Table of Contents:

• Taxonomy Information
• Lifecycle Information
• Genome Information
• Biosafety Information
• Culturing Information
• Epidemiology Information
• Diagnostic Tests Information
• Infected Hosts Information
• Phinet: Pathogen-Host Interaction Network
• Lab Animal Pathobiology & Management
• References
• Data Provenance and Curators

1. Species:
   1. Rickettsia rickettsii (Website 1):
      1. GenBank Taxonomy No.: 783
      2. Description: R. ricketsii is native to the New World and causes the malady known as Rocky Mountain spotted fever (RMSF). RMSF is transmitted by the bit of an infected tick while feeding on warm-blooded animals, including humans. Man is an accidental host in the rickettsia-tick life cycle and is not required to maintain the rickettsiae in nature(Weiss, 1988). Wolbach deserves the credit for the first detailed description of the etiologic agent in 1919. He clearly recognized it as an intracellular bacterium which was seen most frequently in endothelial cells. He was struck by the fact that in the tick, and also in mammalian cells, the microorganism was intranuclear. The nucleus was often completely filled with minute particles and often was distended. Although Wolbach recognized its similarity to the agent of typhus and tsutsugamushi fever, he did not regard the designation 'rickettsia' as appropriate. He proposed the name Dermacentroxenus rickettsi. Brumpt felt that the etiologic agent of RMSF, despite some uncertainty about its properties, belonged in the genus Rickettsia and in 1922 proposed the name Rickettsia rickettsi(Weiss, 1988B).

1. R. rickettsii life cycle
   1. Stage Information:
      1. Rickettsia rickettsii vegetative state:
         • Size: R. rickettsii, the causative agent of RMSF, is a small (0.2 to 0.5 by 0.3 to 2.0 um), obligate, intracellular bacterium.
         • Shape: Ricketts described small diplococcoid bodies or diplobacilli in infected animals, particularly in tick eggs.
         • Picture(s):
           • Rickettsia rickettsii (Website 3)
             
             
             
             Description: Gimenez stain of tick hemolymph cells infected with R. rickettsii(Website 3).
   2. Picture(s):
      • Rickettsial rickettsii (Website 2)
        
        
        
        Description: Life cycle of Rickettsia rickettsii in its tick and mammalian hosts(Website 2).
   3. Description: Rickettsia rickettsii are maintained in nature by transstadial passage within, and transovarial (vertical) transmission between generations of ixodid ticks. These ticks also vector R. rickettsii to and from various rodent reservoirs and other small mammals. Naive larval and nymphal ticks become infected while feeding on small rodents (eg, mice, voles, squirrels, or chipmunks) with acute rickettsemia. To enable transovarial transmission, female ticks need to ingest numerous rickettsiae or be infected transtadially. Male ticks can transfer R. rickettsii to females during the mating process via spermatozoa or other body fluids, thus contributing to the maintenance of the organism from one generation to another. Ticks can remain infective for life (possibly 2 to 5 years), especially if there are long periods between blood feeding. Ticks transmit R. rickettsii to a vertebrate principally during their feeding behavior. However, human infection has occurred much less often following transdermal or inhalation exposure to tick fluids (hemolymph), tick feces, or crushed tick tissues. In the natural history of R. rickettsii transmission, human and domestic dog infections are considered incidental events(Warner and Wallace, 2002).

1. Genome of Rickettsia rickettsii
   1. Description: .
   2. Chromosome
      1. GenBank Accession Number: Website5
      2. Size: 1257710 bp(Website 5).

1. General biosafety information
   1. Level: 2 and 3.
   2. Precautions: Biosafety Level 2 practices and facilities are recommended for nonpropagative laboratory procedures, including serological and fluorescent antibody procedures, and for the staining of impression smears. Biosafety Level 3 practices and facilities are recommended for all other manipulations of known or potentially infectious materials, including necropsy of experimentally infected animals and trituration of their tissues, and inoculation, incubation, and harvesting of embryonate eggs or cell cultures. Animal Biosafety Level 2 practices and facilities are recommended for the holding of experimentally infected mammals other than arthropods. Level 3 practices and facilities are recommended for animal studies with arthropods naturally or experimentally infected with rickettsial agents of human disease(Website 12).

1. R. rickettsii culture techniques :
   1. Description: Isolation of rickettsiae in cell culture can be achieved in 4 to 7 days in many cases, but use of antibiotic-free cell culture is mandatory because most antimicrobial agents inhibit rickettsial growth in virto. The reliance on antimicrobial agents in the medium to cover up for minor lapses in technique and contamination with normal flora is virtually universal. Cultivation of rickettsiae depends on meeting the technical challenge of antimicrobial agent-free cell culture. The work should be performed in a biohazard containment safety cabinet in a room under relative negative pressure with an anteroom. The worker must wear mask, gloves, and gown. R. rickettsii can be isolated from blood, plasma and tissues in Vero cells, L cells, primary chicken fibroblasts, and other primary and continuous cell lines. The shell vial centrifugation method offers and attractive approach. Rickettsiae can also be isolated by inoculation of the yolk sac of antiobiotic-free, 5- to 6-day-old embryonated hen eggs. Cultivated rickettsiae are identified provisionally by stianing with immunofluorescence and the Gimenez method(Walker, 1989).

1. Outbreak Locations:
   1. Currently no epidemic outbreak information is available.
2. Transmission Information:
   1. From: Ticks , To: Ticks (Warner and Wallace, 2002)
      Mechanism: Rickettsia rickettsii are maintained in nature by transstadial passage within, and transovarial (vertical) transmission between generations of ixodid ticks(Warner and Wallace, 2002). To enable transovarial transmission, female ticks need to ingest numerous rickettsiae or be infected transtadially. Male ticks can transfer R. rickettsii to females during the mating process via spermatozoa or other body fluids, thus contributing to the maintenance of the organism from one generation to another(Warner and Wallace, 2002).
   2. From: Ticks , To: Mammals
      Mechanism: Eggs from a female tick infected with R. rickettsii develop into infected larvae, which then feed on and infect small rodents with rickettsiae that are present in their saliva(McDade and Newhouse, 1986). Larvae infected with R. rickettsii molt to become infected nymphs that can infect medium-sized animals while feeding. After the nymphs molt, the resulting adult ticks can also infect larger animals(McDade and Newhouse, 1986). Rickettsiae are inoculated into the pool of blood in the dermis from which the tick is feeding. After the tick has fed for 6 hours, some rickettsiae, along with digestive secretions, are released from its salivary glands. Some ticks feed for even longer times before inoculation rickettsiae into the host's skin(Walker, 1995).
   3. From: Mammals , To: Ticks
      Mechanism: Naive larval and nymphal ticks become infected while feeding on small rodents (eg, mice, voles, squirrels, or chipmunks) with acute rickettsemia(Warner and Wallace, 2002).
   4. From: Human , To: Human
      Mechanism: Cases have been rarely acquired by laboratory personnel through direct inoculation or inhalation of aerosols containing R. rickettsii, by transfusion, or by needlestick injury from an infected patient(Weber and Walker, 1991). Aerosol infection from dried feces is unlikely because R. rickettsii loses its infectiousness rather rapidly in such material. Nevertheless, infections via the respiratory tract have been reported, especially among laboratory personnel(Burgdorfer, 1988).
3. Environmental Reservoir:
   1. Ticks:
      1. Description: Rocky Mountain spotted fever is a vector-borne disease transmitted by certain species of ticks that also serve as the reservoir or natural hosts(Weber and Walker, 1991). Even in highly endemic ares, such as the southeastern coastal states of Virginia and North Carolina, and Oklahoma, only a few ticks are infected with R. rickettsii(Sexton and Kaye, 2002).
      2. Survival: In its tick vectors, R. rickettsii produces a generalized infection that persists throughout the life span of the tick. Hemocytes and tissues of the hypodermis, Malpighian tubules, salivary glands, and digestive and genital systems usually have moderate to heavy infections that often become massive as a result of intense rickettsial multiplication during the feeding process of the tick(Burgdorfer, 1988). One should not conclude, however, that R. rickettsii and its acarine hosts have developed a perfect symbiotic relationship, or that infections of various tick species with R. rickettsii are always generalized, continuous, or mutually beneficial. Some tick infections are incomplete and cannot sustain the transmission of R. rickettsii. Other infections, although complete, can result in decreased fecundity or viability, or even death of the tick. For example, in established hosts like Dermacentor variabilis and D. andersoni high mortality rates were observed among naturally infected engorged female ticks beginning with the fifth filial generation, and these infected females also began to deposit less than half the number of eggs deposited by uninfected ticks. It should be noted, however, that 100% filial infection was observed among the viable ticks through 12 generations of infected D. andersoni, despite the high tick mortality(McDade and Newhouse, 1986). Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever, was lethal for the majority of experimentally and transovarially infected Rocky Mountain wood ticks (Dermacentor andersoni). Overall, 94.1% of nymphs infected as larvae by feeding on rickettsemic guinea pigs died during the molt into adults and 88. 3% of adult female ticks infected as nymphs died prior to feeding. In contrast, only 2.8% of uninfected larvae failed to develop into adults over two generations. Infected female ticks incubated at 4 C had a lower mortality (80.9%) than did those held at 21 C (96.8%). Rickettsiae were vertically transmitted to 39.0% of offspring, and significantly fewer larvae developed from infected ticks. The lethal effect of R. rickettsii may explain the low prevalence of infected ticks in nature and affect its enzootic maintenance(Niebylski et al., 1999).
4. Intentional Releases:
   1. Intentional Release Information:
      1. Description: .
      2. Containment: Biosafety Level 2 practices and facilities are recommended for nonpropagative laboratory procedures, including serological and fluorescent antibody procedures, and for the staining of impression smears. Biosafety Level 3 practices and facilities are recommended for all other manipulations of known or potentially infectious materials, including necropsy of experimentally infected animals and trituration of their tissues, and inoculation, incubation, and harvesting of embryonate eggs or cell cultures. Animal Biosafety Level 2 practices and facilities are recommended for the holding of experimentally infected mammals other than arthropods. Level 3 practices and facilities are recommended for animal studies with arthropods naturally or experimentally infected with rickettsial agents of human disease(Website 32).

