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ROCKY MOUNTAIN SPOTTED FEVER

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Acute infectious disease caused by Rickettsia rickettsii and transmitted from the bite of the wood tick and the dog tick.
    B) Most frequently reported rickettsial disease in US; endemic throughout US, although most cases occur in mid- and south-Atlantic coastal states; peak season is June through July; incubation period is 2 to 14 (average 7) days. It is the most common fatal tickborne illness in US; however, the case fatality rate has declined to 0.5% in 2010.

Specific Substances

    1) Rickettsia rickettsii
    2) Rhipicephalus sanguineus
    3) Dermacentor andersoni
    4) Dermacentor variabilis
    5) American dog tick
    6) Rocky mountain wood tick
    7) Brown dog tick

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) TOXIC CLASS: Rocky Mountain Spotted Fever (RMSF) is one of many tick-, mite-, and flea-borne zoonotic infections in the spotted fever group.
    B) TOXICOLOGY/PATHOGENICITY: RMSF is caused by Rickettsia rickettsii, a small gram-negative obligate intracellular bacteria which is transmitted from the bite of the Rocky Mountain wood tick (Dermacentor andersoni), the American dog tick (D. variables), or the brown dog tick (Rhipicephalus sanguineus). The tick is both the vector and the reservoir for R. rickettsii. Once infected, rickettsiae invade the cytoplasm of vascular endothelial cells of small blood vessels throughout the body. As rickettsiae multiply in small blood vessels in various tissues and organs, endothelial damage leads to cell necrosis and proliferative hypertrophy of the intima, possible necrosis of the media, and mononuclear and plasma cell infiltration of the adventitia. The resulting diffuse thrombosis and microinfarction cause partial or total occlusion of the vessel lumen, leading to infarction of skin, heart, kidney, adrenal glands, and brain. Necrosis of arteriolar wall leads to rupture with local areas of hemorrhage. This widespread vasculitis is responsible for such clinical manifestations as rash, increased extravascular fluid space, hypotension, edema, gangrene, and coagulation abnormalities.
    C) EPIDEMIOLOGY: Most frequently reported and most commonly fatal rickettsial disease in the US. Cases have been reported in all contiguous US except Vermont and Maine with over 60% of cases reported from 5 states (North Carolina, Oklahoma, Arkansas, Tennessee, and Missouri) by the American dog tick (Dermacentor variabilis Dermacentor andersoni). Peak season is June and July although illness can occur year-round; seasonality can vary depending on different regions of the country based on climate and the tick vector. In recent years, RMSF has become more common in certain areas of Arizona. Between 2003 and 2012, over 250 cases have been reported with a case fatality rate of 19%. Annual incidence increased to a peak of 8.4 cases per million in 2008 and declined to over 6 cases per million in 2010. The incidence is highest among children (especially those aged 5 to 9 years) and persons in age groups 55 to 59 and 60 to 64 years-old. Overall, the case fatality rate has declined to 0.5% in 2010. Internationally, RMSF has been described in Canada, Mexico, Panama, Costa Rica, Argentina, Brazil and Columbia.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE EFFECTS: ONSET: Flu-like prodrome (fever, chills, malaise, myalgias, severe frontal headache) usually begins a week (range: 2 to 14 days) after a tick bite(s). Maculopapular rash usually develops 2 to 5 days after the onset of fever. The rash generally begins on the wrists and ankles, then spreads to extremities, trunk, and face; may become petechial; palms and soles are involved. However, the rash can develop late in the disease process. Some patients (9% to 12%) never demonstrate a rash. The illness can be difficult to diagnose in the early stages. Confounding symptoms such as nausea, vomiting, diarrhea, abdominal pain and cough can lead to a misdiagnosis (ie, enterocolitis, acute abdomen, pneumonia). Eschar at the tick bite site is unusual with RMSF but may be present with other tickborne rickettsial diseases. Other effects may include tachycardia, hypotension, generalized edema, dysrhythmias, anorexia, muscular rigidity, splenomegaly, arthralgias, restlessness, irritability, altered mental status, and dehydration.
    2) SEVERE EFFECTS: As the infection progresses, manifestations, of secondary damage to vital organs may include encephalitis, scattered/discrete microinfarcts with CNS involvement, myocardial inflammation/necrosis, focal area of fatty degeneration in the liver, focal interstitial vascular lesions in the kidneys/renal failure, interstitial pneumonitis or acute respiratory distress syndrome (primary cause of death), disseminated intravascular coagulation, shock, and rapid death. In one case series, 15% of children surviving RMSF developed residual neurologic deficits including global encephalopathy, ataxia, speech and/or swallowing dysfunction and cortical blindness.
    0.2.3) VITAL SIGNS
    A) Fever and tachycardia are common symptoms. Hypotension may occur with severely ill patients.
    0.2.20) REPRODUCTIVE
    A) It is not known whether R rickettsii can cross the placenta and adversely affect the fetus.

