AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

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

INTRODUCTION

Section 2 of 10  

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

Background

Rocky Mountain spotted fever (RMSF) is a tick-borne disease caused by the organism Rickettsia rickettsii. Though RMSF can be lethal, it is curable. RMSF is the most common rickettsial infection. The organism is endemic in parts of North, Central, and South America, especially in the southeastern and south-central United States. Sophisticated microbiologic and serologic methods to distinguish infection by different members of the spotted fever group reveal that RMSF may be more common in the tropics and subtropical regions of the Americas than previously thought.

RMSF has been described as a "wolf in sheep's clothing" and "the great imitator" of other disease processes. Because of its diverse clinical features, RMSF often is confused with other infections. The hallmark of RMSF is a petechial rash beginning on the palms of the hands and soles of the feet.

The 2 principal tick vectors of RMSF in North America are Dermacentor variabilis (dog tick) in the eastern United States and Dermacentor andersoni in the Rocky Mountain region and Canada. Other species also identified are Rhipicephalus sanguineus in Mexico and Central America and Amblyomma cajennense in Central and South America. Amblyomma cooperi, Amblyomma americanum, Ixodes pacificus, and Haemaphysalis leporispalustris are infrequent vectors for human infection.

Major Marshall H. Wood, a US Army physician in Boise, Idaho, first recognized R rickettsii and reported on RMSF in 1896. The first report in the medical literature of a case in the Snake River Valley of Idaho was published in 1899. In 1902, 7 people died from RMSF in Bitterroot Valley. Then, 111 cases of RMSF were studied on the west side of the Bitterroot River; 69% of these cases were fatal. From the history of tick exposure and the season, researchers concluded that the wood tick spreads RMSF.

Howard Ricketts, for whom the etiologic agent is named, identified R rickettsii, its vector, and the route of transmission of RMSF. In 1906, Ricketts demonstrated tick transmission of RMSF to guinea pigs, showed that the etiologic agent was present in blood from infected humans, and demonstrated that it could be removed via filtration. Ricketts reported "minute polar staining bacilli" in freshly laid eggs of infected ticks.

In 1916, Wolbach published 2 papers also describing the appearance of R rickettsii using the Giemsa stain. In 1919, he reported that R rickettsii is an intracellular pathogen, and he described the vasculitic lesion.

In the late 1940s, the broad-spectrum antibiotics chloramphenicol and the tetracyclines were first shown to be effective in the treatment of RMSF.

Pathophysiology

R rickettsii is a small (0.3 µm X 1 µm), gram-negative, obligate intracellular coccobacillus.

R rickettsii possesses outer-membrane protein (Omp)A and OmpB, 2 major immunodominant surface-exposed proteins with species-specific conformational epitopes. OmpB is the most abundant outer-membrane protein that shares genetic sequences and limited antigens with typhus group rickettsiae.

Ticks become infected by feeding on the blood of infected animals, through fertilization, or by transovarial passage. Rickettsiae are transmitted from tick to human during feeding. The tick needs to be attached to a host for 6-10 hours for rickettsiae to be released from the salivary glands, although transmission may not occur for 24 hours. In addition, this organism can infect people who remove ticks from other people or animals via contact with tick tissues and fluids.

The organism spreads through the body via both blood and the lymphatic system. The incubation phase of infection ranges from 3-12 days, depending on the volume of the inoculum.

Notable characteristics of R rickettsii are its marked tropism for endothelial cells that line blood vessels and its ability to invade throughout the body when compared to other rickettsiae. The organisms attach via OmpA to the endothelial membrane, where they induce their own engulfment. Once intracellular and effectively escaping destruction by professional phagocytes, they replicate via binary fission in the cytosol and spread from cell to cell, propelled by polar polymerization of the host cell's actin, without producing cell lysis.

The rickettsial diseases, especially RMSF, are model examples of vasculitis with localization in endothelial cells. The major pathophysiologic effect of endothelial cell injury is increased vascular permeability, which results in edema, hypovolemia, hypotension, and hypoalbuminemia. The organisms also routinely infect vascular smooth-muscle cells.

