Rocky Mountain Spotted Fever

Are You Confident of the Diagnosis?

What you should be alert for in the history

Rocky Mountain spotted fever (RMSF), originally termed ‘black measles’ because of the characteristic appearance, was first described in 1896 by Major Marshal H. Wood in the Snake River Valley of Idaho. It wasn’t until 1906 that Howard Ricketts identified the organism, Rickettsia rickettsii, and its transmission through tick bites in the Bitterroot Valley of western Montana.

RMSF is currently the most frequently reported rickettsial infection in the United States of America. Physicians must have a high index of suspicion for Rocky Mountain spotted fever as it may be easily mistaken for more common diseases and, if not treated early, can be fatal.

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A detailed history should be taken to elicit recent travel, medication history, exposure to animals or wooded areas, tick bites, ill-contacts, and occupational and home exposures. Specific information regarding timing of symptoms, especially onset of fever and rash, direction of spread, and presence of pruritus or associated pain should be noted.

Interestingly, approximately one-third of patients do not give a history of tick bites or exposure. In patients with an unexplained febrile illness, RMSF needs to be considered early.

Characteristic findings on physical examination

Symptoms of RMSF usually present within 3-7 days after tick exposure; however, they can occur anywhere between 1-14 days. Approximately 60% of patients will have the classic triad of fever, headache, and rash; however, they are not typically identified together early in the course at initial presentation (Figure 1).

Characteristic petechial eruption of RMSF

High fever (>102ºF or 38.9ºC) usually presents first with non-specific symptoms such as severe headache, malaise, myalgias, arthralgias, nausea with or without vomiting, and abdominal pain mimicking other infectious disorders or an acute abdomen.

Approximately three days after the onset of fever, patients will begin to have a morbiliform eruption that begins classically on the wrists and ankles and spreads centripetally over the next 6-18 hours. Palms and soles are typically involved with relative sparing of the face. This may be difficult to discern in darker skinned patients. Involvement of scrotum or vulva may help aid in diagnosis.

Approximately 6 days after the onset of symptoms, the initial blanchable pink macules turn into the classic petechial rash characteristic of RMSF. The rash is not typically pruritic but may be painful. Periorbital and acral edema are characteristic; however, cough, confusion, focal neurologic signs and calf pain can also be appreciated.

Necrosis induced by systemic vasculitis is rare can be seen in areas such as the digits, penis, or scrotum. Diagnostic confusion can occur due to conjunctival involvement, retinal abnormalities, and EKG changes.

Expected results of diagnostic studies

Laboratory abnormalities include thrombocytopenia, anemia, mild hyponatremia and transaminitis. Other levels may be elevated including creatine kinase, serum bilirubin, alkaline phosphatase, BUN, creatinine, or lactate dehydrogenase. The white blood cell count may be normal, elevated, or decreased; however, there may be an increase in bands. CSF may show a leukocytosis and moderately elevated protein level with normal glucose levels.

Severe life-threatening cardiac, pulmonary, neurologic, gastrointestinal, hepatic, ophthalmologic and renal complications can occur without prompt treatment.

Long-term sequelae can result from acral necrosis or neurologic injury. Fulminant RMSF has been reported to occur more frequently in alcoholics and patients with G6PD deficiency. Atypical ‘spotless’ fever can be seen in approximately 20% of cases, more common in darker skinned patients and the elderly. These patients usually have a worsened prognosis since diagnosis is often delayed.

Diagnosis is initially made clinically, based on a suggestive history and consistent physical examination. If RMSF enters the differential diagnosis, empiric treatment should be started before confirmatory test results are available. There are no reliable rapid tests early in the illness; however, diagnosis can be confirmed later in the disease by histology and serologic examination.

A punch biopsy can help support the diagnosis; however, this is not specific for RMSF as most rickettsial diseases share a similar histology. Early lesions demonstrate dermal edema and a perivascular lymphohistiocytic infiltrate with extravasated erythrocytes. This may progress into a leukocytoclastic vasculitis.

Basal cell vacuolization, lymphocytic exocytosis, fibrin thrombi formation, and capillary wall necrosis can be seen in a minority of biopsies. Direct immunofluorescence, or alternatively immunoperoxidase or Giemsa staining, can be used in the acute setting to directly visualize R. rickettsii on biopsy; however, it is only about 70% sensitive. Polymerase chain reaction may also be used; however, this may not be positive until later in the course of the disease.

