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Clinical manifestations and diagnosis of Rocky Mountain spotted fever

Clinical manifestations and diagnosis of Rocky Mountain spotted fever
Authors:
Daniel J Sexton, MD
Micah T McClain, MD, PhD
Section Editors:
Stephen B Calderwood, MD
Sheldon L Kaplan, MD
Deputy Editor:
Keri K Hall, MD, MS
Literature review current through: Sep 2021. | This topic last updated: Jun 24, 2020.

INTRODUCTION — Rocky Mountain spotted fever (RMSF) is a potentially lethal, but curable tick-borne disease, which was first described in Idaho in the 19th century. In 1906, Howard Ricketts demonstrated that RMSF was an infectious disease transmitted by ticks [1]. The clinical spectrum of human infection ranges from mild to fulminant disease [2].

The epidemiology, clinical manifestations, and diagnosis of RMSF will be reviewed here. The basic biology of Rickettsia rickettsii infection, the mechanisms of disease, and the treatment of this disorder are discussed separately. (See "Biology of Rickettsia rickettsii infection" and "Treatment of Rocky Mountain spotted fever".)

PATHOGENESIS — The etiologic agent, R. rickettsii, is a gram-negative, obligate intracellular bacterium with a tropism for vascular endothelial cells. Rickettsial infection leads to direct vascular injury; endothelial cells produce prostaglandins that may contribute to increased vascular permeability [3]. Activation of clotting factors ensues, but true disseminated intravascular coagulation rarely occurs. Hyponatremia results from release of antidiuretic hormone as an appropriate response to hypovolemia and reduced tissue perfusion [4]. The host response, which is secondary to vascular injury, can lead to a variety of clinical manifestations such as interstitial pneumonitis, myocarditis, and encephalitis.

MICROBIOLOGY — R. rickettsii does not grow in cell-free culture media. Growth of R. rickettsii requires living host cells (such as the yolk sac of embryonated eggs or cell culture). Gimenez or acridine orange stains are required for visualization of rickettsia on microscopy, since they do not take up routine Gram stain; rickettsiae are also small in size (ie, 0.3 by 1.0 micrometers). The cell wall contains peptidoglycan and lipopolysaccharide (LPS), similar to gram-negative bacteria.

Rickettsiae have surface proteins that are used for serotyping; these surface proteins (OmpA and OmpB) contain epitopes, which are the targets for humoral antibodies [5].

The rickettsial family of pathogens also includes the organisms in the spotted fever group (eg, Rickettsia conorii, Rickettsia africae, Rickettsia sibirica). These additional organisms are discussed elsewhere. (See "Other spotted fever group rickettsial infections".)

EPIDEMIOLOGY

Geographic variation — Rocky Mountain spotted fever (RMSF) occurs throughout the United States, Canada, Mexico, Central America, and in parts of South America (Bolivia, Argentina, Brazil, and Colombia). The ease and frequency of interstate and international travel means that patients with RMSF acquired in endemic areas may present to clinicians practicing in locations where RMSF is uncommon or unknown.

RMSF is the most common rickettsial infection in the United States. In 2008, 2553 cases of RMSF were reported to the Centers for Disease Control and Prevention (CDC). In 2009, the Council for State and Territorial Epidemiologists changed the reporting designation from "RMSF" to the more broad "spotted fever rickettsiosis," which includes RMSF as well as diseases caused by other rickettsial species, including R. parkeri and R. philipii. Using this new definition, there were 4269 cases of probable and confirmed spotted fever rickettsiosis reported in 2016, the majority of which were presumed to be RMSF [6].

The incidence rate of RMSF ranges by state (figure 1) [7]. The infection is most prevalent in the southeastern and south-central states. The geographic distribution of RMSF reflects the different populations of transmitting ticks [6,8]. This was illustrated in Arizona, where RMSF has emerged as a significant cause of morbidity and mortality on Indian reservations, and has been associated with infestations of the tick vector, Rhipicephalus sanguineus [9,10]. In addition, family clusters of infection are a well-recognized feature of RMSF because of shared residence and risk for vector exposure [11,12]. (See 'Transmission' below.)

Although RMSF is more common in rural and suburban locations, it may occasionally occur in residents of urban areas. For example, cases of RMSF have been described in New York City in patients who presumably acquired the infection from tick bites in urban parks [13].

Disease severity can vary significantly from mild to fulminant disease. In one effort to identify any variations in disease severity by geographic location, 4533 cases of RMSF were coded by county and classified according to disease severity. Of these reported cases, there were 1089 hospitalizations and 23 deaths. Significant clusters of hospitalizations and deaths were detected in southwestern Tennessee while low rates of severity were found in some areas of North Carolina [14]. Similar clusters of severe disease have been reported in several locations in South America and along the United States-Mexico border [15,16]. However, the causes of these differences in severity are unknown, nor is it known whether treatment delays may have contributed to these results.

Seasonal variation — The seasonal distribution of RMSF parallels the activity of the transmitting ticks (see 'Vectors' below). Most cases of RMSF occur in the spring and early summer, when outdoor activity is most frequent [17]. However, in Arizona, cases transmitted by the vector R. sanguineus peaked in July and September [9]. Rare cases have also been reported in the cold weather months among residents living in the southern United States [18]. Whether these unseasonal cases are due to infection with R. rickettsii or other more benign spotted fever group rickettsiae has been questioned [19].

Risk factors — Although previous studies found that the highest incidence of RMSF occurred in children <10 years, surveillance during 2003 demonstrated the highest age-specific incidence was among persons aged 40 to 64 years [20]. Individuals with frequent exposure to dogs and who reside near wooded areas or areas with high grass may also be at increased risk for infection [2].