1. Organism Detection Test:
   1. Indirect immunofluorescence assay (IFA) :
      1. Time to Perform: unknown
      2. Description: Serologic assays are the most widely available and frequently used methods for confirming cases of Rocky Mountain spotted fever. The indirect immunofluorescence assay (IFA) is generally considered the reference standard in Rocky Mountain spotted fever serology and is the test currently used by CDC and most state public health laboratories. IFA can be used to detect either IgG or IgM antibodies. Blood samples taken early (acute) and late (convalescent) in the disease are the preferred specimens for evaluation. Most patients demonstrate increased IgM titers by the end of the first week of illness. Diagnostic levels of IgG antibody generally do not appear until 7-10 days after the onset of illness. It is important to consider the amount of time it takes for antibodies to appear when ordering laboratory tests, especially because most patients visit their physician relatively early in the course of the illness, before diagnostic antibody levels may be present. The value of testing two sequential serum or plasma samples together to show a rising antibody level is considerably more important in confirming acute infection with rickettsial agents because antibody titers may persist in some patients for years after the original exposure(Website 4). The IFA is performed on whole rickettsiae, which contain a vast array of protein and carbohydrate antigens. The organisms are affixed to microscopic slides and are reacted with serial dilutions of serum. The presence of antibody attached to the rickettsia is detected by fluorescein-conjugated antibodies to human immunoglobulins. Variations in the technique have included detection of antibody of immunoglobulin M class and demonstration of antibodies by immunoperoxidase instead of immunofluorescence. The availability of an ultraviolet microscope is required for the IFA test. Variations in the endpoint titer may occur because the anti-immunoglobulin conjugate, and the skill of the microscopist. The IFA is generally accepted as the best serologic test presently available, the one with which new assays should be compared(Walker, 1989). The IFA is generally considered to be the gold standard, although cross-reaction with other spotted fever group rickettsiae may occur even with this method. Despite its superior sensitivity and specificity, the IFA is inconvenient. Generally, it can be performed only at public health laboratories or other research or commercial reference facilities(Silber, 1996).
      3. Picture(s):
         • IFA reaction (Website 4)
           
           
           
           Description: IFA reaction of a positive human serum on Rickettsia rickettsii grown in chicken yolk sacs, 400X. Copyright: CDC(Website 4).
   2. Plaque Assay :
      1. Time to Perform: unknown
      2. Description: Primary cultures of human umbilical vein endothelial cells were inoculated with plaque-purified Rickettsia rickettsii. After adsorption of rickettsiae, monolayers were overlaid with medium containing 0.5% agarose. Small plaques appeared on day 4 postinoculation, and distinct 1- to 2-mm plaques were observed on day 5. Plaquing efficiency was less than that of primary chicken embryo cells in the same medium. Human endothelial cell monolayers were susceptible to infection by R. rickettsii and underwent necrosis as demonstrated by supravital staining. The topographic association of endothelial cell necrosis and rickettsial infection in the plaque model confirmed the direct cytopathic effect of R. rickettsii on human endothelium. Uninfected cells appeared normal by supravital staining and transmission electron microscopy. This model offers the possibility of investigating rickettsial pathogenesis and mechanisms of enhanced severity of Rocky Mountain spotted fever in specific genetically determined conditions(Walker et al., 1982). A plaque technique for the assay of Rickettsia rickettsii is described. The method employs primary chick or green monkey kidney monolayer cell cultures with either an agarose or special Noble agar overlay. Plaques were counted in 6 days and resultant titers correlated well with LD50 end points obtained by a standard assay in embryonated eggs. Identification of the plaque-forming organisms was accomplished by direct observation of rickettsiae-like bodies in the monolayer lesions, inhibition of plaques by antibiotics, sensitivity of plaques to specific immune serum, and failure to cultivate other microorganisms from the infected cells. Versatility of the test was demonstrated by assaying samples of rickettsiae from several different sources commonly used in our laboratory. These included infected yolk sacs, various cell cultures, and infected guinea pig tissue. Sufficient numbers of viable rickettsiae were present in the cells of a single lesion to permit direct recovery(Weinberg et al., 1969).
   3. Immunoperoxidase Staining of Parafin-Embedded Tissue :
      1. Time to Perform: 1-to-2-days
      2. Description: Immunoperoxidase (IP) staining is also an effective means of staining R. rickettsii. Immunoperoxidase methods can be applied with relative ease to paraffin-embedded biopsies. Tissues stained by the IP method can be examinied by conventional bright-field microscopy. Although paraffin embedding and peroxidase staining are more time-consuming than IF staining of frozen sections, new rapid embedding and IP staining protocols may achieve conclusive results in less than 24 hours(Procop et al., 1997). The IP staining method, although not as rapid as the IF method, is usually available on a next-day basis in most pathology laboratories(Procop et al., 1997).
      3. False Negative: Three patients had false negative IP results(Procop et al., 1997).
   4. Immunofluorescence :
      1. Time to Perform: unknown
      2. Description: Not until 1976 were spotted fever rickettsiae identified by immunofluorescence diagnostically in cutaneous biopsies and autopsy tissues. Extensive experience with this acute diagnostic approach led to its use as a routing procedure in some medical centers. Best results are obtained by selection of a classic petechial lesion centered in an erythematous maculopapule and removal of this sample of skin with a 3 mm punch under local anesthesia. The sample is mounted in polyethylene glycol. Frozen sections are cut perpendicular to the epidermal layer at 4 um thickness at 5 to 12 levels extending through the petechia or through two-thirds of the tissue of a nonpetechial lesion. After fixation in absolute acetone for 10 min and air drying, the sections are reacted with an anti-spotted fever group rickettsial antibody conjugated with fluorescein isothiocyanante for 30 min, and mounted under a cover slip for fluorescence microscopy. A well-characterized conjugate prepared at the CDC has been in standard use for 13 years(Walker, 1989). RMSF is diagnosed when three or more fluorescent structures compatible with rickettsiae are identified in the blood vessel wall in the dermis. With experience, the test is highly specific (100%) and sufficiently sensitive (70%) to be useful in making clinical decisions(Walker, 1989).
      3. False Negative: False-negative results increase after 48 h of antirickettsial treatment(Walker, 1989).
   5. Intraperitoneal inoculation of Guinea pigs :
      1. Time to Perform: unknown
      2. Description: Institutions with facilities for handling animals infected with biohazard class 3 agents can isolate R. rickettsii from human blood or tissues by intraperitoneal inoculation of adult male guinea pigs. Infected animals develop fever of more than 40 C and rickettsia-induced edemea of the scrotum, which sometimes proceeds to hemorrhage and necrosis. Rickettsiae are demonstrable in smears and frozen sections of tunica vaginalis, epididymis, and spleen within days after the onset of fever in the animal. Animals that survive are bled, and convalescent sera are examined for antibodies to R. rickettsii. For major medical centers in endemic regions, maintenance of a few adult male guinea pigs during May to September for isolation of R. rickettsii offers the opportunity to make the definitive diagnosis of RMSF. Reluctance to work with animals impairs the ability to investigate infectious diseases(Walker, 1989). It is important to maintain sensitive methods of recovering fastidious microorganisms such as rickettsiae, even if they are quite old-fashioned. It is erroneous to believe that they have been supplanted by other more sensitvie methods(Walker, 1989).
   6. Geimsa or Gram stain for light microscopy :
      1. Time to Perform: unknown
      2. Description: After the development of the Giems method for demonstraction of R. rickettsii by Wolbach, for three decades there was no pressure to apply the technique as an actue diagnostic test because there was no effective treatment. Subsequently, the histologic demonstration of rickettsia by Giemsa stain in infected tissues has become virtually a lost art. The Brown-Hopps method, a tissue Gram stain, detects only a small portion of the organisms that are observed by immunofluorescence(Walker, 1989).
   7. Immunostaining :
      1. Time to Perform: unknown
      2. Description: Another approach to Rocky Mountain spotted fever diagnostics is immunostaining. This method is used by taking a skin biopsy of the rash from an infected patient prior to therapy or within the first 48 hours after antibiotic therapy has been started. Because rickettsiae are focally distributed in lesions of Rocky Mountain spotted fever, this test may not always detect the agent. Even in laboratories with expertise in performing this test, the sensitivity is only about 70% on biopsied tissues. This assay may also be used to test tissues obtained at autopsy and has been used to confirm Rocky Mountain spotted fever in otherwise unexplained deaths. Immunostaining for spotted fever group rickettsiae is offered by the CDC, a few state health departments, and some university-based hospitals and commercial laboratories in the United States(Website 4).
      3. False Negative: 30%(Website 4).
      4. Picture(s):
         • Immunostaining (Website 4)
           
           
           
