Rocky Mountain Spotted Fever (RMSF)

Background

Rocky Mountain spotted fever (RMSF) is a tick-borne disease caused by the organism Rickettsia rickettsii.^[1] Although RMSF can be lethal, it is curable. RMSF is the most common rickettsial infection. The organism is endemic in parts of North, Central, and South America, especially in the southeastern and south-central United States. 

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In the United States, the American dog tick (Dermacentor variabilis) is the most commonly identified source of transmission. This tick is actually fou....

Sophisticated microbiologic and serologic methods to distinguish infection by different members of the spotted-fever group reveal that RMSF may be more common in the tropics and subtropical regions of the Americas than previously thought. 

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

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The patient's rash is a major diagnostic sign of Rocky Mountain spotted fever (RMSF). Courtesy of the Centers for Disease Control and Prevention (CDC)....

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An adult female Dermacentor variabilis (American dog tick). Courtesy of the Centers for Disease Control and Prevention (CDC) (https://www.cdc.gov/rmsf....

See also 7 Bug Bites You Need to Know This Summer, a Critical Images slideshow, for helpful images and information on various bug bites.

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

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

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

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

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

Mortality rates as high as 30% were reported for RMSF in the preantibiotic era. Although its clinical manifestations and treatment of the disease are well known, RMSF still causes significant mortality and morbidity. The current mortality rate is 1.4%. A significant portion of this persistent mortality is likely due to delay in diagnosis and treatment.

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Etiology and Pathophysiology

R rickettsii is a small (0.3 µm X 1 µm), gram-negative, obligate, intracellular coccobacillus. It possesses outer-membrane protein A (OmpA) and OmpB, 2 major immunodominant, surface-exposed proteins with species-specific conformational epitopes. OmpB is the most abundant outer-membrane protein that shares genetic sequences and limited antigens with typhus group rickettsiae.

Ticks become infected by feeding on the blood of infected animals, through fertilization, or by transovarial passage.^[1] Rickettsiae are transmitted from tick to human during feeding. The tick needs to be attached to a host for 6-10 hours for rickettsiae to be released from the salivary glands, although transmission may not occur for 24 hours. In addition, this organism can infect people who remove ticks from other people or animals via contact with tick tissues and fluids.

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

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

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

The distribution of rickettsiae within the blood vessels causes vascular injury and the subsequent development of a host mononuclear-cell tissue response. Consequences of vascular injury include interstitial pneumonia, interstitial myocarditis, and perivascular glial nodules of the central nervous system (CNS), with similar vascular lesions in the skin, gastrointestinal (GI) tract, pancreas, liver, skeletal muscles, and kidneys. Large amounts of rickettsiae in damaged cells support the concept of direct injury.

The inflammation and damage to the blood vessels and capillaries activate platelets, generate thrombin, and activate the fibrinolytic system as part of the body's homeostatic physiologic response to endothelial injury.

As R rickettsii proliferates in the endothelial lining, it also causes thrombi to form.^[1] In severe cases, extensive vasculitis can lead to small-vessel occlusion. Vascular necrosis and thrombosis are more common in RMSF than in typhus and may mimic collagen-vascular disease.

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Epidemiology

Occurrence in the United States

Rocky Mountain spotted fever (RMSF) is a tick-borne disease primarily found in the Western Hemisphere, initially recognized in the Rocky Mountain states but now occurring throughout the United States, as well as in Central and South America.^[1] The disease is most prevalent from March to September, coinciding with the active season of adult ticks, although sporadic cases can occur year-round in southern states. Children under 15 years and individuals who frequently visit tick-infested areas for work or recreation are at the highest risk for infection.

RMSF is caused by the bacterium Rickettsia rickettsii, which is transmitted through hard-shelled ticks of the family Ixodidae. The American dog tick (Dermacentor variabilis) is the primary vector in the eastern and southern United States, whereas the Rocky Mountain wood tick (Dermacentor andersoni) serves as the main vector in the western United States. The brown dog tick (Rhipicephalus sanguineus) has also been identified as a source of RMSF, particularly in the southwestern United States and along the United States-Mexico border.

