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Rocky Mountain spotted fever and other rickettsial infections
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Courtesy of Frederick A. Perieira, MD
The taxonomy of the Rickettsiales order has been reclassified based upon updated genetic and molecular analysis. Coxiella genus and Bartonella genus are no longer considered to be a part of the Rickettsial order. Coxiella is now a part of the Legionellales Gram-negative order and Bartonella is in the Rhizobiales Gram-negative bacteria order. The Rickettsiale order comprises Gram-negative bacteria and includes the genera Rickettsia , Neorickettsia , Anaplasma , Ehrlichia , and Orientia . These different bacterial orders remain mentioned together in this chapter, as they are vectorborne diseases that have similar clinical presentations and treatments. These diseases are divided into the spotted fevers (including Rocky Mountain spotted fever [RMSF]), the typhus group, rickettsialpox, Q fever, and ehrlichiosis.
Rickettsial Spotted Fevers
These infections include African tick bite fever (Rickettsia africae) , Astrakhan fever (R. conorii) , Flinders Island spotted fever (R. honei) , Indian tick typhus (R. conorii) , Israeli spotted fever (R. conorii) , Japanese spotted fever (R. japonica) , Mediterranean spotted fever (R. conorii) , Queensland tick typhus (R. australis) , Siberian tick typhus (R. sibirica) , and RMSF (R. rickettsii) . All of the spotted fevers are first evident with a maculopapular rash; 50–90% of them worldwide have an eschar, except for RMSF, with less than 1% of patients developing an eschar.
RMSF is caused by Rickettsia rickettsii and is endemic to most areas of the United States with a high degree of prevalence in North Carolina, Tennessee, and Oklahoma. RMSF is transmitted by Dermacentor andersoni in the western United States and by D. variabilis in the eastern United States. The classic triad of fever, headache, and rash is only seen in about 3% of the patients during the first 3 days of the disease, but by day 14 up to 70% of them may have this triad. The tick bite is typically painless, so the patient may not recall it happening. The infection is characterized by an acute onset of fever (95%), headache (90%), and myalgia (85%), followed by vomiting (60%) and a rash (90%). The rash first appears as erythematous blanching macules over the forearms, wrists, and ankles 2–4 days after the onset of fever. These macules often spread to include the trunk, palms, hands, and feet. After the 5th day of illness, the macules change to petechiae. Antibiotic treatment should be initiated before the development of the petechial rash, as this is a sign of severe disease. Bilateral calf pain is the most common presenting complaint. Gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, and vomiting occur in nearly half of patients, usually early in the course of the illness. These findings often lead to a misdiagnosis or delay in therapy. Vascular injury to the small intestine, appendix, and gallbladder may occur, in some cases mimicking acute cholecystitis, or even appendicitis.
Diagnosis is most often based on clinical presentation, as patients may have a history of a tick bite after spending time in an endemic area. Clinical suspicion requires rapid initiation of therapy even while skin biopsies and confirmatory tests are pending. Serologic tests, including indirect immunofluorescence, latex agglutination, and enzyme immunoassay that detect antirickettsial antibodies, are available. However, these tests usually yield negative readings in the critical first days of the disease, as antibodies are not detectable until 7–10 days after the onset of the illness. Confirmation of the diagnosis using acute- and convalescent-phase serum samples is possible with these tests. The indirect hemagglutination antibody and immunofluorescent antibody tests are most useful because of their high sensitivity and specificity. The immunofluorescent test is especially beneficial because of its capacity to assess IgG and IgM levels. Highly specific and sensitive pan- Rickettsia and R. rickettsii -specific polymerase chain reaction (PCR) assays for the detection of the spotted fever and typhus group of Rickettsiae have been developed for rapid diagnostic confirmation when rickettsial loads are low. Detection by PCR of DNA in cutaneous lesional specimens or an acute phase whole blood specimen should be considered with testing available at some local and state health departments in the United States. A complete blood count and liver function tests should be obtained. Most patients will have some degree of anemia or leukopenia, though in some cases the white blood count may be elevated. Thrombocytopenia may occur in severe cases. Hepatic enzymes, bilirubin, and lactate dehydrogenase may be elevated. Skin biopsy can aid in the diagnosis of RMSF; Giemsa staining and direct immunofluoresce (DIF) can facilitate the diagnosis. Blood cultures or a skin biopsy specimen may be used to confirm the diagnosis, but are not helpful in the initial diagnosis of spotted fevers due to the length of time they require for results.
