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Am. J. Trop. Med. Hyg., 66(5), 2002, pp. 448–449 Copyright © 2002 by The American Society of Tropical Medicine and Hygiene EDITORIAL RICKETTSIA RICKETTSII: AS VIRULENT AS EVER DAVID H. WALKER Department of Pathology, University of Texas Medical Branch, Galveston, Texas events, identification of rickettsial virulence genes), mechanisms of immunity (e.g., the role of dendritic cells and regional lymphatic spread and identification of host genes responsible for resistance and susceptibility), rickettsial antigens stimulating protective immunity, and interactions of cytoplasmic rickettsiae with host cell signal transduction.6–8 However, few persons undertake the challenge of cultivating these obligately intracellular bacteria in antibiotic-free systems in a biosafety level 3 environment or designing experiments that unravel the host cell and rickettsial effects in the intracellular location. Improvement in the case-fatality rate of RMSF requires prompt consideration of the diagnosis in all febrile Dermacentor variabilis and Dermacentor andersoni tick-exposed patients in the United States and investigation of febrile patients in Latin America, where the incidence and distribution of Amblyomma cajennense- and Rhipicephalus sanguineustransmitted Rickettsia rickettsii as well as other rickettsioses are undoubtedly underestimated.9,10 Perhaps the eventual adoption of well-designed electronic medical records will lead to automated prompting of physicians to inquire about potential tick exposure when fever is entered into the record between May and September and to consider the diagnosis of RMSF. Further, the use of a realistic case of RMSF in the problem-based learning curriculum of all medical schools would stimulate learning related to not only rickettsioses but also many other important entities in the differential diagnosis. A reckoning of the plaintiff lawyer’s view of failure to diagnose and treat fatal RMSF would be a sobering learning experience for the students. Of course, the plaintiff lawyer is wrong to consider the diagnosis of RMSF to be easy or to expect all patients to recover from this deceptively difficultto-diagnose, highly virulent infection. However, the fact is that a fatal outcome often ends up in a malpractice suit, a situation that would be best avoided altogether. There is room for more scientists in rickettsiology, and the tools of molecular biology and cell biology allow more to be accomplished. Medical science needs to develop better early diagnostic tests (e.g., identification of the epitopes that stimulate the earliest detectable antibody response) and to provide those tests that do exist (e.g., immunohistochemical detection of rickettsiae in dermal endothelial cells) at least as referral tests. However, in 2002, the best that can be achieved is the appropriate empiric use of doxycycline except in cases involving pregnancy or known hypersensitivity. The less effective antimicrobial agent, chloramphenicol, is an alternative, but -lactams, aminoglycosides, macrolides, and sulfonamides provide no benefit, as is repeatedly proven in fatal cases, in which, inevitably, substantial quantities of one or more of these antimicrobial agents were administered. In their article on epidemiologic surveillance and risk factors for fatal Rocky Mountain spotted fever (RMSF), Childs and Paddock provide scholarly insight into the history of public health epidemiology of an American infectious disease.1 The time frame spans from the period preceding knowledge of the concept of infectious disease and of the rickettsial cause of RMSF to the contemporary era.2 Their review of the previous analyses of risk factors for a fatal outcome of RMSF is comprehensive and stimulates a series of questions: Why is RMSF misdiagnosed? Why is the problem neglected, including in the tropics? What could be done to improve the situation? The misdiagnosis of RMSF is a failing of American physicians and medical education. Too many family physicians, pediatricians, internists, and even emergency physicians do not consider the possibility of RMSF in a febrile patient with any number of other systemic symptoms and potential tick exposure. The