Rocky Mountain spotted fever (RMSF) is the most common rickettsial infection and the second most commonly reported tick-borne disease (after Lyme disease) in the United States. Rocky Mountain spotted fever is a reportable disease in the United States.
The causative agent is Rickettsia rickettsii (named after Howard T. Ricketts, the discoverer of the organism). This organism is an Alphaproteobacteria and member of the spotted fever group of rickettsial infections.
Rocky Mountain spotted fever was first described in the late 1800s in the Bitterroot Valley of Idaho, and for several decades, the disease was thought to be limited to the Rocky Mountain area; however, it now has a high documented prevalence in the eastern United States.
The disease is spread mainly through the bites of infected ticks. The dog tick, wood tick, and Lone Star tick are all potential carriers and are responsible for Rocky Mountain spotted fever in different parts of the United States.
RMSF has the highest mortality of any tick-borne illness in the United States (up to 30%). Because of this, the Rocky Mountain Laboratory was established in Hamilton, Montana, to help investigate the disease. This laboratory is now part of the National Institute of Allergy and Infectious Diseases (NIAID).
Early treatment is critical to the outcome in RMSF and must be started on the basis of clinical diagnosis (see Clinical). Consider the possibility of RMSF in any patients with potential tick exposure who develop fever, myalgia, or headache, even if they do not have a rash. If suspected, promptly begin antibiotic (doxycycline) treatment even before confirmation of the diagnosis, as delay in the initiation of treatment is associated with significantly higher mortality.
For additional discussion of the disease, see Rocky Mountain Spotted Fever. For patient education information, see the Bites and Stings Center, as well as Ticks.
RMSF is a reportable disease in the United States.
Rocky Mountain spotted fever is a diffuse, small-vessel vasculitis. R rickettsii is a small, gram-negative, obligate intracellular coccobacillus with a tropism for human endothelial cells. This bacterium causes membrane disruption and increased permeability.
Rickettsiae can be demonstrated in the cytoplasm and the nucleus of cells. Possible mechanisms for cellular injury include injury to the cell membrane, depletion of adenosine 5-triphosphate (which leads to failure of the sodium pump), and damage to the cell caused by toxic products of rickettsial metabolism.
Vascular lesions are responsible for the clinical manifestations, including rash, headache, alteration in the level of consciousness, heart failure, and shock. Vascular lesions can be found throughout the body, with highest predilection for the skin, gonads, and adrenal glands.
Profound hyponatremia is common. Several mechanisms have been postulated, including a shift in water from the intracellular spaces to the extracellular spaces; increased loss of sodium in the urine; and an exchange of sodium for potassium at the cellular level.
Edema of the medulla oblongata may contribute to fatality in some patients.
Concentrations of antidiuretic hormone and aldosterone are increased in some patients.
Ticks are the natural hosts, reservoirs, and vectors of R rickettsii. The species of tick acting as the vector varies by geographic location. R rickettsii is usually transmitted to humans by the bite of an infected tick. On occasion, transmission occurs by scratching or rubbing infectious tick feces into the skin.
Adult ticks transmit the disease to humans during feeding. At least 6 hours of tick attachment is needed for the transmission of R rickettsii.
Primary hosts of R rickettsii include the following:
Dermacentor variabilis (dog tick) in the eastern United States and eastern Canada
Dermacentor andersoni (wood tick) in the western United States and western Canada
Amblyomma americanum (Lone Star tick) in the southwestern United States
Rhipicephalus sanguineus (brown dog tick) recently implicated as a vector in Arizona[1]
Laboratory personnel can be infected by inoculation or inhalation of aerosolized infectious specimens. For this reason, only specially equipped laboratories should attempt to culture and isolate Rickettsia species. Detection by other means (eg, serology) is more readily available than culture and isolation.
