Thursday, July 21, 2011

Measles Part 1: The Virus, the Disease, and the Dynamics


This week at Infection Landscapes I will discuss measles. Caused by one of the most infectious human pathogens known, this disease translates to very considerable morbidity and mortality in the developing world. In addition, while this disease was practically eliminated from the developed world with the introduction and wide dissemination of the measles vaccine, the virus has rebounded dramtically because of poor adherence to safe, and well-established vaccination schedules. This measles discussion is comprised of 2 parts. The first part will describe the virus, the disease, and its transmission dynamics. The second part will describe the vaccine, the successes and failures of elimination in various regions of the world, and the current newly emerging epidemics that threaten new generations of children.

The Pathogen: Measles is caused by measles virus, also known as rubeola virus, which is in the genus Morbillivirus in the Paramyxoviridae family. Measles virus is a negative sense, single-stranded RNA virus with an envelope. Here is a picture:


The measles virus genome only encodes 8 proteins, 6 of which are structural and 2 of which are involved in viral entry. Hemagglutinin (H) and fusion protein (F) are components of the viral envelope which together mediate fusion with host epithelial cells in the upper respiratory tract. H, which binds to CD46 and CD150 cellular receptors,  is very immunogenic in the host. Indeed, the lifelong immunity that follows natural infection (if the host survives the infection and potential secondary complications) is due to the establishing of cell-mediated memory and the production of neutralizing antibodies against H protein. Synthesis of mRNA, translation, and replication all take place in the cytoplasm of the host cell. Here is a nice graphic of the infection cycle published in Nature Reviews Microbiology:



Transmission of the virus is by the droplet or airborne route. The virus invades the epithelial cells of the upper respiratory tract, however the infection is not limited to this site. After initial viral replication takes place in the respiratory epithelium, the virus moves to the local lymphatic tissue where it replicates again in the lymph nodes and then from there disseminates widely to many different organ systems. The virus can target the kidney, liver, gastrointestinal tract and the skin. In each of these systems, the virus replicates in epithelial and endothelial cells as well as in macrophages. The pathogen has a broad tissue tropism after it successfully accesses the respiratory epithelium, undergoes its initial round of replication, and sends forth new virions to invade new host cells.

The Disease. The pathogenicity of measles virus passes through several distinct stages.

The first stage is the prodrome, and is characterized by non-specific symptoms that may be confused with many other respiratory infections. Fever, cough, coryza, and conjunctivitis are the most common symptoms, so identifying measles based on these alone can be difficult. However, an additional symptom can present during the prodrome that is very specific for measles, but it requires an experienced clinical eye. A few small white spots may be apparent on the mucous membrane along the parotid duct in the mouth (or sometimes even around the eye):

Koplik spots

These spots are known as Koplik spots and precede the appearance of the rash by a couple days. They are good diagnostic markers. However, while common, they do not necessarily present in all infections and they also require clinical experience to recognize. So, for example, in India or in many countries in sub-Saharan Africa where measles is endemic, physicians are excellent at diagnosing measles. Whereas in the US and Europe, where currently practicing physicians have likely never seen a case of measles (although this is rapidly changing with decreasing vaccination rates), measles will almost never be diagnosed during the prodrome. As the prodome proceeds the symptoms typically intensify, which corresponds to increasing viremia.

The end of the prodrome is marked by the onset of the rash, which corresponds to the highest level of viremia in the host and the second clinical stage. The measles rash is the most distinctive clinical sign of measles, and is erythamatous and maculopapular in nature:


This rash is due to the immune response to infected capillary endothelium and the associated mononuclear cell infiltrate. The rash develops first on the face and then extends down to the trunk and finally extends out to the extremities as depicted in this image below:


The rash usually lasts for 3 to 4 days and then fades following the same pattern from face, to trunk, to the upper and lower limb. The appearance of the rash also marks the beginning of viral clearance, which is typically complete by the end of the first week after the rash onset. Even though virion clearance is established with in a week of the rash, viral RNA can still be detected by polymerase chain reaction for up to one month in some children. If measles is uncomplicated, full recovery begins quite soon after the appearance of the rash.

The third clinical stage can take many forms and appears when immunosuppression caused by measles virus infection is so severe that secondary complications arise. Infection with measles virus induces an intense immune response, which leaves the host immunologically compromised. Subsequent decreases in CD4+ T helper cells and CD8+ cytotoxic cells, as well as generalized incapacitation of the clonal activation of cell mediated and humoral immunity, follow measles viral clearance. Antigen presenting capacity is also diminished because dendritic cells fail to maturate. Because the post-infection immunosuppression can affect aspects of both adaptive and innate immunity, and because this state of immunocompromise can last for weeks to months beyond the point of measles viral clearance, the host, now resolved of measles, is often in a state of dangerous vulnerability. This vulnerability leads to a much increased risk of secondary bacterial and viral infections with other pathogens. Severe diarrhea and pneumonia are the most common complications secondary to measles infection. These are also responsible for much of the morbidity and mortality associated with measles. Tragically, most of this mortality is in children.