Management Strategy
Clinical suspicion of a spotted fever is sufficient to warrant treatment. Serologic confirmation should not delay the initiation of appropriate therapy. Diagnosis is difficult, as the characteristic rash is not a reliable sign, and the classic triad of a tick bite, rash, and fever is often not evident.
Specific Investigations
See https://www.cdc.gov/rmsf/healthcare-providers/ClinLab-Diagnosis.html (accessed June 2020).
Immunofluorescence antibody (IFA) assay for IgG against the R. rickettsii antigen should be performed twice to show a fourfold seroconversion to establish the diagnosis. The first serology should be done 7–10 days after the beginning of symptoms and the second IFA should be done 2–4 weeks later. Antibodies to R. rickettsii may continue to be elevated for years after the disease is cured and a single serological test may lead to the misdiagnosis of the disease, as more than 10% of the population in endemic areas may have elevated antibody titer.
Diseases from North America: focus on tick-borne infections
Nathavitharana RR, Mitty JA. Clinical Medicine 2015; 15: 74–7.
The sensitivity of serology is poor during the first days of infection, and only starts to reach a substantial sensitivity of 94% on days 14–21. CSF shows mild elevation in protein levels and an elevation of lymphocytes. Direct immunofluorescence on skin biopsies has an approximate sensitivity of 70% and a specificity of 100%.
As spotted fevers progress rapidly, immediate treatment is required, ideally in the first 3–4 days. Doxycycline is the best first-line agent for treating RMSF and other spotted fevers. Doxycycline is administered at a dose of 100 mg twice daily orally in adults. Children under 45.4 kg should receive 2.2 mg/kg twice daily orally. The therapeutic benefit provided by doxycycline in the treatment of RMSF outweighs the potential risk for tooth discoloration in children receiving doxycycline. These oral antibiotics are taken for a minimum of 7 days and are continued until the patient is afebrile for 72 hours. Within 24 hours of the initiation of treatment, a response may be observed. Within the first 48 hours, considerable clinical improvement is seen; apyrexia is often achieved by 72 hours. In severe cases requiring hospitalization, a loading dose of doxycycline at a dose of 200 mg every 12 hours is given intravenously for the first 72 hours followed by the normal dose of 100 mg every 12 hours.
Azithromycin at a dose of 500 mg once daily by mouth can also be used as a second-line treatment. Chloramphenicol can be employed at a dose of 50–100 mg/kg divided into four doses for 7 days; however, close monitoring is prudent due to the increased risk of complications including gray baby syndrome in pregnant women and aplastic anemia in children. Thus, the use of chloramphenicol is recommended with caution as a third-line treatment option.
Death occurs at a higher rate if patients are untreated beyond the 5th day of illness onset. Of note, early discontinuation of therapy may result in relapse. RMSF has a case-fatality rate as high as 30% in certain untreated patients. Even with treatment, hospitalization rates of 72% and case-fatality rates of 4% are seen.
Supportive care is also an important component in successful treatment. A high-protein diet, adequate hydration, and continuous monitoring of blood volume are critical. In cases in which renal, pulmonary, or cardiac complications occur, other specialized therapies may be required.