The distribution of rickettsiae within the blood vessels causes vascular injury and the subsequent development of a host mononuclear-cell tissue response. Consequences of vascular injury are interstitial pneumonia, interstitial myocarditis, and perivascular glial nodules of the CNS, with similar vascular lesions in the skin, gastrointestinal tract, pancreas, liver, skeletal muscles, and kidneys. Large amounts of rickettsiae in damaged cells support the concept of direct injury. The inflammation and damage to the blood vessels and capillaries activate platelets, generate thrombin, and activate the fibrinolytic system as part of the body's homeostatic physiologic response to endothelial injury.

As R rickettsii proliferates in the endothelial lining, it also causes thrombi to form. Extensive vasculitis leading to small vessel occlusion can result in severe cases. Vascular necrosis and thrombosis are more frequent in RMSF than in typhus and may mimic collagen vascular disease.

Frequency

United States

RMSF is the most frequent cause of fatal tick-borne disease in the United States. Anyone bitten by an infected dog tick and on whom the infected tick remains for several hours can get RMSF. In spite of its name, RMSF is more common in the southeastern US tick belt than in the Rocky Mountain region. The disease is more common in rural and suburban locations; however, it does occur in urban areas such as New York City.

• The regions with the highest incidences include the Southeast, the western South Central region (including Oklahoma and northern Texas), and selected areas of the Northeast (Cape Cod and Long Island). Most cases are reported from eastern and central states, such as North and South Carolina, Virginia, Georgia, Tennessee, Arkansas, Missouri, Kansas, and Oklahoma. The 2 states with the highest incidence are North Carolina and Oklahoma. Cases have been reported in 48 states, with Vermont and Hawaii being the exceptions. In the northern United States, infections commonly occur in the spring; in the South, cases may occur in any month, including winter months.
• From 1989-1996, more than 4700 cases were reported in 46 states. Of these reported cases, 90% occurred between April and September. More than 1400 cases were reported in 2004.
• A prospective study of RMSF infection in residents of a known endemic area in North Carolina suggests an annual incidence in children aged 5-9 years of 42 cases per 100,000 population.

International

Canada, Mexico, and Central and South America, particularly Panama, Columbia, Argentina, Costa Rica, Bolivia, and Brazil have reported cases of RMSF. Serologic evidence of RMSF has been found in 6 Brazilian states ranging from Rio Grande de Sol in the south to Bahia in the north. In Brazil, RMSF was unrecognized or unreported for decades in regions such as Espiritu Santo. In southern Brazil, the disease is more common from October to February, but in the tropics, seasonal variation is less striking.

Mortality/Morbidity

• The mortality rate in untreated cases is 20-25%. The mortality rate for patients treated with appropriate antibiotic therapy is 5%. In a 1994 study, the odds of dying from RMSF were more than 5 times greater for patients who did not receive antirickettsial therapy by the fifth day of their illness compared to those treated earlier.
• In elderly patients who are not treated, the mortality rate can be as high as 70%. The mortality rate is less than 20% in untreated children. RMSF tends to be more severe in individuals with glucose-6-phosphate dehydrogenase deficiency.
• The diverse clinical features of RMSF lead clinicians to confuse it with many community-acquired infections. This delays proper therapy and contributes to higher mortality.

Race

• RMSF occurs more often in blacks, but rash is harder to recognize in dark-skinned individuals.

Sex

• Males account for approximately two thirds of all cases.
• The fatality to case ratio is higher for males than for females.

Age

• Two thirds of the cases of RMSF occur in young and middle-aged adults, followed by children aged 5-14 years.
• Approximately one third of patients are younger than 20 years. The fatality to case ratio increases with each decade of life after 20 years.
• RMSF occurs more often in elderly individuals.

CLINICAL

Section 3 of 10  

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

History

• Physicians must maintain a high index of suspicion for RMSF in patients with the following:
• • Febrile illness
  • History of potential tick exposure
  • Travel to endemic area
  • Presentation in the spring or fall
• RMSF also should be considered in patients with unexplained febrile illness, even if they have no history of a tick bite or travel to an endemic area.
• History of a tick bite is reported by only 70% of patients.
• People with RMSF generally present within a week after a tick bite.
• The triad of manifestations in RMSF is fever, rash, and history of tick exposure. However, in a recent study, this triad is present in only 18% of patients upon initial presentation. Other common symptoms include chills, severe headache, conjunctival redness, cough, myalgias, gastrointestinal disturbances, and malaise. Patients may report insomnia and photophobia.
• A petechial rash commonly appears 3-5 days into the illness. The absence or delayed appearance of a rash increases the difficulty of making a diagnosis.

