The laboratories in the GMRLN must follow established criteria to discard a suspected case that had a positive or equivocal IgM result when the clinical and epidemiologic data based on the case investigation indicates that the result may be a false positive or due to recent vaccination [3]. However, it is understood that some non-cases will be included as confirmed cases based on laboratory confirmation by IgM detection. Collection of a second serum specimen to test for a rise in IgG may be warranted in certain instances to support an IgM positive or equivocal result when prevalence of disease is low. An accurate vaccination history is critical since an individual may have a rash due to a recent vaccination (section 8.1.2). Detection of virus-specific RNA by RT-PCR is a valuable diagnostic tool to support a positive or equivocal IgM result. In addition, collection of good quality virologic specimens can provide the means to distinguish vaccine strains from wild-type virus. However, as discussed in section 8.2, a negative RT-PCR result should not be relied upon as sole justification to discard a case.
8.1.1 Positive predictive value and low prevalence of disease
In low prevalence settings, there is a considerable decrease in the positive predictive value (PPV) for IgM positive results since the specificity of EIAs (and most serologic assays) is less than 100%. The PPV is the proportion of suspected cases with a positive laboratory result that are correctly identified as having the disease (true positive cases). While the relationship of PPV to disease prevalence is well-understood, the extent of the effect due to low prevalence is often not fully appreciated. In a study of IgM positive results in Ontario (2009-2014), the PPV for IgM positive cases that was calculated for measles was 17.4% and the PPV for rubella was 3.6% [4]. However, the authors of that study speculated that some of the IgM positive results in the study were obtained from testing healthy individuals because the IgM tests were requested inappropriately by the physician. Regardless, the study highlights the fact that an assay with less than 100% specificity will produce a PPV that is quite low when the disease is rare, even when only individuals who meet the case definition for measles or rubella are tested.
It is critical that the interpretation of laboratory results for the classification of suspected cases of measles and rubella is consistent throughout the GMRLN. The default interpretation for a suspected case with a positive or equivocal IgM result is to confirm the case. Communication between the laboratory and health personnel investigating the suspected case is essential to determine whether additional testing is appropriate and feasible. Information provided about local outbreaks or recent notifications of non-measles/non-rubella rash illnesses in the area can aid in decisions regarding whether other testing and/or collection of additional specimens may be justified. Section 8.4 provides guidelines for additional testing including a flowchart (Figure 8).
8.1.2 Suspected cases among individuals with a rash following MR/MMR vaccination
The proportion of individuals (without exposure to wild-type measles) who develop rash 7-14 days following vaccination with a measles-containing vaccine (generally the rash is attributed to the measles component of the MR or MMR vaccination) is estimated to be 5%. However, heightened surveillance for rash illness can inflate that number. In an elimination setting, particularly when recent measles or rubella activity has raised the index of suspicion, specimens from individuals with a vaccination-associated rash may surge.
The cases that have a possible exposure to wild-type measles virus and a recent vaccination cannot be distinguished by IgM testing. Often, the determination of true case status for these suspected cases is critical for decisions on whether exposed infants receive immune globulin for post exposure prophylaxis. This situation may occur following outbreak control measures that include vaccination of susceptible contacts and as well as unimmunized individuals in the surrounding community. Consequently, the increased vigilance for measles will result in notifications of suspected measles cases among recently vaccinated children with rash, most with a mild rash that would not normally generate suspicion of a wild-type infection.
Identification of a vaccine strain by sequence analysis of clinical specimens from a recently vaccinated, suspected measles case demonstrates that the rash illness was not due to a wild-type infection, and the case can be discarded. If genotyping cannot be performed, the case may be discarded and classified as a vaccine-related rash provided that the suspected case meets all the necessary epidemiologic and clinical criteria for a vaccine-associated rash, including the absence of any possible exposure to wild-type measles (see Chapter 4. Antibody detection methods for laboratory confirmation of measles, rubella, and CRS. A specialized real-time RT-PCR assay that targets nucleotide sequences common to measles vaccine strains (genotype A) may be available in some NLs and RRLs to provide more rapid confirmation of vaccine reactions [11]. This method is particularly helpful when amplification of the full sequence required for genotyping is unsuccessful (Chapter 7. Molecular epidemiology of measles and rubella).
8.1.3 Measles and rubella cases in presumptively immune, vaccinated individuals
In elimination settings, where vaccine coverage is high, many of the confirmed cases of measles/rubella will occur among individuals who have a past history of vaccination and are presumptively immune. This situation can be confusing and may sometimes lead to delays in appropriate specimen collection and testing. For example, upon evaluation of a rash illness in a previously vaccinated patient, a healthcare provider may consider an alternative etiology such as Kawasaki disease rather than measles or rubella.
Many of the confirmed measles cases, and nearly all of the confirmed rubella cases that occur among vaccinated individuals will be due to a primary vaccine failure (PVF), in which the individual failed to seroconvert following vaccination. The clinical presentation and laboratory evaluation for a case with a PVF is no different from that for a primary measles infection in an unvaccinated individual. A confirmed measles or rubella case with a PVF can be demonstrated by measurement of low avidity, virus-specific IgG (for a discussion of avidity testing, see Chapter 4. Antibody detection methods for laboratory confirmation of measles, rubella, and CRS).
While symptomatic reinfections with rubella are extremely rare, there are numerous reports of confirmed measles cases that were identified as having a measles reinfection by demonstration of the presence of high avidity measles IgG in acute serum [5-10]. The clinical presentation of a measles reinfection case varies, from a mild fever with transient rash to an illness that meets the clinical case definition. Regardless of the clinical presentation, the serologic confirmation of measles reinfection cases can be challenging, and RT-PCR offers the best method to confirm these cases. The characteristics of measles reinfection cases and the additional testing that may be necessary to identify these cases are presented in Chapter 8. Laboratory testing in support of measles and rubella surveillance in elimination settings, section 8.5.