Laboratory Monitoring

    A) Early laboratory data only lend nonspecific support to the diagnosis of RMSF. Antibodies to R rickettsii are not detectable until 7 to 10 days after disease onset and should not be relied upon to initiate treatment. Confirmation should be obtained by testing for rickettsial antibody in paired sera.
    B) Monitor ECG, complete blood count, electrolytes, ABGs, creatine kinase, renal and hepatic function. Thrombocytopenia, hyponatremia, elevated aminotransferase levels and depressed or normal leukocyte counts have been reported.
    C) Diagnosis is confirmed by immunofluorescent antibody (IFA) tests or enzyme immunoassay with a 4-fold rise in titer in paired testing or convalescence titer greater than 1:64. Immunofluorescence or immunoenzyme demonstration of R rickettsii in a biopsy specimen of skin or organ tissue is both sensitive (50% to 70%) and specific (100%); however, a rash must be present for the skin biopsy to be useful, and test availability is limited. PCR amplification of rickettsial DNA may be specific for the causative agent but lacks sensitivity and; therefore, has limited utility in the diagnosis of RMSF.
    D) PCR for the diagnosis of RMSF is limited because of its poor sensitivity in detecting R rickettsii DNA in blood specimens.

Treatment Overview

    0.4.7) BITES/STINGS
    A) INFECTION OF TICK BITE
    1) There are many infectious diseases that can be transmitted via tick bites. For further information on tickborne illnesses, please SEE the following managements: Lyme Disease, Crimean-Congo Hemorrhagic Fever, Ehrlichiosis, and Tularemia. This management is limited to the clinical effects and management of Rocky Mountain Spotted Fever (RMSF). Risk of acquiring RMSF can be decreased by avoiding tick habitats, wearing light-colored clothing with long sleeves and long pants, using tick repellents, checking the entire body for ticks daily, and promptly removing the attached ticks before the transmission of R rickettsi can occur.
    B) MANAGEMENT OF MILD TO MODERATE EXPOSURE
    1) Treatment is symptomatic and supportive. Doxycycline is the drug of choice to treat RMSF. Vigorous treatment with cooling blankets, mist and fan technique, or tepid sponging may be used. IV fluids may be indicated to manage mild hypotension, decreased oral intake due to altered mental status or vomiting.
    C) MANAGEMENT OF SEVERE EXPOSURE
    1) Treatment is symptomatic and supportive. Patients that develop severe illness (ie acute respiratory distress syndrome, renal failure and coma) may require specific interventions including mechanical ventilation, dialysis and neurologic intensive care.
    D) TICK REMOVAL/DERMAL EXPOSURE
    1) Remove ticks with blunt, wide blade forceps or tweezers rather than directly handling them. Grasp the tick firmly and as close to the skin as possible. Pull the tick out with a steady pull and try to avoid jerking, as that may lead to the head remaining in the skin. Be sure to remove the head of the tick, including its mouth parts, and examine the area with hand lens afterwards. Do NOT crush, puncture, burn or damage the tick as its parts or fluids may contain infective agents. In addition, do NOT apply large amounts of petroleum jelly to the tick to smother it as that may result in greater difficulty in removing it. There is also NO benefit in subcutaneous injections of local anesthesia for tick removal. After removal, clean and disinfect the bite site with soap, water, and alcohol. Place a sterile dressing or adhesive bandage over the wound, and one may apply a topical antibiotic as well. Most pain can be treated with ice applied over the injured area. Local itching or inflammation can be treated with topical corticosteroids, antihistamines and/or anesthetics. Tetanus prophylaxis should be considered.
    E) DECONTAMINATION
    1) PREHOSPITAL: There is no utility for prehospital activated charcoal. The focus of prehospital care should include tick removal, wound care, and supportive care (see DERMAL EXPOSURE).
