CLICK AQUI
Clinical manifestations and diagnosis of Rocky Mountain spotted fever
Author
Daniel J Sexton, MD
Section Editors
Stephen B Calderwood, MD
Sheldon L Kaplan, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jan 2013. | This topic last updated: mar 16, 2011.
INTRODUCTION — Rocky Mountain spotted fever (RMSF) is a potentially lethal but usually curable tick-borne disease. It is the most common rickettsial infection in the United States. The etiologic agent, Rickettsia rickettsii, is a gram-negative, obligate intracellular bacterium with tropism for human endothelial cells. The clinical spectrum of human infection with R. rickettsii ranges from mild to fulminant. The epidemiology, clinical manifestations, and diagnosis of RMSF will be reviewed here.
The basic biology of R. 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".)
EPIDEMIOLOGY
Geography — RMSF occurs throughout the United States, in Canada, Mexico, Central America,
and in parts of South America (Bolivia, Argentina, Brazil, and Colombia). In the United States,
RMSF is most prevalent in the southeastern and south central states. In 2007, there were 2221
cases of RMSF reported to the Centers for Disease Control and Prevention (CDC); this represented
an increase from the 1130 cases reported in 2003 [1]. The estimated national average annual
incidence of RMSF was 2.2 cases per million persons in 2003, but incidence varied by geographic
area from 1 to >15/100,000 persons (figure 1) [1,2]. However, epidemiologic studies that attempt to assess the frequency of RMSF have been hampered by the fact that serologic assays that do not distinguish RMSF from other spotted fever group rickettsiae species and by imprecise case
definitions [3,4].
An outbreak of RMSF in 16 patients from 2002 through 2004 was reported from rural eastern
Arizona, a state that had previously only rarely reported the disease (three cases from 1981 through
2001) [5]. Of these patients, 13 (81 percent) were children ≤12 years of age; all had contact with
tick-infested dogs (see 'Transmission' below).
Although RMSF is more common in rural and suburban locations, it also 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 [6]. The ease and
frequency of interstate travel means that patients with RMSF acquired in endemic areas may
present to physicians practicing in locations where RMSF is uncommon or unknown. In addition,
family clusters of infection are a well-recognized feature of RMSF because of shared residence and
risks for vector exposure [7,8].
An investigation of clusters of cases in Tennessee and North Carolina concluded that significant
geographic differences in disease severity were present [9]. Similar clusters of severe disease have
been reported in several locations in South America [10].
Seasonal variation — Most cases of RMSF occur in the spring and early summer, when outdoor
activity is most frequent. However, rare cases are seen in the cold weather months in residents of
the southern United States [11]. Whether these "out of season" cases are due to infection with R.
rickettsii or other more benign spotted fever group rickettsiae has recently been questioned [3].
Risk factors — The frequency of reported cases of RMSF is highest among males. Although
previous studies found that the highest incidence of RMSF occurred in children <10 p="" years="">surveillance during 2003 demonstrated the highest age-specific incidence was among persons
aged 40 and 64 years [12]. Individuals with frequent exposure to dogs and who reside near wooded
areas or areas with high grass are probably also at increased risk for infection.
A retrospective study utilizing a national surveillance database found that the incidence of RMSF
among American Indians was 16.8/100,000 during the period from 2000 to 2005. In contrast, the
incidence among whites and blacks was 4.2 and 2.6/100,000, respectively [13].
TRANSMISSION
Route — RMSF is usually transmitted via a tick bite; tick bites are painless and many occur in body
areas obscured by hair or skin folds. Thus it is not surprising that up to one-third of patients with
proven RMSF do not recall a recent tick bite or recent tick contact [14,15]. Transmission rarely
occurs from infective tick tissues or feces by conjunctival contamination, transcutaneous
transmission, or inhalation (eg, after crushing blood-engorged ticks).