           Description: Red structures indicate immunohistological staining of Rickettsia rickettsii in endothelial cells of a blood vessel from a patient with fatal RMSF. Copyright: CDC(Website 4).
   8. Microimmunofluorescence test :
      1. Time to Perform: unknown
      2. Description: A microimmunofluorescence test was used to study antibody responses to various spotted fever group and typhus group rickettsiae during Rocky Mountain spotted fever (RMSF) and epidemic typhus (ET). Patients with RMSF reacted most strongly to Rickettsia rickettsii; those with ET reacted predominantly to R. prowazekii. The degree of cross-reaction to other rickettsial strains varied from patient to patient, but a particular pattern of cross-reaction was consistently observed in serial sera from the same patient(Philip et al., 1976).
      3. False Positive: Cross-reactions of varying degree sometimes occurred to antigens both within and between the spotted fever and typhus group(Philip et al., 1976).
2. Immunoassay Test:
   1. Weil-Felix test :
      1. Time to Perform: unknown
      2. Description: The Weil-Felix test is based on the detection of antibodies to various Proteus species which contain antigens with cross-reacting epitopes to antigens from members of the genus Rickettsia with the exception of R. akari. Whole cells to Proteus vulgaris OX-2 react strongly with sera from persons infected with SFG rickettsia with the exception of those with RMSF, and whole cells of P. vulgaris OX-19 react with sera from persons infected with typhus group rickettsiae as well as with RMSF(La Scola and Raoult, 1997). By the Weil-Felix test, agglutinating antibodies are detectable after 5 to 10 days following the onset of symptoms, with the antibodies detected being mainly of the immunoglobulin M (IgM) type(La Scola and Raoult, 1997). The poor sensitivity and specificity of the Weil-Felix test are now well demonstrated for the diagnosis of RMSF, MSF, murine typhus, epidemic typhus, and scrub typhus. Although a good correlation between the results of the Weil-Felix test and detection of IgM antibodies by an immunofluorescence assay is often observed, with the development of techniques that are used to grow rickettsiae, this test should be used only as a first line of testing in rudimentary hospital laboratories(La Scola and Raoult, 1997). In most hospitals the laboratory diagnosis of RMSF is synonymous with the archaic, nonspecific, insensitive Weil-Felix test. Early in this century, the agglutination of certain strains of Proteus vulgaris by sera of patients convalescent from typhus fever was recognized. This phenomenon depends on antigens shared by P. vulgaris OX-19 and OX-2 and R. prowazekii, R. typhi, R. rickettsii, R. conorii, R. sibirica, and R. australis. Between 5 and 12 days after onset os symptoms, antibodies appear that agglutinate P. vulgaris OX-19 in 70% of patients and agglutinate P. vulgaris OX-2 in 47%. In addition to this poor level of sensitivity, another drawback is lack of specificity. Many healthy persons have agglutinating antibodies to P. vulgaris OX-19(Walker, 1995).
   2. Latex Agglutination :
      1. Time to Perform: unknown
      2. Description: Both indirect hemagglutination assay (IHA) and latex agglutination rely on a common source of rickettsial antigen, a protein-carbohydrate complex extracted from R. rickettsii by heat and alkaline conditions. This antigenic material is coated onto sheep or human type O erythrocytes for IHA and onto latex beads for latex agglutination. Serologic reactivity and binding to the erythrocytes require carbohydrate constituents, and trypsin digestion of the protein constituents does not affect the reaction of the antigen with antibody. Even though IHA demonstrated the earliest, steepest rise in antibody titer of all serologic tests for RMSF, it is seldom diagnostic in the acute stage of illness. The median antibody titer during days 4 to 16 of illness, when antirickettsial treatment must be initiated, is 16. Only 19% of patients with RMSF had an acute titer of 40, a lower value than the CCD criterion for the single titer indicating a probable diagnosis (greater than or equal to 128). The latex agglutination test is technically simple and rapid and requires no elaborate equipment. Endpoint determination seems to be difficult for some technologists. Antibodies to R. rickettsii are detcted 7 to 9 days after onset of illness and fall to nondiagnostic titers within 2 months. Perisitently detectable antibodies by IFA make this test appropriate for study of the prevalence of antibodies. The latex agglutination test is inappropriate for serosurveys and is more diagnostically discriminaotry for establishing the diagnosis of a recent infection. It is quite logical that hospital laboratories should replace the insensitive nonspecific Weil-Felix test with the commercially available latex agglutination test(Walker, 1989). The most imporant concept regarding serologic diagnosis is the emphatic insistence that it must be regarded as a retrospective confirmation of the clinical diagnosis. Currently, available serologic methods should not be considered as rapid acute diagnostic tests. Very seldom are specific antibodies to R. rickettsii detected during the acute stage of illness when empiric treatment must begin(Walker, 1989).
   3. Indirect Hemagglutination Assay :
      1. Time to Perform: unknown
      2. Description: Both indirect hemagglutination assay (IHA) and latex agglutination rely on a common source of rickettsial antigen, a protein-carbohydrate complex extracted from R. rickettsii by heat and alkaline conditions. This antigenic material is coated onto sheep or human type O erythrocytes for IHA and onto latex beads for latex agglutination. Serologic reactivity and binding to the erythrocytes require carbohydrate constituents, and trypsin digestion of the protein constituents does not affect the reaction of the antigen with antibody. Even though IHA demonstrated the earliest, steepest rise in antibody titer of all serologic tests for RMSF, it is seldom diagnostic in the acute stage of illness. The median antibody titer during days 4 to 16 of illness, when antirickettsial treatment must be initiated, is 16. Only 19% of patients with RMSF had an acute titer of 40, a lower value than the CCD criterion for the single titer indicating a probable diagnosis (greater than or equal to 128)(Walker, 1989). The most important concept regarding serologic diagnosis is the emphatic insistence that it must be regarded as a retrospective confirmation of the clinical diagnosis. Currently, available serologic methods should not be considered as rapid acute diagnostic tests. Very seldom are specific antibodies to R. rickettsii detected during the acute stage of illness when empiric treatment must begin(Walker, 1989).
   4. Agglutination by Convalsecent Serum :
      1. Time to Perform: unknown
      2. Description: Agglutination of convalsecent serum of microorganisms that are the etiologic agents of an infection was one of the earliest assays for antibodies to antigens of the microorganism itself. Unfortunately, it is virtually impossible to produce sufficient quantites of purified rickettsiae to use diagnostic agglutination tests routinely even with micromethods. Cultivation and purification of large concentrations of R. rickettsii require particular care to avoid inhalation of infectious aerosols. In addition, these pathogenic organisms destroy the host cells in which they are cultivated before a substaintial quantity of rickettsiae have accumulated, and separation of these oligate, intracellular bacteria from host cell components is quite inefficient. It is unreasonable to believe that R. rickettsii will ever be commercially available for the microaggluutination assay. Although the assay is specific, the sensitivity has varied according to the methods of purifiction of the rickettsiae. At a titer of greater than or equal to 32, the sensitivity of the assay for diagnosis of RMSF was reported as 56%(Walker, 1989).
      3. False Negative: 44%(Walker, 1989).
   5. Complement Fixation :
      1. Time to Perform: unknown
      2. Description: For a generation, the complement fixation test, using a soluble mixture of ether-extracted protein and LPS antigens of R. rickettsii, R. conorii, R. sibirica, R. akari, and R. australis. Washed rickettsial antibodies to species-specific antigens may be used to detect antibodies to species-specific antigens, but more effort is required to produce them. The complement fixation test is highly reproducible and specific. False-positive results are rare at a serum dilution of 1:16. Unfortunately, the sensitivity of the test is poor, because complement fixation antibodies are detected late in convalescence and in relatively small proportion of patients. Another drawback is that 5 to 10% of sera are anticomplementary. That is, they fix complement even in the absence of rickettsial antigen. The complement fixation test is rarely performed in the United States at present. It has become mainly a subject of historic concern because the major producer of rickettsial antigen for the assay, the CDC, recently ceased supplying the antigen to laboratories in this country(Walker, 1989). The most important concept regarding serologic diagnosis is the emphatic insistence that it must be regarded as a retrospective confirmation of the clinical diagnosis. Currently, available serologic methods should not be considered as rapid acute diagnostic tests. Very seldom are specific antibodies to R. rickettsii detected during the acute stage of illness when empiric treatment must begin(Walker, 1989).
      3. False Positive: False-positive results are rare at a serum dilution of 1:16(Walker, 1989).
3. Nucleic Acid Detection Test:

1. Human
   1. Taxonomy Information:
      1. Species:
         1. Homo sapiens (Website 7):
            • Common Name: Homo sapiens
            • GenBank Taxonomy No.: 9606
            • Description: Rocky Mountain spotted fever has been a reportable disease in the United States since the 1920's. In the last 50 years, approximately 250-1200 cases of Rocky Mountain spotted fever have been reported annually, although it is likely that many more cases go unreported. CDC compiles the number of cases reported by the state health departments(Website 6).
   2. Infection Process:
      1. Infectious Dose: Volunteer experiments have documented that as few as 10 rickettsiae are sufficient to cause infection. Experimentally induced infections in humans demonstrated that increasing the rickettsial dose of inoculum was associated with a shorter incubation period, a more severe infections as measured by the total febrile period, and an increased frequency of clinical relapse following 5 days of therapy(Weber and Walker, 1991),
      2. Description: Human infection with R. rickettsii is initiated when the organism is inoculated into the skin from the tick saliva while an infected tick feeds. Transmission of infection from the tick to humans requires two conditions. First, the rickettsiae must undergo reactivation from a dormant avirulent state to a highly pathogenic one which occurs while the tick ingests a rich blood meal. Exposure to thermal or nutritional factors for 6 to 48 hours is required for reactivation of rickettsial pathogenicity. Second, a period of time is required for release of rickettsiae from the tick salivary glands and their inoculation into human skin. Thus, prompt removal of ticks can prevent infection(Weber and Walker, 1991),
   3. Disease Information:
      1. RMSF, BSF(i.e., Rocky Mountain Spotted Fever, Brazilian Spotted Fever) :
         1. Incubation: 6 to 8 days (range 2 to 14 days)(Walker and Lane, 1988),
         2. Prognosis:
            Most patients treated early in the course of illness with tetracycline, doxycycline, or chloramphenicol respond promptly with defervescence in 2 to 3 days in mild to moderate cases and in up to a week in severe illness. Patients treated with other antibiotics fail to respond. Patients treated late in the course respond much more slowly and may die despite rickettsiostatic drugs and intensive supportive care. Convalescence may be prolonged, particularly in untreated cases and severe illness. Sequelae may include deafness, impaired vision, neurologic defects, amputation of gangrenous extremities, and intellectual deficits(Walker and Lane, 1988), The mortality rate of patients with clinical RMSF treated with inappropriate antibiotics may be as high as 15% to 20%. In patients treated with doxycycline, tetracycline, or chloramphenicol, the mortality rate ranges from 3% to 6%. Factors associated with an increased mortality rate ranges include age greater than 15 years, male gender, no history of tick exposure, lack of a rash, delay in diagnosis. lack of appropriate antibiotic therapy, and black race. A delay in diagnosis may result when patients return an appropriate travel history is not obtained. A mortality rate of over 10% has been reported among persons older than 40 years(Weber and Walker, 1991),
         3. Diagnosis Summary: It should be apparent that the diagnosis of RMSF during the early phase of the illness is by no means easy. There are many pitfalls. The physician who has taken a careful history, performed a complete physical examination, and evaluated the appropriate laboratory data may have no specific clues that the diagnosis is RMSF. Only 3% of patients with RMSF have the classic triad of fever, rash, and history of tick bite during the first 3 days of illness, the time during which the patient usually seeks medical care. Gastrointestinal, pulmonary, or central nervous system signs and symptoms may mislead the clinician to an erroneous initial diagnosis of nonspecific viral syndrome, gastroenteritis, acute surgical abdomen, bronchitis, pneumonia, meningoencephalitis, or other misdiagnoses. A reliance upon classic book manifestations of the disease often delays the diagnosis and appropriate lifesaving treatment. Regarding the previously mentioned triad, fever is present from the onset. Rash and history of tick bite are frequently not present. Even for patients with a rash, the physician's insistence on the book appearance of the petechial component, and involvement of the palms and soles will result in failure or delay in making the diagnosis. A rash is absent in approximately 10% of the cases, may appear first on the trunk, lacks petechiae in half of patients with RMSF, and involves the palms and soles of only 36 to 82% of patients who do have a rash. Features sometimes relied on for the clinical diagnosis, petechiae and involvement of the palms and soles, tend to develop rather late in the course, sometimes after the point of irreversible injury. Tick bite is generally painless, often goes unnoticed, and may not be recalled by the patient with central nervous system involvement. A history of tick bite is reported in only 60% of patients. On the other hand, in regions where ticks are abundant, a history of tick bite was obtained from 85% of RMSF patients and also from 54% of matched uninfected controls during the period corresponding to incubation period(Walker, 1989),
         4. Symptom Information :
            • Syndrome -- Rocky Mountain Spotted Fever :
              • Description: RMSF is a protean systemic illness. Although the disease in some patients who have been treated early may be characterized as mild, most patients suffer moderate or severe illness. Asymptomatic infection with R. rickettsii has never been convincingly documented. Rickettsiae infect and damage blood vessels throughout the body. The general pathophysiologic effects of the vascular infection are the consequences of increased vascular permeability and include edema in the tissues surrounding the leaky blood vessels, hypovolemia and the hypoproteinemia owing to loss of protein-rich fluid from the plasma into the tissues, diminished serum oncotic pressure, and reduced perfusion of various organs. Multifocal lesions are associated with intense localized rickettsial infection of numerous contiguous endothelial cells(Walker, 1989).
              • Observed:
                During 1993 through 1996, 2,313 cases of Rocky Mountain spotted fever (RMSF) were reported to the Centers for Disease Control and Prevention (CDC) by 42 states and the District of Columbia through the National Electronic Telecommunications System for Surveillance (NETSS). During this same interval, 1,752 case report forms (CRFs) were submitted to CDC and 1,253 (70%) of the cases were categorized as confirmed RMSF by laboratory testing. On the basis of analyses performed with NETSS data, the average annual RMSF incidence during 1993-1996 was 2.2 cases per million persons; the incidence rose from 1.8 in 1993 to 3.3 per million persons in 1996. Incidence for confirmed cases was highest among children 5-9 years of age (3.7 per million) and lowest among individuals older than 70 years of age (1.4 per million). The south Atlantic region accounted for the largest proportion of confirmed cases (52%). The case-fatality rate was highest among persons 70 years of age and older (9.0%) and lowest among adults 40-49 years of age (0.6%)(Treadwell et al., 2000),
              • Symptom -- RMSF General Symptoms :
                • Description: Rocky Mountain Spotted Fever (RMSF) causes the most severe clinical manifestations of any rickettsiosis with the virulence to kill even previously healthy, well-nourished children and young adults. After an incubation period of approximately 6 to 8 days (range 2 to 14 days) following the introduction of Rickettsia rickettsii into the skin by the bite of an infected tick, the patient notes the onset of malaise, chills, severe headache, myalgia, and fever. During the next few days, these symptoms continue and may be accompanied by anorexia, nausea, vomiting, abdominal pain, diarrhea, photophobia, and cough. A rash usually appears on day 3 of illness. Progressive worsening occurs in moderate and severe cases at the end of the first week and during the second week of illness, with mild cases improving by the end of the second week. Severe cases often develop noncardiogenic pulmonary edema, renal failure, hemorrhagic rash, peripheral edema, hypovolemic hypotension, delirium, seizures, and coma. Most patients treated early in the course of illness with tetracycline, doxycycline, or chloramphenicol respond promptly with defervescence in 2 to 3 days in mild or moderate cases and in up to a week in severe illness. Patients treated with other antibiotics fail to respond. Patients treated late in the course respond much more slowly and may die despite rickettsiostatic drugs and intensive supportive care. Convalescence may be prolonged, particularly in untreated cases and severe illness. Sequelae may include deafness, impaired vision, neurologic defects, amputation of gangrenous extremities, and intellectual deficits(Walker and Lane, 1988).
            • Symptom -- Rash (Walker, 1989):
              • Description: A rash usually appears on day 3 of illness, although appearance varies from day 1 in 14% of cases to day 6 or thereafter in 20%. Absence of a rash altogether is reported in 9 to 12% of patients. So-called spotless fever occurs in higher proportions of fatal cases, older patients, and blacks. Initially, the rash consists of lesions 1 to 5 mm in diameter where dilation of the small blood vessels imparts a pink color to the skin and surrounding the foci of rickettsial vascular infection. At this stage of illness, pressure applied to the pink spot results in temporary blanching of the rash by removal of blood from the dilated vessels. Later in the course, particularly in severely ill patients, a pinpoint hemorrhage occurs in the center of the pink spot where the damage caused by the intense rickettsial infection is most pronounced. At this later stage, compression of the rash does not blanch its color. These small hemorrhagic spots which give the disease its name are observed in approximately half of the patients with RMSF. The rash is an example of a component of the disease in which the clinical manifestations are due directly to the rickettsial damage to the local tissue(Walker, 1989).
              • Picture(s):
                • Early (macular) rash on sole of foot. Copyright: CDC (Website 31)
                  
                  
                  
                  
                • Late (petechial) rash on palm and forearm. Copyright: CDC (Website 31)
                  
                  
                  