    2) HOSPITAL: GI decontamination is not indicated. Treatment should include tick removal or thorough inspection of the site to be sure that all parts of the tick have been removed if performed prior to hospital care (use hand lens for examination), wound care, and supportive care.
    F) AIRWAY MANAGEMENT
    1) If the patient is hypoxic, supplementary oxygen should be given as needed. Ventilatory support may be necessary for severely ill patients.
    G) ANTIBIOTIC THERAPY
    1) DOXYCYCLINE is the drug of choice for presumed or confirmed RMSF. DOSE: ADULT: 100 mg twice daily orally or IV (maximum: 100 mg/dose); CHILD: 2.2 mg/kg for children less than 45.4 kg twice daily orally or IV. Treatment should be started regardless of age, because of potential for severe or fatal illness. Doxycycline should be given for 5 to 7 days and for at least 48 hours after the patient is afebrile.
    2) ALTERNATIVE THERAPY: Chloramphenicol is an alternative drug therapy recommended for patients with hypersensitivity to doxycycline or who are pregnant. DOSE: ADULT: 50 to 75 mg/kg/day IV divided into 4 doses, given for 7 days, or until 2 days after the fever has subsided. CHILD: 50 mg/kg/day IV divided into 4 doses at 6 hour intervals. OTHER: Erythromycin, penicillins, aminoglycosides, and cephalosporins are ineffective. Sulfonamides may worsen the infection.
    H) ENHANCED ELIMINATION
    1) Hemodialysis may be necessary for patients with acute renal failure as a supportive measure.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with early, mild illness may be treated on an outpatient basis with oral antibiotics if they are reliable and close follow-up observation can be arranged. Family clustering of RMSF has been reported; family members of a patient with suspected RMSF should be warned that they have an increased risk of contracting the disease.
    2) OBSERVATION CRITERIA: Early, mild illness may be observed if either the patient is unreliable or outpatient follow up is not available.
    3) ADMISSION CRITERIA: All patients with RMSF in whom the diagnosis is uncertain or with moderate to severe RMSF symptoms should be hospitalized.
    4) CONSULT CRITERIA: Consultation with an infectious disease specialist may be helpful, particularly for those patients who have not yet developed a rash. Consultation with a dermatologist to obtain a skin biopsy specimen for early pathologic confirmation of diagnosis is indicated as soon as RMSF is suspected.
    5) TRANSFER CRITERIA: Transport is necessary when facilities for intensive care and invasive monitoring of the critically ill patient are not available.
    J) PITFALLS
    1) RMSF should be considered in patients with unexplained febrile illness, particularly if there is a history of tick bite or travels to known endemic area. Do not wait for confirmatory testing to begin treatment. Initiate treatment with doxycycline based on clinical suspicion.
    K) PREDISPOSING CONDITIONS
    1) Higher incidences of disease associated with children age 5 to 9 years, adults age 55 to 64 years, male gender, and American Indian ethnicity. Fatal outcome associated with age greater than 60 years, delay of appropriate antibiotic therapy (greater than 5 days from onset), lack of typical rash, glucose-6-phosphate dehydrogenase deficiency, and treatment only with chloramphenicol.
    L) DIFFERENTIAL DIAGNOSIS
    1) Infectious entities that may present a similar clinical picture include: ehrlichiosis, meningococcemia, gonococcemia, rubella, rubeola infectious mononucleosis, leptospirosis, toxic shock syndrome, dengue fever, viral hemorrhagic fevers, and Kawasaki disease.

Range Of Toxicity

    A) TOXIC DOSE: The mean infectious dose is 23 organisms, but as few as one bacillus of R rickettsii may be sufficient to cause infection. A single tick may cause infection. Risk increases with tick attachment longer than 48 to 72 hours.

