AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

Rocky Mountain spotted fever (RMSF), classically characterized by fever, myalgias, headache, and a petechial rash, is the most common fatal tick-borne disease in the United States. As one of the spotted fevers, it belongs to a large group of tick- and mite-borne infections caused by closely related rickettsiae. These organisms are small, gram-negative bacteria that grow strictly in eukaryotic cells. Rickettsia rickettsii is the organism responsible for RMSF.

The tick that functions as the vector and the reservoir in RMSF is usually the American dog tick (Dermacentor variabilis) in the eastern United States or the Rocky Mountain wood tick (Dermacentor andersoni) in the western United States. However, a 2002-2004 outbreak in Arizona was traced to the common brown dog tick (Rhipicephalus sanguineus), a tick common worldwide but not previously recognized as a vector of disease. 

The chance for an individual tick to harbor Rickettsia rickettsii is slight. Although an estimated 4% of the American dog ticks are infected with Rickettsia species, the vast majority of these organisms are nonpathogenic Rickettsia. Therefore, prophylactic treatment of a tick bite is not indicated.

Mortality rates as high as 30% were reported for RMSF in the preantibiotic era. The current mortality rate is 1.4%. A significant portion of this persistent mortality likely is due to delay in diagnosis and treatment.

Pathophysiology

Rickettsia are introduced into humans after an infected tick feeds for more than 6 hours. The tick bite is painless and frequently goes unnoticed. Rickettsia enter the skin and spread via lymphatics to the bloodstream and attach to their target cells, vascular endothelial cells.

Rickettsia replicate intracellularly and after an average of 1 week (range, 3-12 d), the patient develops clinical manifestations of infection. Illness is characterized by increased vascular permeability with a subsequent host mononuclear cell response. Systemic increase in vascular permeability leads to edema, hypovolemia, and hypoalbuminemia.

In skin, vascular injury initially appears as blanchable erythematous macules (1-5 mm in diameter). Eventually, progression to the classic petechial rash of RMSF usually occurs, although from 10-15% of patients will not have any clinically apparent dermatologic involvement (Rocky Mountain spotless fever).

Central nervous system (CNS) manifestations include encephalitis and meningoencephalitis secondary to vascular injury. Seizures, cranial nerve damage, and permanent blindness and deafness have been documented.

Pulmonary involvement may lead to noncardiogenic pulmonary edema, interstitial pneumonia, and adult respiratory distress syndrome (ARDS), contributing significantly to mortality.

Myocarditis may occur secondary to microcirculatory vasculitis. 

Renal manifestations include decreased glomerular filtration rates (GFRs) and prerenal azotemia from hypovolemia.

Focal hepatocellular necrosis occurs in 38% of patients, as evidenced by moderately increased serum aminotransferase levels. Autopsies of patients with RMSF have revealed portal triaditis and vasculitis. However, hepatic failure does not typically occur.

Gastrointestinal (GI) endothelial cell injury leads to abdominal pain, nausea, vomiting, and diarrhea. Many patients have guaiac positive stools. Thirty percent of patients are anemic, and death has been reported from massive GI bleeding.

Remember that RMSF is a multisystem disease. In any particular patient, one organ system may be more affected than the others.

Frequency

United States

In 2004, 1514 cases were reported—more than 4 times the 365 cases reported in 1998. The reasons for this increase are not known, but wide swings in the incidence of RMSF have occurred since 1920.

Seasonal outbreaks of RMSF parallel the activity of the tick; 90% of cases are reported from April 1 to September 30, with peaks in May and June.

Cases are geographically distributed; North Carolina and Oklahoma account for one third of total cases reported. South Carolina, Tennessee, and Georgia accounted for the third, fourth, and fifth highest number of cases. Less than 2% of the total number of cases are found in the Rocky Mountain states.

Asymptomatic infection may be common; in one study, 12% of children living in high-risk zones had positive serology test results, indicating past exposure to RMSF.¹

International

Rocky Mountain spotted fever has been extensively documented in Canada, Mexico, Central America, Colombia, and Brazil. No reports document RMSF infection outside of the Americas. However, a wide range of related spotted fever group (SFG) rickettsioses has been described across Europe, Africa, Asia, and Oceania. The true incidence of spotted fever infections internationally is not known.