Complications occur in approximately 40% of measles cases in the developing world. As mentioned above, pneumonia and diarrhea account for most measles complications but they can occur in any organ system, with encephalitis also being especially important, which is associated with substantial brain damage in survivors. Extremes of age (young children are by far the most affected) are associated with more severe disease and higher mortality. In addition, because immune suppression is responsible for measles complications, malnutrition both exacerbates and is increased by (particularly due to severe diarrheal disease) the secondary infections that follow.

Estimates of the global burden of disease are not very good because of poor surveillance in those areas that experience the greatest number of infections. Nevertheless, we do have some estimates, imperfect though they may be. While the World Health Organization (WHO) reported about a quarter of a million cases worldwide for 2009 based on passive surveillance, population-based survey estimates put the global incidence closer to 10 million cases each year. There are about 200,000 measles deaths per year. Roughly half of these deaths occur in India and half occur across many countries in sub-Saharan Africa. By contrast, in the United States between 2000 and 2007 an average of 62 cases per year were reported, most of which were imported, and a case-fatality between 1 and 3 per 1000 cases. Despite the high likelihood of under-reporting present in WHO estimates, the WHO chart below provides a good visualization of the drastically higher rates of measles experienced each year in the Southeast Asia Region (SEAR) and Africa Region (AFR) relative to the other regions of the Americas (AMR), Europe (EUR), Eastern Mediterranean (EMR), and Western Pacific (WPR):



Also notice the dramatic increases in measles incidence in the Europe Region in recent years, which has followed from the decreases in vaccination in several European countries.

The Dynamics of Communicability: A Unique Social Landscape. Almost all of the diseases covered at Infection Landscapes so far have been vector-borne, which, as we have seen, create some very complex layers of ecology in the landscape that are directly relevant to disease transmission. We will now be covering more diseases that are transmitted person-to-person, and thus do not require an intermediate arthropod to infect the human host. Infections that can be transmitted directly between people with no need for either an intermediate vector or contact with an animal reservoir, represent a specific chain of transmission in communicable disease that can follow several distinct pathways. This person-to-person train of transmission is very broad and can follow droplet, airborne, fecal-oral, sexual, parenteral, or contact pathways, or routes, of infection. We will certainly explore all modes in the person-to-person chain of transmission in the context of different communicable diseases covered at Infection Landscapes. But, in the context of the current discussion, droplet and airborne transmission are most relevant for measles.

The transmission of measles virus, as with any infection, is influenced by the landscape. However, with measles, social rather than physical elements of the landscape play the most important role in transmission. To begin, measles can be transmitted by either the droplet or airborne route, as mentioned briefly above. As with any pathogen following this route of infection, transmission is enhanced by increased rates of contact between members of a population. As such, one of the key universal factors facilitating airborne disease transmission is population density. The greater the number of people living in a space of constant geometry, or the smaller the geometry for a constant number of people, the greater the potential for contact among the people living in a given space. In other words, the denser the population, the more extensive the contacts between its members. And the more extensive the contacts, the greater the potential for transmission of airborne infection. Measles virus fits this model quite well, in fact, because it also happens to be one of the most infectious human pathogens most of us can encounter in a practical sense.

Because of measles' extremely high infectivity, it can pass through populations of sufficient density fairly quickly. But also because of this infectivity, it requires populations of sufficient size to be maintained in nature ("nature" here being the human environment). Specifically, a population of several hundred thousand, with between 5,000 and 10,000 new births per year, is required to maintain measles virus transmission. Critically, humans are the sole reservoir for measles virus. Some non-human primates can become infected and experience similar measles illess to humans, but no sylvan cycle of measles can exist because sylvan primate populations are simply too small to maintain the virus.

