Rocky mountain spotted fever

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Rocky Mountain spotted fever (RMSF)? What are the typical findings for this disease?

Primary manifestations:

  • Early diagnosis currently must be based on clinical grounds alone, and is critical to preclude adverse outcomes.

  • The most common symptoms include fever (98%), any macular, maculopapular, or petechial rash (97%), and nausea or vomiting (73%).

  • The next most common signs and symptoms include headache (61%), myalgia (45%), and abdominal pain (36%), all except in children <2 years of age.

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  • Rash is not frequent at presentation, appearing from day 1 to 4; only 58% of patients have fever, rash, and headache, and only 45% have fever, rash, and tick attachment history.

  • RMSF is an acute, sudden onset disease, escalating over days.

    An incubation period of approximately 7 to 14 days can be expected after tick bite or exposure.

    Illness lasts generally less than 2 weeks if untreated, although non-febrile clinical sequelae can persist.

    Defervescence occurs around 9 days after onset, and hospital discharge at 12 days in most cases.

Other considerations:

1. Chronic, persistent, or mild disease with low or no fever is unlikely to be RMSF.

Central nervous system involvement

1. Evidence of CNS involvement (altered mental status) is identified in 33% of cases. Photophobia, seizures, and meningismus are observed in about 15%-20%.

What other disease/condition shares some of these symptoms?

1. Other rickettsial infections, such as human monocytic ehrlichiosis, human granulocytic anaplasmosis, and murine typhus.

2. Rash and septic-like presentations can occur also with meningococcemia.

3. Viral infections, including enteroviruses, are strong mimics.

4. Other mimics include typhoid fever, secondary syphilis, Lyme disease, leptospirosis, toxic shock syndrome, scarlet fever and rheumatic fever, rubella, parvovirus infection, Kawasaki disease, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), and Henoch-Schönlein purpura/hemolytic-uremic syndrome (HSP/HUS), among others.

What caused this disease to develop at this time?

  • RMSF virtually only occurs after tick bites; thus, a history of tick bite or exposure to tick habitats is an important feature, especially within the prior 10 days, since the incubation period is about 1 week.

  • Most exposures occur during spring and summer, when the weather is warm and outdoor activity frequent.

  • Exposure to rural and suburban environments, and outdoor pets like dogs, increase the risk for tick bites.

  • Family clusters occur, suggesting common environmental exposures where infected ticks are more prevalent.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Diagnosis of RMSF should not depend upon any specific laboratory diagnostic test, but rather, depends on clinical, historical and limited laboratory findings.

  • The white blood cell count is usually within normal limits, although both leukopenia (9%) and leukocytosis (24%) are sometimes observed.

  • Platelet counts are low in 59% of cases (mean 128,000 platelets/μL).

  • CSF pleocytosis is modest (25 WBC/μL), and usually mononuclear cells dominate; although neutrophils can comprise up to 56% of cells. Glucose is usually normal, but protein is elevated.

  • The only pathogen-specific diagnostic test useful at presentation of disease is antigen detection of R. rickettsii in skin biopsy of rash by immunofluorescence or immunohistochemistry. This is not widely available, turn-around-time could be several days, and a skin rash must be present.

  • While promising, PCR methods for amplification of R. rickettsii DNA from blood are not proven to be sensitive for early diagnosis.

  • Although serum for acute phase serology should be obtained, it is very unlikely to provide useful diagnostic information since antibody responses develop over several weeks.

Would imaging studies be helpful? If so, which ones?

  • Imaging studies are rarely helpful.

Confirming the diagnosis

  • No clinical decision algorithms are available for suspecting/confirming the diagnosis of RMSF.

If you are able to confirm that the patient has RMSF, what treatment should be initiated?

  • If clinical suspicion warrants consideration of RMSF, treatment should be instituted promptly, as it could be life-saving.

  • The American Academy of Pediatrics recommends the use of doxycycline as the drug of choice for treatment of RMSF in children of ANY age.

  • Early treatment, before day 5 of illness, is advocated for the likelihood of a good outcome.

  • Doxycycline treatment should be continued until 3 days after fever resolves and clinical improvement is observed. Typically, treatment duration is 7 to 10 days.

  • For children <45 kg, doxycycline is given at 4.4 mg/kg/day intravenously, or orally in 2 divided doses.

  • For children >45 kg, doxycycline is given as 100 mg twice daily intravenously or orally.