Rocky Mountain spotted fever has been reported in almost every state in the continental United States, with an age-related annual incidence of 0.5-3 cases per million population. In 1997-2002, the mean annual incidence was 2.2 cases per million population.[2] Those rates increased to 7 cases per million population in 2007, a finding that has been attributed at least in part to increased awareness and testing for the disease, as the percentage of confirmed cases among the total reported, and the case fatality rate, have both decreased.[3] The figures for 2010 are 6 cases per million population.[4]
The term Rocky Mountain spotted fever is a misnomer because the disease is relatively rare in the Rocky Mountain states. States reporting the highest rate of disease include North Carolina, Missouri, Tennessee, Oklahoma, and Arkansas; these states have accounted for more than half the total cases. (See the image below.)
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Geographic distribution of Rocky Mountain spotted fever incidence in 2010, cases per million: Courtesy of the US Centers for Disease Control and Preve....
About 90% of cases occur between April and September, the time of the year when ticks have maximal activity and when people participate in outdoor recreational activities.
International statistics
Rocky Mountain spotted fever is also found in Canada, Mexico, Central America, and South America. However, the arthropod vector differs by location. Other rickettsial illnesses similar to Rocky Mountain spotted fever are also found worldwide (see the table below).
Table 1. Human Disease Around the World Caused by Spotted Fever Group Rickettsiae.
View Table
See Table
Racial, sexual and age-related differences in incidence
Prior to 2000, Native Americans had rates of Rocky Mountain spotted fever similar to those of other races in the United States.[5] From 2001-2005, rates increased disproportionately (16.8 cases per million vs 0.5-4.2 cases per million for other races). The highest rates were in Oklahoma (113.1 cases per million).[6]
Darker-skinned individuals tend to have a worse clinical course, probably due to delays in recognizing the rash. Native American have higher rates of incidence, as well as worse outcomes. The annual incidence of Rocky Mountain spotted fever was 277.2 cases per million in the Southern plains, 104.6 cases per million in the East, and 49.4 cases per million in the Southwest regions.[7] Rates described through the national surveillance network are approximately 5-fold lower than those described in the review by Folkema et al.
The incidence is higher in males than in females, with a male-to-female ratio of 1.7:1. Children are at greater risk of acquiring Rocky Mountain spotted fever than are adults. The highest incidence occurs in children aged 5-9 years. However, the highest mortality is in those aged 50 years or older.
Outcomes can vary from complete resolution to death. The mortality rate during the preantibiotic era was as high as 30%; however, the mortality rate now ranges from approximately 2% in children to 9% in elderly persons.
The outcome greatly depends on the early start of appropriate treatment. The case-fatality rate is higher (6.2%) for persons whose treatment begins more than 3 days after onset of symptoms than for those treated within the first 3 days of illness (1.3%).
The importance of early treatment may help explain the poorer prognosis in African Americans. Rocky Mountain spotted fever may be diagnosed later in blacks than in people with lighter skin because of the difficulty in detecting the early macular rash. In addition, people with glucose-6-phosphate dehydrogenase (G6PD) deficiency tend to have a severe course of Rocky Mountain spotted fever, and the prevalence of G6PD deficiency in black males is 12%.
Severe disease may result in long-term sequelae, such as the following:
Partial paralysis of the lower extremities
Gangrene requiring amputation of fingers, toes, arms, or legs
The incubation period for Rocky Mountain spotted fever (RMSF) is 2-8 days after the tick bite. A history of tick bite is present in only two thirds of cases.
Symptoms can begin gradually or abruptly. Fever, headache, rash, toxicity, myalgia, and mental confusion are the major clinical manifestations.
The patient's body temperature usually exceeds 38.8°C (101.8°F). Headache is the most common neurologic manifestation. In older children and adults, the headache may be intractable and may be ongoing day and night. Young children may not complain of headache.
Nausea, vomiting, and abdominal pain may occur. Conjunctival hyperemia and photophobia may be observed.