Native Americans appear to be at greater risk for RMSF than the general United States population [21]. A retrospective study utilizing a national surveillance database found that the incidence of RMSF among Native Americans was 16.8/100,000 during the period from 2000 to 2005. In contrast, the incidence among White and Black Americans was 4.2 and 2.6/100,000, respectively [22]. However epidemiologic studies that attempt to assess the frequency of RMSF have been hampered by imprecise case definitions, inherent limitations in diagnostic assays, and lack of pathologic confirmation [19,23]. For example, only 5.8 percent of 7796 case report forms received by the CDC from 2000 to 2007 were classified as "confirmed" infections [6].

Mortality — Antimicrobial therapy has resulted in a marked reduction in the case fatality (CF) rate of patients with RMSF. In the preantibiotic era, the CF rate ranged from 20 to 30 percent in the eastern United States to as high as 80 percent in the Bitterroot Valley in Montana. However, during the period from 1981 to 1998, the average annual CF rate was 3.3 percent (range 1.1 to 4.9 percent) [24]. The mortality from RMSF has continued to decrease. As an example, in a series of 7796 cases reported to the United States Centers for Disease Control and Prevention, the overall CF rate declined from 2.2 percent in the year 2000 to 0.3 percent in 2007; this rate remained essentially unchanged from 2007 to 2010 [6,7]. Despite this overall decrease, mortality associated with RMSF has remained high in certain areas. The CF rate has been reported to be 7 percent on several American Indian reservations in Arizona, due in part to delays in initiating antimicrobial therapy [25].

The accuracy of published data on CF rates for RMSF remains controversial. Some experts believe that the remarkably low CF rates reported for RMSF in the United States since 2000 represent either misdiagnosis of other less virulent rickettsioses (eg, Rickettsia parkeri) or poorly understood regional geographic variations in strains of R. rickettsii [19]. In addition, cases of fatal RMSF may escape diagnosis, as death can occur before serologic evidence of infection is obtained, and autopsy will not identify the organism unless special histochemical staining of tissue is performed [26].

The CF rate is highest in the very young (≤4 years, 3 to 4 percent) and in older adults (≥60 years, 4 to 9 percent) (figure 2) [27]. Other host factors associated with severe or fatal RMSF include [6,27-29]: male sex; Black race (the cause of this discrepancy has not been adequately studied or clarified); chronic alcohol abuse; and glucose-6-phosphate dehydrogenase deficiency.

In addition, early therapy for RMSF (ie, within five days of symptom onset) is important since a delay in treatment has been associated with an increased risk of mortality. (See 'Empiric diagnosis and early initiation of therapy' below and "Treatment of Rocky Mountain spotted fever", section on 'Importance of early therapy'.)

TRANSMISSION

Route — As noted above, Rocky Mountain spotted fever (RMSF) is usually transmitted via tick bite. However, up to one-third of patients do not report a history of a tick bite, since the inoculation site is generally painless and often obscured by hair or a skin fold [30,31]. The tick transmits infection to humans during feeding. After the tick has been attached to the host for 6 to 10 hours, rickettsiae are released from the salivary glands of the ticks. In addition, humans may become infected by contact with tick tissues or fluids during the process of tick removal. Laboratory workers may acquire rickettsial infection through inhalation of contaminated aerosols [32].

Vectors — The various ticks, which serve as the vector and reservoir of R. rickettsii, vary by location.

Within the United States — The principal vector of RMSF in the eastern and south central United States is Dermacentor variabilis (the American dog tick) (picture 1). In contrast, Dermacentor andersoni (the Rocky Mountain wood tick) (picture 2) is the primary vector in the mountain states west of the Mississippi River.

Rhipicephalus sanguineus, the common brown dog tick (picture 3), is also a vector for RMSF in the southwestern United States [10].

Outside the United States — The Cayenne tick (Amblyomma cajennense) is a vector for R. rickettsii transmission in Central and South America. The brown dog tick (Rhipicephalus sanguineus) is a vector in Mexico. The yellow dog tick (Amblyomma aureolatum) has also been implicated as a vector in Brazil [33].

INCUBATION PERIOD — Infected patients become symptomatic 2 to 14 days after being bitten by an infected tick, with most clinical cases occurring between five and seven days after exposure.

CLINICAL MANIFESTATIONS — Classic symptoms of Rocky Mountain spotted fever (RMSF) include fever, headache, and rash in a person with a history of a tick bite [34]. However, all of these diagnostic clues are rarely identified on the initial patient encounter, leading to delays in appropriate therapy. In fulminant cases of RMSF, death may occur as early as within five days. Poor outcomes have been associated with delay of appropriate antibiotics [35,36].

Early nonspecific symptoms — In the early phase of illness, most patients have nonspecific signs and symptoms, such as fever (which is typically present in a high percentage of patients), headache, malaise, myalgias, and arthralgias [37]. The onset of symptoms may be gradual or abrupt and the headache is often severe [35].

Nausea, with or without vomiting, is a common complaint. Some patients, especially children, may also have prominent abdominal pain that may be severe; the onset of abdominal pain before the onset of rash may lead to erroneous diagnoses such as acute appendicitis, cholecystitis, and even bowel obstruction [38,39].

Rash — Rash occurs in approximately 88 to 90 percent of patients, but is uncommonly seen at initial clinical presentation. Most patients with RMSF develop a rash between the third and fifth days of illness (picture 4) [12,37]. Only 14 percent of patients have rash on the first day, and less than one-half develop a rash in the first 72 hours of illness [35]. As a result, rash is often absent when patients first contact a clinician for evaluation [35,40].