absence of rash during the early days of illness, presence of other symptoms (e.g., gastrointestinal), and lack of physician inquiry or patient knowledge of tick exposure are frequently the case rather than the textbook description of a petechial rash involving the palms and soles as may occur in the late state, particularly in the most severe cases.3 Often by then it is too late. In some areas where nearly all physicians recognize RMSF as endemic, many unreported cases are likely treated early and successfully with doxycycline. Unfortunately, RMSF occurs throughout most of the United States, and in many states physicians are less aware of the disease. Patients die of RMSF without ever being diagnosed accurately. Another problem is that the clinical laboratory, the usual source of a timely definitive diagnosis of infectious diseases, seldom offers effective assistance in the diagnosis of RMSF in the acute stage. Serologic results generally reflect the absence of antibodies detectable by the available assays at this time in the course of illness.4 Diagnostic skin biopsy immunohistochemistry requires the presence of rash lesions and is seldom performed except as a reference test. RMSF is a neglected disease because its brutal effects are dispersed, hidden by misdiagnosis, and often dismissed as easily treated.5 If all of the RMSF cases in the United States for a single year were to occur in an affluent suburb of Washington, DC, during 1 week, much attention would be paid. Moreover, old, unresolved problems do not receive the attention that new, interesting issues do. For instance, compare the efforts placed on researching West Nile virus or hantavirus pulmonary syndrome with the application of medical science to RMSF. Only a handful of molecular microbiologists, immunologists, and experimental pathologists are actually working in the laboratory with spotted fever rickettsiae. The scientific issues are actually very interesting, including elucidation of the pathogenic mechanisms (e.g., reactivation of rickettsial pathogenicity in the feeding tick, the effect of tick saliva on the early Author’s address: David H. Walker, Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, 448 RICKETTSIA RICKETTSII Galveston, TX 77555-0609, Telephone: 409-772-2856, Fax: 409-7722500, E-mail: [email protected]. 6. REFERENCES 1. Childs JE, Paddock CD, 2002. Passive surveillance as an instrument to identify risk factors for fatal Rocky Mountain spotted fever: is there more to learn? Am J Trop Med Hyg 66: 450–457. 2. Harden VA, 1990. Rocky Mountain Spotted Fever: History of a Twentieth-Century Disease. Baltimore, MD: Johns Hopkins University Press. 3. Walker DH, 1995. Rocky Mountain spotted fever: a seasonal alert. Clin Infect Dis 20: 1111–1117. 4. Walker DH, Bouyer DH, 2002. Rickettsia. Manual for Clinical Microbiology. Eighth edition. Washington, DC: ASM Press. In press. 5. Paddock CD, Greer PW, Ferebee TL, Singleton J Jr, McKechnie DB, Treadwell TA, Krebs JW, Clarke MJ, Holman RC, Olson JG, Childs JE, Zaki SR, 1999. Hidden mortality attributable to Rocky Mountain spotted fever: immunohistochemical detec- 7. 8. 9. 10. 449 tion of fatal, serologically unconfirmed disease. J Infect Dis 179: 1469–1476. Van Kirk LS, Hayes SF, Heinzen RA, 2001. Ultrastructure of Rickettsia rickettsii actin tails and localization of cytoskeletal proteins. Infect Immun 68: 4706–4713. Eremeeva ME, Silverman DJ, 1998. Effects of the antioxidant ␣-lipoic acid on human umbilical vein endothelial cells infected with Rickettsia Rickettsii. Infect Immun 66: 2290–2299. Crocquet-Valdes PA, Diaz-Montero CM, Feng H-M, Li H, Barrett ADT, Walker DH, 2002. Immunization with a portion of rickettsial outer membrane protein A stimulates protective immunity against spotted fever rickettsiosis. Vaccine 20: 979–988. Ripoll CM, Remondegui CE, Ordonez G, Arazamendi R, Fusaro H, Hyman MJ, Paddock CD, Zaki SR, Olson JG Santos-Buch CA, 1999. Evidence of rickettsial spotted fever and ehrlichial infections in a subtropical territory of Jujuy, Argentina. Am J Trop Med Hyg 61: 350–354. Zavala-Velazquez JE, Ruiz-Sosa JA, Sánchez-Elias RA, BecerraCarmona G, Walker DH, 2000. Rickettsia felis rickettsiosis in Yucatán. Lancet 9235: 1079–1080.