Rocky Mountain Spotted Fever — Changing Ecology and Persisting Virulence
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《新英格兰医药杂志》
The explosive growth of emerging infections during the past 20 years has made it difficult to issue a call to arms about any pathogen with ecologic and epidemiologic features that are not conducive to a risk of dramatic regional or global spread. Such is the case with Rocky Mountain spotted fever, which is still one of the most virulent human infections ever identified. Nearly 100 years have elapsed since Howard T. Ricketts first described the pathogen transmitted by Montana ticks that killed up to 75 percent of the patients it infected. Despite a century of study, the causative bacterial agent is still reluctant to reveal its secrets, and no definitive virulence mechanisms have been identified. Infections are sporadic but persistent, with only small proportions of vectors infected, allowing many observers to assume that the disease is not a significant threat to human health. Yet 5 to 10 per 100 children and adults who are unfortunate enough to be infected will die, and many more will require intensive care and have sequelae such as amputation, deafness, or permanent learning impairment despite the availability of a simple and highly effective treatment.
Rocky Mountain spotted fever occurs when Rickettsia rickettsii in the salivary glands of a vector tick is transmitted into the dermis, spreading and replicating in the cytoplasm of endothelial cells and eliciting widespread vasculitis, hypoperfusion, and end-organ damage induced by vascular permeability, which is most dangerous in the lungs and brain. Diagnosis is difficult because of the nonspecific presentation of the disease; its symptoms include fever, headache, myalgia, and (usually after three to five days) a rash that evolves from macular to maculopapular to petechial (see figure). Organ-specific symptoms such as nausea, vomiting, abdominal pain, and cough confound diagnosis by distracting attention from systemic manifestations. Early clinical suspicion and empirical therapy are essential, since severe illness and death are associated with a delayed diagnosis, which can stem from an absence of rash or a presentation during a season with a low level of tick activity. Awareness of these risks is critical for the successful treatment of Rocky Mountain spotted fever.
Evolution of Rash in Rocky Mountain Spotted Fever.
Most physicians are taught that the predominant rash of Rocky Mountain spotted fever is petechial. However, a spectrum of findings is more typical, including rashes that are initially macular or maculopapular (Panel A), petechial (Panels B and C), or purpuric, as seen in advanced or fatal disease (Panel E, courtesy of Grover Hutchins, M.D.). Rickettsia rickettsii can be seen in the endothelium of dermal vasculitic lesions by immunohistochemical analysis (Panel D).
In the United States, R. rickettsii is predominantly transmitted by the American dog tick (Dermacentor variabilis) and the Rocky Mountain wood tick (D. andersoni). Vertical transmission hinges on a tick with an infected ovary, which ensures infected tick progeny. However, R. rickettsii takes a substantial toll even on the tick, since few larvae emerge from eggs of ticks that carry the infection, and even fewer mature into adults. The alternative horizontal transmission depends on transient rickettsemia in nonimmune hosts, on which uninfected ticks feed, creating newly infected ticks to replace those that do not survive. Perhaps feeding adjacent to an infected tick also allows for the acquisition of R. rickettsii without the presence of infection in the host, a mechanism that is well demonstrated in viruses carried by mosquitoes.
Since tick species have distinctive ecologic features and feeding preferences among animal hosts, the transmission of Rocky Mountain spotted fever is in part determined by tick biology. For example, Rhipicephalus sanguineus, the brown dog tick, feeds predominantly on dogs in peridomestic habitats and is now recognized as important in the transmission of Rocky Mountain spotted fever to humans, as described by Demma et al. (pages 587–594). By virtue of this relationship, R. rickettsii transmitted by the brown dog tick presents a threat owing to unique epidemiologic features that differentiate it from the American dog tick (D. variabilis) that resides in rural and suburban regions with its small mammal hosts. It is not known to what degree various tick vectors, such as Amblyomma cajennense and A. aureoloatum, along with their specific ecologic features and hosts, determine the prevalence and incidence of Rocky Mountain spotted fever in Mexico, Central America, and South America. How other changing ecologic and environmental conditions affect the viability of ticks, the immunity and abundance of reservoir hosts, the prevalence of infection in tick populations, and the proximity to humans are critical issues that require much more study.
