Technology Evolving Slowly in U.S. Pertussis Testing

Oral fluid testing holds the potential to improve pertussis surveillance efforts, particularly for diagnosis of milder cases in patients who seek care later in the course of illness, according to a study published in June in Emerging Infectious Diseases. These patients represent a well-known gap in current surveillance efforts, which contributes to suboptimal identification of cases. Pertussis, commonly known as whooping cough, is a nationally notifiable disease, and all cases are supposed to be reported through health departments to the U.S. Centers for Disease Control and Prevention (CDC) through the National Notifiable Diseases Surveillance System. Caused by the bacterium Bordetella pertussis, whooping cough has been classified as a rapidly re-emerging disease and has even reached epidemic status in some states like California, where 4,558 new pertussis cases have been identified in 2014 (through June 24), surpassing the total number of reported cases in 2013. Nationally the CDC reports a 24 percent increase in the number of cases this year (through mid-June) over 2013. While the current surveillance system is useful for monitoring epidemiologic trends, limitations in laboratory diagnostics make reliance on the number of actual reported cases “problematic.” Existing pertussis surveillance systems tend to underidentify less severe cases, particularly among older children and adults, in part due to testing technology constraints, which are limited in comparison to those used in Europe. “We are currently having discussions to incorporate serology into case definitions. We haven’t even considered oral fluid testing yet,” Stacey Martin, an epidemiologist and CDC subject expert, tells DTET. “There are more than 40 serological assays, but none are FDA-cleared. If serology makes it to the case definition there must be tight parameters and standardization to international references, otherwise we won’t know the accuracy of individual tests.” Despite the fact that the United States is likely years away from incorporating oral fluid testing into case definitions (Martin says serological incorporation is likely one to two years away), the CDC and other organizations are taking note of assay development and acceptance in other countries, as oral fluid has some advantages from both a public health and a patient preference and acceptability perspective. The Emerging Infectious Diseases article details a national pilot study conducted (June 2007–August 2009) in the United Kingdom, where serologic testing is already widespread. The pilot tested the feasibility of noninvasive oral testing for routine follow-up of notified, nonconfirmed, clinically diagnosed pertussis cases. Researchers mailed oral fluid sampling kits either directly to the patients, their parents or guardians (the kit was suitable for use at home), or to their general practitioner. The researchers found that 66 percent of test kits were returned with submitted samples. During the study period, 1,852 cases of pertussis were confirmed by established laboratory methods and another 591 cases (24 percent of all cases) by oral fluid testing only. Oral fluid testing increased laboratory ascertainment of pertussis by 32 percent overall, with the greatest increase (124 percent) among children aged 5 years to 9 years. Although patients over 20 years of age submitted the largest number of oral fluid samples, the highest proportion with positive results (61 percent) were seen in children aged 10 years to14 years. Cases confirmed by oral fluid testing were least likely to be hospitalized, suggesting that milder community cases were being identified by this method. “Oral fluid testing is an easily administered, noninvasive surveillance tool that could further our understanding of pertussis epidemiology and thereby contribute to decisions on vaccination strategies,” write the authors, led by Helen Campbell, from Public Health England in the United Kingdom. “Furthermore, underascertainment of milder infections causes bias, leading to overestimation of vaccine effectiveness.” Takeaway: International acceptance of oral fluid testing in pertussis surveillance is years ahead of U.S. criteria. Domestically, the focus is on standardization of commercially available serological assays, which will improve identification of later-stage pertussis cases, particularly in older children and adults. Side Box: Current Diagnostic Methods Current diagnostic methods used in the United States for pertussis include the following:

• »Culture, the standard diagnostic test, has excellent specificity but takes up to seven days to get results back. Culture requires nasopharyngeal (NP) specimens collected during the first two weeks of cough, when viable bacteria are still present.
• »Polymerase chain reaction (PCR) is the most rapid test for pertussis and has become the dominant test. While the NP specimen does not require viable bacteria, it should still ideally be collected during the first three weeks of illness. Epidemiologists and CDC experts express concern over the lack of standardized PCR assays, saying that sensitivity and specificity can vary greatly between laboratories, leading to variance in interpretation criteria for diagnosis.
• »Serology, while used in 20 European countries, Japan, and Australia, can be used for confirmatory reporting purposes only by the Massachusetts state public health laboratory. The CDC and U.S. Food and Drug Administration (FDA) have also developed a serologic assay for confirming diagnosis, especially during suspected outbreaks. CDC says it is currently engaged in efforts to compare commercially available serologic tests. The advantage of serologic tests is that they are more useful for diagnosis in later phases of the disease—two to eight weeks following cough onset, when the antibody titers are at their highest.

Side Box: Oral Fluid Assay Specifications The enzyme-linked immunosorbent assay was developed by Public Health England (then known as the Health Protection Agency) to detect IgG against pertussis toxin in oral fluid. The agency reports that the oral fluid assay detects seropositivity with a sensitivity of 79.7 percent and a specificity of 96.6 percent. Using oral fluid titers of greater than 70 arbitrary units (in the absence of pertussis vaccination within the previous 12 months) the assay has a positive predictive value of 76.2 percent to 93.2 percent for pertussis among children with chronic cough, assuming disease prevalence between 12 percent and 37 percent.