Eye on ID

Measles: No longer gone and forgotten

It is almost certain that very few infectious diseases physicians who started practicing after 1993 have ever seen even one case of measles in the United States. Yet those of us who started seeing patients before the late 1950s (and those of us who worked and studied overseas) saw measles as one of the most common recognizable viral diseases occurring in children, usually by age 15 years. Before the introduction of live measles vaccine in 1963 — and subsequently a measles vaccine combined with rubella, and another measles vaccine combined with rubella and mumps, or MMR, in 1971 — virtually every single human in the U.S. over 15 years of age had experienced an infection with measles virus. During the decade before a measles vaccine was available, it is estimated that 3 to 4 million people were infected each year, causing up to 500 deaths and more than 45,000 hospitalizations, many with encephalitis.

Marjorie P. Pollack
Donald Kaye

Measles is one of the most highly contagious diseases on the planet. According to the CDC, measles is so contagious that if one person has it, 90% of the people close to that person who are not immune will also become infected. On average, a person with measles infects 12 to 18 unvaccinated people. In comparison, a person with influenza infects one to four, and someone with Ebola infects two to three. Serosurveys on individuals born before 1957 (6 years before the availability of a vaccine) have demonstrated that 95% to 98% of the population have immunity to measles. Hence, those individuals born before 1957 are assumed to have had measles and are therefore immune. Documentation of measles immunity among health care workers born before 1957 is the current recommendation, although there are debates on the cost-benefit of such a recommendation.

Measles worldwide

Although the occurrence of measles has markedly decreased worldwide, it was still responsible for about 90,000 deaths in 2016, mostly among children aged younger than 5 years. Globally, there were 146,744 cases of measles reported to WHO in 2017, and as of June 2018, 81,635 cases have been reported for this year.

In September 2016, the Pan American Health Organization (PAHO) and WHO declared the Americas free of measles. In spite of this declaration, in the first 6 months of 2018, there have been 1,685 cases of measles reported in the Americas — most a result of imported cases initiating transmission chains among unvaccinated or incompletely vaccinated individuals. Noteworthy is that within 2 years of proclaiming the Americas free of measles, the disease recurred in Venezuela because of the breakdown of its public health infrastructure. According to PAHO and WHO, 2,154 cases were reported in the country in a 12-month period — from July 1, 2017, through June 30, 2018 — including 35 related deaths.

The situation is much worse in Europe, Asia and the Middle East than in the Americas because of low immunization rates. There have been many cases of measles in Europe — not unrelated to the antivaccination movement, whose influence is increasing. From 2016 to 2018, more than 20,000 measles cases were reported from Europe. Specifically, from May 2017 through April 2018, more than 13,000 cases were reported from the Ukraine, and in 2017, almost 1,000 cases were reported from Greece and more than 4,000 cases were reported from Italy.

The Democratic Republic of the Congo led the world in 2017 with more than 45,000 cases, and India went one better with more than 50,000 cases between May 2017 through April 2018.

Measles in the U.S.

According to the CDC, measles was eliminated in the U.S. in 2000. Elimination means that no outbreak starts with an endemic case but instead begins with an imported case who transmits the disease to secondary and tertiary nonimmune individuals.

There have been 55 to 220 cases of measles yearly in the U.S. during the past 10 years, except for 2014, when there were 667 cases. The increased number of cases in 2014 was in large part fueled by an outbreak consisting of 383 cases, mainly involving unvaccinated Amish communities in Ohio.

Clinical syndrome

With apologies to the relatively few readers who have actually seen cases of measles, we thought it would be appropriate to describe the clinical syndrome.

Measles is caused by a paramyxovirus. It is transmitted primarily through airborne droplet nuclei produced by the coughing or sneezing of an infected person. It can also be transmitted by direct contact with nasopharyngeal secretions. After an incubation period ranging from 7 to 21 days (usually 10 to 12 days), the infection starts with fever and malaise, followed within 24 hours by coryza, cough and conjunctivitis, with continuing fever and malaise. In another 3 to 5 days (usually 4 days after onset of illness), a maculopapular erythematous rash appears. The rash starts on the forehead at the hairline and spreads downward to involve the rest of the body. Fever climbs to a maximum (often at 104°F) when the rash reaches its peak. After that, defervescence rapidly occurs. The conjunctivitis is often accompanied by photophobia. Koplik spots, which are blue-white spots on the buccal mucosa, occur up to 48 hours before the measles rash appears and last up to up to 4 days. Koplik spots are considered to be pathognomonic for measles. The typical case of measles lasts 7 to 10 days.

