Hidden Mortality Attributable to Rocky Mountain Spotted Fever: Immunohistochemical Detection of Fatal, Serologically Unconfirmed Disease

Abstract

Rocky Mountain spotted fever (RMSF) is the most severe tickborne infection in the United States and is a nationally notifiable disease. Since 1981, the annual case-fatality ratio for RMSF has been determined from laboratory-confirmed cases reported to the Centers for Disease Control and Prevention (CDC). Herein, a description is given of patients with fatal, serologically unconfirmed RMSF for whom a diagnosis of RMSF was established by immunohistochemical (IHC) staining of tissues obtained at autopsy. During 1996-1997, acute-phase serum and tissue samples from patients with fatal disease compatible with RMSF were tested at the CDC. As determined by indirect immunofluorescence assay, no patient serum demonstrated IgG or IgM antibodies reactive with Rickettsia rickettsii at a diagnostic titer (i.e., >/=64); however, IHC staining confirmed diagnosis of RMSF in all patients. Polymerase chain reaction validated the IHC findings for 2 patients for whom appropriate samples were available for testing. These findings suggest that dependence on serologic assays and limited use of IHC staining for confirmation of fatal RMSF results in underestimates of mortality and of case-fatality ratios for this disease.

Phylogeography of Rickettsia rickettsii Genotypes Associated with Fatal Rocky Mountain Spotted Fever

“…Among the casepatients from the United States, no significant differences were noted between the percentages of male (54%) and nonwhite (18%) individuals evaluated in our study and the corresponding percentages (59% and 18%, respectively) among RMSF deaths documented by CRF surveillance data during 1983-2007. 22, 23 However, our analysis included significantly more United States case-patients 10 years of age (40% versus 15%, P value 0.0001), and significantly fewer casepatients 40 years of age (29% versus 63%, P value 0.0001) when compared with the ages of United States RMSF decedents reported to CDC during the same approximate period.…”

“…A diagnosis of RMSF was established for each by using an immunohistochemical (IHC) staining method for spotted fever group (SFG) Rickettsia species. 22 Tissues were selected for molecular analysis based primarily on availability and on the relative abundance of SFG Rickettsia antigens identified by the IHC stain. When available, information was collected for year of death, age, gender, geographical location, and survival time.…”

“…24 Nonetheless, the actual burden of fatal RMSF remains difficult to assess, and contemporary estimates of the case-fatality rate are confounded by underreporting of laboratory-confirmed deaths. 22 In this series, approximately half of the laboratory-confirmed United States case-patients were not matched to a CRF, and were therefore absent from national surveillance estimates of fatal RMSF. These data corroborate previous capture-recapture analyses of national mortality statistics for fatal RMSF, which estimated that~65% of the RMSF deaths that occurred during 1983-2007 were not reported for national surveillance.…”

Assessing the magnitude of fatal Rocky Mountain spotted fever in the United States: comparison of two national data sources.

“…Under-reporting is perhaps the primary explanation for approximately 64% of RMSF-associated deaths recorded by death certificates but not included in the CRF source. However, absence of confirmatory diagnostic criteria, particularly serologic criteria, which are often non-diagnostic in patients with fatal RMSF, 31 may dissuade a physician from reporting a case. This is suggested by the observation that only 22% of reported deaths were classified as unconfirmed, while 42% of all (fatal and non-fatal) CRF cases reported during the period 1981−1996 were categorized as unconfirmed.…”

“…30,33,34 Although data in this study indicate recent declines in reporting of fatal cases of RMSF, coincident decreases in the number of RMSF-associated deaths recorded on death certificates also suggests a true reduction of RMSF mortality in the United States during the period 1983−1998, perhaps due to increased general awareness of tickborne diseases and contemporary treatment recommendations. 30,31,35 Rocky Mountain spotted fever remains a medical curiosity to many and poses formidable diagnostic challenges to most clinicians, even to those familiar with the disease. Because of the devastating consequences associated with a missed or delayed diagnosis, 36,37 any information that enhances a clinician's ability to consider, correctly diagnose, and initiate appropriate therapy for RMSF represents effective public health intervention.…”