Transmission of RMSF occurs when an infected tick remains attached to a host for several hours. It is important to note that RMSF is not transmitted directly from person to person. The disease is the most common cause of fatal tick-borne illness in the United States, with cases reported more frequently in rural and suburban areas, although urban cases, such as those in New York City, have also been documented.^{[2, 3, 4]} Each reported case is linked to the infected person's county of residence, not necessarily the location of infection.

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Annual incidence (per million persons) of Spotted Fever Rickettsiosis (SFR) in the United States, 2018. As of January 1, 2010, cases of Rocky Mountain....

The regions with the highest incidences include the Southeast, the western South Central region (including Oklahoma and northern Texas), and selected areas of the Northeast (Cape Cod and Long Island). Most cases are reported from eastern and central states. Five states (North Carolina, Oklahoma, Arkansas, Tennessee, Missouri) account for over 60% of cases.

Cases have been reported in 48 states, with Vermont and Hawaii being the exceptions. Although cases can occur during any season, most cases reported illness in May through August (CDC/1). From 1989-1996, more than 4700 cases were reported in 46 states. Of these reported cases, 90% occurred between April and September. In the northern United States, infections commonly occur in the spring; in the South, cases may occur at any time of the year, including winter. This correlates during the season during which adult Dermacentor ticks are most active.

A prospective study of RMSF infection in residents of a known endemic area in North Carolina suggested an annual incidence of 42 cases per 100,000 children aged 5-9 years. Asymptomatic infection may be common; in one study, 12% of children living in high-risk zones had positive serology test results, indicating past exposure to RMSF.^[5]

In 2005, 1936 cases were reported—more than 4 times the 365 cases reported in 1998. The reasons for this increase are not known, but wide swings in the incidence of RMSF have occurred since 1920. Due to underdiagnosis, lack of testing, and lack of reporting, it is likely that the actual number of cases is much higher than surveillance data suggest.

RMSF has become increasingly more common in certain areas of Arizona. Between 2003 and 2018, approximately 430 cases were reported with an associated case-fatality rate of approximately 5%.

International occurrence

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

There have been no documented cases of RMSF infection outside of the Americas. However, a wide range of related spotted fever group (SFG) rickettsioses has been described across Europe, Africa, Asia, and Oceania. The true incidence of spotted fever infections internationally is not known.

Race-related demographics

Whites have twice the incidence of African Americans; however, African Americans have a higher case-fatality rate. This may be due to the greater difficulty of appreciating a rash in highly pigmented individuals.

American Indians are at greater risk for RMSF than the general population.^[7] From 2001-2005, the average annual incidence of RMSF reported among American Indians was 16.8 per 1,000,000 persons compared with 4.2 for whites, 2.6 for blacks, and 0.5 for Asian/Pacific Islanders. The incidence of RMSF in American Indians increased at a disproportionate rate during this period, although from 1990-2000, the rate was comparable to those for other races from 1990-2000.^[8]

Sex- and age-related demographics

The male-to-female ratio for RMSF is 1.7:1. The mortality risk is also higher in males than in females.

The incidence of Rocky Mountain spotted fever is highest among adults aged 60-69 years (3.1 cases/million persons) and children aged 5-9 years (an estimated 3.3 cases/million persons).