Mortality/Morbidity

The overall case-fatality rate of RMSF has been reported as 1.4%.² Children younger than 5 years have a reported fatality rate of 5%.² Adults older than 70 years have a reported case-fatality rate of 9%.³ Death occurs on average 8 days after onset of symptoms.⁴ Long-term scarring, blindness, and deafness have been documented.⁵

• Patients treated 5 or more days after onset of symptoms experienced 3 times the mortality rate of patients treated earlier. Long-term morbidity is most usually seen in patients in whom treatment has been delayed.
• Patients who died received antibiotics an average of 2 days later than patients who lived.

Race

Whites have twice the incidence of African Americans. However, African Americans have a higher case-fatality rate, likely due to the greater difficulty of appreciating a rash in highly pigmented individuals. 

American Indians are at greater risk for RMSF than the general population.⁶

Sex

The male-to-female ratio is 1.7:1.

Age

• Incidence is highest among adults aged 60-69 years (3.1 cases/million persons) and children aged 5-9 years (estimated 3.3 cases/million persons).
• The highest case-fatality rate (5%) occurs among children younger than 5 years.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

A high index of suspicion is the most important aspect of diagnosing Rocky Mountain spotted fever (RMSF). Diagnosis is typically delayed. In the case series by Buckingham et al, of 92 patients eventually diagnosed with RMSF, the median delay between first visiting a health care provider and starting antirickettsial therapy was 5 days; only 49% reported a tick bite.⁷

In other studies, 66% of reported cases had a history of tick attachment 14 days prior to illness. An additional 26% of patients reported being in a tick-infested area.

Children may often present without a known history of tick exposure.

• Fever greater than 102°F - 94% of reported cases
• Fever within 3 days after tick bite - 66% of reported cases
• Headache, frequently severe - 86% of reported cases
• Myalgias - 85% of reported cases
• CNS - 25% of patients develop signs of encephalitis (ie, confusion, lethargy). This may progress to stupor, delirium, seizures, or coma.
• GI - Some patients present with anorexia, nausea, vomiting, diarrhea, and abdominal pain.

Physical

• Temperature usually is greater than 102°F.
• Seventeen percent of patients are hypotensive on presentation.
• Rash
• • Rash affects 85-90% of patients overall, usually after onset of fever, headache, myalgias, and GI symptoms.
  • Fifteen percent have a rash on the first day.
  • Fifty percent have a rash by the third day.
  • Approximately 10-15% of patients have Rocky Mountain spotless fever. This more often is reported in older patients and African American patients. Spotless fever is not synonymous with mild or early illness because substantial proportions of the deaths occur in patients without a rash.
  • Rash typically begins around the wrists and ankles, but it may start on the trunk or be diffuse at the onset.
  • Classic distribution of RMSF rash on the palms and soles occurs relatively late in the course, in 43% of patients only after the fifth day of symptoms.
  • Some reports have documented 36-80% of patients with RMSF lack the classic distribution of rash on the palms and soles.
  • Four percent have skin necrosis or gangrene secondary to hypoperfusion.
• Jaundice occurs in 8-9% of patients.
• CNS
• • Confusion and lethargy are present in 26-28% of cases.
  • Ataxia is present in 18% of cases.
  • Coma occurs in 9-10% of cases.
  • Seizures are present in 8% of cases.
  • Many other findings have been reported, including cranial nerve palsies, hearing loss, meningismus, photophobia, severe vertigo, dysarthria, aphasia, hemiplegia, paraplegia, complete paralysis, nystagmus, hyperreflexia, spasticity, fasciculations, and neurogenic bladder.
• Pulmonary findings can be consistent with pulmonary edema or focal infiltrates.
• Patients may present with an acute abdomen leading to an exploratory laparotomy. Ten percent of patients have heme-positive stools.

Causes

R rickettsii is the organism responsible for RMSF.