Physical

RMSF presents with a wide clinical spectrum, ranging from mild fever (99-100%), headache (79-91%), and myalgias (72-83%) to disseminated intravascular coagulation (DIC) (32-53%), shock (7-17%), and death (4-8%).

• Adults tend to present with typical symptoms.
• Fever with relative bradycardia is the rule. In mild untreated cases, the fever subsides at the end of the second week.
• Rash
• • Rash is a major diagnostic sign.
  • It appears in a low percentage of patients the first day and in only 49% during the first 3 days.
  • The maculopapular rash usually (88-90% of the time) appears 2-6 days after onset of fever and progresses through stages and distribution that are never pathognomonic.
  • The rash begins as a maculopapular eruption on the wrists and ankles and spreads centripetally to involve the trunk and extremities. The rash involves the palms of the hands and soles of the feet.
  • Later in the illness, the rash becomes petechial (45-49%). In dark-skinned patients, the rash is difficult to see.
  • Nonproductive cough may occur with the rash (33%).
  • The rash is absent at presentation in 10-15% of patients. RMSF without a rash (ie, spotless RMSF) should be considered ehrlichiosis until proven otherwise.
  • Later in the illness, purpura and skin necrosis or gangrene may develop, although rarely.
• Head, ears, eyes, nose, and throat
• • Conjunctival suffusion is uniformly present (30%).
  • Bilateral edema is present. Periorbital edema is a key diagnostic finding, especially in children.
  • Transient deafness occurs in 7% of patients.
• Cardiovascular
• • Myocarditis may develop.
  • Relative bradycardia may occur.
  • Arrhythmias are present in 7-16% of patients.
  • Hypotension occurs in 7-17% of patients.
  • RMSF is the only tick-borne disease that can directly cause congestive heart failure secondary to myocarditis (5-26%).
• Pulmonary
• • Pulmonary edema occurs in severe cases.
  • Pneumonitis is present in 12-17% of cases.
• Gastrointestinal
• • Anorexia may develop.
  • Abdominal pain and tenderness (diffuse in right upper quadrant) are present in 34-52% of patients.
  • Jaundice develops in severe cases (8-9%).
  • Hepatomegaly and splenomegaly occur in 12-15% and 14-16% of cases, respectively.
  • Diarrhea develops in 19-20% of patients.
  • Increased aspartate aminotransferase (AST) levels are present in 36-62% of patients.
• Musculoskeletal
• • Severe myalgia may be present, especially in the legs, abdomen, and back (72-82%).
  • Diffuse arthralgias may occur.
  • Edema on the dorsum of the hands and feet is a key sign (18-20%).
  • Lymphadenopathy develops in 27% of cases.
• Central nervous system
• • Restlessness and irritability may occur.
  • Altered mental status may include delirium, lethargy, and coma.
  • Photophobia sometimes is present.
  • Meningoencephalitis may develop (confusion, seizures [8%], focal neurologic deficits).
  • Cranial neuropathies may be present.
  • Patients may have urinary or fecal incontinence.
  • Paralysis may develop.
  • Ataxia is present in 5-18% of cases.
  • Meningismus develops in 18% of patients.
• Miscellaneous presentations include dehydration, generalized edema, and chills.
• Effects of disseminated R rickettsii infection of endothelial cells include increased vascular permeability that leads to edema, hypovolemia, hypotension, and prerenal azotemia.
• In fatal cases, myocarditis is the cause of death.

Causes

R rickettsii is the only cause of RMSF.