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Prognosis

Mortality rates in Rocky Mountain spotted fever (RMSF) vary according to the following criteria:

• Delay in diagnosis
• Delay in effective antibiotic treatment - In a 1995 study, antirickettsial therapy within the first 5 days of illness reduced the risk of mortality 5-fold compared with treatment initiation after the 5-day mark^[9]
• Age
• Race
• Gender - Mortality risk is higher in males
• Severity of the disease
• Presence of chronic alcohol abuse
• Presence of glucose-6-phosphate-dehydrogenase deficiency

The mortality rate in untreated cases of RMSF is 20-25%. Mortality rates can be as low as 5% with proper antibiotic therapy and as high as 70% in untreated elderly individuals. Death in 5 days can be expected in fulminant cases.^[3]

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Complications

Complications may include the following^{[10, 11, 12]} :

• Disseminated intravascular coagulation
• Noncardiogenic pulmonary edema
• Acute tubular necrosis
• Shock with myocarditis
• Skin necrosis and gangrene - Particularly in fingers, toes, elbows, ears, and scrotum
• Myocarditis - Usual cause of death
• Seizures
• Encephalopathy
• Peripheral neuropathy
• Bowel and bladder incontinence
• Cerebellar and vestibular dysfunction
• Hearing loss
• Blindness - The frequency of long-term ocular sequelae is low; in most cases, good binocular visual acuity is preserved
• Scarring
• Hemophagocytic histiocytosis - Has been described in fatal cases of RMSF

Factors at presentation associated with development of acute renal failure (ARF) include increased bilirubin, advancing age, thrombocytopenia, and the presence of neurologic involvement. Age and decreased platelet count at presentation have been independently associated with the development of ARF by multivariate analysis. ARF development increases the odds ratio of dying by a factor of 17.

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History

People with RMSF generally present within a week after a tick bite.^[1] Physicians must maintain a high index of suspicion for Rocky Mountain spotted fever (RMSF) in patients with the following:

• Febrile illness
• History of potential tick exposure
• Travel to endemic area
• Presentation in spring, summer, or fall (although not limited to these seasons)

RMSF should be considered in patients with unexplained febrile illness even if they have no history of a tick bite or travel to an endemic area. History of a tick bite is reported by only 70% of patients. (Most tick bites are painless and may be in hidden areas of the body.)

In a case series by Buckingham et al, of 92 patients eventually diagnosed with RMSF, the median delay between first visiting a health care provider and starting antirickettsial therapy was 5 days. Only 49% of the patients reported a tick bite.^[13]

In other studies, 66% of reported cases of RMSF included a history of tick attachment 14 days prior to illness. An additional 26% of patients reported being in a tick-infested area.

The classic clinical triad of fever, headache, and rash may be present in less than 5% of patients in the first 3 days of illness but increases to 60-70% by the second week after tick exposure. The absence or delayed appearance of a rash increases the difficulty of diagnosis.

The most common symptom complaints include the following^[1] :

• Fever greater than 102°F - 94% of reported cases
• Fever within 3 days after tick bite - 66% of reported cases
• Headache, frequently severe - 86% of reported cases
• Myalgias - 85% of reported cases
• CNS symptoms - 25% of patients develop signs of encephalitis (ie, confusion, lethargy); this may progress to stupor, delirium, seizures, or coma
• GI symptoms - Some patients present with anorexia, nausea, vomiting, diarrhea, and abdominal pain

Patients may also report insomnia and photophobia.

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Physical Examination

Rocky Mountain spotted fever (RMSF) presents with a wide clinical spectrum, ranging from mild fever (usually greater than 102°F), headache, and myalgia to disseminated intravascular coagulation (DIC; 32-53% of patients), shock (7-17%), hypotension (17%), and death (4-8%).

Adults tend to present with typical symptoms. Fever with relative bradycardia is the rule. In mild, untreated cases, the fever subsides at the end of the second week.

Skin

Rash is a major diagnostic sign that appears in a low percentage of patients on the first day of infection and in only 49% of patients during the first 3 days. 

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The patient's rash is a major diagnostic sign of Rocky Mountain spotted fever (RMSF). Courtesy of Springer Nature [Bal AK, Kairys SW. Kawasaki disease....

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The patient's rash is a major diagnostic sign of Rocky Mountain spotted fever (RMSF). Courtesy of the Centers for Disease Control and Prevention (CDC)....

In 88-90% of RMSF cases, the maculopapular rash appears 2-6 days after onset of fever and progresses through stages and distribution that are never pathognomonic. The rash begins as a maculopapular eruption on the wrists and ankles and spreads centripetally to involve the trunk and extremities.

