LIVING THE LAB LIFE
A BLOG FOR ASCLS REGION V
Any who has been paying attention to the news recently knows that Hennepin County in Minnesota has been facing a public health crisis. There is an active outbreak of measles (rubeola) among young children, all who are unvaccinated. So far, no fatalities have been reported, but this event has highlighted the potential dangers associated with failing to vaccinate children as recommended by medical professionals. As laboratory professionals, we must be prepared to handle these outbreaks and appropriately consult other members of the healthcare team.
The measles virus is a member of the Paramyxovirus family, along with the mumps virus, respiratory syncytial virus, parainfluenza viruses, Nipah virus, and Hendra virus. They are single-stranded, enveloped RNA viruses. These viruses are transmitted via the respiratory route, which is what makes them so contagious.
The measles virus has a few tricks up its sleeve that aide in its ability to causes serious infection in hosts. Unlike most respiratory viruses, the measles virus readily disseminates throughout the body by binding to receptors on various somatic cells (a skill few viruses have). By latching on to dendritic cells in the respiratory mucosa, the measles virus scores a free ride the lymphatic system. From there, the virus can spread throughout the body and can cause mischief.
Children are most likely to be infected with measles, particularly under the age of five. The first symptoms to appear in a measles infection include cold-like symptoms (coryza), high fever, cough, sore throat, and conjunctivitis. While these symptoms are present, the patient is most contagious (which is a problem since these symptoms are so nondescript, those around the patient likely have no idea of how serious of an illness they are exposing themselves to).
Next, Koplic’s spots (lesions on the oral mucosal membrane) appear, followed quickly by the hallmark symptoms of measles: the distinctive maculopapular rash. T cell activity targeting measles-infected endothelial cells lining blood vessels causes the characteristic rash in measles. For this reason, immunocompromised patients often do not have the rash. Patients are considered contagious for a period of four days before the rash appears to four days after.
Due to the measles virus’ ability to infect many cell types in the body, including B cells, T cells, macrophages, and NK cells, infection causes a general immunosuppression that lasts for months after initial infection. Many deaths from measles virus are caused by secondary infections that take root during this phase of immunosuppression.
Laboratory testing to diagnose measles infection is often unnecessary, due to the hallmark presentation of symptoms. Growing the virus in culture is doable using monkey cells or primary human cells, but the measles virus is difficult to grow. The virus can be isolated from respiratory secretions, urine, blood, or brain tissue. It is recommended that these specimens be collected no later than two days after appearance of the measles rash. PCR testing can also be used to detect the measles virus genome. Serological titers can be performed for Measles IgM and IgG. Measles IgG is a common test to verify vaccination status of an individual. At my facility, the majority of this testing is done for employee health or obstetric patients. Histology of any tissue infected with measles will demonstrate Warthin-Finkedley giant cells, which are multi-nucleated cells with nuclear and cytoplasmic inclusions. For acute infections, the best route for confirmation of diagnosis is detection of viral genome using PCR or serological titers of Measles IgM.
Severe side effects of measles infection have been noted in infected individuals. Otitis media is the most frequently reported complications from measles infection. This is likely precipitated by the fact that those infected with measles are typically children, who have a narrower eustachian tube. Pneumonia accounts for the most fatalities in measles-related complications. The combination of measles-induced immunosuppression and the subsequent vulnerability of the respiratory tract makes secondary respiratory infections even more dangerous. The most serious complications associated with the measles virus relate to central nervous system afflictions: ADEM, MIBE, and SSPE.
Acute disseminated encephalomyelitis (ADEM) occurs about five days after the measles rash appears. The occurrence rate is about one in 1,000 cases of measles. In these patients, widespread demyelination of nerves adjacent to vasculature and infiltration of mononuclear cells causes such symptoms as decreased level of consciousness, seizures, and high fever. The mortality rate is approximately 20%.
Measles inclusion body encephalitis (MIBE) appears two to six months after the initial measles infection. The disease state presents with an altered mental state and seizures. The mortality rate is 75%. Of those fortunate enough to have survived either ADEM or MIBE, about one-third will suffer long-term neurological complications such as mental retardation, blindness, motor impairment, and hemipharesis.
