Importance Of Immunology And Serology
Gibert Chisholm
Measles is an acute viral illness caused by a virus in the family paramyxovirus, genus Morbillivirus. Measles is characterized by a prodrome of fever (as high as 105F) and malaise, cough, coryza, and conjunctivitis, followed by a maculopapular rash. [1] The rash spreads from head to trunk to lower extremities. Measles is usually a mild or moderately severe illness. However, measles can result in complications such as pneumonia, encephalitis, and death. Approximately one case of encephalitis [2] and two to three deaths may occur for every 1,000 reported measles cases. [3]
Measles incidence has remained below one case per million since 1997, except in 2014, when 667 measles cases were reported, representing a reported incidence of 2.08 cases per million. [14] The epidemiology of measles in 2014 was characterized by (1) a high proportion (92%) of cases among U.S. residents who were unvaccinated or who had unknown vaccination status and (2) more spread from imported cases than in other years. In 2015, 191 measles cases were reported; 28 (15%) were importations, and 142 (80%) of 178 cases among U.S. residents were unvaccinated or had an unknown vaccination status. In recent years, most of the importations were the result of unvaccinated U.S. travelers who had traveled to measles endemic countries, including countries in the World Health Organization (WHO) European and Western Pacific Regions. [14]
Although measles elimination has been achieved in the United States, importation of measles will continue to occur as measles remains endemic in many other parts of the world. Thus, current measles epidemiology in the United States is determined by characteristics of the imported cases and their susceptible contacts.
Responding to measles cases and outbreaks is time consuming and costly for local and state health departments.[21,22] The overall costs to health departments to contain 16 outbreaks during 2011 amounted to an estimated $2.7 million to $5.3 million U.S. dollars. The economic burden of controlling measles spread in health care settings amounts to an estimated $19,000 to $114,286 U.S. dollars per case.
Despite tremendous achievements towards global measles mortality reduction and elimination goals, globally, in 2015, there were 254,928 measles cases reported and an estimated 134,200 measles deaths (i.e., approximately 367 deaths/day).[23] During 2015, measles outbreaks were reported in several countries in the African, European, and Eastern Mediterranean regions.[23]
Important measures are also underway to achieve measles elimination in other regions. Countries in all six WHO regions have adopted measles elimination goals, and four WHO regions endorsed the Global Vaccine Action Plan to eliminate measles by 2015; although these elimination goals were not accomplished. The Global Vaccine Action Plan has also set a target for measles elimination in five WHO regions by 2020. [23]
Live attenuated measles virus vaccine is incorporated into combination MMR vaccine and combination measles, mumps, rubella, and varicella (MMRV) vaccines. Monovalent measles vaccine is not available in the United States.
For prevention of measles, two doses of MMR vaccine are recommended routinely for children, with the first dose at age 12 through 15 months and the second dose at ages four through six years (school entry). [28]
For prevention of measles among adults, two doses of MMR vaccine are also recommended for adults at high risk, including international travelers, college and other post-high school students, and health care personnel born during or after 1957. [28] All other adults, born during or after 1957, without other presumptive evidence of measles immunity, should be vaccinated with one dose of MMR vaccine.
The following case definition for case classification of measles cases, including case classifications for importation status, has been approved by the Council of State and Territorial Epidemiologists (CSTE) and was published in 2012. [29]
Note: Genotype identification by a WHO reference laboratory (CDC or a public health laboratory that has validated their measles virus sequence analysis) is required to distinguish wild type from vaccine strain if vaccinated within 21 days of rash onset.
US-acquired case: An US-acquired case is defined as a case in which the patient had not been outside the United States during the 21 days before rash onset or was known to have been exposed to measles within the United States.
Imported-virus case: A case for which an epidemiologic link to an internationally imported case was not identified, but for which viral genetic evidence indicates an imported measles genotype, i.e., a genotype that is not occurring within the United States in a pattern indicative of endemic transmission.
Unknown source case: A case for which an epidemiological or virological link to importation or to endemic transmission within the United States cannot be established after a thorough investigation. These cases must be carefully assessed epidemiologically to assure that they do not represent a sustained US-acquired chain of transmission or an endemic chain of transmission within the United States.