The hallmark of RMSF is a blanching erythematous rash with macules (1 to 4 mm in size) that become petechial over time [35]. However, the evolution of skin rash may vary; some patients may suddenly develop a petechial rash without a prior maculopapular eruption. The appearance of the rash usually begins on the ankles and wrists and spreads to the trunk; rash that appears on the palms and soles is highly characteristic of RMSF, but usually occurs in later-stage disease.

In a small percentage of patients, the rash is atypical, remaining confined to one body region. In severe cases, the rash may become confluent, with some areas of skin undergoing necrosis due to pathogen-induced damage to the microcirculation, especially in regions supplied by terminal arteries, such as the fingers, toes, nose, ears, and genitals [2].

Eschars at the site of the tick bite are rarely seen and would be suggestive of other diagnoses, such as boutonneuse fever or African tick bite fever, which would have other epidemiologic clues, such as travel history to Europe or Africa, respectively. Urticaria and pruritus are not characteristic of RMSF and their presence makes the diagnosis unlikely. (See 'Differential diagnosis' below.)

A potential diagnostic problem is that rash never occurs in up to 10 percent of patients. These cases of "spotless" RMSF may be severe with a fatal outcome [41]. In addition, the rash can be easily overlooked in dark-skinned individuals. These observations are important clinically because a delay in the institution of antimicrobial therapy beyond five days is associated with an increased mortality rate (22.9 versus 6.5 percent in those treated earlier in one report) [40]. (See "Treatment of Rocky Mountain spotted fever".)

Other clinical manifestations — In addition to early nonspecific symptoms, abdominal pain, rash, cough, bleeding, edema (especially in children), confusion, focal neurologic signs, and seizures may also be present [38]. Conjunctivitis, retinal abnormalities, and electrocardiographic abnormalities may also rarely occur and lead to diagnostic confusion.

Major complications include: encephalitis, noncardiogenic pulmonary edema, adult respiratory distress syndrome, cardiac arrhythmias, coagulopathy, gastrointestinal bleeding, and skin necrosis. The onset of neurologic involvement is associated with increased risk of mortality and morbidity; in one retrospective study of 92 children with RMSF, 13 had neurologic sequelae at discharge including encephalopathy, ataxia and blindness, which were attributed to delays in diagnosis and treatment [38].

Physical examination — The physical examination may be notable for rash, pedal edema (especially in children), confusion, conjunctival erythema, and retinal abnormalities. Meningismus may suggest central nervous system involvement. Late in the disease course, the examination may be notable for abnormal mentation, seizures, and focal neurologic deficits such as cranial nerve palsies or transient deafness. Gangrene of the digits, ears, and scrotum can also occur in severe cases [42,43]. Fundoscopic examination may show retinal vein engorgement, arterial occlusion, and flame hemorrhage.

LABORATORY STUDIES — Most patients with Rocky Mountain spotted fever (RMSF) have a normal white blood cell count at presentation. As the illness progresses, thrombocytopenia becomes more prevalent and may be severe; this is a helpful diagnostic clue to the possibility of rickettsial disease, but a normal platelet count does not exclude the diagnosis. Thrombocytopenia is thought to result from increased destruction at sites of rickettsia-mediated vascular injury [35]. The low platelet count may be accompanied by a reduced fibrinogen concentration and elevated fibrin split products; however, disseminated intravascular coagulation is rare.

Other findings that are common in advanced cases include hyponatremia, elevations in serum aminotransferases and bilirubin, azotemia, and prolongation of the partial thromboplastin and prothrombin times [38]. Hyponatremia is a particularly common finding in patients with central nervous system involvement. The cerebrospinal fluid analysis may demonstrate pleocytosis; both monocytic and polymorphonuclear predominance have been described; elevated cerebrospinal fluid (CSF) protein is seen in approximately one-third of patients.

Azotemia is common and usually due to hypovolemia; acute tubular necrosis may result from systemic hypotension with multi-organ involvement. In the latter group of patients, urinalysis may reveal coarse granular casts. In a small number of cases, jaundice and renal failure dominate and confuse the clinical presentation [43,44]. In a review of 114 patients from our hospital, 19 percent developed acute renal failure (defined as an elevation in the serum creatinine concentration above 2 mg/dL [177 micromol/L]) [44]. A variety of mechanisms may contribute to this complication, including hypotension-induced acute tubular necrosis, intravascular thrombosis, and interstitial vascular inflammation due to direct infection of the endothelial cells by R. rickettsii. (See "Biology of Rickettsia rickettsii infection".)

If a lumbar puncture is performed in a patient with RMSF, CSF analysis usually shows a white blood count (WBC) of <100 cells per microL with either a polymorphonuclear or lymphocytic predominance [38]. Moderately elevated protein (100 to 200 mg/dL) and a normal glucose level are common [45,46]. These findings may not help distinguish RMSF from meningococcal disease.

IMAGING STUDIES — Patients with cough may have interstitial infiltrates on chest x-ray, consistent with early pulmonary edema. Echocardiographic studies show minimal myocardial dysfunction and normal pulmonary capillary wedge pressure measurements during intensive care monitoring, supporting the noncardiogenic nature of the pulmonary edema.

DIFFERENTIAL DIAGNOSIS — In the first few days of fever, Rocky Mountain spotted fever (RMSF) is commonly mistaken for a nonspecific viral illness. The appearance of rash and the increasing severity of the illness may prompt consideration of rickettsial infection.

In view of the protean clinical features of RMSF, it is not surprising that this disorder is often confused with a wide array of other conditions.