• Vectors
• • D variabilis - American dog tick in the eastern United States
  • D andersoni - Rocky Mountain wood tick in the western United States
  • Rhipicephalus sanguineus - Common brown dog tick in Mexico and Arizona (R rickettsii has been detected in this tick in California.)
  • Amblyomma cajennense - Central America and South America

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Influenza
Enterovirus infection
Typhoid fever
Bacterial sepsis
Meningococcemia
Disseminated gonococcal infection
Drug hypersensitivity
Immune complex vasculitis
Staphylococcal sepsis
Murine typhus
Rickettsialpox
Recrudescent typhus
Sylvatic flying squirrel-associated Rickettsia prowazekii infection

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• Basic laboratory tests should be obtained, including the following: CBC count, electrolytes, renal function tests, liver function tests, and coagulation panel.
• Hyponatremia, secondary to increased ADH secretion in response to hypovolemia, is observed in 56% of patients.
• Thrombocytopenia is observed in 50% of patients.
• Anemia, abnormal liver function test results, or increased BUN level is found in 30% of patients.
• Blood culture
• • Isolation of R rickettsii from the blood is possible, but few laboratories perform this isolation because of biohazard concerns.
  • This is an insensitive test because most of the Rickettsia are found in the vascular endothelial cells, not in the bloodstream.

Imaging Studies

• Obtain a chest radiograph in patients who appear significantly ill or have abnormal lung findings on physical examination.
• Computed tomography or MRI are indicated for altered mental status or neurologic deficits, and may reveal infarction, edema, and meningeal enhancement. 

Other Tests

• No microbiological or immunological tests are sensitive enough to exclude the diagnosis of RMSF within the time frame of emergency evaluation and management. The decision to administer antibiotics should be based on history, physical examination, and clinical suspicion, not confirmatory tests.
• Serologic testing is frequently used as a confirmatory test. However, it is only useful after acute infection because serum antibodies become detectable during convalescence.
• Indirect immunofluorescence has a sensitivity of 94-100% and a specificity of 100%.
• • According to the Centers for Disease Control and Prevention (CDC), titers of 1:64 are considered evidence of current or past infection. A 4-fold increase of titers at a 3-week interval demonstrates new infection.⁸
  • Indirect immunofluorescence is the most commonly used serologic test.
• Indirect hemagglutination has a sensitivity of 71-94% and a specificity of 96-99%; 1:128 titers are diagnostic.
• Latex agglutination can be used; titers of 1:64 are diagnostic.
• Complement fixation is a much less sensitive test; titers of 1:16 are diagnostic.

Procedures

• Direct immunofluorescence of cutaneous biopsy specimens is the only timely diagnostic method during the acute phase.
• • Results can be available in 3 hours.
  • It has a sensitivity of 70% and a specificity of 100%.
  • However, with a 30% false-negative rate patients should be treated even if the test is negative and the suspicion is high.
• Lumbar puncture
• • Lumbar puncture usually is performed as part of the workup for suspected meningitis.
  • Pleocytosis is found in 34-38% of cases. Usually 10-100 cells/µL with a mononuclear cell predominance are found.
  • Increased protein is found in 30-35% of cases.
  • The glucose level usually is normal.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Prehospital Care

Deliver supportive care, including airway support and intravenous fluids, as determined by severity of the patient's condition.

Emergency Department Care

• Intravenous hydration if hypotension or prerenal azotemia is present
• Supplemental oxygen and endotracheal (ET) intubation for airway protection and ventilatory support, as indicated
• Packed red blood cells (pRBCs) for anemia or severe life-threatening GI bleeding
• Platelet transfusion for severe thrombocytopenia with active bleeding
• Hemodialysis for oliguric or anuric acute tubular necrosis
• Pulmonary artery catheter placement for judicious fluid replacement in patients with hypovolemia and ARDS

Consultations

Because the differential diagnosis includes many rare diseases, consultations from a dermatologist and/or infectious diseases subspecialists may be needed.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Tetracyclines are the drugs of choice (DOC) for Rocky Mountain spotted fever (RMSF). Despite the risk of teeth staining, tetracycline is now preferred over chloramphenicol for children younger than 9 years. In the review by Holman et al of 6388 cases of RMSF reported between 1981 and 1998, patients treated with chloramphenicol only had an odds ratio for mortality of 5.5, after adjustment for other risk factors.⁹ 

Doxycycline therapy also treats Lyme disease, ehrlichiosis, and relapsing fever—entities often clinically confused with RMSF.

No human data exist to support use of fluoroquinolones in RMSF. Penicillin, cephalosporins, erythromycin, aminoglycoside, and trimethoprim and sulfamethoxazole are not effective against rickettsia.