Laboratory confirmation is essential for all outbreaks and all sporadic measles cases. Detection of measles-specific IgM antibody and measles RNA by real-time RT-PCR are the most common methods for confirmation of measles infection. Efforts should be made to obtain a serum sample and throat swab (or nasopharyngeal swab) from suspected cases at first contact. Urine samples may also contain virus and when feasible to do so, collection of both respiratory and urine samples can increase the likelihood of detecting virus. Staff at the CDC Measles Laboratory are available for consultation and can assist with confirmatory testing as needed for measles. For details on all types of specimens (serum, respiratory, urine) collection and transport, see the CDC Measles Lab website.
Because measles is a rare disease in the United States, even with the excellent laboratory tests available, false positive results for measles IgM will occur. To minimize the problem of false positive laboratory results, it is important to restrict case investigation and laboratory tests to patients most likely to have measles (i.e., those who meet the clinical case definition, especially if they have risk factors for measles, such as being unvaccinated, recent history of travel abroad, without an alternate explanation for symptoms, for example epi-linked to known parvovirus case) or those with fever and generalized maculopapular rash with strong suspicion of measles.
During a measles investigation when community awareness is increased, many cases of febrile rash illness may be reported as suspected measles, and the magnitude of the situation may be exaggerated if these cases are included in the absence of laboratory confirmation. This is particularly important as the investigation is ending; at that point, laboratory confirmation should be sought for all suspected cases. Occasionally, suspected cases may include vaccinated individuals. For these cases, laboratory confirmation may be challenging. An overview of diagnostic tools is described below.
Clinical specimens for real-time polymerase chain reaction (RT-PCR) and virus isolation should be collected at the same time as samples taken for serologic testing. The preferred specimens for virus isolation or RT-PCR are throat or nasopharyngeal swabs, but urine may also contain virus. Virus isolation and RNA detection are more likely to be successful when the specimens are collected early (ideally within three days of rash onset, but up to ten days post rash may be successful). Isolation of measles virus in cell culture or detection of measles RNA by RT-PCR in clinical specimens confirms the diagnosis of measles.
However, a negative virus isolation or negative RT-PCR results do not rule out measles because both methods are affected by the timing of specimen collection and the quality and handling of the clinical specimens.
Successful isolation of measles virus in culture or direct detection of measles RNA by RT-PCR in the clinical sample is particularly helpful for case confirmation when serology results are inconclusive. The Vero/hSLAM cell line, a recombinant cell line with a receptor for measles virus, has greatly improved the ability to isolate measles virus in cell culture.
Determination of the measles genotype provides the only means to distinguish between wild type virus infection and a rash caused from a recent measles vaccination. In addition, the collection of appropriate specimens from which virus or viral RNA can be obtained or amplified is extremely important for molecular epidemiologic surveillance to identify the genotypes associated with imported cases of measles. This information is used to track transmission pathways, link cases to countries overseas, and to document the absence of endemic circulation of measles in the United States. [30] Sequence analysis and genotyping for measles virus is conducted at the CDC Measles Laboratory. Refer to the CDC Measles Laboratory website for additional information on sample collection, processing and the genetic analysis of measles.
The state health department can provide guidance regarding available laboratory services. At the direction of the state health department, health care providers and state and local health departments may send serum specimens from suspected measles cases to the CDC Measles Laboratory. For detailed information on blood collection and shipping, refer to the CDC Measles Laboratory website.
There is no single serologic laboratory test capable of confirming with 100% confidence every true case of measles. Public health laboratories that use commercial measles assay kits are encouraged to fully characterize and validate the kits in their laboratories using known test panels of positive and negative specimens. Information regarding the performance characteristics of many of the commercially available enzyme immunoassays (EIA) kits is available by contacting the CDC Measles Laboratory. The reference laboratory at CDC uses an IgM assay developed at CDC for measles serologic testing of IgM. The assay is a capture IgM format EIA that utilizes a recombinant measles nucleoprotein (NP) antigen and tends to have high sensitivity and specificity compared to some commercial EIAs.
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