Partially immune individuals (by virtue of maternal antibodies, administration of gamma globulin or immunization) can develop a mild case of measles with a prolonged incubation period (modified measles).

Complications

Measles tends to be more severe in children aged younger than 5 years and adults aged 20 years and older. The immediate dangers include diarrhea (with subsequent dehydration in the very young) in 8% of cases; otitis media in 7% of cases; primary viral or secondary bacterial pneumonia (the most common cause of death) in 6% of cases; and acute encephalitis in one of every 1,000 cases (with a case-fatality rate of approximately 15%, and residual brain damage in 25%). A sobering statistic is that as many as 30% of reported measles cases have one or more complications, and one to two per 1,000 with measles die from complications.

A devastating long-term sequelae of measles infection is the fatal complication of subacute sclerosing panencephalitis (SSPE). According to data reported to the California Department of Public Health during 1988 to 1991, the incidence of SSPE was one case per 1,367 for children aged younger than 5 years when they had measles, and one per 609 for children who had measles when they younger than 12 months of age. Before this, the estimated incidence rate ranged from a high of one per 3,584 to a low of one per 25,000. SSPE has a latent period of years (usually 7 to 10 years) before the onset of this lethal disease.

Individuals who are immunocompromised (from chemotherapy or acquired or inherited disorders of cell-mediated immunity) can develop severe measles with a prolonged course. This occurs in persons with T-cell deficiencies (certain leukemias and lymphomas, and AIDS). It may occur without the typical rash, and a patient may shed virus for several weeks after the acute illness.

Atypical measles was a severe syndrome that was seen in children exposed to the disease who were immunized only with killed measles vaccine, which was available in the U.S. from 1963 to 1967. It was manifested by the acute onset of fever and headache, followed by a rash that developed peripherally and moved centrally. The rash was most pronounced on the ankles and wrists and could involve palms and soles. The rash was usually maculopapular but could be urticarial, petechial or purpuric and could even become vesicular. Pulmonary involvement on radiograph was universal.

Diagnosis

Specimens for virus culture should be obtained from every person with a clinically suspected case of measles and should be shipped to the state public health laboratory or CDC. Although often positive earlier, a positive enzyme immunoassay for immunoglobulin M antibody after 72 hours of rash is diagnostic of measles. A fourfold rise in the titer of immunoglobulin G antibody against measles virus over a period of weeks is also diagnostic.

Treatment

There is no specific treatment for measles. Supportive measures ensuring adequate fluid intake and electrolyte balance are required.

Ribavirin is active against measles virus in vitro and has been used in treatment of patients with severe complications, especially in those who are immunocompromised.

In children, two doses of vitamin A supplements (50,000 IU for infants aged younger than 6 months, 100,000 IU for infants aged 6 to 11 months, and 200,000 IU for children aged 12 months and older) are recommended to correct low vitamin A levels that can occur even in well-nourished children. Vitamin A supplements have been shown to reduce the number of deaths from measles by 50%.

Prevention

Measles vaccine, usually provided as the MMR vaccine, is a highly effective live virus vaccine. One dose is about 93% effective in preventing measles, and two doses are about 97% effective. The CDC recommends two doses of MMR vaccine, starting with the first dose at 12 through 15 months of age, and the second dose at 4 through 6 years of age.

To prevent clinical measles in nonimmune people who have been exposed (including infants), measles vaccine should be given within 72 hours of exposure. Even if measles still develops, the illness is usually milder and of shorter duration if the vaccine is administered. People who are exposed to the virus and are at risk for severe illness should be given measles immune globulin intramuscularly (IG IM). When given within 6 days of exposure, IG can prevent measles or make symptoms less severe and should be considered for those who did not receive the vaccine within 3 days. If measles vaccine is not administered within 72 hours of exposure, the vaccine should still be offered anyway to protect against future exposures, but it should be delayed for 5 months to allow antibodies from the measles IG to decay. For nonimmune pregnant women, IG should be administered intravenously. For severely immunocompromised individuals, IG should be given intravenously regardless of vaccination history. The recommended dose of IG IM is 0.5 mL/kg of body weight (maximum dose = 15 mL), and the recommended dose of IG IV is 400 mg/kg.