In the patient with fever, rash, and headache, the key other diagnostic consideration is meningococcal meningitis, which has a high mortality rate if prompt therapeutic interventions are not offered. The results of a lumbar puncture and/or blood culture are the most reliable way to differentiate these syndromes. (See "Clinical manifestations of meningococcal infection" and "Diagnosis of meningococcal infection".)

Additional diagnostic considerations include West Nile virus meningitis or encephalitis, enteroviral meningitis, syphilitic meningitis, or Lyme disease. (See "Aseptic meningitis in adults".).

In the patient with fever and petechial rash, the main considerations include meningococcemia, thrombotic thrombocytopenic purpura, immune complex vasculitis, ehrlichiosis, anaplasmosis, leptospirosis, and bacterial sepsis. (See "Clinical manifestations of meningococcal infection" and "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Human ehrlichiosis and anaplasmosis".)

Patients with prominent gastrointestinal symptoms may be misdiagnosed with gastroenteritis or an acute abdomen. (See "Evaluation of the adult with abdominal pain" and "Causes of acute abdominal pain in children and adolescents".)

With the onset of maculopapular rash, RMSF has also been confused with measles, infectious mononucleosis, viral hepatitis, ehrlichiosis, streptococcal infection, primary HIV, secondary syphilis, parvovirus infection (Fifth disease), Kawasaki disease, and roseola. (See "Measles: Clinical manifestations, diagnosis, treatment, and prevention" and "Infectious mononucleosis" and "Acute and early HIV infection: Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of parvovirus B19 infection" and "Kawasaki disease: Clinical features and diagnosis".)

In tropical areas, typhoid fever, leptospirosis, and dengue may be confused with RMSF. (See "Epidemiology, microbiology, clinical manifestations, and diagnosis of enteric (typhoid and paratyphoid) fever".)

The clinical features of RMSF overlap with those of both monocytic ehrlichiosis and granulocytic anaplasmosis. Distinguishing between RMSF and ehrlichiosis on the basis of clinical features is rarely possible, although the presence of leukopenia and the absence of rash are more typical of ehrlichiosis (table 1). However, the preferred treatment of ehrlichiosis, doxycycline, is the same as that of RMSF. (See "Human ehrlichiosis and anaplasmosis" and "Treatment of Rocky Mountain spotted fever".)

Other novel pathogens, such as a new Phlebovirus (Heartland virus) seen mostly in Missouri, and a new rickettsial species (Rickettsia amblyommii) seen in North Carolina, may present similarly to infection with R. rickettsii [47-49]. (See "Emerging viruses" and "Other spotted fever group rickettsial infections".)

Fever and rash may also be associated with noninfectious diseases, such as drug hypersensitivity and vasculitis [50]. As an example, if penicillin or a cephalosporin is administered empirically during the early phase of illness, the subsequent rash may then be incorrectly diagnosed as a drug eruption, rather than the rash of RMSF. (See "Drug eruptions".)

DIAGNOSIS

Empiric diagnosis and early initiation of therapy — A presumptive diagnosis of Rocky Mountain spotted fever (RMSF) is initially made based upon consistent clinical signs and symptoms in the appropriate epidemiologic setting [51]. (See 'Clinical manifestations' above and 'Epidemiology' above.)

Therapy should be initiated within five days of symptom onset. Thus, most patients will require empiric therapy since RMSF can rarely be confirmed or disproved in its early phase. Clinicians should not wait for the skin rash to develop before initiating treatment. A discussion on the approach to treatment in patients with probable or confirmed RMSF is found elsewhere. (See "Treatment of Rocky Mountain spotted fever", section on 'Approach'.)

Definitive diagnosis — R. rickettsii cannot be cultured in most clinical laboratories. Thus, the clinical diagnosis must be confirmed through serologic testing or through the use of polymerase chain reaction (PCR) testing or special stains on a skin biopsy.

Acute and convalescent serology should be sent on patients clinically suspected of having RMSF. (See 'Serologic testing' below.)

Clinically available polymerase chain reaction testing of blood samples for RMSF may also be helpful to confirm the diagnosis, but a negative test does not rule out rickettsial infection. (See 'DNA testing of blood' below.)

Testing of skin biopsies offers another potential method of disease confirmation, although these results are often delayed. (See 'Skin biopsy' below.)

Serologic testing — The clinical diagnosis of RMSF is usually confirmed retrospectively through serologic testing since test results are usually not available at the time of clinical decision-making [52]. Indirect immunofluorescence (IFA) testing is available commercially and at no cost through most state health departments in areas where spotted fever group infections are endemic. The overall sensitivity of paired IFA testing is approximately 95 percent [52].

IgM and IgG antibodies typically appear 7 to 10 days after the onset of the illness, and the optimal time to obtain a convalescent antibody titer is at 14 to 21 days after the onset of symptoms [52,53]. A fourfold rise in IgG titers between acute and convalescent sera is diagnostic of seroconversion and recent illness.

IgM assays alone should not be used to make a diagnosis of acute RMSF [54]. A false-positive IgM titer may occur if there is cross-reactivity to lipopolysaccharide from a bacterial pathogen [55]; thus, the utility of this test has been called into question.

Although serologic testing using the IFA test remains the standard method of diagnosis of RMSF, there are some important limitations to this approach when using serologic assays for clinical decision-making. As examples:

Serologic testing is usually not helpful during the first five days of symptoms (when therapy should be initiated), because the antibody response is not yet detectable [40]. Thus, a negative serology should not dissuade a clinician from initiating appropriate therapy in a patient with compatible illness. (See "Treatment of Rocky Mountain spotted fever".)