Classic distribution of RMSF rash on the palms and soles occurs relatively late in the course, appearing in 43% of patients only after the fifth day of symptoms. (The hands and the feet are both involved 49-74% of the time.) Some reports have documented 36-80% of patients with RMSF lack the classic distribution of rash on the palms and soles.

The face is usually spared. Involvement of the scrotum or the vulva is a diagnostic clue. Nonproductive cough may accompany the rash (33%).

In the early phases, the rash may be blanching, nonpruritic, and macular. In 45-49% of patients, it eventually becomes petechial; in rare cases, purpura and skin necrosis or gangrene develop. In dark-skinned patients, the rash is difficult to see.

The rash is absent at presentation in 10-15% of patients. RMSF without a rash (ie, spotless RMSF) should be considered ehrlichiosis until proven otherwise. Spotless fever is not synonymous with mild or early illness, because substantial proportions of the deaths occur in patients without a rash.

In older patients and in severe or fatal cases of RMSF, the rash tends to appear later and with less frequency.

Other cutaneous abnormalities that may develop in RMSF include postinflammatory hyperpigmentation, jaundice, and mucosal ulcers. An erythema migrans–like rash has also been reported.

Head, ears, eyes, nose, and throat

Conjunctival suffusion develops in 30% of patients. Bilateral edema is present. Periorbital edema is a key diagnostic finding, especially in children. Transient deafness occurs in 7% of patients.

The incidence of ocular changes in RMSF is considered low but probably is underestimated. Such changes can include petechial conjunctivitis, which occurs as part of the generalized rash, and anterior uveitis.

Retinal vascular dysfunction may result in retinal hemorrhages, retinal ischemia manifested by cotton-wool spots and nerve fiber layer hemorrhages, retinal vascular engorgement and tortuosity, and branch retinal arteriolar occlusion.

Optic disc edema due to ischemia and inflammation and orbital edema from increased extravascular volume may be present. Optic disc edema may be associated with peripapillary subretinal fluid extending into the macula (neuroretinitis).

Cardiovascular

Cardiovascular presentations of RMSF can include the following:

• Myocarditis
• Relative bradycardia
• Arrhythmias - Present in 7-16% of patients
• Hypotension - Occurs in 7-17% of patients

RMSF is the only tick-borne disease that can directly cause congestive heart failure secondary to myocarditis (5-26%).

Pulmonary

Pulmonary edema occurs in severe cases. Pneumonitis is present in 12-17% of patients.^[14]

Gastrointestinal

GI presentations of RMSF can include the following:

• Anorexia
• Abdominal pain and tenderness (diffuse in right upper quadrant) - Present in 34-52% of patients
• Jaundice - Develops in severe cases; it is found in 8-9% of patients
• Hepatomegaly and splenomegaly - Occur in 12-15% and 14-16% of cases, respectively
• Diarrhea - Develops in 19-20% of patients
• Increased aspartate aminotransferase (AST) levels - Present in 36-62% of patients

Musculoskeletal

Musculoskeletal presentations of RMSF can include the following:

• Severe myalgia - Especially in the legs, abdomen, and back; occurs in 72-82% of patients
• Diffuse arthralgias
• Edema on the dorsum of the hands and feet - A key sign; occurs in 18-20% of patients
• Lymphadenopathy - Develops in 27% of cases

Central nervous system

CNS presentations can include the following:

• Restlessness and irritability
• Altered mental status - May include delirium, lethargy, and coma
• Photophobia
• Meningoencephalitis (confusion, seizures [8%], focal neurologic deficits)
• Cranial neuropathies
• Urinary or fecal incontinence
• Ataxia - Present in 5-18% of cases
• Meningismus - Develops in 18% of patients
• Cranial nerve palsies
• Hearing loss
• Photophobia
• Severe vertigo
• Dysarthria
• Aphasia
• Hemiplegia, paraplegia, or complete paralysis
• Nystagmus
• Hyperreflexia
• Spasticity
• Fasciculations

Additional presentations

Miscellaneous presentations include dehydration, generalized edema, and chills. Effects of disseminated R rickettsii infection of endothelial cells include increased vascular permeability that leads to edema, hypovolemia, hypotension, and prerenal azotemia.