We can actually quantify the extent of measles infectivity by calculating something called the basic reproductive number (R0), also known as the basic reproductive ratio. This is the mean number of secondary cases generated from an index (or primary) case in a completely susceptible population. Measuring this empirically, while not impossible, is extraordinarily difficult because completely susceptible populations are very rare. However we can estimate this for measles if we know 1) the age of infection (A), 2) the average life expectancy (L), and 3) the average duration of protection from maternally acquired antibodies (M), which is usually about 9 months. The simplified equation is simply:

(L - M)/A - M)

Which is the ratio of the differences between maternally acquired immunity and life expectancy, and maternally acquired immunity and average age of infection. As such the R0 for measles ranges between 12 and 18, meaning that an average infected person will generate between 12 and 18 infections in other people in populations of non-uniform but extensive susceptibility. By comparison, the R0 ranges between 5 and 7 for smallpox, and between 2 and 3 for SARS. The picture below gives a graphical representation of the generation of secondary cases from a given infected or index case of some generic disease. On the left, you can see that each infected case, starting with the index case at time 0, produces 3 secondary cases in subsequent generations of infections. Therefore, the R0 is 3. On the right, each infected case only produces 1 secondary case, so the R0 is 1.


One of the important features of the basic reproductive number is that larger numbers, or the greater the infectivity, the larger the population required to maintain the pathogen in the population. Highly communicable infections require large pools of susceptible individuals in order for the disease to be endemic in the population. Highly infectious agents in small populations will only produce epidemic disease since the infection will quickly exhaust itself once all the susceptibles are exhausted.

During the first months of life, young infants are protected from measles infection by IgG antibodies acquired from the mother in utero and, subsequently, during breastfeeding. This is, of course, dependent on the presence of measles antibodies in the mother, which would be present either from successful vaccination or due to a natural infection. If neither of these circumstances are met, then the mother will transfer no immunity to her child at birth.

The presence of these maternal antibodies are also a critical determinant for the age at which to begin vaccination in the infant. On average in most human populations, maternal measles antibodies will circulate and provide protection from measles infection until 9 months of age. When administering measles vaccine it is important to do so at a point in time when the presence of maternal antibodies are minimal so that the vaccine does not cross-react with the the maternal antibodies. I will discuss the effect of maternal antibody cross-reaction on vaccine efficacy in Measles Part 2, which will cover the vaccine.

The Dynamics of Age and Measles Communicability. The average age of measles acquisition in any given geographic region depends on 1) the rate of contact with infected persons (which itself is dependent on population size and density, and routes of movement within the population), 2) the rate of decline of protective maternal antibodies, and 3) the vaccine coverage rate. Since most infants are protected from infection during the first several months of life, infection at this age is rare, regardless of endemicity.

Level 1: Densely populated ubran settings with low vaccine coverage rates define areas where measles is a disease of young children. In this setting the cumulative distribution can reach 50% by one year of age. Since a significant proportion of children acquire measles at 9 months of age, this is the typical routine age of vaccination in this geographic setting. The importance of level 1 endemicity is that infection occurs in the most vulnerable cross-section of the population: young infants and toddlers.

Level 2: As population density decreases, or as vaccine coverage increases, the age distribution shifts toward older children. In geographies characterized by this setting, measles is a disease of school-age children. Although infants and young children are still susceptible in this setting if they are not protected by vaccination, their exposure rate to measles virus is not sufficient to cause significant disease burden in this age group. The diminished exposure rate can be due to decreased overall contact rates in less dense geographical settings, or due to less contact with infected individuals in settings where there is some level of vaccine coverage, or due to a combination of both.

Level 3: As the vaccine coverage improves even more, the age distribution is shifted into adolescence and young adulthood as seen in the United States, Europe, and Brazil. Outbreaks among older age groups in this setting typically require targeted measles vaccination to control measles spread (i.e. among communities with low vaccination coverage).

This concludes part 1 of measles. Part 2 will discuss the measles vaccine, specifically examining it's safety and effectiveness, as well as the scope for measles elimination and eradication.

26 comments:

  1. Hi all,

    I'm wondering if there's a correlation between measles' high infectivity and the simplicity of its genome, coding for only 8 proteins. Is it often the case that infective agents with simple genomes have high infectivities?

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    1. I don't think that infectivity is related to the simplicity of the genome. Rotavirus, is also highly infective, and yet it is a much more complex virus with 11 unique double helical structures.

      It probably has more to do with the fact that it infects the respiratory tract, can be airborne, and is relatively robust outside of the body for an enveloped virus. It lasts for up to two in the air.

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  2. The progression of the disease is described as prodromic, the rash and possible third stage of immunosuppression. At which of these points are treatments most successful? And what is the standard of care in regards to treating a measles infected patient (where access to healthcare isn't a limiting factor)?

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  3. You mention that secondary infections occur in malnourished and immunocompromised children. Could you elaborate a bit more on secondary infections? Because of malnourishment, are diarrheal diseases common as secondary infections?