Antibiotics usually are administered for 7 days or until the patient is afebrile for 2 days.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Drug Name	Chloramphenicol (Chloromycetin)
Description	Recommended by the CDC as an alternate drug for the treatment of pregnant women to avoid the risks of tooth and bone malformations. No longer routinely recommended for children because of reduced effectiveness and deleterious side effects. If administered on an outpatient basis, 30% of patients subsequently will require hospitalization, compared to 11% of patients treated with tetracyclines.
Adult Dose	500 mg IV divided qid for 7 d
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity
Interactions	Concurrently with barbiturates, chloramphenicol serum levels may decrease while barbiturate levels may increase causing toxicity; manifestations of hypoglycemia may occur with sulfonylureas; rifampin may reduce serum chloramphenicol levels, presumably through hepatic enzyme induction; may increase effects of anticoagulants; may increase serum hydantoin levels, possibly resulting in toxicity; chloramphenicol levels may be increased or decreased
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Use only for indicated infections, or as prophylaxis for bacterial infections; serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) can occur; evaluate baseline and perform periodic blood studies approximately every 2 d while in therapy; discontinue upon appearance of reticulocytopenia, leukopenia, thrombocytopenia, anemia or findings attributable to chloramphenicol; adjust dose in liver or kidney dysfunction; caution in pregnancy at term or during labor because of potential toxic effects on fetus (gray syndrome)

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Inpatient Care

• Seventy-two percent of confirmed cases of RMSF reported to the CDC required hospitalization.
• • Hospitalization occurred a median of 4 days after onset of symptoms.
  • Admit moderately to severely ill patients to the hospital.
  • Admit severely ill patients to the intensive care unit.

Further Outpatient Care

• RMSF can progress rapidly. Because roughly 10% of outpatients subsequently required admission, close follow-up is necessary if outpatient management is planned.

Deterrence/Prevention

• No vaccine for RMSF exists, but this disease can be prevented. The populace should avoid areas such as the woods or fields where ticks are found. If this is not possible, the following precautions are suggested:
• • Use tick repellents such as DEET and wear proper clothing, such as long sleeved shirts and pants that fit tightly around your wrists, waist, and ankles. When in the woods, people should check at least twice a day for attached ticks.
  • If a tick is attached, immediate removal may prevent infection. Gently grasp the tick with tweezers as close as possible to the skin and slowly pull it away. If tweezers are not available, fingers covered with tissue paper can be used. Do not attempt to remove the tick with petroleum jelly, hot objects, such as matches or cigarettes, or by other methods. After handling ticks, be sure to wash hands thoroughly with soap and water.
  • Antibiotics are not routinely recommended for the prevention of RMSF in the asymptomatic patient after tick-bite.
  • If fever, headaches, rash, or nausea occurs within 2 weeks of a possible tick bite or exposure, see a doctor immediately.

Complications

• Data from long-term follow-up studies suggest that significant long-term morbidity is common in patients with severe illness due to RMSF.
• CNS complications include paraparesis, hearing loss, blindness, peripheral neuropathy, bladder and bowel incontinence, cerebellar, vestibular and motor dysfunction, behavioral problems, and language disorders.
• Acute renal failure
• • Factors at presentation associated with development of acute renal failure (ARF) included increased bilirubin, advancing age, thrombocytopenia, and the presence of neurological involvement.
  • Age and decreased platelet count at presentation were independently associated with the development of ARF by multivariate analysis.
  • ARF development increased the odds ratio of dying by a factor of 17.
• Dermatological sequelae
• • Some patients develop minute cicatrices marking the location of focal cutaneous necrosis.
  • In others, progression to digital ischemia occurs transiently or evolves to severe ischemic changes without gangrene. This may result in permanent impairment. Gangrene requiring amputation occurs rarely.

Patient Education

• For excellent patient education resources, visit eMedicine's Bites and Stings Center. Also, see eMedicine's patient education article Ticks.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• In endemic areas, a high index of suspicion of RMSF is necessary to prevent delays in diagnosis and treatment.
• RMSF must be considered in any febrile patient in an endemic area, regardless of atypical presentation, lack of rash, or apparent lack of tick exposure.
• Most fatalities and permanent disabilities resulting from RMSF are associated with delayed antibiotic therapy.

Special Concerns

• Pregnancy is a contraindication to doxycycline therapy and mandates admission for chloramphenicol therapy.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous editor, Charles V Pollack Jr, MD, and previous author, Richard Medlin Jr, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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Article Last Updated: Jan 15, 2008