                  
              • Observed:
                The prevalence of rash in RMSF ranges from 73.9 to 96%(McGinley-Smith and Tsao, 2003), Only 14% of patients manifest rash on the first day of illness, and only 49% develop rash by the third day(Silber, 1996), Spotless fever is present throughout the course in approximately 10% of patients. It is possible that the true rate of spotless RMSF is lower, and that some of these cases were actually cases of ehrlichiosis that presented before the latter disease was well recognized. Conversely, the true frequency of RMSF without rash may be even higher than 10% because patients without rash have no skin lesion to biopsy(Silber, 1996),
            • Symptom -- Fever :
              • Description: Fever is seen virtually 100% of the time, and is greater than 102 F in a large majority of cases(Silber, 1996).
              • Observed:
                100%(Silber, 1996),
            • Symptom -- Peripheral Gangrene :
              • Description: The well-recognized potential of Rocky Mountain spotted fever (RMSF) to follow a severe course that culminates in circulatory collapse and death is feared by experienced clinicians. Less well appreciated is the fact that even with successful treatment RMSF can produce complications that results in permanent disability. Extensive skin necrosis and gangrene of the extremities are two particularly devastating complications of RMSF that have received little attention in the medical literature(Kirkland et al., 1992).
              • Observed:
                Progression to skin necrosis or gangrene has been reported in 2% to 4% of patients(Weber and Walker, 1991),
            • Symptom -- Skin necrosis :
              • Description: The most severe cutaneous effect of RMSF is necrosis of skin. Full-thickness loss of 45 to 50% of the skin requiring debridement and burn would care with repeated skin grafts has been described(Walker and Lane, 1988).
              • Observed:
                In the series of 131 patients of Kaplowitz et al., 4% had skin necrosis or peripheral gangrene(Walker and Lane, 1988),
            • Symptom -- Neurologic disease :
              • Description: The nervous system appears to be the most crucial target organ in RMSF. Neurologic features are frequently the cause of death(Walker and Lane, 1988).
              • Observed:
                Overall severe neurologic dysfunction has been noted in 23 to 38 percent of patients(Weber and Walker, 1991),
            • Symptom -- Encephalitis :
              • Description: Another critical target is the central nervous system. Involvement of the blood vessels in the brain manifests as rickettsial encephalitis, a grave prognostic indicator(Walker, 1989). Signs and symptoms of encephalitis include confusion, stupor or delirium, ataxia, coma, and seizures. Papilledema, transient hearing loss, sensory neuropathy, inappropriate secretion of antidiuretic hormone, and tardive dyskinesia have been reported. Although survivors usually experience return of much neurologic function, untreated and other severely ill patients may suffer permanent neurologic sequelae, including impairment of fine motions, hypotonia, hyperreflexia, ataxia, gait disturbance, mental retardation, weakness, aphasia, paraplegia, neurogenic bladder, transverse myelitis, severe depression, learning disabilities, decreased intelligence, and behavioral disturbances(Weber and Walker, 1991).
              • Observed:
                Clinically recognized encephalitis occurs in 26 to 28% of patients(Walker, 1989),
            • Symptom -- Confusion :
              • Description: Clinically recognized encephalitis occurs in 26 to 28% of patients with RMSF, with signs and symptoms including confusion (28%), stupor or delirium (21 to 26%), ataxia (5 to 18%), coma (9 to 10%), and seizures (8%)(Walker, 1989).
              • Observed:
                28%(Walker and Lane, 1988),
            • Symptom -- Stupor or delerium :
              • Description: Clinically recognized encephalitis occurs in 26 to 28% of patients with RMSF, with signs and symptoms including confusion (28%), stupor or delirium (21 to 26%), ataxia (5 to 18%), coma (9 to 10%), and seizures (8%)(Walker, 1989).
              • Observed:
                21%(Walker and Lane, 1988),
            • Symptom -- Ataxia :
              • Description: Occasionally, the neurologic manifestations of illness may progress to ataxia, sensory neuropathy, cranial nerve palsies, paraparesis, confusion, hallucinations, delirium, stupor, or coma(Silber, 1996).
              • Observed:
                5%(Walker and Lane, 1988),
            • Symptom -- Coma :
              • Description: Clinically recognized encephalitis occurs in 26 to 28% of patients with RMSF, with signs and symptoms including confusion (28%), stupor or delirium (21 to 26%), ataxia (5 to 18%), coma (9 to 10%), and seizures (8%)(Walker, 1989).
              • Observed:
                9 to 10%(Walker, 1989), Coma appears much more frequently in fatal cases (86%) than in nonfatal cases (6%)(Walker, 1989),
            • Symptom -- Seizures :
              • Description: Clinically recognized encephalitis occurs in 26 to 28% of patients with RMSF, with signs and symptoms including confusion (28%), stupor or delirium (21 to 26%), ataxia (5 to 18%), coma (9 to 10%), and seizures (8%)(Walker, 1989).
              • Observed:
                8%(Walker, 1989),
            • Symptom -- Headache :
              • Description: Patients may describe the headache as the most severe that they can remember(Silber, 1996). Virtually all adult patients and most older children with RMSF complain of headache early in the course of illness. The headache often is accompanied by intense myalgias and malaise(Sexton and Kaye, 2002).
              • Observed:
                64 to 100% reported(Weber and Walker, 1991),
            • Symptom -- Myalgia :
              • Description: Whereas myalgia is a frequent complaint in RMSF, frank muscle tenderness is much less common. Several cases of skeletal muscle involvement with extreme elevations of the creatine kinase have been reported(Silber, 1996).
              • Observed:
                31 to 72% reported(Weber and Walker, 1991),
            • Symptom -- Decreased Hearing :
              • Description: Long-term neurological sequelae included paraparesis, hearing loss, peripheral neuropathy, bladder and bowel incontinence, cerebellar, vestibular, and motor dysfunction, and language disorders(Archibald and Sexton, 1995). Hearing loss has been reported in association with RMSF. Helmick et al. in a review of 262 cases recorded an incidence of 7 percent but failed to offer any details conceringing the deafness. Dolan et al. reported sensorineural hearing loss in a case of RMSF that began on about the sixth day of illness and resolved between the third and fourth weeks. He reports a good prognosis for hearing loss in RMSF but does not cite a reference for this statement(Steinfeld et al., 1988).
              • Observed:
                7%(Weber and Walker, 1991),
            • Symptom -- Nausea and vomiting :
              • Description: Extracutaneous signs and symptoms, particularly gastrointestinal finding such as nausea and vomiting, may predominate early in the course of disease(Silber, 1996).
              • Observed:
                36 to 58%(Weber and Walker, 1991),
            • Symptom -- Abdominal pain :
              • Description: During the early part of the course of RMSF when rash is usually absent, nausea or vomiting (38 to 56%), abdominal pain (30 to 34%), and diarrhea (9-20%) are common. When the entire course of illness is considered, the frequency of these symptoms is even greater(Walker and Lane, 1988).
              • Observed:
                30 to 34%(Walker and Lane, 1988),
            • Symptom -- Diarrhea :
              • Description: During the early part of the course of RMSF when rash is usually absent, nausea or vomiting (38 to 56%), abdominal pain (30 to 34%), and diarrhea (9-20%) are common. When the entire course of illness is considered, the frequency of these symptoms is even greater(Walker and Lane, 1988).
              • Observed:
                9 to 20%(Walker and Lane, 1988),
            • Symptom -- Jaundice :
              • Description: Jaundice is seen in up to 8% of patients, and usually indicates serious illness and a complicated course. The etiology is thought to be multifactorial, involving both hepatic and hemolytic factors(Silber, 1996).
              • Observed:
                8%(Silber, 1996),
            • Symptom -- Renal failure :
              • Description: Approximately 10% to 15% of patients with RMSF will develop significant elevations of their blood urea nitrogen (BUN). Early in the course of RMSF the etiology of renal failure appears to be reversible prerenal azotemia because of hypovolemia, which results from leakage of fluid from injured vessels. In severe RMSF, hypotensive shock may develop where renal blood flow is extensively curtailed and acute tubular necrosis develops. Acute renal failure indicates a poor prognosis, complicates fluid and electrolyte management, and may require dialysis. Myoglobinuiria disseminated intravascular coagulation, and glomerulonephritis do not appear to be important in the pathogenesis of RMSF-associated renal failure(Weber and Walker, 1991).
            • Symptom -- Ocular manifestations :
              • Description: Ocular impairment is a common accompaniment of RMSF. Conjunctivitis is present in at least 30% of cases. Endothelial changes similar to those seen at other body sites may also occur in the retina. Vascular permeability and thrombosis are associated with flame-shaped hemorrhages, papilledema, arterial occlusion, and retinal vein engorgement(Silber, 1996).
              • Observed:
                Conjunctivitis is present in at least 30% of cases(Silber, 1996),
            • Symptom -- Respiratory involvement :
              • Description: Respiratory involvement may result in cough, dyspnea, pulmonary edema, infiltrates visible by chest radiographs, and systemic hypoxemia. Occasionally, respiratory symptoms may be sufficiently prominent to lead to a misdiagnosis of lower respiratory infection(Weber and Walker, 1991). Kaplowitz and coworkers noted that 9 of 10 patients who required mechanical ventilation died(Weber and Walker, 1991).
              • Observed:
                Severe respiratory failure ensues in 6% to 12% of patients(Weber and Walker, 1991),
            • Symptom -- Pneumonitis :
              • Description: >. Pneumonitis is a common and potentially life-threatening clinical feature of RMSF(Weber and Walker, 1991). The pulmonary microcirculation is a major target of infection by R. rickettsii. Pneumonitis then results from rickettsial vascular damage, which causes leakage of edema fluid into the interstitial tissues and airspaces(Weber and Walker, 1991).
              • Observed:
                It has been reported in 2% to 17% of patients early in their course and 12% to 13% during their illness(Weber and Walker, 1991),
            • Symptom -- Myocarditis :
              • Description: In contrast to infection due to typhus group organisms, the heart is relatively spared in RMSF. Myocarditis is present in a minority of cases of RMSF, although electrocardiographic abnormalities consistent with this diagnosis are seen with greater frequency(Silber, 1996). Abnormal electrocardiograms are frequently noted in RMSF. Kaplowitz and coworkers reported that 26% of patients in their series had an electrocardiogram consistent with myocarditis and 16% had an electrocardiogram demonstrating an arrhythmia (i.e. nodal rhythm, atrial fibrillation, or terminal conduction disturbances)(Weber and Walker, 1991).
              • Observed:
                Overt myocarditis has been reported in only 5% of patients(Weber and Walker, 1991),
            • Symptom -- Photophobia :
              • Description: In up to 40% of cases, patients may also develop lethargy, photophobia, meningismus, amnesia, bizarre behavior suggestive of psychiatric illness, or transient deafness(Silber, 1996).
              • Observed:
                ,
         5. Treatment Information:
            • Tetracycline derivatives : R. rickettsii is susceptible to a number of antimicrobial agents, including chloramphenicol, tetracycline derivatives, and rifampin(Silber, 1996). Among the tetracycline antibiotics, doxycycline is the best agent. Doxycycline can be administered to children and adults and is available in intravenous and oral preparations. Doxycycline absorption is less affected by food intake than other forms of tetracycline and its twice-daily dosing schedule is more convenient and improves compliance among outpatients receiving therapy(Sexton and Kaye, 2002). Prompt treatment with tetracycline-class antibiotics wihin the first few days of onset of illness significantly reduces the risk of death(Holman et al., 2001).
