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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 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:
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):
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 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:
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.
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.