Serologic testing using the indirect immunofluorescence antibody (IFA) assay to detect convalescent antibodies is the gold standard for diagnosis of RMSF and is available through all state health departments. It has an approximately 95% sensitivity and is currently the diagnostic test used by the Center of Disease control. A 4-fold rise in titers to greater than or equal to 1:64IgG (or 1:32IgM) 2-3 weeks apart is considered diagnostic. Single samples are not diagnostic since they can be detected years after initial exposure.

Unfortunately, IFA is seldom diagnostic before the seventh day of disease and may be falsely negative until well into the second week. Although it is very sensitive, it cannot reliably distinguish R. rickettsii infection from other rickettsial pathogens. Also, patients who are treated within the first 48 hours of disease may not develop convalescent antibodies making this method imperfect.

Diagnosis confirmation

The differential diagnosis for RMSF is very broad as there are many diseases that present with fever and a rash. These can be divided into infectious, hematologic or autoimmune disorders, iatrogenic or idiopathic.

RMSF is frequently misdiagnosed as a viral exanthem and may even be treated inappropriately with antibiotics leading to the diagnosis of a drug reaction. Different viral infections that may mimic RMSF include self-limiting enteroviral infections, roseola infantum (HHV6), mononucleosis, viral meningitis, viral hepatitis, or erythema infectiosum (parvovirus B19).

These patients are typically not as ill-appearing as patients with RMSF and do not decompensate. Erythema infectiosum typically presents in later winter to early summer and has a characteristic ‘slapped cheek’ appearance on presentation associated with a low-grade fever.

Roseola infantum typically presents all year round, usually in patients under the age of two, with a morbilliform eruption upon defervescence on the trunk that fades rather quickly. Enteroviral infections do not always have an associated exanthem. If present, a morbilliform eruption starts on the face and trunk and spreads centrifugally.

In specific geographic locations or travelers from endemic areas, other infectious diseases such as tick-borne viral fevers (e.g. Colorado tick fever) typhoid fever, dengue, leptospirosis, tularemia, Lyme disease, or viral hemorrhagic fevers must be considered and specific exposures should be elicited in the history.

Common infections such as streptococcal infection or mycoplasma pneumonia may also be considered. Streptococcal pharyngitis usually occurs in fall or winter with an associated sore throat and patients are not very ill appearing. It is also important to recognize that RMSF can masquerade as an acute abdomen when fever and extreme abdominal pain are presenting features.

The most concerning infectious disease to closely mimic RMSF is meningococcemia, which can present very similarly to RMSF. These patients are usually ill-appearing and have a rapid onset of the characteristic stellate purpura with a “gunmetal-gray” hue. Because meningococcemia can be rapidly progressive, therapy is usually administered before diagnostic conformation is achieved.

Leukocytosis is usually present in meningococcemia by presentation. Blood cultures and rapid gram stains from body fluids (CSF, joint fluid, skin scrapings or biopsy) can confirm the diagnosis and differentiate it early from RMSF. Disseminated gonoccocemia may present similar to meningococcemia and must be ruled out as well.

Kawasaki disease must always be considered in children with fever for more than 5 days and nonspecific exanthem. Kawasaki disease also classically presents with unilateral cervical lymphadenopathy, acral edema, erythema and desquamation, conjunctivitis with perilimbal sparing, strawberry tongue, and cheilitis. Although the rash of Kawasaki is not typically purpuric it should always be considered in children with fevers of unknown origin.

It is important to note that the presentation of fever and rash does not always indicate infection. Thrombotic thrombocytopenic purpura can present with fever and severe thrombocytopenia producing purpuric macules simulating RMSF. These patients typically have signs of hemolytic anemia (schistocytes) on peripheral blood smears and platelet counts less than 50 x 10
⁹/L that may help distinguish this early on from RMSF.

Other life-threatening entities that must be considered are toxic shock syndrome and Stevens-Johnson syndrome/toxic epidermal necrolysis that usually have a more confluent tender erythema and a classic history. As the “great imitator”, secondary syphilis can present similarly and should be ruled out with appropriate serological testing (RPR).

Ehrlichiosis is another tick-borne disease that can present similarly to RMSF; however, a rash is rarely seen. Leukocytopenia is more common in ehrlichiosis and can be diagnosed by characteristic intracellular morulae on peripheral blood smear. Endemic typhus caused by Rickettsia typhi can also present similarly, with a morbilliform or petechial eruption involving the trunk more than the extremities. Regardless, treatment remains the same for all three diseases.