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  4. At which stage of the disease is a person most likely to spread measles to others and is someone still contagious when viral RNA is detected by the polymerase chain reaction even if viron clearance is established.

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  5. How long does it take it for an individual immune system to recover from measles after the initial strong response yet subsequently weakened immune system?

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  6. I don't know if you will touch on this in part 2, but I think it is worth mentioning the Wakefield report and its subsequent effect on measles vaccination practices in Europe. It also might be important to mention the DeStefano study which was a large case control study that found no evidence of a link between the measles vaccine and autism.

    Also, I am not quite understanding the concept of measles shifting to older people as vaccine coverage increases or population density decreases. Is this because adolescent are less likely to have been vaccinated because vaccine coverage was low when they were infants or because they are more likely to have more contact with others?

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  7. I was wondering whether measles was more prevalent in individuals with autoimmune disorders since immune supression is a risk factor. And would vaccination be safe for these people ?

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    1. This is an interesting point. The MMR vaccine uses live attenuated viruses to vaccinate individuals against these once common childhood illnesses. By definition of being a live attenuated virus, there is a risk of horizontal transmission to immunocompromised individuals. I would imagine that even the immunocompromised can be vaccinated against measles, however the vaccine may be an inactivated vaccine. I also recall from my infectious disease class that the attenuated vaccine for measles is not contraindicated for close contacts of immunocompromised individuals, and, thus is probably safe for them as well. As for people with autoimmune disorders, the immune system is by definition not functioning properly since it is expending its b and t cells for attacking its own antigens. Measles would probably have an easier time being "successful" in an immunocompromised individual.

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    2. There is no risk of horizontal transmission of measles from the MMR vaccine in immunocompromised or immunocompetent people. Also, MMR is safe for immunocompromised individuals.

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  8. Claire,
    In response to your question about autoimmune disorders, this article claims that adolescents with autoimmune hepatitis were able to receive the measles vaccine and it was just as effective in producing measles antibodies as in patients without autoimmune hepatitis.

    http://www.ncbi.nlm.nih.gov/pubmed/15690693

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  9. It is troubling that since Measles is highly infective, that scientist would risk using faulty science to discretid the use of measles vaccination. After reading various text for Chronic disease Epidemiology, I realize that some individuals who are advocates against use of MMR vaccine may not know better. However, scientists who are aware of the risk that they are taking should know better than to disseminate such information without longstanding concrete scientific proof.

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  10. Max
    One article suggested that the main reason for the shift in risk to older children is primary vaccine failure as young children.
    Another article agreed with your suggestion about increased density citing college dorms, and social activities common in teenage years. http://archfami.ama-assn.org/cgi/reprint/3/7/619.pdf

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  11. Jamal-

    I totally agree with you. I think that the fact that the Wakefield scandal happened at the turn of the 20th century is no coincidence-- as information becomes more easily availiable, we as scientists and public health officials need to learn to choose our words a little better. I feel that this sort of thing would not have been printed in 2011, now that we (hopefully?) know a little better. With great power comes great responisbility, or something like that.

    Robin Brehm

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  12. Craig-

    Treatment for measles kind of stinks, because there is no cure. You can give the vaccine within 72 hours of initial infection (if not already vaccinated), which appears to help ameliorate symptoms but it's obviously time-sensitive. You can also give immune serum globulin (antibodies) to children, immunocompromised folks, and pregnant women to help symptoms (within 6 days of exposure).
    Otherwise, it's just antibiotics for secondary infections, Vitamin A, and fever reducers.

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  13. Thank you for all this very valuable information. People should take Measles more seriously... As it is only a harbinger of the breakdown in immunization practices and overall infection control.

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    1. I agree with you completely Rubeola. Before reading this post and taking this class I did not know that measles was an issue . I thought it was a disease that had been completely eradicated. It should be taken more seriously and there should be more awareness because I think many people are like me and don't know that measles is still a problem and what the risks are. This is especially important for those with young children who think vaccines make their children sick and are delaying getting them for their children.

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  14. The recent outbreak in NYC has raised more awareness of this disease, being that measles is rarely seen in developed countries. I personally would not be able to know when a child has a acquired measles because I have never witness anyone with this condition before. Having a clear understanding about the virus as well as the symptoms and complications of the disease can decrease transmission.

    There is one problem, a lot of individuals are dependent of herd immunity, and many parents are less willing to vaccinate their children, is it safe to say that these decisions would untimely change the occurrence of this virus in the U.S., making it similar to those in undeveloped countries?

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    1. You raised a very important question. Many believe that herd immunity will protect them therefore they should not put their bodies through another vaccine and some believe that vaccines cause mental disorders therefore believe that either the herd immunity will protect them or they absolutely do not believe they will get measles regardless.