              • Contraindicator: Tetracyclines are contraindicated during pregnancy, and in this setting chloramphenicol should be sued. Whereas tetracycline should not be used in patients with renal failure, doxycycline is an acceptable therapeutic option in that clinical setting. Tetracyclines are relatively contraindicated for children under the age of 8, and chloramphenicol should be considered in the treatment of pediatric infection(Silber, 1996).
              • Complication: .
              • Success Rate: In a retrospecitive study of 103 patients with RMSF, Kirkland et al showed that treatment administered within the first 5 days of illness was significantly more effective than treatment started after the fifth day of onset of clinical symptoms. Most studies have shown that the outcome of RMSF is worse among patients older than age 40(Sexton and Kaye, 2002).
              • Drug Resistance: The organism is routinely resistant to penicillins, cephalosporins, aminoglycosies, trimethoprim-sulfamethoxazole, and erythromycin(Silber, 1996).
            • Fluoroquinolones : Although some fluorquinolones, including ciprofloxacin and ofloxacin, also have in vitro activity against R. rickettsii, data are insufficient for use of this class of drugs to be recommended in the treatment of RMSF(Silber, 1996).
              • Contraindicator: The potential toxicity of doxycycline and fluoroquinolones contraindicate their use during pregnancy and childhood(Rolain et al., 1998).
            • Chloramphenicol : The original description of chloramphenicol in 1947 was accompanied by a report showing that this antibiotic inhibits the growth of R. rickettsii in embryonated eggs and in experimentally infected animals. Clinical experience with use of chloramphenicol to treat human patients with RMSF accumulated rapidly and showed that patients treated with this antibiotic had relatively rapid favorable clinical responses. The use of this antibiotic and of tetracycline-class drugs, which were also discovered in the late 1940's, resulted in dramatic declines in annual case-fatality rates (CFRs) over the course of the next 50 years. Until relatively recently, it was thought that chloramphenicol and tetracyclines were equally efficacious for treatment of RMSF. However, recent epidemiologic studies that used CDC case report data have suggested that RMSF patients treated with chloramphenicol have a greater risk of dying than do persons who receive tetracycline as primary therapy(Holman et al., 2001).
              • Complication: Risks associated with chloramphenicol use include dose-related bone marrow depression, hemolytic anemia in patients with the Mediterranean form of glucose-6-phosphate dehydrogenase deficiency, 'gray baby' syndrome in premature infants and neonates, and rarely aplastic anemia(Weber and Walker, 1991). Because of the risk of aplastic anemia, a recommendation for treatment with chloramphenicol should be questioned(Raoult and Drancourt, 1991).
              • Success Rate: Older patients, patients treated with chloramphenicol only, patients for whom tetracycline antibiotics were not the primary therapy, and patients for whom treatment was delayed 5 or more days after the onset of symptoms were at higher risk for death(Holman et al., 2001). The case fatality rate for patients treated only with chloramphenicol during 1981-1998 was greater than for patients treated only with tetracyclines (7.6% vs. 5.5 [OR, 5.5;95% CI, 3.9-7.7]), a difference apparent during both 9-year periods(Holman et al., 2001).
            • Supportive care : In addition to antibiotic therapy, patients with RMSF often require aggressive supportive care, including oxygen supplementation, vigorous nutritional support, intravenous hydration, and occasionally hemodialysis. To optimize fluid and hemodynamic management in the setting of capillary leakage, placement of a Swan-Ganz catheter may be indicated(Silber, 1996).
   4. Prevention:
      1. Tick Avoidance
         • Description: For humans, the following personal protective measures ensure the most effective risk reduction when tick-infested areas cannot be avoided(Warner and Wallace, 2002), Apply tick repellents to exposed skin. The most effective is DEET (N,n-diethyl-m-toluamide)(Warner and Wallace, 2002), Spray permethrin-containing products on outer clothing and footware(Warner and Wallace, 2002), Wear long-sleeved shirts and long pants. Tuck pant legs into socks(Warner and Wallace, 2002), Wear light-colored clothing to facilitate seeing ticks that crawl on the surface(Warner and Wallace, 2002), Conduct body checks immediately after returning from outdoor activities in tick-infested areas. Use mirrors to view all body areas. Remove all ticks found(Warner and Wallace, 2002), Check children returning from infested areas, especially behind the ears, back of the neck, around the waist, and in and along the hairline(Warner and Wallace, 2002), Remove attached ticks by using fine-tipped tweezers. Alternatively, shield fingers with tissue paper, a foil-covered gum wrapper, or plastic sandwich bag and grasp the tick as close to the skin as possible, pulling upward with steady, even pressure. Do not burn, puncture, squeeze, or crush the tick's body because its fluids may be infectious. Wash the affected area with soap and water, and disinfect the bite site and your hands. Ordinary household brands of 70% isopropyl (rubbing) alcohol or 2% tincture of iodine are adequate skin-surface disinfectants(Warner and Wallace, 2002),
   5. Model System:
      1. Mice
         1. Model Host: .
            Mus musculus(Sammons et al., 1977),
         2. Model Pathogens: Rickettsia rickettsii.
         3. Description: An attempt was made to find a suitable animal model for studies of spotted fever group rickettsiae. Inbred and outbred mice, the guinea pig, ferret, gerbil, hamster, wild rabbit, cotton rat, sheep, and miniature swine were tested. Of these, only certain strains of the mouse [Mai:(S) and BALB/cJ] and the guinea pig [Hla:(HA)] exhibited, overtly, the desired characteristics of disease(Sammons et al., 1977),
      1. Guinea pig
         1. Model Host: .
            Cavia porcellus,
         2. Model Pathogens: Rickettsia rickettsii.
         3. Description: An attempt was made to find a suitable animal model for studies of spotted fever group rickettsiae. Inbred and outbred mice, the guinea pig, ferret, gerbil, hamster, wild rabbit, cotton rat, sheep, and miniature swine were tested. Of these, only certain strains of the mouse [Mai:(S) and BALB/cJ] and the guinea pig [Hla:(HA)] exhibited, overtly, the desired characteristics of disease(Sammons et al., 1977), Formalin-killed, purified Rickettsia rickettsii vaccine was evaluated in a guinea pig model of R. rickettsii infection. Vaccinated guinea pigs were partially protected by the vaccine when challenged with virulent, viable rickettsiae. Greater protection was observed when higher doses of vaccine were given and when frequent booster injections were administered. Stimulation of cell-mediated immunity to the vaccine antigens was variable and also appeared to be achieved more reproducibly with booster vaccinations. Serum antibody was elicited by high doses of vaccine and by booster vaccinations. The presence of serum antibody was useful in predicting immunity to challenge with R. rickettsii(Folds et al., 1983),
      1. Rhesus monkey
         1. Model Host: .
            Macaca mulatta(Sammons et al., 1976),
         2. Model Pathogens: Rickettsia rickettsii(Sammons et al., 1976).
         3. Description: Forty-seven male Macaca mulatta, 3 to 4 kg weight, were inoculated intravenously or subcutaneously with various doses of yolk sac-grown Rickettsia rickettsii. Thirty-four macaques became febrile and exhibited signs of infection ranging from transient illness with a few days of fever to severe illness with subsequent death. The rash appeared more frequently in the macaques inoculated subcutaneously. Febrile macaques that survived had leukocytosis, with concomitant neutrophilia. Febrile macaques that died had, in addition, marked terminal leukopenia and thrombocytopenia. Packed cell volume of all febrile macaques decreased. In almost all of the febrile macaques, there were increased serum urea nitrogen, glutamic-oxaloacetic transaminase, and lactate dehydrogenase and decreased total serum protein and amylase concentrations. A few febrile macaques had increased bilirubin values and decreased sodium, chloride, phosphorus, and alkaline phosphatase concentrations. Changes did not occur in serum glucose, potassium, calcium, and glutamic-pyruvic transaminase values. The experimental form of Rocky Mountain spotted fever in the macaque provides a subhuman primate model for studying the pathophysiology of this disease(Sammons et al., 1976),
2. Ticks
   1. Taxonomy Information:
      1. Species:
         1. Dermacentor andersoni (Website 8):
            • Common Name: Dermacentor andersoni
            • GenBank Taxonomy No.: 34620
            • Description: In the literature, it is generally stated that in the United States 5 species of ixodid ticks, the wood tick, D. andersoni, the American dog tick, D. variabilis, the lone star tick, Amblyomma americanum, the rabbit tick, Haemaphysalis leporispalustris, and the rabbit dermacentor, D. parumapertus, are vectors of spotted fever rickettsiae. The first 3 species mentioned are considered to be efficient vectors of R. rickettsii to man, the others are said to be responsible for maintaining R. rickettsii among their host animals in nature(Burgdorfer, 1975).
         2. Dermacentor variabilis (Website 9):
            • Common Name: Dermacentor variabilis
            • GenBank Taxonomy No.: 34621
            • Description: In the literature, it is generally stated that in the United States 5 species of ixodid ticks, the wood tick, D. andersoni, the American dog tick, D. variabilis, the lone star tick, Amblyomma americanum, the rabbit tick, Haemaphysalis leporispalustris, and the rabbit dermacentor, D. parumapertus, are vectors of spotted fever rickettsiae. The first 3 species mentioned are considered to be efficient vectors of R. rickettsii to man, the others are said to be responsible for maintaining R. rickettsii among their host animals in nature(Burgdorfer, 1975).
         3. Amblyomma americanum (Website 10):
            • Common Name: Amblyomma americanum
            • GenBank Taxonomy No.: 6943
            • Description: A. americanum, which is not a major vector of virulent Spotted Fever Group (SFG) rickettsiae, is known to harbor a nonpathogenic SFG rickettsia, isolate WB-8-2(Weller et al., 1998).
         4. Haemaphysalis leporispalustris (Website 11):
            • Common Name: Haemaphysalis leporispalustris
            • GenBank Taxonomy No.: 34624
            • Description: In the literature, it is generally stated that in the United States 5 species of ixodid ticks, the wood tick, D. andersoni, the American dog tick, D. variabilis, the lone star tick, Amblyomma americanum, the rabbit tick, Haemaphysalis leporispalustris, and the rabbit dermacentor, D. parumapertus, are vectors of spotted fever rickettsiae. The first 3 species mentioned are considered to be efficient vectors of R. rickettsii to man, the others are said to be responsible for maintaining R. rickettsii among their host animals in nature(Burgdorfer, 1975).
         5. Dermacentor parumapertus (Website 12):
            • Common Name: Dermacentor parumapertus
            • GenBank Taxonomy No.: 60255
            • Description: In the literature, it is generally stated that in the United States 5 species of ixodid ticks, the wood tick, D. andersoni, the American dog tick, D. variabilis, the lone star tick, Amblyomma americanum, the rabbit tick, Haemaphysalis leporispalustris, and the rabbit dermacentor, D. parumapertus, are vectors of spotted fever rickettsiae. The first 3 species mentioned are considered to be efficient vectors of R. rickettsii to man, the others are said to be responsible for maintaining R. rickettsii among their host animals in nature(Burgdorfer, 1975).
         6. Amblyomma cajennense (Website 13):
            • Common Name: Amblyomma cajennense
            • GenBank Taxonomy No.: 34607
            • Description: Amblyomma cajennense is the main transmitter of Rickettsia rickettsii (=R. rickettsi), the causative agent of spotted fever in Brazil(Figueiredo et al., 1999).
         7. Ixodes brunneus (Website 25):
            • Common Name: Ixodes brunneus
            • GenBank Taxonomy No.: 213681