Clinical Effects

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH POISONING/EXPOSURE
    a) Initially, the rash is macular, red, and flat, blanching with pressure and resembling measles with irregular lesions 1 to 4 mm in diameter. Within hours to days, the rash becomes papular, darker, and slightly dusky, and can be felt on light palpation. Within 2 to 3 days, it becomes petechial or purpuric with a positive Rumpel-Leede test (Walker, 1995; Middleton, 1993).
    b) The rash may become coalescent or even ulcerate. It may occur only with fever spikes (Spach, 1993). Eschars have been reported in cases of fatal laboratory-confirmed RMSF (Walker et al, 1981).
    c) During the 3rd week in severe cases, necrosis of dependent peripheral parts, including the scrotum, prepuce, fingers, toes, and external ear may occur (Dumler & Walker, 1994).
    d) Atypical rashes, including erythema migrans-like lesions resembling Lyme disease, also have been reported (Hughes, 1995).
    e) LOCATION: Begins on the flexor surface of the ankles and wrists and spreads proximally to the arms, legs, and trunk and, in about 15% of cases, distally to the palms and soles (Dantas-Torres, 2007; CDC, 1986).
    f) COURSE
    1) Rash usually appears between days 3 and 5 of illness (Walker, 1995). However, in one series, onset of rash and fever was simultaneous in 28% of patients (Linneman, 1978).
    2) Rash may not be present during the first 3 days of illness in up to 50% of cases (Helmick et al, 1984) and may not appear until after day 6 in up to 20% (Walker, 1995).
    3) Rash may appear as late as the 9th day or may be absent in up to 10% of patients (Rocky Mountain spotless fever) (Morrison, 1991; Hattwick, 1978; (Westerman, 1982; Helmick et al, 1984; Sexton & Corey, 1992).
    B) PETECHIAE
    1) WITH POISONING/EXPOSURE
    a) Petechiae are present in 40% to 60% of cases. When present, it appears after day 6 in 75% of patients (Linneman, 1978; (Walker, 1995). It is caused by a vasculitis secondary to rickettsial invasion of vascular endothelium (Sexton & Clapp, 1977).
    C) GANGRENE
    1) WITH POISONING/EXPOSURE
    a) Gangrene is a rare complication. It is probably related to vasculitis leading to small-vessel occlusion; DIC and hypotension also may play a role (Kirkland, 1993).
    b) It most commonly involves fingers, toes, and penis/scrotum. It may require amputation or surgical debridement (Kirkland, 1993).
    c) Rickettsial organisms have been identified by immunoperoxidase staining in the ischemic margins of gangrenous lesions as long as 7 weeks after onset of disease (Hove & Walker, 1995).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH POISONING/EXPOSURE
    a) Myalgias, especially in legs, abdomen, and back, are present in about 85% of patients (CDC, 1986).
    b) TENDERNESS, MUSCLE: Exquisite tenderness may restrict joint movement to the extent of simulating arthralgias. Almost 8% of patients develop back pain from muscle tenderness (Linnemann & Janson, 1978).
    B) JOINT PAIN
    1) WITH POISONING/EXPOSURE
    a) Patients may present with arthralgia, however, exquisite muscle tenderness may restrict joint movement to the extent of simulating arthralgias.
    b) Aseptic arthritis of the knee and elbow joints has been described in patients with RMSF (Sundy et al, 1996; Verne & Myers, 1994).
    C) MENINGEAL IRRITATION
    1) WITH POISONING/EXPOSURE
    a) Meningismus is found in about 20% of patients (Linnemann & Janson, 1978) Massey 1985).
    D) ARTHRITIS
    1) WITH POISONING/EXPOSURE
    a) Aseptic arthritis of the knee and elbow joints has been described in patients with RMSF (Sundy et al, 1996; Verne & Myers, 1994).
    E) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Rhabdomyolysis may occur (Tenenbaum & Markowitz, 1980).