Leukocytoclastic vasculitis (LCV) can occur for a multitude of reasons, including medications, post-infectious, collagen vascular diseases, immune complex diseases, as well as malignancy associated. Patients with LCV due to causes other than RMSF do not appear as ill as patients with RMSF or decompensate as rapidly.

Who is at Risk for Developing this Disease?

RMSF has been reported in every state excluding Maine and Vermont. It is most prevalent in the Eastern United States. Over 50% of RMSF reported in the United States are from the South-Atlantic region (Delaware, Maryland, Washington D.C., Virginia, West Virginia, North and South Carolina, Georgia, and Florida). It also occurs in the Pacific region (Washington, Oregon, and California) and west South-central region (Arkansas, Louisiana, Oklahoma, and Texas).

The states with the two highest incidences of RMSF are North Carolina and Oklahoma. Worldwide it can be seen in Argentina, Brazil, Columbia, Costa Rica, Mexico, Panama, and Canada.

RMSF is most frequent between April and September, especially during the summer months when outdoor activity is most frequent. Although any age can be affected, the highest frequency of cases reported is among Caucasian males.

Children under 10 years of age are classically noted to have the highest incidence of RMSF; however, surveillance data in 2003 by the Center of Disease control showed a higher reported incidence of persons aged 40-64 years. Individuals residing in rural areas are also at increased risk, especially those with frequent exposure to dogs; however, there have been case reports of infection in urban settings.

Laboratory technicians who handle specimens infected with R. rickettsii are at risk for infection as well as anyone coming in contact with tick fluids during removal.

What is the Cause of the Disease?

Pathophysiology

RMSF is caused by the gram-negative bacteria R. rickettsii. It is an obligate intracellular coccobacillus that is transmitted to humans through the bites of infected ticks.

The vector mainly responsible for the transmission of R. rickettsii in the eastern two-thirds of the United States is the American dog tick, Dermacentor variabilis. In the western United States, the Rocky Mountain wood tick, Dermacentor andersoni is most responsible. Rhipicephalus sanguineus (brown dog tick) and Amblyomma cajennense are ticks that serve as vectors in Mexico and Central and South America, respectively.

Amblyomma americanum (lone star tick) and Haemaphysalis leporispalustris (rabbit tick) have also been reported to transmit R. rickettsii. Once the tick is attached to the human host, it usually takes 24 hours for transmission; however, transmission can take as little as 6-8 hours.

R. rickettsii enters the bloodstream through the saliva of the feeding tick and then spreads through the hematogenous and lymphatic systems with an affinity for endothelial cells. Once it attaches to the endothelial cell membrane through bacterial outer membrane proteins it is phagocytosed and replicates in the endothelial cell cytoplasm.

Subsequently, it induces host-cell reactive oxygen species formation and actin polymerization to aid in their extrusion from the cell to invade adjacent cells. This in turn produces a proinflammatory and hypercoagulable state. This proliferation of bacteria within the vascular endothelium results in the systemic vasculitis and microvascular leakage that produces the characteristic purpura of RMSF, as well fatal hypovolemia and pulmonary and cerebral edema.

Systemic Implications and Complications

As described above, R. rickettsii replicates in the vascular endothelium producing vascular injury leading to vasculitis and microvascular leakage. Depending on which vessels are affected, complications can be devastating.

Ocular involvement can present as petechial conjunctivitis, anterior uveitis, retinal hemorrhages, or neuroretinitis. Periorbital edema is characteristic, especially in children. Pulmonary vasculature involvement can present as a non-productive cough or shortness of breath from pulmonary edema, leading to acute respiratory distress syndrome.

Cardiac involvement can produce myocarditis leading to congestive heart failure, arrhythmias, and severe hypotension due to third-spacing effects. Gastrointestinal involvement can present with severe abdominal pain mimicking an acute abdomen, hepatosplenomegaly, bleeding, diarrhea, and jaundice.

Central nervous system involvement can cause irritability, altered mental status, meningismus, coma, photophobia, seizures, cranial neuropathies, bowel and bladder incontinence, ataxia, peripheral neuropathy, hemiparesis, or deafness, which can be permanent. It may even trigger Guillain-Barré syndrome. Renal function may deteriorate and in rare cases hematologic dysfunction may culminate into DIC.

Fatal outcomes have been reported in 5% of treated cases, and as high as 20% of untreated cases. All affected patients with systemic complications require hemodynamic monitoring in an intensive care unit as they may need mechanical ventilation, fluid management with dialysis, blood transfusions, or seizure treatment to prevent permanent complications.