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Approach Considerations

Rocky Mountain spotted fever (RMSF) diagnosis relies on clinical (fever, rash, myalgia) and epidemiologic (tick exposure) criteria; however, a clinical diagnosis of RMSF is difficult to establish, and laboratory findings are nonspecific. Even so, basic laboratory tests should be obtained, including the following: complete blood count (CBC), electrolytes, renal function tests, liver function tests, and coagulation panel.^[15]

After exposure to vector ticks, patients who develop fever, petechial rash, and vomiting require antibiotic therapy. Antibiotic therapy should be initiated before laboratory confirmation is available.

Laboratory findings can include the following:

• White blood cell (WBC) count - Leukopenia is present initially, then mild leukocytosis; patients usually have a normal WBC count
• Platelets - Thrombocytopenia (< 150,000 cells/µL) occurs in 32-52% of patients; abnormalities indicative of DIC are present in severely ill patients
• Hemoglobin and hematocrit - Anemia is present in 5-24% of patients
• Aminotransferase levels - Mildly elevated in 36-62% of patients
• Hyponatremia - Present in 19-56% of cases
• Bilirubin levels – Increased in 8-9% of patients.
• Mild cerebrospinal fluid pleocytosis with monocyte predominance
• Azotemia - Develops in 12-14% of cases
• Prothrombin time and activated partial thromboplastin time - May be elevated

Anemia, an increased blood urea nitrogen (BUN) level, or abnormal liver function test results are found in 30% of patients. Late findings associated with advanced disease include signs of multiorgan failure, such as elevated BUN, creatinine, and creatinine kinase levels.

Serology

Diagnosis is confirmed based on indirect immunofluorescent antibody (IFA) test results, latex agglutination, or enzyme immunoassay. Serology specific for R rickettsii infection develops within 6-8 weeks. Serologic test results are negative prior to convalescence.

Blood culture

Isolation of R rickettsii from the blood is possible, but few laboratories perform this isolation because of biohazard concerns. This is an insensitive test because most Rickettsia is found in the vascular endothelial cells, not in the bloodstream.

Imaging studies

Obtain a chest radiograph in patients who appear significantly ill or have abnormal lung findings on physical examination. Chest radiographs that show an early pulmonary infiltrate should prompt consideration of a different diagnosis.

Computed tomography (CT) scanning or magnetic resonance imaging (MRI) are indicated for altered mental status or neurologic deficits and may reveal infarction, edema, and meningeal enhancement.

Lumbar puncture

Lumbar puncture usually is performed as part of the workup for suspected meningitis. Pleocytosis is found in 34-38% of cases. Usually 10-100 cells/µL with either lymphocytic or polymorphonuclear cell predominance are found. Increased protein is found in 30-35% of cases; the glucose level usually is normal.

Other tests

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

Electrocardiography may be used to indicate whether myocardial or conduction abnormalities are present.

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Skin Biopsy

Direct immunofluorescent microscopy, if available, may be used for rapid histologic diagnosis of Rocky Mountain spotted fever (RMSF). Immunofluorescent or immunoperoxidase staining of R rickettsii in a biopsy skin or organ specimen is sensitive (73%) and specific (100%).^[16] However, because direct immunofluorescence has a 30% false-negative rate, patients should be treated even if the test is negative and the suspicion is high.

Antibodies to specific rickettsial antigens are detected by indirect immunofluorescence (most specific), latex agglutination, and enzyme immunoassay. The diagnostic titer is 1:64 for indirect immunofluorescence and latex agglutination.