  • Chloramphenicol is considered an effective alternative, but is associated with rare serious adverse effects, the requirement for monitoring of serum drug levels, and the lack of an oral preparation in the United States. Chloramphenicol is further epidemiologically linked to worse outcomes compared with doxycycline use.

  • Chloramphenicol is given as four 500 mg doses daily by intravenous route; serum levels need to be maintained between 20-30 μg/mL, especially in children <2 years old.

  • Very little evidence supports the use of fluoroquinolones for RMSF.

What are the adverse effects associated with each treatment option?

Doxycycline can be associated with tooth staining in children; however, this adverse effect is related to total dosage during childhood years and doxycycline is now used sparingly.

Chloramphenicol is associated with idiosyncratic aplastic anemia and neurological toxicity.

What are the possible outcomes of RMSF?

Most children with RMSF do well after treatment, especially if treated within the first 5 days after onset. With doxycyline treatment, most will defervesce within 2 days.

Most infections (90%) are severe enough to require hospitalization. ICU admission is required in 33%, mechanical ventilation is needed in 16%, and the case fatality rate is approximately 4%.

Long-term sequelae, especially neurological sequelae, are observed in 15% of children, including speech/swallowing dysfunction, encephalopathy, ataxia, cortical blindness, and behavioral and learning disabilities, especially if severely impaired during the active infection. The deficits can persist for months to years.

Ischemic injury can result in autoamputation of digits, even limbs, and can cause long-term disability.

Owing to the high case fatality rate (3%-8%) with RMSF, treatment with doxycycline or another anti-rickettsial regimen can be life-saving. Compared with the risks of tooth staining, gastrointestinal disturbances, or photosensitivity, the benefits of treatment far outweigh any risks.

What causes this disease and how frequent is it?

  • RMSF is caused by infection with the obligate intracellular bacterium,
    Rickettsia rickettsii. The bacterium lives in a cycle between ticks and their normal small mammal hosts, like field mice. When an infected tick bites a human and transmits the organism, it disseminates to infect endothelial cells in all tissues and organs, compromising vascular function by eliciting vasculitis, increased vascular permeability, and possibly end-organ ischemia and damage.

  • Epidemiology:

    Incidence, seasonal variation, age distribution.

    Infection occurs only where tick infection and endemic cycles exist. For RMSF, this includes all states in the US except Alaska and Vermont, although the incidence is much higher in the South Central, Southeast, and Mountain states, and in the Four-Corners region of the Southwest.

    The majority of RMSF cases reported to the CDC in the US occur in summer (June-August), when tick activity is at a peak, but cases occur regularly in both spring and fall, and infrequently (approximately 4%) in winter.

    In the US, a minority of cases of RMSF (19%) is reported in persons 19 years of age and younger.

    Infection is acquired by the bites of infected ticks, usually adult (large) ticks.

    The American dog tick (Dermacentor variabilis) is the predominant vector east of the Rocky Mountains and in parts of California.

    The wood tick (Dermacentor andersoni) can transmit R. rickettsii in the Rocky Mountains and Pacific coast states.

    The brown dog tick (Rhipicephalus sanguineus) is an important emerging vector in the Southwest states, Mexico, and Central America; it is well adapted to peridomestic environments and is often carried on pets like dogs and cats.

    Amblyomma species ticks, such as A. cajennense, are vectors in South America.

    Tick attachment for approximately 24 hours is needed to reactivate rickettsial virulence, providing a short window for tick removal and transmission prevention.

    Predisposing exposures.

    Exposure to tick-infested environments is the primary risk factor for the transmission of R. rickettsii and the development of RMSF.

    Activity outdoors during warm months when ticks are active, especially in areas where RMSF has occurred, increase risk.

    Domestic pets, such as dogs, are potential vehicles for exposure to infected ticks, and pose an especially high risk for children.

  • What’s known about the genetics?

    RMSF has increased severity among individuals with pre-existing illnesses.

    Those with glucose-6-phosphate dehydrogenase (G6PD) deficiency are particularly prone to a rapid (<5 days) and severe course called “fulminant RMSF” that develops in the absence of significant host immune or inflammatory response.

How do these pathogens/genes/exposures cause the disease?

  • Rickettsia rickettsii, and other related species, enter the bloodstream at some interval after tick bite.

  • The rickettsiae attach to and enter endothelial cells in all tissues and organs.

  • R. rickettsii grows within the cytosol of endothelial cells, perturbing endothelial barrier function, leading to increased vascular permeability, the primary defect in RMSF.

