Studies had shown that these animals had become resistant as no symptoms of disease were seen. These studies were then forwarded in prone children and again retrieved with similar results.
(((It has been recognised that the Live attenuated RNA viruses has comparatively been the most effective vaccine. MV vaccine is one amongst them which is highly safe and shown high effective rate when it was injected into the huge number of children. There are some characteristics of MV vaccine which makes it more efficient than the others like induction of life-long immunity, high level of production at a cheaper cost as well as stability in pathogenicity. Because of the positive incomparable characteristics than others, the MV vaccine can be modified as a vector, which would be able to work as a multivalent vaccine and would be utilised for the immunisation of children, not only against measles but also against other contagious agents like HIV, flaviviruses as well as malaria. Because of its low cost production, the development of recombinant vaccine would be economical and striking for the emerging world. )))
Thus a recombinant vaccine was then prepared which is a modified vector generated from a live attenuated Schwarz strain of MV. The detailed study has revealed that this vector has the capability of expressing the genes which could encode for proteins from HIV and also have the ability to encourage both the immune responses (Humoral as well as Cellular) in vivo. During the studies, the scientists have also noticed that when these vectors were injected with two dozes in an animal model, these vectors had the ability to avoid the existing immunity of measles virus. The scientists are still proceeding with some clinical trials to achieve the confirmation of this study in the vaccinated adults. Later on some other vectors were also developed which possessed genes which could express proteins from west Nile virus and also of Flaviviruses. These vectors are considered to be recombinant measles viruses which not only have the capability of immunisation against measles but also against other flaviviral contagious diseases like Dengue or Japanese Encephalitis in the emerging world.
Implementation of MV vaccine in UK:
(((The very first trial of the vaccine for this contagious disease had started in the year 1961. The trials were carried out in terms of three live attenuated vaccines. (1). The studies were still in progress to build a safe and better vaccine and this trial was carried out after three years of gap from the first trial. (2) )))
Medical Council Research - 2007
The recent studies have shown a newer and an improved form of vaccine. The newer vaccine is in the form of Dry Powder and it is been studied that this powder vaccine is able to completely protect against measles in a single dose. Two types of inhalers were introduced named the Puff haler and the other one BD solvent. These two inhalers were used to deliver the vaccine through the aerosol. This latest vaccine has not shown any side effects.
Subacute Sclerosing Panencephalitis:
Subacute Sclerosing Panencephalitis generally occurs after the patient is been affected by a measles virus, generally after a period of six years. SSPE is a prolonged encephalitis disease and its occurrence would depend on the intake of the vaccination for MV. The pathology of the disease is not yet revealed although studies have claimed that Humoral immunity is favoured for this virus. In this case the virus disturbs the affinity of neurons and stays in a dormant stage in it. The main symptoms lie in the indication of mental disturbances. Gradually it is been noticed that occurrence of myoclonic seizures takes place followed by akinetic mutism. Thus for managing the disease firstly the seizures has to be controlled. Different treatment measures have been applied for better results of curing this disease, which includes the usage of interferon and Isoprinosine and proved to obtain positive results.
Progression: - The initial symptoms of this disease in the first stage is mental and behavioral disturbances which becomes unpredictable at times either they become irritable as well as change in personality is also been observed. Some other complications like memory loss as well as some mental disorders are been noticed as a result of which the person may develop some jerks or extreme spams. This may lead to walking disabilities which is very common in most of the patients even some may loose the ability to speak properly as well as not able to comprehend the language. The final stage is very traumatic wherein the complication in stage 2 becomes adverse and most of the functions of the body becomes deterioted and al last patient may become mute or get into the comma.
Diagnosis: - The diagnosis of this disease is carried out using EEG (electroencephalography) which studies the complexity of the brain susceptible to disease. Other procedures also include analysis of demyelination by brain imaging as well as studies of prior infection of MV.
http://en.wikipedia.org/wiki/Subacute_sclerosing_panencephalitis
The above picture indicates a cortical dysfunction and is known as Rademecker complex. This image is taken using an EEG. As shown in the above image, white substance on the hemispheres as well as the brainstems have been affected. Some inclusion substances are also been noticed in the nuclei of neurons.
Conclusion: Though measles is found to be highly transmissible disease, a thread of researches and modern ways of vaccination has dramatically reduced its effect. The new researches evaluated that the mortality rate has been reduced up to 90% since 2000.