Amplification of R rickettsii deoxyribonucleic acid (DNA) with polymerase chain reaction (PCR) assay has not been proven to be a sensitive diagnostic method except for later in the disease course, particularly in fatal cases. It has been successful when applied to biopsy skin samples during rickettsioses and also when applied to ticks. According to Walker and Raoult in 2000, the primers used amplify genes of the 17-kD protein citrate synthetase and rickettsial OmpA and allow the identification of any rickettsial organism.

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Laboratory Studies

Serology

The standard serologic test for diagnosing Rocky Mountain spotted fever (RMSF) is the indirect fluorescent antibody (IFA) test for immunoglobulin G (IgG) using R rickettsii antigen.^[17] To confirm a diagnosis, IgG IFA assays should be conducted on paired acute and convalescent serum samples collected 2 to 10 weeks apart to demonstrate a fourfold seroconversion. Antibody titers are often negative during the first week of illness, and RMSF cannot be confirmed with a single acute antibody result. While immunoglobulin M (IgM) IFA assays are available, they may be less specific for recent infections compared to IgG assays.

R rickettsii shares similarities with other pathogenic spotted fever group Rickettsia species, which can lead to cross-reactivity in serologic tests, making it difficult for most commercial labs to differentiate between various spotted fever infections. Antibodies to R rickettsii can remain elevated for months after recovery, with some individuals showing high titers for up to 4 years post-illness. Additionally, a significant percentage of healthy individuals in certain regions may have elevated antibody titers due to past exposure. Therefore, comparing appropriately timed paired serologic assays provides the most reliable evidence of recent infection, as single or improperly timed tests can result in misinterpretation of results.

Polymerase chain reaction (PCR) amplification

Polymerase chain reaction (PCR) amplification is conducted on DNA extracted from whole blood, serum, or plasma to detect R rickettsii, which infects the endothelial cells lining blood vessels and may not be present in significant quantities in the bloodstream until the infection has progressed to a severe stage.^[17] While a positive PCR result can aid in diagnosis, a negative result does not exclude the possibility of RMSF, and treatment should not be delayed based on a negative finding. Additionally, PCR can be utilized to amplify DNA from skin biopsy samples of rash lesions or from post-mortem tissue specimens.

Immunohistochemistry (IHC) and culture

Culture and immunohistochemistry (IHC) assays can be conducted on skin biopsies from rash lesions or on post-mortem tissue specimens.^[17] However, the isolation of R rickettsii through culture and IHC assays is only possible at specialized laboratories, as routine hospital blood cultures are unable to detect this organism.

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Approach Considerations

Doxycycline is the primary treatment for Rocky Mountain spotted fever (RMSF) and other tick-borne rickettsial diseases.^[18] It is recommended for presumptive treatment in patients of all ages, including those under 8 years old and pregnant individuals. The use of antibiotics other than doxycycline is linked to a higher risk for fatal outcomes from RMSF. Starting doxycycline within the first 5 days of illness is crucial, as it significantly reduces the mortality rate from 20% to about 5% and helps prevent severe complications.

In addition to antibiotic therapy, patients may experience dehydration due to high fever and vomiting, making aggressive fluid management with isotonic fluids essential. Continuous monitoring of urine output and blood pressure is important, and some patients may require a Swan-Ganz catheter for hemodynamic assessment. Early intervention and comprehensive care are vital for improving patient outcomes in RMSF.

Pregnancy

Whether R rickettsii can cross the placenta and adversely affect the fetus remains unknown. In a case report, a pregnant patient with RMSF was treated with chloramphenicol successfully, with no apparent adverse maternal or neonatal effects.^[19]

Transfer

Proper personnel trained in complicated airway intervention and treatment of shock should be available to patients with RMSF who are comatose, convulsing, or hypotensive.

Outpatient care

Clinically mild cases may be treated on an outpatient basis. However, RMSF can progress rapidly. Because roughly 10% of outpatients subsequently required admission, close follow-up is necessary if outpatient management is planned.