A positive single time-point IgG antibody titer in early disease does not confirm a diagnosis of RMSF, as low to moderate IgG antibody titers can persist for many years [56]. A fourfold rise in IgG titers between acute and convalescent sera is diagnostic of recent illness. However, when an acute sample is absent, an isolated high convalescent IgG titer (eg, >1:640 or 1:1280) obtained more than two weeks after illness onset is suggestive of recent infection, since extremely high IgG titers are unlikely to persist for long periods of time.

Early treatment for RMSF may blunt antibody responses. In one report, a few patients who were treated within the first 48 hours after onset of symptoms did not develop convalescent antibodies [52]. However, the frequency at which this phenomenon occurs is unknown.

Serologic assays are insufficient to identify conclusively the specific rickettsial agent responsible for the infection due to cross reactivity between species. A study of 15 serum specimens with antibodies reactive with R. rickettsii from the US Centers for Disease Control and Prevention (CDC) examined the specimens by microimmunofluorescence and Western blot assays against antigens of R. rickettsii and R. parkeri [57]. Four patients had higher titers of antibody to R. rickettsii, five had higher titers to R. parkeri, and in six patients, titers were equivalent to both rickettsial pathogens. Thus, spotted fever group rickettsiae other than R. rickettsii may be responsible for cases of tick-borne rickettsiosis in the United States, even when antibodies to R. rickettsii are detected by commercial assays. This lack of species-level specificity has led to a trend towards referring to these collective illnesses as "spotted fever group" rickettsial infections.

Although IFA tests are most commonly used, other serologic tests that may be employed include enzyme immunoassay (EIA), complement fixation (CF) and latex agglutination (LA), indirect hemagglutination (IHA), or microagglutination (MA) assays. Recent RMSF may be suggested by a convalescent titer of 1:128 or greater by LA, IHA, or MA. The Weil-Felix test, which detects cross-reacting antibodies against Proteus vulgaris antigens (OX2 and OX19), lacks sensitivity and specificity and its use is no longer recommended [37,52].

DNA testing of blood — Several major clinical labs, including the CDC, offer PCR-based tests on tissue or blood specimens to support the diagnosis of RMSF, although these vary in technique and sensitivity. The utility of PCR amplification of R. rickettsii DNA from blood is limited due to low sensitivity, particularly in early or mild disease, which is likely a result of low numbers of circulating rickettsial organisms in the blood [58]. Thus, while a positive result from PCR testing of blood for rickettsial spp can be confirmatory, a negative result does not rule out the diagnosis. While there are data suggesting that some real-time PCR methods may offer improved sensitivity over older methodologies [59], further clinical experience is needed before these can be recommended for routine clinical use.

Skin biopsy — Direct immunofluorescence testing or immunoperoxidase staining can be performed for R. rickettsii on a skin biopsy specimen and may offer a more timely diagnosis in those facilities that have access to a laboratory with the personnel and reagents to apply the appropriate methodology [60]. A skin biopsy has been shown to be approximately 70 to 90 percent sensitive if performed either before or within 12 hours of administering antibiotics [61]. Molecular assays for detection of rickettsial DNA in biopsy samples are also effective but are generally restricted to research laboratories [62].

Biopsy of a skin lesion obtained with a 3 mm punch biopsy can establish the diagnosis of RMSF. Fresh or formaldehyde-fixed tissue should be examined for rickettsiae using direct immunofluorescence or immunoenzyme methods [63]. Direct immunofluorescence staining can provide an answer in a few hours if the necessary conjugates are available locally. If local facilities are not able to do direct immunofluorescence, reference laboratories can perform immunoperoxidase stains on fixed tissue specimens. However, the delay in obtaining results makes this technique of little or no use for initial patient management.

The sensitivity of detecting R. rickettsii in skin biopsies by direct immunofluorescence staining is approximately 70 percent with a specificity of 100 percent; however, the sensitivity rapidly declines after antirickettsial therapy is begun [63]. It is therefore not useful to obtain a skin biopsy in patients who have received a tetracycline (usually doxycycline) or chloramphenicol for more than 48 hours.

Hematoxylin and eosin staining of biopsy specimens shows a lymphocytic vasculitis in early disease; in later lesions, fibrin thrombi and capillary-wall necrosis may be seen [60].

IMMUNITY — Immunity to RMSF in humans is thought to be life-long after natural infection occurs. This is based upon findings from animal studies that suggest guinea pigs experimentally infected with R. rickettsii develop durable immunity to reinfection after treatment. In a few cases, IgG antibodies have been present at remarkably high levels many years after infection occurred [64].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Tick-borne infections (Lyme disease, ehrlichiosis, anaplasmosis, babesiosis, and Rocky Mountain spotted fever)".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topic (see "Patient education: Rocky Mountain spotted fever (The Basics)")

SUMMARY AND RECOMMENDATIONS

Rocky Mountain spotted fever (RMSF) is a potentially lethal but usually curable tick-borne disease. (See 'Introduction' above.)

RMSF occurs throughout the United States, Canada, Mexico, Central America, and in parts of South America (Bolivia, Argentina, Brazil, and Colombia). (See 'Geographic variation' above.)

Most cases of RMSF occur in the spring and early summer, when outdoor activity is most frequent. (See 'Seasonal variation' above.)

RMSF is usually transmitted via a tick bite, although up to one-third of patients with proven RMSF do not recall a recent tick bite or recent tick contact. (See 'Transmission' above.)

In the early phases of illness, most patients have nonspecific signs and symptoms such as fever, headache, malaise, myalgias, arthralgias, and nausea with or without vomiting. Children may also have prominent abdominal pain that may be mistaken for other intra-abdominal processes, like appendicitis. Most patients with RMSF develop a rash between the third and fifth days of illness. (See 'Clinical manifestations' above.)