Rash
The rash of Rocky Mountain spotted fever is an important pathognomonic feature of the disease and is present in 80-90% of patients. Rash begins as blanching maculopapular lesions. These lesions become petechial or purpuric in approximately one half of patients, accounting for the disease’s former name of black measles.[8]
The rash first appears peripherally on the wrists and ankles. It spreads centripetally over the next 2-3 days. Involvement of the palms and soles is an important diagnostic feature.
In most patients, rash usually appears by the second or third day. However, it may be delayed until the sixth day.
Early recognition of the blanching macular eruption is vital, because the classic petechial rash does not typically appear until 6 days or so after the initial symptoms become apparent.
Body temperature exceeds 38.8°C (101.8°F). The patient may have a toxic appearance. The characteristic skin rash is present in 80-90% of infected individuals. Hepatomegaly and splenomegaly are present in approximately 33% of patients. Signs of meningoencephalitis include restlessness, irritability, mental confusion, and delirium.
Meningismus may occur. Findings may include neck stiffness, photophobia, a positive Kernig sign (pain on knee extension when the hip is flexed to 90°), and a positive Brudzinski sign (knee and hip flexion when the neck is flexed).
Ataxia may be present. Spastic paralysis may occur. Sixth nerve palsy may be observed. Muscle tenderness is a common feature.
Laboratory findings may be nonspecific in Rocky Mountain spotted fever (RMSF). On the complete blood count, the total leukocyte count may be normal, elevated, or decreased but usually shows a left shift.
Mild anemia and thrombocytopenia of less than 150 × 109/L (< 150 × 103/µL) occur in approximately one third of patients. Severe thrombocytopenia of less than 20 × 109/L (< 20 × 103/µL) occurs in approximately 10% of patients.
On a comprehensive metabolic panel, the following may be noted:
Hyponatremia (serum sodium < 130 mEq/L) in 20% of patients
The serum alanine aminotransferase level is usually increased
Serum albumin values may be low
The blood urea nitrogen (BUN) level is increased
Results of cerebrospinal fluid (CSF) analysis are generally normal. However, mild pleocytosis may be present, and approximately 50% of patients have a predominance of polymorphonuclear cells. An elevated CSF protein level may also be observed.
Serologic assays to detect anti– R rickettsii immunoglobulin G (IgG) antibodies are usually performed for definitive diagnosis.[9] Testing of acute-phase and convalescent-phase sera is recommended to demonstrate a 4-fold or higher increase in the titer.
Enzyme immunoassays (EIAs) and immunoglobulin M (IgM) antibody-capture immunoassays are new serologic tests that potentially allow for early diagnosis.
In research laboratories, isolation of rickettsiae from tissues or direct detection of rickettsiae in tissues by means of direct immunofluorescence is used to confirm the diagnosis. Polymerase chain reaction tests have been developed but are not widely available.
CT imaging is typically normal, whereas MRI seems more sensitive at revealing abnormalities. Published findings include diffuse edema, effacement of the sulci, arterial infarctions, prominent perivascular spaces, and enhancement of the meninges (ie typical findings of meningoencephalitis). In 3 recent pediatric cases of Rocky Mountain spotted fever (RMSF) with encephalitis, scattered nonenhancing punctate lesions were described throughout the cerebral white matter, visible on T2- and diffusion-weighted MRI.[10, 11, 12]
Early treatment is critical to the outcome in Rocky Mountain spotted fever (RMSF) and must be started on the basis of clinical diagnosis.[2] Consider the possibility of RMSF and promptly begin antibiotic treatment in any patient with potential tick exposure who develops fever, myalgia, or headache, even if they do not have a rash.
Never delay treatment while awaiting a confirmatory laboratory diagnosis or the development of a rash. The best outcomes are achieved when treatment is started within 4 days of symptom onset, and the classic petechial rash may not appear until day 6.
Doxycycline
Doxycycline is considered to be first line treatment for both adults and children and should be started as soon as RMSF is suspected.[13] The use of any other antibiotics has been associated with a higher risk of death (see Table 2, below).