Vectors — 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
some areas of the United States [5]. This tick was implicated in the outbreak of RMSF in rural
eastern Arizona, noted above. R. sanguineus ticks in all life-stages of growth were abundantly found in and around many of the patients' homes and R. rickettsii was detected on polymerase chain reaction (PCR) and cultured from engorged and nonengorged ticks. Neither of the primary vectors for RMSF in the United States, D. variabilis nor D. andersonii ticks, was recovered from the homesites. Although the ecology of rural eastern Arizona that allowed the infestation of R.
sanguineous ticks may not be generalizable to other regions of the United States, the R.
sanguineus tick is widely distributed across North America, and should be considered as a potential
vector. The Cayenne tick (Amblyomma cajennense) is a vector for R. rickettsii transmission in
Central and South America. The yellow dog tick (Amblyomma aureolatum) has also been implicated as a vector in Brazil [16].
Incubation period — Infected patients become symptomatic 2 to 14 days after being bitten by an
infected tick, with most cases occurring between five and seven days after exposure.
CLINICAL MANIFESTATIONS
Early nonspecific symptoms — In the early phases of illness, most patients have nonspecific
signs and symptoms such as fever (in virtually all cases), headache (often severe), malaise,
myalgias, arthralgias, and nausea with or without vomiting (each in about 60 percent) [17]. Some
patients, especially children, may also have prominent abdominal pain that may be severe and may
lead to erroneous diagnoses such as acute appendicitis, cholecystitis, and even bowel obstruction
[18,19]. A small number of patients in the early phases of RMSF have been admitted to surgical
services and some have undergone laparotomy.
Rash — Most patients with RMSF develop a rash between the third and fifth days of illness (picture4) [8,17].
PICTURE 4: Rocky mountain spotted fever rash
Child with Rocky Mountain spotted fever has the rash that is characteristic but typically does not appear until several days after fever onset.
From:
Fatal Cases of Rocky Mountain Spotted Fever in Family Clusters --- Three
States, 2003. MMWR Morb Mortal Wkly Rep 2004; 53(19):407. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5319a1.htm.
However, 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 [20]. As a result, rash is often absent when patients
first contact a physician [20,21]. In a small percentage of patients, the rash is delayed in onset past
five days and/or is atypical (eg, confined to one body region).
A potential diagnostic problem is that rash never occurs in up to 10 percent of patients. These cases
of "spotless" RMSF may be severe and end fatally [22]. 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) [21]. (See "Treatment of Rocky
Mountain spotted fever".)
The typical rash of RMSF begins on the ankles and wrists and spreads both centrally and to the
palms and soles. The evolution of skin rash may vary among patients. Although the rash commonly
begins as a maculopapular eruption and then becomes petechial, some patients may suddenly
develop a petechial rash without a prior maculopapular eruption. Urticaria and pruritus are not
characteristic of RMSF and their presence makes the diagnosis unlikely.
Other symptoms — In addition to early nonspecific symptoms, abdominal pain, and rash, cough,
bleeding, edema (especially in children), confusion, focal neurologic signs, and seizures may also
be present [18]. Conjunctivitis, retinal abnormalities, and electrocardiographic abnormalities may
also rarely occur and lead to diagnostic confusion. The presence or absence of individual clinical
manifestations is in part dependent upon the duration of illness. As an example, physicians in
referral centers often see patients late in the course and are more likely to observe symptoms such
as 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, as
can widespread organ dysfunction [23,24].
Mortality — An estimated 612 deaths were attributable to RMSF in the United States between
1983 and 1998 [25]. The case-fatality rate was highest in the very young (≤4 years, 3 to 4 percent)
and elderly persons (≥60 years, 4 to 9 percent) (figure 2) [26].
DIFFERENTIAL DIAGNOSIS — 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.
· RMSF is commonly mistaken for an undifferentiated viral illness during the first few days of
illness. If penicillin or a cephalosporin is administered empirically during this phase of
illness, the subsequent rash may then be incorrectly diagnosed as a drug eruption.