Summary Of Exposure

    A) TOXIC CLASS: Rocky Mountain Spotted Fever (RMSF) is one of many tick-, mite-, and flea-borne zoonotic infections in the spotted fever group.
    B) TOXICOLOGY/PATHOGENICITY: RMSF is caused by Rickettsia rickettsii, a small gram-negative obligate intracellular bacteria which is transmitted from the bite of the Rocky Mountain wood tick (Dermacentor andersoni), the American dog tick (D. variables), or the brown dog tick (Rhipicephalus sanguineus). The tick is both the vector and the reservoir for R. rickettsii. Once infected, rickettsiae invade the cytoplasm of vascular endothelial cells of small blood vessels throughout the body. As rickettsiae multiply in small blood vessels in various tissues and organs, endothelial damage leads to cell necrosis and proliferative hypertrophy of the intima, possible necrosis of the media, and mononuclear and plasma cell infiltration of the adventitia. The resulting diffuse thrombosis and microinfarction cause partial or total occlusion of the vessel lumen, leading to infarction of skin, heart, kidney, adrenal glands, and brain. Necrosis of arteriolar wall leads to rupture with local areas of hemorrhage. This widespread vasculitis is responsible for such clinical manifestations as rash, increased extravascular fluid space, hypotension, edema, gangrene, and coagulation abnormalities.
    C) EPIDEMIOLOGY: Most frequently reported and most commonly fatal rickettsial disease in the US. Cases have been reported in all contiguous US except Vermont and Maine with over 60% of cases reported from 5 states (North Carolina, Oklahoma, Arkansas, Tennessee, and Missouri) by the American dog tick (Dermacentor variabilis Dermacentor andersoni). Peak season is June and July although illness can occur year-round; seasonality can vary depending on different regions of the country based on climate and the tick vector. In recent years, RMSF has become more common in certain areas of Arizona. Between 2003 and 2012, over 250 cases have been reported with a case fatality rate of 19%. Annual incidence increased to a peak of 8.4 cases per million in 2008 and declined to over 6 cases per million in 2010. The incidence is highest among children (especially those aged 5 to 9 years) and persons in age groups 55 to 59 and 60 to 64 years-old. Overall, the case fatality rate has declined to 0.5% in 2010. Internationally, RMSF has been described in Canada, Mexico, Panama, Costa Rica, Argentina, Brazil and Columbia.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE EFFECTS: ONSET: Flu-like prodrome (fever, chills, malaise, myalgias, severe frontal headache) usually begins a week (range: 2 to 14 days) after a tick bite(s). Maculopapular rash usually develops 2 to 5 days after the onset of fever. The rash generally begins on the wrists and ankles, then spreads to extremities, trunk, and face; may become petechial; palms and soles are involved. However, the rash can develop late in the disease process. Some patients (9% to 12%) never demonstrate a rash. The illness can be difficult to diagnose in the early stages. Confounding symptoms such as nausea, vomiting, diarrhea, abdominal pain and cough can lead to a misdiagnosis (ie, enterocolitis, acute abdomen, pneumonia). Eschar at the tick bite site is unusual with RMSF but may be present with other tickborne rickettsial diseases. Other effects may include tachycardia, hypotension, generalized edema, dysrhythmias, anorexia, muscular rigidity, splenomegaly, arthralgias, restlessness, irritability, altered mental status, and dehydration.
    2) SEVERE EFFECTS: As the infection progresses, manifestations, of secondary damage to vital organs may include encephalitis, scattered/discrete microinfarcts with CNS involvement, myocardial inflammation/necrosis, focal area of fatty degeneration in the liver, focal interstitial vascular lesions in the kidneys/renal failure, interstitial pneumonitis or acute respiratory distress syndrome (primary cause of death), disseminated intravascular coagulation, shock, and rapid death. In one case series, 15% of children surviving RMSF developed residual neurologic deficits including global encephalopathy, ataxia, speech and/or swallowing dysfunction and cortical blindness.