Consultations

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

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Prehospital and Emergency Department Care

In emergency prehospital care for Rocky Mountain spotted fever (RMSF), deliver supportive therapy, including airway support and intravenous (IV) fluids, as determined by the severity of the patient's condition. Emergency department care in RMSF includes early empiric therapy with doxycycline and hemodynamic support, as needed.

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Inpatient Care

Hospitalization was required in 72% of confirmed cases of Rocky Mountain spotted fever (RMSF) reported to the Centers for Disease Control and Prevention (CDC). Hospitalization, when required, usually occurs on the fourth day after symptom onset.

Admit moderately to severely ill patients to the hospital. Indications for admission may include altered mental status or other neurologic manifestations of RMSF, abdominal pain (may mimic an acute surgical abdomen), thrombocytopenia, or hypotension due to RMSF myocarditis. Admit severely ill patients to the intensive care unit (ICU).

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Ophthalmic Care

Supportive therapy according to the needs of individual patients is indicated. Moderate to severe uveitis may be treated with topical cycloplegics and corticosteroids, although no reliable information on efficacy is available. Artificial tears and ocular lubricating ointment may help to relieve discomfort from periorbital edema and petechial conjunctivitis.

Patients with Rocky Mountain spotted fever (RMSF) usually do not present initially to an ophthalmologist. Usually, these patients are already under the care of an internist or infectious disease physician.

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Prevention

Protective measures against tick bites include the following:

• Avoid dogs with ticks and tick-infected areas
• Use protective, light-colored clothing that covers arms and legs; tuck pants in socks to protect legs
• Apply tick-repellent chemicals, such as diethyltoluamide (DEET, Autan) or permethrin, to pants and sleeves
• Search the entire body every 3-4 hours when in an infested area; common areas of attachment are in scalp, pubic, or axillary hair

When a tick is present, it should be promptly removed using gentle, steady traction with tweezers. Care should be taken not to crush the tick or to leave any mouthparts. Hands should be protected with gloves.

Because the tick needs 6-10 hours of feeding to transmit the disease, early discovery and removal of ticks can prevent infection. Prophylaxis with doxycycline for 7 days is recommended after tick removal.

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Medical Care

Doxycycline is the primary treatment for both adults and children of all ages^[18] :

• Adults: 100 mg every 12 hours
• Children under 45 kg (100 lbs): 2.2 mg/kg of body weight administered twice daily

Patients suspected of having RMSF should continue doxycycline treatment for at least 3 days after the fever has resolved and there are signs of clinical improvement. The minimum duration of treatment is 5 to 7 days.

In cases of severe doxycycline allergy, rapid desensitization procedures may be considered in an inpatient setting. Physicians should evaluate the benefits of doxycycline against the risks of adverse effects on a case-by-case basis, often consulting with infectious disease specialists. Chloramphenicol is the only alternative treatment for RMSF; however, studies indicate that patients treated with chloramphenicol face a higher risk of death compared to those receiving tetracycline-class antibiotics.

In the United States, oral formulations of chloramphenicol are unavailable, and its use carries risks such as aplastic anemia and Grey baby syndrome. Sulfa-containing drugs may worsen the clinical course of RMSF and increase mortality risk. Other broad-spectrum antibiotics are ineffective against RMSF, and post-tick bite antibiotic prophylaxis is not recommended. Individuals who have been bitten by a tick should monitor for symptoms and consult a healthcare provider if fever, rash, or other signs develop within two weeks of the bite.

Treatment for asymptomatic individuals is not recommended. Although doxycycline is generally considered safe during pregnancy, potential risks should be discussed with pregnant patients when making treatment decisions. Healthcare providers should exercise caution when considering alternatives to doxycycline, given its effectiveness in treating various tick-borne diseases, including anaplasmosis, ehrlichiosis, and Lyme disease.

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Guidelines Summary

Doxycycline is the primary treatment for both adults and children of all ages^[18] :

• Adults: 100 mg every 12 hours
• Children under 45 kg (100 lbs): 2.2 mg/kg of body weight administered twice daily

Patients suspected of having RMSF should continue doxycycline treatment for at least 3 days after the fever has resolved and there are signs of clinical improvement. The minimum duration of treatment is 5 to 7 days.