Treatment Options

Treatment options are summarized in Table I.

	First-line	Second- line
Adults	Doxycycline 100 mg orally or intravenously every 12 hours x 5-10 days (or until 3 days after pyrexia)	Chloramphenicol 50-75 mg/kg orally or intravenously, divided every 6 hours x 5-10 days (or until 3 days after pyrexia)orTetracycline 500 mg orally (or 250 mg intravenously) every 6 hours x 5-10 days (or until 3 days after pyrexia)
Children (<45 mg)	Doxycycline 2.2 mg/kg daily orally or intravenously every 12 hours x 5-10 days (or until 3 days after pyrexia)	Chloramphenicol 12.5-25 mg/kg daily orally or intravenously divided every 6 hours x 5-10 days (or until 3 days after pyrexia)
Pregnancy	Doxycycline 100 mg orally or intravenously every 12 hours x 5-10 days (or until 3 days after pyrexia)	Chloramphenicol 50-75 mg/kg orally or intravenously divided every 6 hours x 5-10 days (or until 3 days after pyrexia)

Optimal Therapeutic Approach for this Disease

Treatment for RMSF should be started promptly at the first sign of illness. Therapy beyond the fifth day of the illness is associated with increased risk of death. Tetracyclines are the first-line treatment of RMSF in patients of all ages, even during pregnancy.

First-line treatment for all non-tetracycline allergic patients is doxycycline 100 mg orally or intravenously every 12 hours for 5-10 days (or until 3 days after pyrexia) in all adults or children weighing over 45 kg. Children weighing under 45 kg should be treated with doxycycline 2.2 mg/kg daily orally or intravenously, divided every 12 hours for 5-10 days (or until 3 days after pyrexia).

Second-line therapy is chloramphenicol 50-75 mg/kg orally or intravenously divided every 6 hours x 5-10 days (or until 3 days after pyrexia) in tetracycline allergic patients or tetracycline 500 mg orally (or 250 mg intravenously) every 6 hours x 5-10 days (or until 3 days after pyrexia). The oral form of chloramphenicol is not available in the United States.

In children, second-line therapy is chloramphenicol 12.5-25 mg/kg daily orally or intravenously, divided every 6 hours x 5-10 days (or until 3 days after pyrexia). If chloramphenicol is administered, serum drug concentrations and reticulocyte counts should be monitored. Chloramphenicol doses should not exceed 4g daily. Tetracycline doses should not exceed 2g daily.

The benefit of the use of doxycycline in children or pregnant women with RMSF greatly outweighs the risk of tooth discoloration or abnormal bone growth in children or the unborn fetus and hepatotoxicity or pancreatitis in the gravid female.

Chloramphenicol is not without risk in pregnancy, as it can cause aplastic anemia, reversible bone marrow suppression, and gray baby syndrome in near-term gravids. Hospitalization is dependent upon clinical presentation and duration of illness. Aggressive supportive care in the intensive care unit monitoring hemodynamics and electrolyte status is crucial to survival.

Since it is difficult to distinguish RMSF and meningococcemia early in the course, patients should receive empiric treatment for both once CSF and blood cultures are obtained. Ceftriaxone 2 grams intravenously every 12 hours or 100 mg/kg daily in two divided doses in children (maximum 4 grams per day) should be administered along with the recommended doxycycline dosages.

Patient Management

All confirmed or probable cases of RMSF should be reported to the state health department. Once patients have defervesced and completed their antibiotic course they do not need routine follow up unless there are specific sequelae, (i.e. peripheral neuropathy). Infection with R. rickettsii is thought to provide lifetime immunity against re-infection. Patients should still practice good tick prevention in the future and seek medical care if they become ill as there are many other tick-borne illnesses that may present similarly to RMSF.

It is important for contacts of patients to also be aware of tick bite prevention. Patients should practice caution when walking in wooded areas, walking in the center of trails rather than through the brush. They should be advised to avoid wooded areas with high grass if possible. If they live in wooded areas, they should control the brush around their homes.

Tick repellents containing DEET (N, N-diethyl-m-toluamide) up to 30% are safe to use in children and adults, avoiding the mouth, hands, and eyes. Reapplication every several hours may be necessary, using caution to not over apply in children as it could have adverse reactions. DEET is not recommended for infants less than 2 months old.