Vital Signs

    3.3.1) SUMMARY
    A) Fever and tachycardia are common symptoms. Hypotension may occur with severely ill patients.
    3.3.3) TEMPERATURE
    A) Diagnosis should be considered in any patient with an unexplained febrile illness, even if there is no history of tick bite or of travel to a known endemic area (CDC, 1988). Fever is present in almost all cases (CDC, 1988).
    B) Abrupt onset of fever occurs 1 to 12 days after the tick bite (average, 5 days) and precedes the rash by 2 to 3 days (Linnemann & Janson, 1978). The triad of fever, headache, and rash is present in about 50% of patients (CDC, 1989).
    C) Temperature is high (to 40 degrees C) and spiking with irregular morning remissions, reaching a maximum during the second week of illness without treatment (Walker, 1995).
    3.3.4) BLOOD PRESSURE
    A) Hypotension accompanied by a feeble, rapid pulse rate may occur in seriously ill patients. Extravasation of fluid (due to loss of vessel wall integrity) causes hypovolemia and hypotension.
    3.3.5) PULSE
    A) Tachycardia is generally proportionate to the degree of fever unless there is involvement of the cardiac conduction system (Thorner et al, 1998; Linnemann & Janson, 1978).

Heent

    3.4.3) EYES
    A) PERIORBITAL EDEMA: Nonpitting, nondependent edema, usually first noted in the periorbital region, is present in 6% of patients.
    B) PHOTOPHOBIA: Photophobia is reported by 8% of patients (Linnemann & Janson, 1978).
    C) PAPILLEDEMA: Papilledema is present in 2% of patients (Linnemann & Janson, 1978). It may occur secondary to increased intracranial pressure or vasculitis of the vasa nervorum of the optic nerve.
    D) RETINAL HEMORRHAGES and exudates and retinal artery occlusion may be seen in patients with papilledema.
    E) SCLERAL ICTERUS: Jaundice of the sclera is found in 2% of patients (Linnemann & Janson, 1978).
    F) CONJUNCTIVAL INFLAMMATION: Conjunctivitis is found in 30% of patients (Linnemann & Janson, 1978).
    G) CONJUNCTIVAL PETECHIAE: These are found on the bulbar conjunctiva (Linnemann & Janson, 1978).
    3.4.4) EARS
    A) HEARING LOSS: Transient deafness is present in 2% of affected individuals. There is usually no residual effect (Centers for Disease Control and Prevention, 2014; Linnemann & Janson, 1978).
    3.4.5) NOSE
    A) EPISTAXIS: Nose bleed occurs in 3% of patients (Linnemann & Janson, 1978).
    B) DISCHARGE, NASAL: 25% of patients report nasal discharge at the initial visit (Donohue, 1980).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CHEST PAIN
    1) WITH POISONING/EXPOSURE
    a) Atypical chest pain is present in almost 20% of patients at the initial visit (Donohue, 1980).
    B) EDEMA
    1) WITH POISONING/EXPOSURE
    a) Generalized, non-pitting edema of the face, hands, ankles, feet, and lower parts of the sacrum is common (Walker, 1995).
    b) In one study, edema was recognized in only a few patients on admission, but occurred in virtually all patients during hospitalization (Linnemann & Janson, 1978).
    C) CONGESTIVE HEART FAILURE
    1) WITH POISONING/EXPOSURE
    a) Congestive heart failure that responded to medical management was present in 1% of children with RMSF in one series (Marin-Garcia et al, 1981).
    b) Myocardial impairment, detectable on ECG, may lead to cardiogenic pulmonary edema (Marin-Garcia et al, 1981). Therefore, intravenous fluid therapy should be used judiciously.
    D) ELECTROCARDIOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) ECG abnormalities are usually nonspecific but may indicate myocardial or conduction system involvement. Changes in rhythm and configurations may include sinus and nodal tachycardia, first-degree AV block, right bundle branch block, intraventricular conduction defects, inferior wall ischemia, nonspecific ST and T wave changes, paroxysmal atrial tachycardia, and nodal tachycardia (Linnemann & Janson, 1978; Marin-Garcia et al, 1981).
    b) Atrial fibrillation and conduction abnormalities may be seen in 16% of patients (Weber & Walker, 1991).
    E) MYOCARDITIS
    1) WITH POISONING/EXPOSURE