Prognosis is related to the timely diagnosis and initiation of effective treatment. Prevention is achieved by avoiding areas with ticks. Covering skin with long protective clothing reduces the risk of exposure. Clothing may be impregnated with acaricidal compounds for added protection. Any uncovered skin should be treated with a topical insect repellent before activities in high-risk areas. Unfortunately, most insect repellents are effective for only short periods and need to be reapplied frequently. Thorough skin examinations should be conducted regularly, at least twice daily in endemic areas, and any ticks removed. The scalp, axillary, and pubic hair require particularly careful examination. There is currently no effective vaccine, although immunogenic surface protein antigens have been cloned and sequenced.
The evaluation and management of Rocky Mountain spotted fever in the emergency department: a review of the literature
Gottlieb M, Long B, Koyfman A. J Emerg Med 2018; 55(1): 42–50.
Two-thirds of cases occur in patients younger than 15 years old; males are more likely to be affected than females. The majority of experts recommend doxycycline as the first-line treatment for children, adults, and pregnant women.
No visible dental staining in children treated with doxycycline for suspected Rocky Mountain spotted fever
Todd SR, Dahlgren FS, Traeger MS, et al. J Pediatr 2015; 166: 1246–51.
This study failed to demonstrate enamel hypoplasia, dental staining, or tooth color changes in children under 8 years of age who received short-term courses of doxycycline. Confidence in the use of doxycycline for children suspected of having RMSF may be improved if the drug’s label was changed to reflect these findings.
Fatal Rocky Mountain spotted fever in the United States, 1999–2007
Dahlgren FS, Holman RC, Paddock CD, et al. Am J Trop Med Hyg 2012; 86: 713–9.
The study highlights several risk groups who are more likely to die of RMSF: children 5–9 years of age, American Indians, immunosuppressed patients, and severe cases experiencing delayed diagnosis and/or treatment. Doxycycline should be used as the first-line drug against RMSF for all ages, even in children less than 8 years old.
Rocky Mountain spotted fever in children
Woods CR. Pediatr Clin North Am 2013; 60: 455–70.
RMSF is often undifferentiated from many infections during the first days of illness. Accordingly, doxycycline should not be delayed pending confirmation even in children under the age of 8 years.
Risk factors for fatal outcome from Rocky Mountain spotted fever in a highly endemic area—Arizona, 2002–2011
Regan JJ, Traeger MS, Humpherys D, et al. Clin Infect Dis 2015; 60: 1659–66.
Treatment with doxycycline during the first 3 days of the disease can decrease morbidity and mortality from RMSF in this region. Risk factors associated with doxycycline delay and fatal outcomes include 1) gastrointestinal symptoms, 2) alcoholism, and 3) chronic lung disease. There should be a low threshold for initiating doxycycline, especially in endemic areas like tribal lands in Arizona.
Revisiting doxycycline in pregnancy and early childhood – time to rebuild its reputation?
Cross R, Ling C, Day NP, et al. Expert Opin Drug Saf 2016; 15: 367–82.
A systematic review of the literature on the use of doxycycline during pregnancy and in children revealed that there is no correlation between the use of doxycycline and teratogenic effects during pregnancy or dental staining in children.
Bilateral sensorineural deafness in a young pregnant female presenting with a fever: a rare complication of a reemerging disease-spotted fever group rickettsioses
Kariyawasam AGTA, Palangasinghe DR, Fonseka CL, et al. Case Rep Infect Dis 2019; Article ID 5923146. doi: 10.1155/2019/5923146.
Sensorineural deafness is a rare complication in spotted fever group rickettsioses. In rickettsial diseases complicated with organ involvement, a prolonged course of antibiotics is recommended. This patient was treated successfully with azithromycin for 10 days, although bilateral sensorineural deafness took several months to resolve.
Rocky Mountain spotted fever and pregnancy: four cases from Sonora, Mexico
Licona-Enriquez JD, Delgado-de la Mora J, Paddock CD, et al. Am J Trop Med Hyg 2017; 97: 795–8.
Chloramphenicol has been effective in the treatment of some cases of RMSF, but it is also associated with many side effects including gray baby syndrome, bone marrow suppression, and aplastic anemia. It has also been associated with increased mortality in some cases of RMSF.
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