Is it reasonable to worry about an infection that was reported in the United States in 1998 only 365 times and for which 0.5 percent of ticks or less are infected in areas of endemic disease? Considering that Rocky Mountain spotted fever is one of the oldest vector-borne infections known, the answer must be yes. The disease is in the midst of its third emergence since 1920, after peaks from 1939 to 1949 and again from 1974 to 1984 (see chart), yet the reasons for the cyclical waxing and waning are unknown. Previous theories that have attributed this phenomenon to suburban development, changes in recreational activities, or long-term changes in climate have not withstood careful investigation, and human exposure has only increased. Since the 1998 nadir, 1514 cases were reported in 2004, an increase by a factor of four to an absolute number higher than ever reported in U.S. history. The gravity of the situation is further weighted by the acknowledgment that the number of deaths from Rocky Mountain spotted fever is at least four times the reported number and that nonfatal cases — even those with severe sequelae — may be far more underreported.
Incidence of Rocky Mountain Spotted Fever in the United States since 1920.
Although Rocky Mountain spotted fever occurs only in countries in the Western Hemisphere — including Canada, Mexico, Costa Rica, Panama, Colombia, Brazil, and Argentina, where it is also reemerging after years of dormancy — rickettsioses caused by pathogens related to the spotted-fever group are also increasing worldwide, including in Europe, Asia, Africa, and Australia. The international toll of these infections is difficult to estimate, but the relentless course of Rocky Mountain spotted fever in the United States suggests a similar effect worldwide.
The reasons for the underrecognition of Rocky Mountain spotted fever fall squarely on physicians and the system that educates and reeducates them. The nonspecific presentation of the disease makes diagnosis difficult. However, far too few physicians consider a diagnosis of Rocky Mountain spotted fever or take the time to inquire about tick bites or exposures — critical information that can lead to the diagnosis and to lifesaving empirical therapy with doxycycline. The laboratory is also a weak link. The most widely applied diagnostic tool, serologic analysis, is not useful during active infection, polymerase-chain-reaction analysis is insensitive, and immunohistochemical analysis of skin-biopsy specimens for R. rickettsii antigen is not widely or promptly available. No longer can we consider Rocky Mountain spotted fever a disease of only rural and southern venues; it has emerged and reemerged again. Only with careful education, clinical vigilance, and continued clinical, ecologic, and fundamental scientific investigation will the specter of Rocky Mountain spotted fever be controlled.(J. Stephen Dumler, M.D., )
Rocky Mountain spotted fever occurs when Rickettsia rickettsii in the salivary glands of a vector tick is transmitted into the dermis, spreading and replicating in the cytoplasm of endothelial cells and eliciting widespread vasculitis, hypoperfusion, and end-organ damage induced by vascular permeability, which is most dangerous in the lungs and brain. Diagnosis is difficult because of the nonspecific presentation of the disease; its symptoms include fever, headache, myalgia, and (usually after three to five days) a rash that evolves from macular to maculopapular to petechial (see figure). Organ-specific symptoms such as nausea, vomiting, abdominal pain, and cough confound diagnosis by distracting attention from systemic manifestations. Early clinical suspicion and empirical therapy are essential, since severe illness and death are associated with a delayed diagnosis, which can stem from an absence of rash or a presentation during a season with a low level of tick activity. Awareness of these risks is critical for the successful treatment of Rocky Mountain spotted fever.
Evolution of Rash in Rocky Mountain Spotted Fever.
Most physicians are taught that the predominant rash of Rocky Mountain spotted fever is petechial. However, a spectrum of findings is more typical, including rashes that are initially macular or maculopapular (Panel A), petechial (Panels B and C), or purpuric, as seen in advanced or fatal disease (Panel E, courtesy of Grover Hutchins, M.D.). Rickettsia rickettsii can be seen in the endothelium of dermal vasculitic lesions by immunohistochemical analysis (Panel D).