Anti-vaxxers

Although vaccines in general are highly effective and have saved many lives, side effects do occur and have contributed to the development of the anti-vaxxer movement. Although some of those who are unvaccinated have true religious reasons for avoiding vaccination, they are in a minority and often clustered without major contact with outsiders. In the case of measles, because of the great success of vaccination programs in developed countries, anti-vaxxers have avoided having their children immunized because they perceive that the chances of side effects are much greater than the chances of being exposed to measles. Adding fuel to the fire is the discredited but still rampant fear of measles-containing vaccines causing autism. The genesis of the autism claim is the discredited article by Andrew Wakefield, published in The Lancet in 1998 and subsequently retracted. Examples of the anti-vaxxer’s deleterious effect can be seen in the increase of measles cases in Great Britain, Italy, Romania and the U.S. in recent years.

In 2015, there was a major outbreak in the U.S. following an exposure at a California amusement park, which eventually involved 188 cases from 24 states and Washington, D.C. Many of the cases were unvaccinated or inadequately vaccinated. The index case was probably someone who was exposed in a foreign country. The virus involved in this outbreak was a measles-B3 virus and was identical to the virus type that caused a large measles outbreak in the Philippines in 2014.

Although the incidence of measles is very low in the U.S., the country is in constant danger of outbreaks due to suboptimal immunization rates, largely because of the activities of anti-vaxxer groups. In 2016, the proportion of children aged 19 to 35 months in the U.S. who had received at least one dose of MMR was reported at 91.9%. Adequate immunization coverage should be 95% with at least two doses of vaccine. Of course, the susceptible population is much larger than these statistics would indicate. For example, those too young for immunization without maternal antibody would be susceptible. If the vaccination rate should fall below 90%, there is the danger of a loss of herd immunity and the occurrence of measles epidemics. Pockets of unprotected individuals — anti-vaxxers and those who are unimmunized for religious reasons — live in areas with seemingly adequate population-based vaccination coverages. They may serve as excellent transmitters of the virus in the community, and as initiators of an outbreak, if and when they travel. The greatest danger is measles virus exposure of an immunocompromised individual or a child too young to be immunized. Measles is particularly deadly in these populations.

Conclusions

Measles is a severe, highly transmissible disease that is still rampant in many parts of the world. It threatens a comeback in industrialized countries whenever and wherever immunization rates drop and, unfortunately, immunization is a prime target of the anti-vaxxer movement, increasing the risk and likelihood of a comeback.

Disclosures: Kaye and Pollack report no relevant financial disclosures.

It is almost certain that very few infectious diseases physicians who started practicing after 1993 have ever seen even one case of measles in the United States. Yet those of us who started seeing patients before the late 1950s (and those of us who worked and studied overseas) saw measles as one of the most common recognizable viral diseases occurring in children, usually by age 15 years. Before the introduction of live measles vaccine in 1963 — and subsequently a measles vaccine combined with rubella, and another measles vaccine combined with rubella and mumps, or MMR, in 1971 — virtually every single human in the U.S. over 15 years of age had experienced an infection with measles virus. During the decade before a measles vaccine was available, it is estimated that 3 to 4 million people were infected each year, causing up to 500 deaths and more than 45,000 hospitalizations, many with encephalitis.

Marjorie P. Pollack
Donald Kaye

Measles is one of the most highly contagious diseases on the planet. According to the CDC, measles is so contagious that if one person has it, 90% of the people close to that person who are not immune will also become infected. On average, a person with measles infects 12 to 18 unvaccinated people. In comparison, a person with influenza infects one to four, and someone with Ebola infects two to three. Serosurveys on individuals born before 1957 (6 years before the availability of a vaccine) have demonstrated that 95% to 98% of the population have immunity to measles. Hence, those individuals born before 1957 are assumed to have had measles and are therefore immune. Documentation of measles immunity among health care workers born before 1957 is the current recommendation, although there are debates on the cost-benefit of such a recommendation.

Measles worldwide

Although the occurrence of measles has markedly decreased worldwide, it was still responsible for about 90,000 deaths in 2016, mostly among children aged younger than 5 years. Globally, there were 146,744 cases of measles reported to WHO in 2017, and as of June 2018, 81,635 cases have been reported for this year.

In September 2016, the Pan American Health Organization (PAHO) and WHO declared the Americas free of measles. In spite of this declaration, in the first 6 months of 2018, there have been 1,685 cases of measles reported in the Americas — most a result of imported cases initiating transmission chains among unvaccinated or incompletely vaccinated individuals. Noteworthy is that within 2 years of proclaiming the Americas free of measles, the disease recurred in Venezuela because of the breakdown of its public health infrastructure. According to PAHO and WHO, 2,154 cases were reported in the country in a 12-month period — from July 1, 2017, through June 30, 2018 — including 35 related deaths.

