Molecular Diagnostic Uptick Needed to Determine Spotted Fever Rickettsiosis Estimates

Although the goal of spotted fever rickettsiosis (SFR) surveillance is to provide temporal, geographic, and demographic information on the incidence of cases to facilitate prevention and control, a new analysis has found that only 1% of cases reported between 2010 and 2015 met the criteria for a confirmed case.

SFR, including Rocky Mountain spotted fever, are bacterial diseases that are spread through tick bites and are nationally notifiable diseases in the United States. The annual incidence of these tick-borne diseases has increased significantly from 1.7 cases per 1 million people reported in 2000 to 13.2 per 1 million people reported in 2016.

Although incident cases have reportedly increased, the investigators on a new analysis published in the US Centers for Disease Control and Prevention (CDC)’s Morbidity and Mortality Weekly Report indicate that the actual magnitude of this increase is questionable, in that the current case definition permits for diagnosis based on “nonspecific laboratory criteria.”

In order to learn more about the accuracy of SFR incidence, the team of investigators from the CDC set out to analyze the quality of the laboratory data that was documented between 2010 and 2015. The team collected supplemental data from case report forms that were provided to the CDC.

The data indicated that among 16,907 cases reported over the 5-year period, only 167 (1%) met the confirmed case definition, with the remaining 99% meeting the probable case definition.

According to the Council of State and Territorial Epidemiologist (CSTE) criteria, a confirmed SFR case requires seroconversion (defined as a fourfold change in anti-SFR immunoglobulin G [IgG] antibody titers) by IFA (using paired serum specimens, one taken in the first week of illness and a second taken 2-4 weeks later) or polymerase chain reaction (PCR), immunohistochemistry (IHC), or culture.

The most common supportive lab evidence for the probable cases was elevated IgG antibody titer by IFA, which was reported for 14,784 (88%) probable cases.

IgG antibodies can persist for months to years following the tick-borne infection, making a single antibody titer unreliable for diagnosing in the absence of a convalescent sample. Further, immunoglobulin M (IgM) antibodies, latex agglutination, and ELISA testing are also insufficient to providing accurate evidence that constitutes a confirmed SFR case. The investigators report that “use of such tests hinders full understanding of SFR epidemiology and the incidence of disease in the United States.”

In the remainder of the probable cases, elevated IFA IgM titers were reported for 2117 (12.7%) cases, positive ELISA results were reported for 2235 (13.4%), and positive latex agglutination was reported for 25 (<1.0%).

Of 167 confirmed cases, 102 were confirmed by seroconversion, 66 via PCR, immunohistochemistry, or culture, and 1 by both seroconversion and PCR.

The investigators also report that a second specimen was collected for 67% of the confirmed cases, and only 17.7% of probable cases, leading the team to conclude that the bulk of probable cases were not confirmed because of incomplete serologic testing.

Based on the data presented in this analysis, the investigators hypothesize that “increased use of molecular assays and IgG could improve understanding on the SFR epidemiology and increase the accuracy of disease incidence estimates.”

The research team advises providers and practitioners to encourage patients to return for convalescent serologic testing to ensure accuracy.

Additionally, it should be noted that species-specific real-time PCR assays are available as of 2018 in qualified state and local public health laboratories. The investigators advocate for increased use of the assays to accurately classify SFR infections and identify the etiologic agent.

“In addition to increased use of molecular detection, eliminating diagnostic tests of limited interpretability as supportive evidence from the case definition of SFR surveillance could be important for understanding trends in species-specific SFR cases in the United States,” the investigators conclude.