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Medication Summary

Doxycycline is the primary treatment for both adults and children of all ages^[18] :

• Adults: 100 mg every 12 hours
• Children under 45 kg (100 lbs): 2.2 mg/kg of body weight administered twice daily

Patients suspected of having RMSF should continue doxycycline treatment for at least 3 days after the fever has resolved and there are signs of clinical improvement. The minimum duration of treatment is 5 to 7 days.

Chloramphenicol is an alternative, although doxycycline is preferable because tetracyclines have been shown to be associated with a higher survival rate than chloramphenicol.^[20] In vitro and in ovo R rickettsii are also susceptible to rifampin.

Doxycycline therapy also treats Lyme disease, ehrlichiosis, and relapsing fever—entities often clinically confused with RMSF.^[21] Oral formulations may be used for patients being treated at home or for hospitalized patients who can take oral medications.

The American Academy of Pediatrics recommends doxycycline as the preferred treatment for children of any age with RMSF because of the potential for severe or fatal cases.

Short courses of doxycycline to treat RMSF do not cause significant dental staining.^[22] Beta-lactam antibiotic coverage does not treat RMSF.

• References

Doxycycline (Adoxa, Oraxyl , Doryx, Vibramycin)

• Dosing, Interactions, etc.

Clinical Context:  Doxycycline is the drug of choice for Rocky Mountain spotted fever (RMSF). It inhibits protein synthesis and, consequently, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

• References

Chloramphenicol

• Dosing, Interactions, etc.

Clinical Context:  Chloramphenicol is the alternative choice for RMSF in pregnant women and patients allergic to tetracyclines. It binds to 50S bacterial ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis.

• References

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

• References

Cyclopentolate 1% (AK-Pentolate, Cyclogyl, Cylate)

• Dosing, Interactions, etc.

Clinical Context:  Cyclopentolate is the drug of choice in corneal abrasions. It blocks the muscle of the ciliary body and the sphincter muscle of the iris from responding to cholinergic stimulation, thus causing mydriasis and cycloplegia. Cyclopentolate induces mydriasis in 30-60 minutes and cycloplegia in 25-75 minutes. These effects last up to 24 hours.

• References

Class Summary

These agents relax any ciliary muscle spasm that can cause a deep, aching pain and photophobia. Cycloplegic agents are also mydriatics, and the practitioner should make sure that the patient does not have glaucoma. This medication could provoke an acute angle-closure attack.

• References

Prednisolone ophthalmic (Omnipred, Pred Forte, Pred Mild)

• Dosing, Interactions, etc.

Clinical Context:  This agent decreases autoimmune reactions, possibly by suppressing key components of the immune system.

• References

Loteprednol etabonate (Lotemax, Alrex)

• Dosing, Interactions, etc.

Clinical Context:  Loteprednol etabonate decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. It is a topical ester steroid drop with decreased risk of glaucoma. Loteprednol etabonate is available in 0.2% and 0.5% drops.

• References

Class Summary

Corticosteroids suppress active disease, which is assumed to be due to inflammatory mechanisms.

• References

Diclofenac ophthalmic (Voltaren Ophthalmic)

• Dosing, Interactions, etc.

Clinical Context:  This agent inhibits prostaglandin synthesis by decreasing the activity of the enzyme cyclooxygenase, which in turn decreases formation of prostaglandin precursors. Diclofenac ophthalmic may facilitate outflow of aqueous humor and decreases vascular permeability.

• References

Ketorolac ophthalmic (Acular, Acuvail)

• Dosing, Interactions, etc.

Clinical Context:  Ketorolac ophthalmic is available in preserved bottles, as well as in preservative-free, single-dose-unit containers.

• References

Class Summary

These drugs have analgesic and anti-inflammatory activities. Their mechanism of action is not known, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.

• References