The diagnosis of RMSF can rarely be confirmed or disproved in its early phase. Thus, most patients will require empiric therapy for RMSF based upon clinical judgment and the epidemiologic setting. (See 'Empiric diagnosis and early initiation of therapy' above.)

The clinical diagnosis of RMSF is usually confirmed retrospectively through serologic testing. Other diagnostic methods include polymerase chain reaction (PCR) testing of blood or special stains on a skin biopsy. (See 'Diagnosis' above.)

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  16. Straily A, Drexler N, Cruz-Loustaunau D, et al. Notes from the Field: Community-Based Prevention of Rocky Mountain Spotted Fever - Sonora, Mexico, 2016. MMWR Morb Mortal Wkly Rep 2016; 65:1302.
  17. Spach DH, Liles WC, Campbell GL, et al. Tick-borne diseases in the United States. N Engl J Med 1993; 329:936.
  18. Lange JV, Walker DH, Wester TB. Documented Rocky Mountain spotted fever in Wintertime. JAMA 1982; 247:2403.
  19. Raoult D, Parola P. Rocky Mountain spotted fever in the USA: a benign disease or a common diagnostic error? Lancet Infect Dis 2008; 8:587.
  20. Hopkins RS, Jajosky RA, Hall PA, et al. Summary of notifiable diseases--United States, 2003. MMWR Morb Mortal Wkly Rep 2005; 52:1.
  21. Folkema AM, Holman RC, McQuiston JH, Cheek JE. Trends in clinical diagnoses of Rocky Mountain spotted fever among American Indians, 2001-2008. Am J Trop Med Hyg 2012; 86:152.
  22. Holman RC, McQuiston JH, Haberling DL, Cheek JE. Increasing incidence of Rocky Mountain spotted fever among the American Indian population in the United States. Am J Trop Med Hyg 2009; 80:601.
  23. Graf PC, Chretien JP, Ung L, et al. Prevalence of seropositivity to spotted fever group rickettsiae and Anaplasma phagocytophilum in a large, demographically diverse US sample. Clin Infect Dis 2008; 46:70.
  24. Holman RC, Paddock CD, Curns AT, et al. Analysis of risk factors for fatal Rocky Mountain Spotted Fever: evidence for superiority of tetracyclines for therapy. J Infect Dis 2001; 184:1437.
  25. Regan JJ, Traeger MS, Humpherys D, et al. Risk factors for fatal outcome from rocky mountain spotted Fever in a highly endemic area-Arizona, 2002-2011. Clin Infect Dis 2015; 60:1659.
  26. Paddock CD, Greer PW, Ferebee TL, et al. Hidden mortality attributable to Rocky Mountain spotted fever: immunohistochemical detection of fatal, serologically unconfirmed disease. J Infect Dis 1999; 179:1469.
  27. Centers for Disease Control and Prevention (CDC). Consequences of delayed diagnosis of Rocky Mountain spotted fever in children--West Virginia, Michigan, Tennessee, and Oklahoma, May-July 2000. MMWR Morb Mortal Wkly Rep 2000; 49:885.
  28. Walker DH, Kirkman HN. Rocky Mountain spotted fever and deficiency in glucose-6-phosphate dehydrogenase. J Infect Dis 1980; 142:771.
  29. Walker, DH, Raoult, D. Rickettsia rickettsii and other spotted fever group rickettsiae (Rocky Mountain spotted fever and other spotted fevers). In: Mandell, GL, Bennett, JE, Dolin, R, eds. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. 6th ed. Philadelphia, PA: Churchill Livingstone; 2005:729.
  30. Treadwell TA, Holman RC, Clarke MJ, et al. Rocky Mountain spotted fever in the United States, 1993-1996. Am J Trop Med Hyg 2000; 63:21.
  31. Dalton MJ, Clarke MJ, Holman RC, et al. National surveillance for Rocky Mountain spotted fever, 1981-1992: epidemiologic summary and evaluation of risk factors for fatal outcome. Am J Trop Med Hyg 1995; 52:405.
  32. Johnson JE 3rd, Kadull PJ. Rocky Mountain spotted fever acquired in a laboratory. N Engl J Med 1967; 277:842.
  33. Dantas-Torres F. Rocky Mountain spotted fever. Lancet Infect Dis 2007; 7:724.
  34. Usatine RP, Sandy N. Dermatologic emergencies. Am Fam Physician 2010; 82:773.
  35. Helmick CG, Bernard KW, D'Angelo LJ. Rocky Mountain spotted fever: clinical, laboratory, and epidemiological features of 262 cases. J Infect Dis 1984; 150:480.
  36. Hattwick MA, Retailliau H, O'Brien RJ, et al. Fatal Rocky Mountain spotted fever. JAMA 1978; 240:1499.
  37. Kirk JL, Fine DP, Sexton DJ, Muchmore HG. Rocky Mountain spotted fever. A clinical review based on 48 confirmed cases, 1943-1986. Medicine (Baltimore) 1990; 69:35.
  38. Buckingham SC, Marshall GS, Schutze GE, et al. Clinical and laboratory features, hospital course, and outcome of Rocky Mountain spotted fever in children. J Pediatr 2007; 150:180.