Subacute sclerosing panencelphalitis (SSPE) appears five to ten years after initial measles infection. The occurrence rate worldwide is about one in 1,000,000 cases of measles (some regions report rates as high as one in 25,000). Early in the disease progression, the patient will show signs of neurological dysfunction like muscle spasms and short attention span. The patient will slip into a vegetative state as the disease progress, which eventually leads to death.
How the measles virus enters the central nervous system is not known at this time, though multiple theories are being explored. Additionally, little is understood about how the viruses causes demyelination and other encephalopathic effects.
A vaccine against the measles virus was first made available in 1963. The vaccine uses a live, attenuated virus to trigger an effective immune response. The effectiveness of the vaccine has been remarkable. For example, before 1963, there were about 500,000 cases of measles each year in the United States. In the post-1963 years, that number dropped to 300 cases. Before vaccination became available, seven to eight million children died from measles each year worldwide. Now, that number has dropped down to one million.
In the United States, the measles vaccine is included in the MMR (measles, mumps, rubella) vaccine series. It is given in multiple doses starting at the age of twelve-to-fifteen months (some countries will give the vaccine earlier if measles outbreaks in infants is commonplace). The vaccine is an injection, which has made mass immunizations more challenging in countries with poor health infrastructure, as trained health professionals are needed to administer the vaccine (in contrast, the polio vaccine is an oral vaccine, therefore trained professionals are not needed to administer each dose).
In the United States and in other first world countries, vaccination rates again measles have seen a downtrend in recent years, largely due to parental noncompliance. From 1989 to 1991, the number of measles cases increased to fifteen times the numbers from the previous years; this increase was attributed to increased numbers of unvaccinated children. This increase of noncompliance has been attributed to a couple of causes. First, parental complacency. If parents do not see measles infection as an imminent threat, they are less likely to strictly adhere to vaccination schedules. Second, parental fears associated with vaccine safety.
After a study published in The Lancet in 1998 supported the hypothesis that the MMR vaccine cause autism in children, compliance with vaccination dropped substantially, leading to outbreaks of measles. While the article stated “we did not prove an association between measles, mumps, and rubella vaccine and the syndrome described,” the tilt of the article proved enough to trigger fear. The authors later retracted the paper, reportedly due to a 2004 article in the Sunday Times (London) which exposed that the lead author, Andrew Wakefield, had failed to properly disclose his conflicts of interest. Wakefield had accepted funding ($103,000) from lawyers within Britain’s legal-aid system to investigate the possible link between autism and the MMR vaccine. These lawyers were representing parents of autistic children who were looking to sue vaccine manufacturing companies for damages. By failing to make full disclosure of his conflicts of interest, he discredited the entirety of the article. Moreover, experts have pointed out that the study was scientifically weak at many points. Conclusions were based on data from a small sample size (n=12). Also, the association between the onset of autism symptoms and the receipt of the MMR vaccine was made by the parents of the children in the study, not any properly trained third party capable of objectivity. Subsequent studies have not established any association between autism and the MMR vaccine. Unfortunately, this has not been enough to convince all parents to vaccinate. This is particularly unfortunate, since public health experts predict that a population needs to have a 95% immunity rate in order to prevent outbreaks within a community.
Fortunately for humans, once exposed the measles virus (either through infection or through vaccination), lifelong immunity will be achieved. This is due to a couple of critical factors. First, there is only one serotype of the measles virus. Since the glycoproteins that are targets for the neutralizing antibodies the human body produces cannot mutate without losing their functionality, no other serotypes can evolve. Second, the major antigenic determinants (what the host immune system looks for and responds to) conveniently sit out on the virus’ envelope glycoproteins.
~ Kelley Weber
Centers for Disease Control and Prevention. (2016, June 17). Measles (Rubeola). Retrieved May 2, 2017, from https://www.cdc.gov/measles/index.html
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Rao, T. S. S., & Andrade, C. (2011). The MMR vaccine and autism: Sensation, refutation, retraction, and fraud. Indian Journal of Psychiatry, 53(2), 95–96. http://doi.org/10.4103/0019-5545.82529