  • Ongoing infection elicits inflammation in and around the infected endothelial cells, leading to vasculitis. Signs and symptoms are generally attributable to areas of most severe vasculitis.

  • The vasculitis rarely leads to thrombosis. It is presumed that thrombocytopenia is related to consumption of platelets in vasculitis lesions.

  • Although vasculitis does occur and the clinical picture may mimic disseminated intravascular coagulation, the pathogenesis is distinct, and coagulopathy is rarely severe enough to support that diagnosis.

  • The most severe sequelae occur with:

    generalized vascular compromise leading to hypotension and multi-organ system failure

    non-cardiogenic pulmonary edema related to massive increase in pulmonary microvascular permeability

    meningoencephalitis resulting in cerebral edema and herniation.

Other clinical manifestations that might help with diagnosis and management

RMSF occasionally presents with signs or symptoms referable to a single organ system, such as acute abdomen, leading to misdiagnosis and unnecessary surgery for appendicitis, cholecystitis, or small bowel obstruction.

What complications might you expect from the disease or treatment of the disease?

Most infections resolve rapidly after doxycycline treatment.

If appropriate anti-R. rickettsii treatment is not provided, the risk of death or long-term neurological sequelae is increased.

Are additional laboratory studies available; even some that are not widely available?

Although not yet proven sensitive or specific, PCR on blood or skin biopsy offers promise for rapid diagnosis at the time when therapeutic decisions are being made.

Testing of ticks after tick bite for the presence of R. rickettsii has no role in therapeutic or prophylaxis decisions.

How can RMSF be prevented?

Prophylactic doxycycline for tick bites is considered contraindicated because it is only bacteriostatic for R. rickettsii, although the evidence basis for this is meager.

No effective vaccine is available.

Key preventive measures include:

  • avoiding tick-infested environments;

  • frequent “tick checks” with prompt removal of any attached ticks;

  • the use of light-colored clothing, including long pants and long sleeve shirts; tick repellants (although these often inactivate sunscreens);

  • use of insecticide/acaricide-treated clothes.

What is the evidence?

Diagnostic tests:


Newhouse, VF, Shepard, CC, Redus, MD. “A comparison of the complement fixation, indirect fluorescent antibody, and microagglutination tests for the serological diagnosis of rickettsial diseases”. Am J Trop Med Hyg. vol. 28. 1979. pp. 387-95.

Philip, RN, Casper, EA, Ormsbee, RA. “Microimmunofluorescence test for the serological study of rocky mountain spotted fever and typhus”. J Clin Microbiol. vol. 2. 1976. pp. 51-61.

Clements, ML, Dumler, JS, Fiset, P. “Serodiagnosis of Rocky Mountain spotted fever: comparison of IgM and IgG enzyme-linked immunosorbent assays and indirect fluorescent antibody test”. J Infect Dis. vol. 148. 1983. pp. 876-80.


Walker, DH, Cain, BG, Olmstead, PM. “Laboratory diagnosis of Rocky Mountain spotted fever by immunofluorescent demonstration of Rickettsia in cutaneous lesions”. Am J Clin Pathol. vol. 69. 1978. pp. 619-23.

Dumler, JS, Gage, WR, Pettis, GL. “Rapid immunoperoxidase demonstration of Rickettsia rickettsii in fixed cutaneous specimens from patients with Rocky Mountain spotted fever”. Am J Clin Pathol. vol. 93. 1990. pp. 410-4.


Sexton, DJ, Kanj, SS, Wilson, K. “The use of a polymerase chain reaction as a diagnostic test for Rocky Mountain spotted fever”. Am J Trop Med Hyg. vol. 50. 1994. pp. 59-63.

Holman, RC, Paddock, CD, Curns, AT. “Analysis of risk factors for fatal Rocky Mountain Spotted Fever: evidence for superiority of tetracyclines for therapy”. J Infect Dis. vol. 184. 2001. pp. 1437-44.

Chen, LF, Sexton, DJ. “What's new in Rocky Mountain spotted fever?”. Infect Dis Clin North Am. vol. 22. 2008. pp. 415-32.

Buckingham, SC, Marshall, GS, Schutze, GE. “Clinical and laboratory features, hospital course, and outcome of Rocky Mountain spotted fever in children”. J Pediatr. vol. 150. 2007. pp. 180-4.

Ongoing controversies regarding etiology, diagnosis, treatment

R. rickettsii serologic studies are often requested for summertime febrile illnesses; low titers or low-level reactivity is not infrequent in single serum samples and should not be the basis for a diagnosis of RMSF.