In the United States, R. rickettsii is predominantly transmitted by the American dog tick (Dermacentor variabilis) and the Rocky Mountain wood tick (D. andersoni). Vertical transmission hinges on a tick with an infected ovary, which ensures infected tick progeny. However, R. rickettsii takes a substantial toll even on the tick, since few larvae emerge from eggs of ticks that carry the infection, and even fewer mature into adults. The alternative horizontal transmission depends on transient rickettsemia in nonimmune hosts, on which uninfected ticks feed, creating newly infected ticks to replace those that do not survive. Perhaps feeding adjacent to an infected tick also allows for the acquisition of R. rickettsii without the presence of infection in the host, a mechanism that is well demonstrated in viruses carried by mosquitoes.
Since tick species have distinctive ecologic features and feeding preferences among animal hosts, the transmission of Rocky Mountain spotted fever is in part determined by tick biology. For example, Rhipicephalus sanguineus, the brown dog tick, feeds predominantly on dogs in peridomestic habitats and is now recognized as important in the transmission of Rocky Mountain spotted fever to humans, as described by Demma et al. (pages 587–594). By virtue of this relationship, R. rickettsii transmitted by the brown dog tick presents a threat owing to unique epidemiologic features that differentiate it from the American dog tick (D. variabilis) that resides in rural and suburban regions with its small mammal hosts. It is not known to what degree various tick vectors, such as Amblyomma cajennense and A. aureoloatum, along with their specific ecologic features and hosts, determine the prevalence and incidence of Rocky Mountain spotted fever in Mexico, Central America, and South America. How other changing ecologic and environmental conditions affect the viability of ticks, the immunity and abundance of reservoir hosts, the prevalence of infection in tick populations, and the proximity to humans are critical issues that require much more study.
Is it reasonable to worry about an infection that was reported in the United States in 1998 only 365 times and for which 0.5 percent of ticks or less are infected in areas of endemic disease? Considering that Rocky Mountain spotted fever is one of the oldest vector-borne infections known, the answer must be yes. The disease is in the midst of its third emergence since 1920, after peaks from 1939 to 1949 and again from 1974 to 1984 (see chart), yet the reasons for the cyclical waxing and waning are unknown. Previous theories that have attributed this phenomenon to suburban development, changes in recreational activities, or long-term changes in climate have not withstood careful investigation, and human exposure has only increased. Since the 1998 nadir, 1514 cases were reported in 2004, an increase by a factor of four to an absolute number higher than ever reported in U.S. history. The gravity of the situation is further weighted by the acknowledgment that the number of deaths from Rocky Mountain spotted fever is at least four times the reported number and that nonfatal cases — even those with severe sequelae — may be far more underreported.
Incidence of Rocky Mountain Spotted Fever in the United States since 1920.
Although Rocky Mountain spotted fever occurs only in countries in the Western Hemisphere — including Canada, Mexico, Costa Rica, Panama, Colombia, Brazil, and Argentina, where it is also reemerging after years of dormancy — rickettsioses caused by pathogens related to the spotted-fever group are also increasing worldwide, including in Europe, Asia, Africa, and Australia. The international toll of these infections is difficult to estimate, but the relentless course of Rocky Mountain spotted fever in the United States suggests a similar effect worldwide.
The reasons for the underrecognition of Rocky Mountain spotted fever fall squarely on physicians and the system that educates and reeducates them. The nonspecific presentation of the disease makes diagnosis difficult. However, far too few physicians consider a diagnosis of Rocky Mountain spotted fever or take the time to inquire about tick bites or exposures — critical information that can lead to the diagnosis and to lifesaving empirical therapy with doxycycline. The laboratory is also a weak link. The most widely applied diagnostic tool, serologic analysis, is not useful during active infection, polymerase-chain-reaction analysis is insensitive, and immunohistochemical analysis of skin-biopsy specimens for R. rickettsii antigen is not widely or promptly available. No longer can we consider Rocky Mountain spotted fever a disease of only rural and southern venues; it has emerged and reemerged again. Only with careful education, clinical vigilance, and continued clinical, ecologic, and fundamental scientific investigation will the specter of Rocky Mountain spotted fever be controlled.(J. Stephen Dumler, M.D., )