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Acute surgical abdomen
Allergic vasculitis
Brill-Zinsser disease
Drug hypersensitivity
Atypical measles
Murine typhus
Rubeola
Undifferentiated viral illness
Drug reactions
Other acute rickettsial infections (eg, Mediterranean spotted fever, North Asian tick typhus, Siberian tick typhus, Astrakhan fever, African tick bite fever, Japanese spotted fever, Queensland tick typhus, Flinders Island spotted fever, Israeli tick typhus, Marseilles tick bite fever)

WORKUP

Section 5 of 10  

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

Lab Studies

• Diagnosis relies on clinical (fever, rash, myalgia) and epidemiologic (tick exposure) criteria.
• After exposure to vector ticks, patients who develop fever, petechial rash, and vomiting require antibiotic therapy. Antibiotic therapy should be initiated before laboratory confirmation is available.
• Clinical diagnosis is difficult to establish, and laboratory findings are nonspecific. Immunologic methods for detection of rickettsiae are unavailable in most clinics.
• White blood cell count
• • Leukopenia is present initially, then mild leukocytosis.
  • Patients usually show normal WBC count.
• Platelets
• • Thrombocytopenia ( <150,000 cells/µL) occurs in 32-52% of patients.
  • Abnormalities indicative of DIC are present in severely ill patients.
• Hemoglobin and hematocrit: Anemia is present in 5-24% of patients.
• Serology
• • Diagnosis is confirmed based on indirect immunofluorescent antibody (IFA) test results, latex agglutination, or enzyme immunoassay.
  • Serology specific for R rickettsii develops in 6-8 weeks.
  • Serological test results are negative until convalescence.
• Other laboratory findings
• • Mildly elevated aminotransferase levels are present in 36-62% of patients.
  • Hyponatremia is present in 19-56% of cases.
  • Increased bilirubin levels are present in 8-9% of patients.
  • Mild cerebrospinal fluid pleocytosis with monocyte predominance may be present.
  • Azotemia develops in 12-14% of cases.
  • Elevated prothrombin time and activated partial thromboplastin time may be present.

Imaging Studies

• Chest radiographs that reveal an early pulmonary infiltrate constitute an argument against a diagnosis of RMSF.

Other Tests

• Electrocardiograms may indicate myocardial or conduction abnormalities.
• The Weil-Felix test detects cross-reacting antibodies against Proteus vulgaris antigens OX-2 and OX-19.
• • This test lacks sensitivity and specificity, and better tests are now available.
  • If the Proteus titer is greater than or equal to 1:320 or if a 4-fold or greater rise to either Proteus OX-19 or OX-2 antigens is observed, an RMSF case that is clinically compatible is considered probable.

Procedures

• Skin biopsy
• • Direct immunofluorescent microscopy, if available, may be used for rapid histologic diagnosis of RMSF.
  • Immunofluorescent or immunoperoxidase staining of R rickettsii in a biopsy skin or organ specimen is both sensitive (73%) and specific (100%).
  • Antibodies to specific rickettsial antigens are detected by indirect immunofluorescence (most specific), latex agglutination, and enzyme immunoassay. The diagnostic titer is 1:64 for indirect immunofluorescence and latex agglutination.
  • Polymerase chain reaction amplification of R rickettsii DNA has not been proven to be a sensitive diagnostic method except for later in the disease course, particularly fatal cases. It has been successful when applied to skin biopsied during rickettsioses and to ticks. According to Walker and Raoult in 2000, the primers used amplify genes of the 17-kD protein citrate synthetase and rickettsial OmpA and allow the identification of any rickettsial organism.
• Lumbar puncture is not routinely indicated but is important to rule out meningitis in some patients with RMSF who have CNS findings.

TREATMENT

Section 6 of 10  

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

Medical Care

Initiating antibiotics early significantly reduces the mortality rate from 20% to approximately 5%. In addition, it prevents early complications.

• Patients may require oxygen or intubation.
• Fluids
• • Dehydration may occur secondary to high fever and vomiting.
  • Appropriate and aggressive fluid management with isotonic fluids should be instituted.
  • Monitor urine output and blood pressure.
• A Swan-Ganz catheter may be needed to monitor hemodynamics in some patients.

Consultations

• Always report tick-borne illnesses to public health authorities.
• Consultation with an infectious disease specialist is advised.
• A dermatologist should be consulted to obtain a skin biopsy specimen for immunofluorescent staining, if available.

MEDICATION

Section 7 of 10  

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

For adults, the preferred drug of choice is doxycycline. Chloramphenicol is an alternative. In vitro and in ovo R rickettsii also is susceptible to rifampin.

In 1997, the American Academy of Pediatrics revised treatment options for children with RMSF. Doxycycline became the preferred drug choice for treating children of any age due to the potential for severe or fatal cases.