PAGE BREAK

The situation is much worse in Europe, Asia and the Middle East than in the Americas because of low immunization rates. There have been many cases of measles in Europe — not unrelated to the antivaccination movement, whose influence is increasing. From 2016 to 2018, more than 20,000 measles cases were reported from Europe. Specifically, from May 2017 through April 2018, more than 13,000 cases were reported from the Ukraine, and in 2017, almost 1,000 cases were reported from Greece and more than 4,000 cases were reported from Italy.

The Democratic Republic of the Congo led the world in 2017 with more than 45,000 cases, and India went one better with more than 50,000 cases between May 2017 through April 2018.

Measles in the U.S.

According to the CDC, measles was eliminated in the U.S. in 2000. Elimination means that no outbreak starts with an endemic case but instead begins with an imported case who transmits the disease to secondary and tertiary nonimmune individuals.

There have been 55 to 220 cases of measles yearly in the U.S. during the past 10 years, except for 2014, when there were 667 cases. The increased number of cases in 2014 was in large part fueled by an outbreak consisting of 383 cases, mainly involving unvaccinated Amish communities in Ohio.

Clinical syndrome

With apologies to the relatively few readers who have actually seen cases of measles, we thought it would be appropriate to describe the clinical syndrome.

Measles is caused by a paramyxovirus. It is transmitted primarily through airborne droplet nuclei produced by the coughing or sneezing of an infected person. It can also be transmitted by direct contact with nasopharyngeal secretions. After an incubation period ranging from 7 to 21 days (usually 10 to 12 days), the infection starts with fever and malaise, followed within 24 hours by coryza, cough and conjunctivitis, with continuing fever and malaise. In another 3 to 5 days (usually 4 days after onset of illness), a maculopapular erythematous rash appears. The rash starts on the forehead at the hairline and spreads downward to involve the rest of the body. Fever climbs to a maximum (often at 104°F) when the rash reaches its peak. After that, defervescence rapidly occurs. The conjunctivitis is often accompanied by photophobia. Koplik spots, which are blue-white spots on the buccal mucosa, occur up to 48 hours before the measles rash appears and last up to up to 4 days. Koplik spots are considered to be pathognomonic for measles. The typical case of measles lasts 7 to 10 days.

PAGE BREAK

Partially immune individuals (by virtue of maternal antibodies, administration of gamma globulin or immunization) can develop a mild case of measles with a prolonged incubation period (modified measles).

Complications

Measles tends to be more severe in children aged younger than 5 years and adults aged 20 years and older. The immediate dangers include diarrhea (with subsequent dehydration in the very young) in 8% of cases; otitis media in 7% of cases; primary viral or secondary bacterial pneumonia (the most common cause of death) in 6% of cases; and acute encephalitis in one of every 1,000 cases (with a case-fatality rate of approximately 15%, and residual brain damage in 25%). A sobering statistic is that as many as 30% of reported measles cases have one or more complications, and one to two per 1,000 with measles die from complications.

A devastating long-term sequelae of measles infection is the fatal complication of subacute sclerosing panencephalitis (SSPE). According to data reported to the California Department of Public Health during 1988 to 1991, the incidence of SSPE was one case per 1,367 for children aged younger than 5 years when they had measles, and one per 609 for children who had measles when they younger than 12 months of age. Before this, the estimated incidence rate ranged from a high of one per 3,584 to a low of one per 25,000. SSPE has a latent period of years (usually 7 to 10 years) before the onset of this lethal disease.

Individuals who are immunocompromised (from chemotherapy or acquired or inherited disorders of cell-mediated immunity) can develop severe measles with a prolonged course. This occurs in persons with T-cell deficiencies (certain leukemias and lymphomas, and AIDS). It may occur without the typical rash, and a patient may shed virus for several weeks after the acute illness.

Atypical measles was a severe syndrome that was seen in children exposed to the disease who were immunized only with killed measles vaccine, which was available in the U.S. from 1963 to 1967. It was manifested by the acute onset of fever and headache, followed by a rash that developed peripherally and moved centrally. The rash was most pronounced on the ankles and wrists and could involve palms and soles. The rash was usually maculopapular but could be urticarial, petechial or purpuric and could even become vesicular. Pulmonary involvement on radiograph was universal.

Diagnosis

Specimens for virus culture should be obtained from every person with a clinically suspected case of measles and should be shipped to the state public health laboratory or CDC. Although often positive earlier, a positive enzyme immunoassay for immunoglobulin M antibody after 72 hours of rash is diagnostic of measles. A fourfold rise in the titer of immunoglobulin G antibody against measles virus over a period of weeks is also diagnostic.