      Many parents must make these decisions for their children which can be very dangerous. The reason is that I believe that children can be considered another “rick factor”. They do not have strong immune systems yet and tend to transmit many viruses, harmless or not.

      I believe that in order to prevent from an epidemic from occurring is by educating parents about vaccines and understand the dynamics of measles.

      There has been a recent outbreak of measles in Manhattan. In order to prevent this from becoming a bigger issue, educating parents is vital.

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    2. Hi Disleiry,

      I agree with you that much of the herd immunity is now waning with the advent of many parents not vaccinating now. However, I don't think here in the US we will have similar incidence rates as those in underdeveloped countries such as in Africa and Asia. The majority of 20 million affected by measles each year occur in countries that don't have reliable consistent health infrastructures (such as vaccination/booster programs). Moreover, infrastructure such as housing and overcrowding in those countries contribute to the high rates of measles since the transmission is through close contact and coughing/sneezing. http://www.who.int/mediacentre/factsheets/fs286/en/. Unfortunately fear and lack of awareness especially from the Wakefield study has jeopardized the herd immunity and will continue unless more effort is done to show the gravity of the situation and show the flaws of the claims of Autism and vaccines.

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  15. I think it is scary that the transmission for measles antibodies independent on the presence of the mothers successful vaccination or due to a natural infection because If neither of these circumstances are met no immunity will transfer to the child. I feel this goes hand in hand with the fact that the disease was practically eliminated from the developed world because of the measles vaccine but has rebounded dramatically because of poor adherence to safe, and well-established vaccination schedules. I feel If mothers did not get themselves vaccinated then the likelihood of them getting their children vaccinated will be very low as well. This may allow the virus to be maintained in the future and not be eradicated.

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  16. I found it interesting that the mortality of measles is due to secondary bacterial infections as opposed to the measles infection itself. It seems that the measles infection itself is not the most lethal part, it is the immune compromised aspect that is the most detrimental part. Therefore, one may argue that even if a person is non vaccinated, measles is not as harsh as people make it if you ensure the person is in a safe and sanitary environment throughout the immune compromised time.

    I would also note the stark contrast between the WHO report of a quarter million cases compared to the population based survey which estimates closer to 10 million!! That is 40! Times greater that the WHO. Is it normal for the WHO or a large institution of such caliber to evaluate so ineffectively?

    Because humans are the sole reservoir for measles, it places a much greater weight on the importance of vaccination. The spread through human contact is best avoided by vaccination. Not to say other vector borne diseases are not best combatted through vaccination; this specific disease can be avoided through killing out mosquitos or sanitary condition. Of course those help too with this disease. We shall expound on these matters in the next post, Measles II.


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  17. From the WHO figures it looks like global incidence of Measles is decreasing since 1980 (along with a decrease in Pertussis and Mumps) and the rate of vaccination increasing so clearly a lot of good work has been underway. However the rate of vaccination is still below 90% in South East Asia and below 80% in Africa so these are regions which need the rate of vaccination to increase.
    It is interesting to wonder if vaccination rates were high enough globally to eradicate measles, how long would we need to keep the whole population vaccinated? It would be very important to know that there was no risk of the virus reappearing because when vaccination stops the whole population will become susceptible again.

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  18. As mentioned, the fact that measles is a rare disease in the developed world is the reason why physicians in the United States and the Europe are hard pressed to diagnose measles during its prodrome stage. Koplik are the tell tale sign that precede the infamous measles rash but it is unfortunately rarely recognized by modern physicians. In 2015 188 people in the United States were infected with measles, most of them between the ages of 0 and 2 with one death reported (Mayo Clinic and other sources). The fact that the majority of infections were of such a young age makes you wonder about the infectivity. With a basic reproductive number of 18, measles is highly infective. Yet, infants are rarely in contact with other infants at that age. Moreover, most children are vaccinated between the ages of 12 to 15 months. Perhaps the fact that the measles vaccine is a live attenuated virus leads to high levels of replication in young hosts that are not capable of intially fending themselves off from the disease. This results in the symptomatic measles rash that garners a diagnosis. However, a lethal viral load for complications is never achieved (just a thought).

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    1. Though infants may not come into direct contact with others at such a young age, it is still very likely that when they are out in public that then can become infected through someone coughing or sneezing nearby. According to the CDC most of the infants infected in 2015 may have come into contact with those from outside the United States or within certain communities where children are usually not vaccinated. It may also possible that they can contract measles at the pediatricians office from other infected children.

      http://www.cdc.gov/measles/cases-outbreaks.html

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