Short courses of doxycycline to treat RMSF do not cause significant dental staining. Doxycycline is preferable to chloramphenicol because tetracyclines have been shown to be associated with a higher survival rate.

Beta-lactam antibiotic coverage does not treat RMSF. Some new quinolones have antirickettsial effects in vitro, but the clinical experience in RMSF is limited.

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	Alternative choice for RMSF in pregnant women and patients allergic to tetracyclines. Binds to 50S bacterial ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis.
Adult Dose	500 mg IV divided qid for 7 d
Pediatric Dose	50 mg/kg PO or 75 mg/kg IV divided qid for 7 d and for at least 48 h after defervescence
Contraindications	Documented hypersensitivity
Interactions	Concurrently with barbiturates, serum levels may decrease while barbiturate levels may increase; rifampin may reduce serum levels; may increase effects of anticoagulants; may increase serum hydantoin levels, chloramphenicol levels may be increased or decreased
Pregnancy	C - Safety for use during pregnancy has not been established.
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 10  

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

Transfer

• In situations in which the patient is comatose, convulsing, or hypotensive, proper personnel trained in complicated airway intervention and treatment of shock should be present.

Deterrence/Prevention

• The best means of prevention is to avoid contact with ticks by using protective clothing and repellants.
• Currently, research is underway to develop an effective vaccine using OmpA expressed in baculovirus for those high-risk patients in endemic areas.
• See Patient Education.

Complications

• Disseminated intravascular coagulation
• Noncardiogenic pulmonary edema
• Acute tubular necrosis
• Shock with myocarditis
• Skin necrosis and gangrene, particularly in fingers, toes, elbows, ears, and scrotum
• Myocarditis - Usual cause of death
• The following complications may occur:
• • Seizures
  • Encephalopathy
  • Peripheral neuropathy
  • Bowel and bladder incontinence
  • Cerebellar and vestibular dysfunction
  • Hearing loss
• Hemophagocytic histiocytosis - Described in fatal cases of RMSF

Prognosis

• Mortality rates vary according to the following criteria:
• • Delay in diagnosis
  • Delay in giving effective antibiotic treatment
  • Age
  • Race
  • Severity of the disease
• Mortality rates can be as low as 5% with proper antibiotic therapy and as high as 70% in untreated elderly individuals.
• Risk factors for fatal outcome in RMSF include the following:
• • Older than 40 years
  • Delay in treatment
  • No treatment by the fifth day of illness
    

Patient Education

• To promote prevention, educate the public about transmission of ticks and means of personal protection.
• • Avoid dogs with ticks and tick-infected areas.
  • Use protective light-colored clothing that covers arms and legs. Tuck pants in socks to protect legs.
  • Apply tick-repellent chemicals such as diethyltoluamide (DEET, Autan) or permethrin to pants and sleeves.
  • Search the entire body every 3-4 hours when in an infested area. Common areas of attachment are in scalp, pubic, or axillary hair.
  • Without crushing the tick, remove it promptly using gentle steady traction with tweezers. Be careful not to leave any mouthparts. Protect hands with gloves.
  • Because the tick needs 6-10 hours of feeding to transmit the disease, early discovery and removal of ticks can prevent infection.
  • Prophylaxis with doxycycline for 7 days is recommended after tick removal.
• For excellent patient education resources, visit eMedicine's Bites and Stings Center. Also, see eMedicine's patient education article Ticks.

MISCELLANEOUS

Section 9 of 10  

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

Medical/Legal Pitfalls

• Failure to promptly evaluate and treat patients with acute febrile illnesses and tick exposure
• Failure to consider RMSF in a febrile patient in an endemic area, regardless of tick exposure

Special Concerns

• Pregnancy
• • Whether R rickettsii can cross the placenta and adversely affect the fetus remains unknown.
  • In a case report, a pregnant patient with RMSF was treated with chloramphenicol successfully with no apparent adverse maternal or neonatal effects.
• Human ehrlichiosis caused by Ehrlichia canis mimics RMSF in its clinical manifestations and geographic and seasonal distribution. Rash is not present with ehrlichiosis. Spotless RMSF usually is ehrlichiosis. Doxycycline is the preferred drug for human ehrlichiosis.

REFERENCES

Section 10 of 10

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

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Article Last Updated: Feb 17, 2006