Products containing permethrin can be used to treat clothing. Light colored clothing facilitates the identification of ticks on the body. Wearing pants that tuck into the socks and long sleeved shirts can decrease the risk of tick attachment. A full body examination should be performed upon return from tick-infested areas paying specific attention to the scalp, ears, umbilicus, groin, and waist. Showering upon returning home may also decrease risk of tick adherence. Animals should also be checked for ticks daily during the summer months.

Local agricultural officials may be able to provide pesticides in heavily tick infested areas. Upon tick removal, it is important to not come in contact with any tick fluids as this may cause inoculation.

Unusual Clinical Scenarios to Consider in Patient Management

As stated previously, pregnant patients and children should still be treated promptly with doxycycline to prevent significant morbidity and mortality. Patients treated within the first 5 days of the disease generally defervesce within 24-72 hours after treatment with appropriate therapy. Severely ill patients with systemic involvement may require longer periods of antibiotics before defervescence.

Failure to respond argues against a diagnosis of RMSF and alternate diagnoses should be entertained.

Immunocompromised patients may present without typical features, so a higher degree of suspicion is necessary (especially in patients with HIV where the differential diagnosis can be vast). Prophylactic antibiotics after tick exposure without symptoms is not recommended. Despite the life-threatening nature, vaccine development is not of high priority because of readily available, effective, safe therapy.

What is the Evidence?

Buckingham, S. “Tick-borne diabetes of the USA: Ten things clinicians should know”. J Infect. vol. Jun 71 Suppl 1. 2015. pp. S88-96. (Review of epidemiology, diagnosis, and management of tick-borne infections in children.)

Chapman, AS, Bakken, JS, Folk, SM, Paddock, CD, Bloch, KC, Krussell, A. “Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted Fever, Ehrlichioses, and Anaplasmosis–United States: A Practical Guide for physicians and Other Health-Care and Public Health Professionals”. MMWR. Recomm Rep. vol. 55. 2006 Mar 31. pp. 1-27. (The review discusses the epidemiologic aspects of a few select tickborne rickettsial diseases as well as how to differentiate them from one another. It also discusses the clinical assessments, appropriate treatments and laboratory diagnoses and encourages physicians to report tickborne diseases to the state health department.)

Dana, AN. “Diagnosis and treatment of tick infestation and tick-borne diseases with cutaneous manifestations”. Dermatol Ther. vol. 22. 2009. pp. 293-326. (This article reviews the presentations of various tickborne illnesses, the differential diagnosis, and medical management. The characteristics and treatments are also shown in very easy to read tabular format.)

Kopp, SA, Halpern, AV, Green, JJ, Heymann, WR, Wolff, K, Goldsmith, LA, Katz, SI, Gilchrest, BA, Paller, AS, Leffell, DJ. “The Rickettsioses, Ehrlichioses, and Anaplasmoses”. Fitzpatrick's Dermatology in General Medicine, 8th ed. (The chapter is the newest version in Fitzpatrick's legendary textbook giving a comprehensive review of etiology, diagnosis, and treatment of rickettsial diseases, ehrlichioses and anaplasmoses.)

Parola, P, Paddock, CD, Raoult, D. “Tickborne rickettsioses around the world: emerging diseases challenging old concepts”. Clin Microbiol Reviews. vol. 18. 2005. pp. 719-56. (Excellent review of the established rickettsial pathogens and new emerging species in respect to clinical history, diagnosis, and treatment.)

Dantas-Torres, F. “Rocky Mountain spotted fever”. Lancet Infect Dis. vol. 7. 2007. pp. 724(A comprehensive review of the epidemiology, pathogenesis, clinical presentation, differential diagnosis, evaluation, and treatment of Rocky Mountain spotted fever.)

Todar, K. “Rickettsial diseases, including typhus and Rocky Mountain spotted fever”. Todar's Online Textbook of Bacteriology. 2009. pp. 2-6. (An amazing electronic text filled with detailed pathogenesis, clinical presentations, diagnosis, and treatment of Rocky Mountain spotted fever. The review is easy to understand and is constantly being updated.)

Walker, DH, Raoult, D, Mandell, GL, Bennett, JE, Dolin, R. “Rickettsia rickettsii and other spotted fever group rickettsiae”. Mandell, Douglas, and Bennett's Principles and Practices of Infectious Diseases. 5th ed. 2000. pp. 2035(A textbook reference reviewing Rocky Mountain spotted fever and other spotted fever entities.)

Walker, D, Bolognia, JL, Jorizzo, JL, Rapini. “Rickettsial diseases”. Dermatology. 2008. pp. 1127-33. (A great review of rickettsial diseases with interesting historical facts and epidemiology.)

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