            • Description: Several tick species other than the principal vectors of R. rickettsii have been found naturally infected with rickettsiae. They include Hemaphysalis leporispalustris, Dermacentor parumapertus, Ixodes dentatus, I. brunneus, and I. texanus. These ticks rarely attack humans and therefore are of little significance in the epidemiology of spotted fever. Nevertheless, they are important in maintaining and disseminating rickettsiae in nature. Rickettsiae closely related to or identical with R. rickettsii have been recovered also from Amblyomma americanum, A. maculatum, D. occidentalis, I. scapularis, I. pacificus, and I. cookei. These ticks do attack humans and must be considered potential vectors of R. rickettsii. As yet, however, no cases of spotted fever have been associated with bites by these ticks(Burgdorfer, 1988).
         8. Amblyomma maculatum (Website 30):
            • Common Name: Amblyomma maculatum
            • GenBank Taxonomy No.: 34609
            • Description: Rickettsiae closely related to or identical with R. rickettsii have been recovered also from Amblyomma americanum, A. maculatum, D. occidentalis, I. scapularis, I. pacificus, and I. cookei. These ticks do attack humans and must be considered potential vectors of R. rickettsii. As yet, however, no cases of spotted fever have been associated with bites by these ticks(Burgdorfer, 1988).
         9. Dermacentor occidentalis (Website 29):
            • Common Name: Dermacentor occidentalis
            • GenBank Taxonomy No.: 60254
            • Description: Rickettsiae closely related to or identical with R. rickettsii have been recovered also from Amblyomma americanum, A. maculatum, D. occidentalis, I. scapularis, I. pacificus, and I. cookei. These ticks do attack humans and must be considered potential vectors of R. rickettsii. As yet, however, no cases of spotted fever have been associated with bites by these ticks(Burgdorfer, 1988).
         10. Ixodes scapularis (Website 26):
             • Common Name: Ixodes scapularis
             • GenBank Taxonomy No.: 6945
             • Description: Rickettsiae closely related to or identical with R. rickettsii have been recovered also from Amblyomma americanum, A. maculatum, D. occidentalis, I. scapularis, I. pacificus, and I. cookei. These ticks do attack humans and must be considered potential vectors of R. rickettsii. As yet, however, no cases of spotted fever have been associated with bites by these ticks(Burgdorfer, 1988).
         11. Ixodes pacificus (Website 27):
             • Common Name: Ixodes pacificus
             • GenBank Taxonomy No.: 29930
             • Description: Rickettsiae closely related to or identical with R. rickettsii have been recovered also from Amblyomma americanum, A. maculatum, D. occidentalis, I. scapularis, I. pacificus, and I. cookei. These ticks do attack humans and must be considered potential vectors of R. rickettsii. As yet, however, no cases of spotted fever have been associated with bites by these ticks(Burgdorfer, 1988).
         12. Ixodes cookei (Website 28):
             • Common Name: Ixodes cookei
             • GenBank Taxonomy No.: 35565
             • Description: Rickettsiae closely related to or identical with R. rickettsii have been recovered also from Amblyomma americanum, A. maculatum, D. occidentalis, I. scapularis, I. pacificus, and I. cookei. These ticks do attack humans and must be considered potential vectors of R. rickettsii. As yet, however, no cases of spotted fever have been associated with bites by these ticks(Burgdorfer, 1988).
3. Mammals
   1. Taxonomy Information:
      1. Species:
         1. Canis familiaris (Website 14):
            • Common Name: Canis familiaris
            • GenBank Taxonomy No.: 9615
            • Description: Rocky Mountain Spotted Fever tends to be more common in young (less than or equal to 3 years old) dogs, and more than 80% of clinical cases occur in dogs that are frequently outside. Incubation ranges from 2 to 14 days, following infection via tick transmission. In the United States, most dogs with RMSF are presented to veterinarians during March through October. German Shepard dogs have been reported to experience a higher incidence of illness, and English Springer Spaniels with suspected phosphofructokinase deficiency are reported to have a more severe and fulminant form of the disease(Warner and Wallace, 2002). In order to obtain information on Brazilian spotted fever, a study in domestic animals was performed in the County of Pedreira, State of Sao Paulo, Brazil, where 17 human cases had been notified. Serum samples obtained from animals were tested by indirect immunofluorescence for detectable antibodies to spotted fever-group rickettsiae. Seropositivity was revealed in 12 (36.4%) of 33 dogs and seven (77.8%) of nine horses from the endemic area. For comparison, blood samples from dogs and horses from non endemic area were tested and four (12.9%) of 31 dogs and three (27.3%) of 11 horses were positive. The highest titers of antibodies by IFA (IgG > or = 1:1024) were found only in three dogs and six horses from endemic area. The results suggest that dogs and horses may serve as environmental sentinels for establishing the prevalence of foci of spotted fever in Brazil(de Lemos et al., 2001).
         2. Equus caballus (Website 15):
            • Common Name: Equus caballus
            • GenBank Taxonomy No.: 9796
            • Description: In order to obtain information on Brazilian spotted fever, a study in domestic animals was performed in the County of Pedreira, State of Sao Paulo, Brazil, where 17 human cases had been notified. Serum samples obtained from animals were tested by indirect immunofluorescence for detectable antibodies to spotted fever-group rickettsiae. Seropositivity was revealed in 12 (36.4%) of 33 dogs and seven (77.8%) of nine horses from the endemic area. For comparison, blood samples from dogs and horses from non endemic area were tested and four (12.9%) of 31 dogs and three (27.3%) of 11 horses were positive. The highest titers of antibodies by IFA (IgG > or = 1:1024) were found only in three dogs and six horses from endemic area. The results suggest that dogs and horses may serve as environmental sentinels for establishing the prevalence of foci of spotted fever in Brazil(de Lemos et al., 2001).
         3. Microtus pennsylvanicus (Website 16):
            • Common Name: Microtus pennsylvanicus
            • GenBank Taxonomy No.: 10058
            • Description: Although a large variety of animals has been identified as hosts for the immature stages of these tick vectors, relatively few isolates of R. rickettsii have been reported so far. They include strains from meadow voles (M. pennsylvanicus, a pine vole (Pitymus pinetorum), white-footed mice (Peromyscus leucopus, a cotton rat (Sigmodon hispidus), cottontail rabbits (Sylvilagus floridanus), a snowshoe hare (Lepus americanus), opossum (Didelphis marsupialis virginiana), chipmunks (Eutamias spp.), and golden-manteled ground squirrels (Spermophilus lateralis tescorum)(Burgdorfer, 1988).
         4. Microtus pinetorum (Website 17):
            • Common Name: Microtus pinetorum
            • GenBank Taxonomy No.: 111839
            • Description: Although a large variety of animals has been identified as hosts for the immature stages of these tick vectors, relatively few isolates of R. rickettsii have been reported so far. They include strains from meadow voles (M. pennsylvanicus, a pine vole (Pitymus pinetorum), white-footed mice (Peromyscus leucopus, a cotton rat (Sigmodon hispidus), cottontail rabbits (Sylvilagus floridanus), a snowshoe hare (Lepus americanus), opossum (Didelphis marsupialis virginiana), chipmunks (Eutamias spp.), and golden-manteled ground squirrels (Spermophilus lateralis tescorum)(Burgdorfer, 1988).
         5. Peromyscus leucopus (Website 18):
            • Common Name: Peromyscus leucopus
            • GenBank Taxonomy No.: 10041
            • Description: Although a large variety of animals has been identified as hosts for the immature stages of these tick vectors, relatively few isolates of R. rickettsii have been reported so far. They include strains from meadow voles (M. pennsylvanicus, a pine vole (Pitymus pinetorum), white-footed mice (Peromyscus leucopus, a cotton rat (Sigmodon hispidus), cottontail rabbits (Sylvilagus floridanus), a snowshoe hare (Lepus americanus), opossum (Didelphis marsupialis virginiana), chipmunks (Eutamias spp.), and golden-manteled ground squirrels (Spermophilus lateralis tescorum)(Burgdorfer, 1988).
         6. Sigmodon hispidus (Website 19):
            • Common Name: Sigmodon hispidus
            • GenBank Taxonomy No.: 42415
            • Description: Although a large variety of animals has been identified as hosts for the immature stages of these tick vectors, relatively few isolates of R. rickettsii have been reported so far. They include strains from meadow voles (M. pennsylvanicus, a pine vole (Pitymus pinetorum), white-footed mice (Peromyscus leucopus, a cotton rat (Sigmodon hispidus), cottontail rabbits (Sylvilagus floridanus), a snowshoe hare (Lepus americanus), opossum (Didelphis marsupialis virginiana), chipmunks (Eutamias spp.), and golden-manteled ground squirrels (Spermophilus lateralis tescorum)(Burgdorfer, 1988).
         7. Sylvilagus floridanus (Website 20):
            • Common Name: Sylvilagus floridanus
            • GenBank Taxonomy No.: 9988
            • Description: Although a large variety of animals has been identified as hosts for the immature stages of these tick vectors, relatively few isolates of R. rickettsii have been reported so far. They include strains from meadow voles (M. pennsylvanicus, a pine vole (Pitymus pinetorum), white-footed mice (Peromyscus leucopus, a cotton rat (Sigmodon hispidus), cottontail rabbits (Sylvilagus floridanus), a snowshoe hare (Lepus americanus), opossum (Didelphis marsupialis virginiana), chipmunks (Eutamias spp.), and golden-manteled ground squirrels (Spermophilus lateralis tescorum)(Burgdorfer, 1988).
         8. Lepus americanus (Website 21):
            • Common Name: Lepus americanus
            • GenBank Taxonomy No.: 48086
            • Description: Although a large variety of animals has been identified as hosts for the immature stages of these tick vectors, relatively few isolates of R. rickettsii have been reported so far. They include strains from meadow voles (M. pennsylvanicus, a pine vole (Pitymus pinetorum), white-footed mice (Peromyscus leucopus, a cotton rat (Sigmodon hispidus), cottontail rabbits (Sylvilagus floridanus), a snowshoe hare (Lepus americanus), opossum (Didelphis marsupialis virginiana), chipmunks (Eutamias spp.), and golden-manteled ground squirrels (Spermophilus lateralis tescorum)(Burgdorfer, 1988).
         9. Didelphis virginiana, Didelphis marsupialis virginiana (Website 22):
            • Common Name: Didelphis virginiana, Didelphis marsupialis virginiana
            • GenBank Taxonomy No.: 9267
            • Description: Although a large variety of animals has been identified as hosts for the immature stages of these tick vectors, relatively few isolates of R. rickettsii have been reported so far. They include strains from meadow voles (M. pennsylvanicus, a pine vole (Pitymus pinetorum), white-footed mice (Peromyscus leucopus, a cotton rat (Sigmodon hispidus), cottontail rabbits (Sylvilagus floridanus), a snowshoe hare (Lepus americanus), opossum (Didelphis marsupialis virginiana), chipmunks (Eutamias spp.), and golden-manteled ground squirrels (Spermophilus lateralis tescorum)(Burgdorfer, 1988).
         10. Tamias, Eutamias (Website 23):
             • Common Name: Tamias, Eutamias
             • GenBank Taxonomy No.: 13712
             • Description: Although a large variety of animals has been identified as hosts for the immature stages of these tick vectors, relatively few isolates of R. rickettsii have been reported so far. They include strains from meadow voles (M. pennsylvanicus, a pine vole (Pitymus pinetorum), white-footed mice (Peromyscus leucopus, a cotton rat (Sigmodon hispidus), cottontail rabbits (Sylvilagus floridanus), a snowshoe hare (Lepus americanus), opossum (Didelphis marsupialis virginiana), chipmunks (Eutamias spp.), and golden-manteled ground squirrels (Spermophilus lateralis tescorum)(Burgdorfer, 1988).
         11. Spermophilus lateralis (Website 24):
             • Common Name: Spermophilus lateralis
             • GenBank Taxonomy No.: 76772
             • Description: Although a large variety of animals has been identified as hosts for the immature stages of these tick vectors, relatively few isolates of R. rickettsii have been reported so far. They include strains from meadow voles (M. pennsylvanicus, a pine vole (Pitymus pinetorum), white-footed mice (Peromyscus leucopus, a cotton rat (Sigmodon hispidus), cottontail rabbits (Sylvilagus floridanus), a snowshoe hare (Lepus americanus), opossum (Didelphis marsupialis virginiana), chipmunks (Eutamias spp.), and golden-manteled ground squirrels (Spermophilus lateralis tescorum)(Burgdorfer, 1988).