Doxycycline treatment is most effective at preventing death if it is begun within the first 5 days after symptoms begin. As a result doxycycline treatment should be started before the return of lab results and before manifestation of severe symptoms, such as petechiae. If the patient is treated within the first 5 days of disease, fever generally subsides within 24-72 hours.[13]
The recommended dosage of doxycycline is 2.2 mg/kg body weight twice daily for children less than 45 kg (100 lb). For adults, the dosage is 100 mg every 12 hours. Patients should be treated for at least 3 days after the fever subsides and until there is evidence of clinical improvement. Standard duration of treatment is 7-14 days.
The recommended dosage of doxycycline for RMSF has not been shown to cause staining of permanent teeth.[14]
Chloramphenicol was previously recommended for the treatment of children younger than 9 years. In national surveillance data, however, patients treated with chloramphenicol were more likely to die than those treated with a tetracycline. Staining of teeth caused by one or more courses of tetracyclines (particularly doxycycline) is negligible.
Some authors have advocated the use of adjunctive corticosteroids, but the specific therapeutic benefits of these drugs are not known. Physicians should be aware that sulfonamide treatment given empirically in a febrile child can worsen Rocky Mountain spotted fever.
Other supportive measures (eg, intravenous administration of fluids, oxygenation, correction of electrolyte impairments, management of disseminated intravascular coagulation) should be provided according to the patient's clinical situation.
Patients with Rocky Mountain spotted fever should be treated in consultation with an infectious disease specialist.
Avoidance of tick-infested areas is the first line of defense against Rocky Mountain spotted fever. If tick-infested areas cannot be avoided, wearing light-colored shirts and trousers that fit tightly around the waist and ankles can minimize the risk of being bitten.
Exposed areas of the skin should be covered with insect repellents containing N -N -diethyl-M -toluamide (DEET). In children, insect repellents should be used carefully on exposed skin. Application to the face and hands should be avoided.
After people leave an endemic area, they should inspect their bodies for attached ticks, with particular attention on areas containing hair.
If ticks are found, any of several commercial removal devices should be used if possible. Otherwise, ticks should be removed by grasping them with fine tweezers at the point of attachment and by pulling them out slowly and steadily. The aim is to remove the tick's mouthparts from the site of insertion without damaging the body of the tick.
After the tick is removed, the skin should be disinfected. Check to make sure that the head of the tick is not still embedded.
Some have recommended keeping the removed tick in a jar along with a dampened paper towel in the refrigerator for a month. This way, if the person later develops symptoms, the tick may be used to help identify what (if any) infection it may have transmitted.
Burning the tick, smothering it in alcohol or petroleum jelly (or another substance), or twisting or rubbing it off is not recommended. These methods have not been shown to decrease the time the tick remains embedded. In addition, they may pose of risk breaking the body of the tick open and releasing bacteria that were otherwise contained within it.
After a tick bite occurs, use of antimicrobial prophylaxis has no role in the prevention of Rocky Mountain spotted fever.
The best outcomes in Rocky Mountain spotted fever (RMSF) are achieved when treatment is started within 4 days of symptom onset. Doxycycline is the antibiotic of choice.
Chloramphenicol was previously recommended for the treatment of children younger than 9 years. In national surveillance data, however, patients treated with chloramphenicol were more likely to die than those treated with a tetracycline. Chloramphenicol poses a risk of permanent aplastic anemia and should be avoided if at all possible.
Clinical Context:
Doxycycline is the drug of choice for RMSF. It is a broad-spectrum, synthetically derived bacteriostatic antibiotic in the tetracycline class. When given orally, it is almost completely absorbed.
It concentrates in bile and is excreted in urine and feces as a biologically active metabolite in high concentrations. This agent is the only tetracycline that does not need dosing adjustment in renal failure.
Doxycycline inhibits protein synthesis and, therefore, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. It may block dissociation of peptidyl transfer RNA (tRNA) from ribosomes, arresting RNA-dependent protein synthesis.