  39. Walker DH, Lesesne HR, Varma VA, Thacker WC. Rocky Mountain spotted fever mimicking acute cholecystitis. Arch Intern Med 1985; 145:2194.
  40. Kirkland KB, Wilkinson WE, Sexton DJ. Therapeutic delay and mortality in cases of Rocky Mountain spotted fever. Clin Infect Dis 1995; 20:1118.
  41. Sexton DJ, Corey GR. Rocky Mountain "spotless" and "almost spotless" fever: a wolf in sheep's clothing. Clin Infect Dis 1992; 15:439.
  42. Kirkland KB, Marcom PK, Sexton DJ, et al. Rocky Mountain spotted fever complicated by gangrene: report of six cases and review. Clin Infect Dis 1993; 16:629.
  43. Conlon PJ, Procop GW, Fowler V, et al. Predictors of prognosis and risk of acute renal failure in patients with Rocky Mountain spotted fever. Am J Med 1996; 101:621.
  44. Green WR, Walker DH, Cain BG. Fatal viscerotropic Rocky Mountain spotted fever. Report of a case diagnosed by immunofluorescence. Am J Med 1978; 64:523.
  45. Gorman RJ, Saxon S, Snead OC 3rd. Neurologic sequelae of Rocky Mountain spotted fever. Pediatrics 1981; 67:354.
  46. Kaplowitz LG, Fischer JJ, Sparling PF. Rocky Mountain spotted fever: a clinical dilemma. In: Current Clinical Topics in Infectious Diseases, Remington JB, Swartz MH (Eds), McGraw-Hill, New York 1981. Vol 2, p.81.
  47. McMullan LK, Folk SM, Kelly AJ, et al. A new phlebovirus associated with severe febrile illness in Missouri. N Engl J Med 2012; 367:834.
  48. Apperson CS, Engber B, Nicholson WL, et al. Tick-borne diseases in North Carolina: is "Rickettsia amblyommii" a possible cause of rickettsiosis reported as Rocky Mountain spotted fever? Vector Borne Zoonotic Dis 2008; 8:597.
  49. Pastula DM, Turabelidze G, Yates KF, et al. Notes from the field: Heartland virus disease - United States, 2012-2013. MMWR Morb Mortal Wkly Rep 2014; 63:270.
  50. Reznicek JE, Mason WJ, Kaul DR, et al. Clinical problem-solving. Avoiding a rash diagnosis. N Engl J Med 2011; 364:466.
  51. Walker DH. Rocky Mountain spotted fever: a seasonal alert. Clin Infect Dis 1995; 20:1111.
  52. Kaplan JE, Schonberger LB. The sensitivity of various serologic tests in the diagnosis of Rocky Mountain spotted fever. Am J Trop Med Hyg 1986; 35:840.
  53. Chapman AS, Bakken JS, Folk SM, et al. 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 2006; 55:1.
  54. McQuiston JH, Wiedeman C, Singleton J, et al. Inadequacy of IgM antibody tests for diagnosis of Rocky Mountain Spotted Fever. Am J Trop Med Hyg 2014; 91:767.
  55. La Scola B, Raoult D. Laboratory diagnosis of rickettsioses: current approaches to diagnosis of old and new rickettsial diseases. J Clin Microbiol 1997; 35:2715.
  56. Straily A, Stuck S, Singleton J, et al. Antibody Titers Reactive With Rickettsia rickettsii in Blood Donors and Implications for Surveillance of Spotted Fever Rickettsiosis in the United States. J Infect Dis 2020; 221:1371.
  57. Raoult D, Paddock CD. Rickettsia parkeri infection and other spotted fevers in the United States. N Engl J Med 2005; 353:626.
  58. Paris DH, Dumler JS. State of the art of diagnosis of rickettsial diseases: the use of blood specimens for diagnosis of scrub typhus, spotted fever group rickettsiosis, and murine typhus. Curr Opin Infect Dis 2016; 29:433.
  59. Kato CY, Chung IH, Robinson LK, et al. Assessment of real-time PCR assay for detection of Rickettsia spp. and Rickettsia rickettsii in banked clinical samples. J Clin Microbiol 2013; 51:314.
  60. Channick RN, Lorenzo ME, Wu CC, Hoang MP. Case records of the Massachusetts General Hospital. Case 11-2012. A 60-year-old man with weakness, rash, and renal failure. N Engl J Med 2012; 366:1434.
  61. Procop GW, Burchette JL Jr, Howell DN, Sexton DJ. Immunoperoxidase and immunofluorescent staining of Rickettsia rickettsii in skin biopsies. A comparative study. Arch Pathol Lab Med 1997; 121:894.
  62. Denison AM, Amin BD, Nicholson WL, Paddock CD. Detection of Rickettsia rickettsii, Rickettsia parkeri, and Rickettsia akari in skin biopsy specimens using a multiplex real-time polymerase chain reaction assay. Clin Infect Dis 2014; 59:635.
  63. Walker DH, Burday MS, Folds JD. Laboratory diagnosis of Rocky Mountain spotted fever. South Med J 1980; 73:1443.
  64. Williams JC, Walker DH, Peacock MG, Stewart ST. Humoral immune response to Rocky Mountain spotted fever in experimentally infected guinea pigs: immunoprecipitation of lactoperoxidase 125I-labeled proteins and detection of soluble antigens of Rickettsia rickettsii. Infect Immun 1986; 52:120.
Topic 7904 Version 17.0