Click here to open the network web page.

NA

Archibald and Sexton, 1995: Archibald LK, Sexton DJ. Long-term sequelae of Rocky Mountain spotted fever. Clin Infect Dis. 1995; 20(5); 1122-1125. [PubMed: 7619986].

Burgdorfer, 1975: Burgdorfer W. A review of Rocky Mountain Spotted Fever tick-borne typhus, its agent, and its tick vectors in the United States. J Med Entomol. 1975; 12(3); 269-278. [PubMed: 810584].

Burgdorfer, 1988: Burgdorfer W. Ecological and epidemiological considerations of Rocky Mountain Spotted Fever and Scrub Typhus. 34-50. In: . Biology of Rickettsial Diseases Volume I.. 1988. CRC Press Inc, Boca Raton, Florida.

Figueiredo et al., 1999: Figueiredo LT, Badra SJ, Pereira LE, Szabo MP. Report on ticks collected in the Southeast and Mid-West regions of Brazil: analyzing the potential transmission of tick-borne pathogens to man. Rev Soc Bras Med Trop. 1999; 32(6); 613-619. [PubMed: 10881097].

Folds et al., 1983: Folds JD, Walker DH, Hegarty BC, Banasiak D, Lange JV. Rocky Mountain spotted fever vaccine in an animal model. J Clin Microbiol.. 1983; 18(2); 321-326. [PubMed: 6413529].

Holman et al., 2001: Holman RC, Paddock CD, Curns AT, Krebs JW, McQuiston JH, Childs JE. Analysis of risk factors for fatal Rocky Mountain Spotted Fever: evidence for superiority of tetracyclines for therapy. J Infect Dis. 2001; 184(11); 1437-1444. [PubMed: 11709786].

Kirkland et al., 1992: Kirkland KB, Marcom PK, Sexton DJ, Dumler JS, Walker DH. Rocky Mountain spotted fever complicated by gangrene: report of six cases and review. Clin Infect Dis.. 1993; 16(5); 629-634. [PubMed: 8507753].

La Scola and Raoult, 1997: La Scola B, Raoult D. Laboratory diagnosis of rickettsioses: current approaches to diagnosis of old and new rickettsial diseases. J Clin Microbiol. 1997; 35(11); 2715-2727. [PubMed: 9350721].

McDade and Newhouse, 1986: McDade JE, Newhouse VF. Natural History of Rickettsia rickettsii. Ann Rev Microbiol. 1986; 40; 287-309. [PubMed: 3096192].

McGinley-Smith and Tsao, 2003: McGinley-Smith DE, Tsao SS. Dermatoses from ticks. J Am Acad Dermatol. 2003; 49(3); 363-392. [PubMed: 12963900].

Niebylski et al., 1999: Niebylski ML, Peacock MG, Schwan TG. Lethal effect of Rickettsia rickettsii on its tick vector (Dermacentor andersoni). Appl Environ Microbiol. 1999; 65(2); 773-778. [PubMed: 9925615].

Philip et al., 1976: Philip RN, Casper EA, Ormsbee RA, Burgdorfer W. Microimmunofluorescence test for the serological study of rocky mountain spotted fever and typhus. J Clin Microbiol. 1976; 3(1); 51-61. [PubMed: 815267].

Procop et al., 1997: Procop GW, Burchette JLJ, Howell DN, Sexton DJ. Immunoperoxidase and immunofluorescent staining of Rickettsia rickettsii in skin biopsies. A comparative study. Arch Pathol Lab Med. 1997; 121(8); 894-899. [PubMed: 9278621].

Raoult and Drancourt, 1991: Raoult D, Drancourt M. Antimicrobial therapy of rickettsial diseases. Antimicrob Agents Chemother. 1991; 35(12); 2457-2462. [PubMed: 1810178].

Rolain et al., 1998: Rolain JM, Maurin M, Vestris G, Raoult D. In vitro susceptibilities of 27 rickettsiae to 13 antimicrobials. Antimicrob Agents Chemother. 1988; 42(7); 1537-1541. [PubMed: 9660979].

Sammons et al., 1976: Sammons LS, Kenyon RH, Burger GT, Pedersen CE Jr, Spertzel RO. Changes in blood serum constituents and hematologic values in Macaca mulatta with Rocky Mountain spotted fever. Am J Vet Res. 1976; 37(6); 725-730. [PubMed: 820224].

Sammons et al., 1977: Sammons LS, Kenyon RH, Hickman RL, Pedersen CE Jr. Susceptibility of laboratory animals to infection by spotted fever group rickettsiae. Lab Anim Sci. 1977; 27(2); 229-234. [PubMed: 857087].

Sexton and Kaye, 2002: Sexton DJ, Kaye KS. Rocky Mountain Spotted Fever. Medical Clinics of North America. 2002; 86(2); 351-360. [PubMed: 11982306].

Silber, 1996: Silber JL. Rocky Mountain spotted fever. Clin Dermatol. 1996; 14(3); 245-258. [PubMed: 8727127].

Steinfeld et al., 1988: Steinfeld HJ, Silverstein J, Weisburger W, Rattner F. Deafness associated with Rocky Mountain spotted fever. Md Med J. 1988; 37(4); 287-288. [PubMed: 3367718].

Treadwell et al., 2000: Treadwell TA, Holman RC, Clarke MJ, Krebs JW, Paddock CD, Childs JE. Rocky Mountain spotted fever in the United States, 1993-1996. Am J Trop Med Hyg. 2000; 63(1-2); 21-26. [PubMed: 11357990].

Walker and Lane, 1988: Walker DH, Lane TW. Rocky Mountain Spotted Fever: Clinical signs, symptoms, and pathophysiology. 63-78. In: . Biology of Rickettsial Diseases Volume I.. 1988. CRC Press Inc, Boca Raton, Florida.

Walker et al., 1982: Walker DH, Firth WT, Edgell CJ. Human endothelial cell culture plaques induced by Rickettsia rickettsii. Infect Immun. 1982; 37(1); 301-306. [PubMed: 6809631].

Walker, 1989: Walker DH. Rocky Mountain spotted fever: a disease in need of microbiological concern. Clin Microbiol Rev. 1989; 2(3); 227-240. [PubMed: 2504480].

Walker, 1995: Walker DH. Rocky Mountain Spotted Fever: A Seasonal Alert. Clin Infect Dis. 1995; 20(5); 1111-1117. [PubMed: 7619984].

Warner and Wallace, 2002: Warner RD, Wallace WM. Rocky Mountain Spotted Fever. J Am Vet Med Assoc. 2002; 221(10); 1413-1417. [PubMed: 12458609].

Weber and Walker, 1991: Weber DJ, Walker DH. Rocky Mounatin Spotted Fever. Infect Dis Clin North Am. 1991; 5(1); 19-35. [PubMed: 1904897].

Website 10: Amblyomma americanum

Website 11: Haemaphysalis leporispalustris

Website 12: Dermacentor parumapertus

Website 13: Amblyomma cajennense

Website 14: Canis familiaris

Website 15: Equus caballus

Website 16: Microtus pennsylvanicus

Website 17: Microtus pinetorum

Website 18: Peromyscus leucopus

Website 19: Sigmodon hispidus

Website 2: Rickettsial Pathogens and Their Arthropod Vectors

Website 20: Sylvilagus floridanus

Website 21: Lepus americanus

Website 22: Didelphis virginiana

Website 23: Tamias

Website 24: Spermophilus lateralis

Website 25: Ixodes brunneus

Website 26: Ixodes scapularis

Website 27: Ixodes pacificus

Website 28: Ixodes cookei

Website 29: Dermacentor occidentalis

Website 3: Rocky Mountain spotted fever. The Organism

Website 30: Amblyomma maculatum

Website 31: Rocky Mountain Spotted Fever. Signs and Symptoms

Website 32: BMBL Section VII. Agent Summary Statements. Section VII-E: Rickettsial Agents

Website 4: Rocky Mountain spotted fever. Laboratory Detection

Website 5: Rickettsia rickettsii Rick_1, whole genome shotgun sequence

Website 6: Rocky Mountain Spotted Fever: Epidemiology

Website 7: Homo sapiens

Website 8: Dermacentor andersoni

Website 9: Dermacentor variabilis

Weinberg et al., 1969: Weinberg EH, Stakebake JR, Gerone PJ. Plaque assay for Rickettsia rickettsii. J Bacteriol. 1969; 98(2); 398-402. [PubMed: 4977475].

Weller et al., 1998: Weller SJ, Baldridge GD, Munderloh UG, Noda H, Simser J, Kurtti TJ. Phylogenetic placement of rickettsiae from the ticks Amblyomma americanum and Ixodes scapularis. J Clin Microbiol. 1998; 36(5); 1305-1317. [PubMed: 9574696].

de Lemos et al., 2001: de Lemos ER, Alvarenga FB, Cintra ML, Ramos MC, Paddock CD, Ferebee TL, Zaki SR, Ferreira FC, Ravagnani RC, Machado RD, Guimaraes MA, Coura JR. Spotted fever in Brazil: a seroepidemiological study and description of clinical cases in an endemic area in the state of Sao Paulo. Am J Trop Med Hyg. 2001; 65(4); 329-334. [PubMed: 11693878].

 

PathInfo: Rebecca Wattam

HazARD: (for the section of Lab Animal Pathobiology & Management)

PHIDIAS: Yongqun "Oliver" He

Link to Advanced Search on Pathogen-Host Interactions