Tetracyclines are the drugs of choice. Although tetracyclines should not be routinely prescribed to children younger than 8 years, the benefits far exceed the risks in RMSF. Doxycycline is the agent of choice because the risk of dental staining is less with this agent than with other tetracyclines.
Nicholas John Bennett, MBBCh, PhD, MA(Cantab), FAAP, Assistant Professor of Pediatrics, Co-Director of Antimicrobial Stewardship, Medical Director, Division of Pediatric Infectious Diseases and Immunology, Connecticut Children's Medical Center
Disclosure: Received research grant from: Cubist<br/>Received income in an amount equal to or greater than $250 from: Horizon Pharmaceuticals, Shire<br/>Medico legal consulting for: Various.
Coauthor(s)
Joseph Domachowske, MD, Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York Upstate Medical University
Disclosure: Received research grant from: Pfizer;GlaxoSmithKline;AstraZeneca;Merck;American Academy of Pediatrics, Novavax, Regeneron, Diassess, Actelion<br/>Received income in an amount equal to or greater than $250 from: Sanofi Pasteur.
Walid Abuhammour, MD, MBA, FAAP, FIDSA, Adjunct Professor, Department of Pediatrics, Hashemite University, Jordan; Head of Pediatric Infectious Diseases, Department of Pediatrics, Al Jalila Children's Hospital, UAE
Disclosure: Nothing to disclose.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Larry I Lutwick, MD, FACP, Editor-in-Chief, ID Cases; Moderator, Program for Monitoring Emerging Diseases; Adjunct Professor of Medicine, State University of New York Downstate College of Medicine
Disclosure: Nothing to disclose.
Chief Editor
Russell W Steele, MD, Clinical Professor, Tulane University School of Medicine; Staff Physician, Ochsner Clinic Foundation
Centers for Disease Control and Prevention. Rocky Mountain Spotted Fever - Statistics and Epidemiology. Available at http://www.cdc.gov/rmsf/stats/. Accessed: January 27, 2013.
Centers for Disease Control and Prevention. Rocky Mountain Spotted Fever. Available at http://www.cdc.gov/rmsf/symptoms/index.html#treatment. Accessed: August 14, 2018.
Geographic distribution of Rocky Mountain spotted fever incidence in 2010, cases per million: Courtesy of the US Centers for Disease Control and Prevention.
Geographic distribution of Rocky Mountain spotted fever incidence in 2010, cases per million: Courtesy of the US Centers for Disease Control and Prevention.
Europe, Asia, Africa, India, Israel, Sicily, Russia, Europe, Asia, Africa, India, Israel, Sicily, Russia
Rickettsia akari
Rickettsialpox
Worldwide
Rickettsia sibirica
Siberian tick typhus, North Asian tick typhus
Siberia, People's Republic of China, Mongolia, Europe
Rickettsia australis
Queensland tick typhus
Australia
Rickettsia honei
Flinders Island spotted fever, Thai tick typhus
Australia, South Eastern Asia
Rickettsia africae
African tick-bite fever
Sub Saharan Africa, Caribbean
Rickettsia japonica
Japanese or Oriental spotted fever
Japan
Rickettsia felis
Cat flea rickettsiosis, flea borne typhus
Worldwide
Rickettsia slovaca
Necrosis, erythema, lymphadenopathy
Europe
Rickettsia heilongjaiangensis
Mild spotted fever
China, Asian region of Russia
Rickettsia parkeri
Mild spotted fever
US
Doxycycline is first-line treatment for both adults and children; antibiotics other than doxycycline increase the risk of death[13]
Dosage: for children < 45 kg (100 lb): 2.2 mg/kg body weight given twice a day
Dosage for adults: 100 mg every 12 hours
Treatment is most effective at preventing death if doxycycline is started within the first 5 days of symptoms; if treatment occurs within 5 days fever generally subsides within 24-72 hours
Patients should be treated for at least 3 days after the fever subsides and until there is evidence of clinical improvement; standard duration of treatment is 7-14 days - "Fever plus 3, at least a week"
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