References

1 : David H. Walker. Rickettsia rickettsii and other spotted fever group rickettsiae. In: Principles and Practice of Infectious Diseases, Gerald Mandell, John Bennett, Raphael Dolin (Eds).

2 : Rocky mountain spotted fever.

3 : Infection of human endothelial cells with spotted Fever group rickettsiae stimulates cyclooxygenase 2 expression and release of vasoactive prostaglandins.

4 : Hyponatremia in Rocky Mountain spotted fever: role of antidiuretic hormone.

5 : Identification of protective components of two major outer membrane proteins of spotted fever group Rickettsiae.

6 : National Surveillance of Spotted Fever Group Rickettsioses in the United States, 2008-2012.

7 : National Surveillance of Spotted Fever Group Rickettsioses in the United States, 2008-2012.

8 : 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.

9 : Rocky mountain spotted fever characterization and comparison to similar illnesses in a highly endemic area-Arizona, 2002-2011.

10 : Rocky Mountain spotted fever from an unexpected tick vector in Arizona.

11 : Family cluster of Rocky Mountain spotted fever.

12 : Fatal cases of Rocky Mountain spotted fever in family clusters--three states, 2003.

13 : A focus of Rocky Mountain spotted fever within New York City.

14 : Spatial clustering by disease severity among reported Rocky Mountain spotted fever cases in the United States, 2001-2005.

15 : Rocky Mountain spotted fever in Argentina.

16 : Notes from the Field: Community-Based Prevention of Rocky Mountain Spotted Fever - Sonora, Mexico, 2016.

17 : Tick-borne diseases in the United States.

18 : Documented Rocky Mountain spotted fever in Wintertime.

19 : Rocky Mountain spotted fever in the USA: a benign disease or a common diagnostic error?

20 : Summary of notifiable diseases--United States, 2003.

21 : Trends in clinical diagnoses of Rocky Mountain spotted fever among American Indians, 2001-2008.

22 : Increasing incidence of Rocky Mountain spotted fever among the American Indian population in the United States.

23 : Prevalence of seropositivity to spotted fever group rickettsiae and Anaplasma phagocytophilum in a large, demographically diverse US sample.

24 : Analysis of risk factors for fatal Rocky Mountain Spotted Fever: evidence for superiority of tetracyclines for therapy.

25 : Risk factors for fatal outcome from rocky mountain spotted Fever in a highly endemic area-Arizona, 2002-2011.

26 : Hidden mortality attributable to Rocky Mountain spotted fever: immunohistochemical detection of fatal, serologically unconfirmed disease.

27 : Consequences of delayed diagnosis of Rocky Mountain spotted fever in children--West Virginia, Michigan, Tennessee, and Oklahoma, May-July 2000.

28 : Rocky Mountain spotted fever and deficiency in glucose-6-phosphate dehydrogenase.

29 : Rocky Mountain spotted fever and deficiency in glucose-6-phosphate dehydrogenase.

30 : Rocky Mountain spotted fever in the United States, 1993-1996.

31 : National surveillance for Rocky Mountain spotted fever, 1981-1992: epidemiologic summary and evaluation of risk factors for fatal outcome.

32 : Rocky Mountain spotted fever acquired in a laboratory.

33 : Rocky Mountain spotted fever.

34 : Dermatologic emergencies.

35 : Rocky Mountain spotted fever: clinical, laboratory, and epidemiological features of 262 cases.

36 : Fatal Rocky Mountain spotted fever.

37 : Rocky Mountain spotted fever. A clinical review based on 48 confirmed cases, 1943-1986.

38 : Clinical and laboratory features, hospital course, and outcome of Rocky Mountain spotted fever in children.

39 : Rocky Mountain spotted fever mimicking acute cholecystitis.

40 : Therapeutic delay and mortality in cases of Rocky Mountain spotted fever.

41 : Rocky Mountain "spotless" and "almost spotless" fever: a wolf in sheep's clothing.

42 : Rocky Mountain spotted fever complicated by gangrene: report of six cases and review.

43 : Predictors of prognosis and risk of acute renal failure in patients with Rocky Mountain spotted fever.

44 : Fatal viscerotropic Rocky Mountain spotted fever. Report of a case diagnosed by immunofluorescence.

45 : Neurologic sequelae of Rocky Mountain spotted fever.

46 : Neurologic sequelae of Rocky Mountain spotted fever.

47 : A new phlebovirus associated with severe febrile illness in Missouri.

48 : Tick-borne diseases in North Carolina: is "Rickettsia amblyommii" a possible cause of rickettsiosis reported as Rocky Mountain spotted fever?

49 : Notes from the field: Heartland virus disease - United States, 2012-2013.

50 : Clinical problem-solving. Avoiding a rash diagnosis.

51 : Rocky Mountain spotted fever: a seasonal alert.

52 : The sensitivity of various serologic tests in the diagnosis of Rocky Mountain spotted fever.

53 : 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.

54 : Inadequacy of IgM antibody tests for diagnosis of Rocky Mountain Spotted Fever.

55 : Laboratory diagnosis of rickettsioses: current approaches to diagnosis of old and new rickettsial diseases.

56 : Antibody Titers Reactive With Rickettsia rickettsii in Blood Donors and Implications for Surveillance of Spotted Fever Rickettsiosis in the United States.

57 : Rickettsia parkeri infection and other spotted fevers in the United States.

58 : State of the art of diagnosis of rickettsial diseases: the use of blood specimens for diagnosis of scrub typhus, spotted fever group rickettsiosis, and murine typhus.

59 : Assessment of real-time PCR assay for detection of Rickettsia spp. and Rickettsia rickettsii in banked clinical samples.

60 : Case records of the Massachusetts General Hospital. Case 11-2012. A 60-year-old man with weakness, rash, and renal failure.

61 : Immunoperoxidase and immunofluorescent staining of Rickettsia rickettsii in skin biopsies. A comparative study.

62 : Detection of Rickettsia rickettsii, Rickettsia parkeri, and Rickettsia akari in skin biopsy specimens using a multiplex real-time polymerase chain reaction assay.

63 : Laboratory diagnosis of Rocky Mountain spotted fever.

64 : Humoral immune response to Rocky Mountain spotted fever in experimentally infected guinea pigs: immunoprecipitation of lactoperoxidase 125I-labeled proteins and detection of soluble antigens of Rickettsia rickettsii.