PAGE BREAK

Treatment

There is no specific treatment for measles. Supportive measures ensuring adequate fluid intake and electrolyte balance are required.

Ribavirin is active against measles virus in vitro and has been used in treatment of patients with severe complications, especially in those who are immunocompromised.

In children, two doses of vitamin A supplements (50,000 IU for infants aged younger than 6 months, 100,000 IU for infants aged 6 to 11 months, and 200,000 IU for children aged 12 months and older) are recommended to correct low vitamin A levels that can occur even in well-nourished children. Vitamin A supplements have been shown to reduce the number of deaths from measles by 50%.

Prevention

Measles vaccine, usually provided as the MMR vaccine, is a highly effective live virus vaccine. One dose is about 93% effective in preventing measles, and two doses are about 97% effective. The CDC recommends two doses of MMR vaccine, starting with the first dose at 12 through 15 months of age, and the second dose at 4 through 6 years of age.

To prevent clinical measles in nonimmune people who have been exposed (including infants), measles vaccine should be given within 72 hours of exposure. Even if measles still develops, the illness is usually milder and of shorter duration if the vaccine is administered. People who are exposed to the virus and are at risk for severe illness should be given measles immune globulin intramuscularly (IG IM). When given within 6 days of exposure, IG can prevent measles or make symptoms less severe and should be considered for those who did not receive the vaccine within 3 days. If measles vaccine is not administered within 72 hours of exposure, the vaccine should still be offered anyway to protect against future exposures, but it should be delayed for 5 months to allow antibodies from the measles IG to decay. For nonimmune pregnant women, IG should be administered intravenously. For severely immunocompromised individuals, IG should be given intravenously regardless of vaccination history. The recommended dose of IG IM is 0.5 mL/kg of body weight (maximum dose = 15 mL), and the recommended dose of IG IV is 400 mg/kg.

Anti-vaxxers

Although vaccines in general are highly effective and have saved many lives, side effects do occur and have contributed to the development of the anti-vaxxer movement. Although some of those who are unvaccinated have true religious reasons for avoiding vaccination, they are in a minority and often clustered without major contact with outsiders. In the case of measles, because of the great success of vaccination programs in developed countries, anti-vaxxers have avoided having their children immunized because they perceive that the chances of side effects are much greater than the chances of being exposed to measles. Adding fuel to the fire is the discredited but still rampant fear of measles-containing vaccines causing autism. The genesis of the autism claim is the discredited article by Andrew Wakefield, published in The Lancet in 1998 and subsequently retracted. Examples of the anti-vaxxer’s deleterious effect can be seen in the increase of measles cases in Great Britain, Italy, Romania and the U.S. in recent years.

PAGE BREAK

In 2015, there was a major outbreak in the U.S. following an exposure at a California amusement park, which eventually involved 188 cases from 24 states and Washington, D.C. Many of the cases were unvaccinated or inadequately vaccinated. The index case was probably someone who was exposed in a foreign country. The virus involved in this outbreak was a measles-B3 virus and was identical to the virus type that caused a large measles outbreak in the Philippines in 2014.

Although the incidence of measles is very low in the U.S., the country is in constant danger of outbreaks due to suboptimal immunization rates, largely because of the activities of anti-vaxxer groups. In 2016, the proportion of children aged 19 to 35 months in the U.S. who had received at least one dose of MMR was reported at 91.9%. Adequate immunization coverage should be 95% with at least two doses of vaccine. Of course, the susceptible population is much larger than these statistics would indicate. For example, those too young for immunization without maternal antibody would be susceptible. If the vaccination rate should fall below 90%, there is the danger of a loss of herd immunity and the occurrence of measles epidemics. Pockets of unprotected individuals — anti-vaxxers and those who are unimmunized for religious reasons — live in areas with seemingly adequate population-based vaccination coverages. They may serve as excellent transmitters of the virus in the community, and as initiators of an outbreak, if and when they travel. The greatest danger is measles virus exposure of an immunocompromised individual or a child too young to be immunized. Measles is particularly deadly in these populations.

Conclusions

Measles is a severe, highly transmissible disease that is still rampant in many parts of the world. It threatens a comeback in industrialized countries whenever and wherever immunization rates drop and, unfortunately, immunization is a prime target of the anti-vaxxer movement, increasing the risk and likelihood of a comeback.

Disclosures: Kaye and Pollack report no relevant financial disclosures.