· RMSF has been confused with measles, meningococcemia, infectious mononucleosis, viral
hepatitis, leptospirosis, streptococcal infection, parvovirus infection (Fifth disease), roseola,
enteroviral infection, and viral meningitis. In tropical areas typhoid fever, leptospirosis, and
even dengue may be confused with RMSF.
· 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 may be impossible, although the presence of leukopenia and the absence
of rash are more typical of ehrlichiosis (table 1). 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".)
· One study reported that a proposed new rickettsial species (Rickettsia amblyommii) present
in the tick Ambylomma americanum may be in fact responsible for some illnesses in North
Carolina that are identical in their clinical presentation to infection with R. rickettsii [27]. At
present this report remains unconfirmed and of unknown significance.
DIAGNOSIS — The diagnosis of RMSF is based upon the probability that individual clinical features represent RMSF in the appropriate epidemiologic setting, as with suggestive symptoms in an endemic area in the spring or early summer [28]. There is no completely reliable diagnostic test in the early phases of illness when therapy should be begun. Later, the diagnosis can be made by skin biopsy and confirmed serologically. Rickettsial blood cultures are highly sensitive and specific but are only available in research centers with specialized laboratories.
Laboratory studies — Most patients with RMSF have a normal white blood cell count at
presentation. However, the white blood cell count may be low, normal, or elevated in individual
patients and is therefore not diagnostically helpful. As the illness progresses, thrombocytopenia
becomes more prevalent and may be severe; it is thought to result from increased destruction at
sites of rickettsia-mediated vascular injury [20]. The low platelet count may be accompanied by a
reduced fibrinogen concentration and elevated fibrin split products; however, true 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 [18]. In a small number of cases, jaundice and renal failure dominate and
confuse the clinical presentation [24,29].
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]) [29]. 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, cerebrospinal fluid (CSF) analysis usually shows a white blood count (WBC) of <100 a="" cells="" either="" microl="" or="" p="" per="" polymorphonuclear="" with="">lymphocytic predominance [18]. Moderately elevated protein (100 to 200 mg/dL) and a normal glucose level are common [30,31]. These findings may not help distinguish RMSF from meningococcal disease.
Skin biopsy — 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 [32]. 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 [32]. 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.
Serologic testing — The diagnosis of RMSF is best confirmed serologically using the indirect
fluorescent antibody (IFA) test [33]. IFA testing is available through all state health departments and through several large reference laboratories. 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. The minimum diagnostic titer in most laboratories is 1:64.
The overall sensitivity of the IFA test is approximately 95 percent. However, there are two settings in which false negative results are more likely:
· 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 [21].
· A small percentage of patients who are treated within the first 48 hours after symptoms
have begun may not develop convalescent antibodies [33].
Although the IFA is sensitive, serologic assays are insufficient to identify conclusively the specific
rickettsial agent responsible for the infection. A study of 15 serum specimens with antibodies
reactive with R. rickettsii from the CDC examined the specimens by microimmunofluorescence and
Western blot assays against antigens of R. rickettsii and R. parkeri [34]. 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.
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. A probable diagnosis of RMSF may be established with a titer of 1:128 or greater by LA, IHA, or MA.
The Weil-Felix test, which detects crossreacting antibodies against Proteus vulgaris antigens (OX2
and OX19), lacks sensitivity and specificity and its use is no longer recommended [17,33].
SUMARY 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 'Geography' 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
intraabdominal 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 is a clinical one based on a constellation of symptoms that is
consistent with the clinical presentation in an appropriate epidemiologic setting (eg, an
endemic area in the spring or early summer). There is no completely reliable diagnostic test
in the early phases of illness when therapy should be initiated. (See 'Diagnosis' above.)
· In later illness, the diagnosis can be made by skin biopsy and confirmed serologically.
(See 'Diagnosis' above.)
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REFERENCES
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