    a) Myocarditis and myocardial necrosis may occur in 5% of patients; however, clinical significance is unclear (Weber & Walker, 1991). Cardiac iso-enzymes are elevated in patients with myocarditis (Bradford & Hackel, 1978).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH POISONING/EXPOSURE
    a) COUGH: One third of patients in one series had nonproductive cough at the initial physician visit (Donohue, 1980).
    B) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) DYSPNEA: 25% of patients report dyspnea at the initial visit (Donohue, 1980).
    C) STRIDOR
    1) WITH POISONING/EXPOSURE
    a) STRIDOR: Rarely, stridor may occur secondary to glottic edema and small laryngeal hemorrhages (Donohue, 1980).
    D) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Lower respiratory tract involvement occurs in about 40% of cases, presumably due to vasculitis-induced noncardiogenic pulmonary edema (Donohue, 1980).
    E) HYPOXEMIA
    1) WITH POISONING/EXPOSURE
    a) An increased alveolar-arterial oxygen gradient may be found in patients with lower respiratory tract involvement (Donohue, 1980).
    F) RESPIRATORY ALKALOSIS
    1) WITH POISONING/EXPOSURE
    a) Respiratory alkalosis may be present in patients with lower respiratory tract involvement (Donohue, 1980).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Severe, unremitting headache is a symptom in 75% to 90% of patients (Dantas-Torres, 2007; Centers for Disease Control and Prevention, 2014; Donohue, 1980; Linnemann & Janson, 1978; CDC, 1986) (Spach, 1993).
    b) The triad of fever, headache, and rash is present in about 50% of patients (CDC, 1989).
    c) The headache is generalized but more intense in the frontal region (Linnemann, 1987).
    B) ALTERED MENTAL STATUS
    1) WITH POISONING/EXPOSURE
    a) Alterations of the sensorium ranging from lethargy to coma are common (Massey, 1985). Altered mental status usually signifies severe disease (Linnemann, 1987).
    C) COMA
    1) WITH POISONING/EXPOSURE
    a) Coma occurs in about 10% of cases and usually indicates poor prognosis with up to 88% mortality. However, complete recovery also has been reported, even after prolonged coma (Baganz et al, 1995; Hove & Walker, 1995; Walker, 1995).
    b) Comatose patients with other signs of neurologic involvement in the acute phase are likely to have persistent neurologic deficits (Massey, 1985; Spach, 1993).
    D) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures occur in about 3% of patients (Linnemann & Janson, 1978).
    E) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) Some patients with RMSF may complain of vertigo (Miller & Price, 1972).
    F) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) In one case series (n=89), 15% (n=13) of children surviving RMSF developed residual neurologic deficits including ataxia, global encephalopathy, speech and/or swallowing dysfunction and cortical blindness (Buckingham et al, 2007).
    b) Bilateral cerebellar ataxia has been reported (Miller & Price, 1972).
    G) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH POISONING/EXPOSURE
    a) Two thirds of cases are associated with focal or generalized neurologic manifestations (Massey, 1985). Neurologic symptoms usually resolve in treated patients.
    b) Focal neurologic deficits occur in 10% to 15% of patients, developing six to eight days after onset of fever.
    c) Most focal deficits are transient and are attributed to rickettsial vasculitis.
    d) Cranial nerve deficits or motor weakness usually signify more severe disease (Linnemann, 1987).
    e) Reported neurologic deficits include cranial nerve palsies, hearing loss, dysarthria, aphasia, hemi- or paraplegia, ankle clonus, nystagmus, spasticity, fasciculations, athetosis, and Babinski sign (Miller & Price, 1972) Massey, 1985; Linneman, 1978; (Walker, 1995).
    f) In one case series (n=89), 15% (n=13) of children surviving RMSF developed residual neurologic deficits including ataxia, global encephalopathy, speech and/or swallowing dysfunction and cortical blindness (Buckingham et al, 2007).
    H) MALAISE
    1) WITH POISONING/EXPOSURE
    a) Malaise occurring two to three days following the tick bite is reported in 100% of cases (Linnemann & Janson, 1978).
    I) HEMIPLEGIA
    1) WITH POISONING/EXPOSURE
    a) Hemiplegia and peripheral neuritis are rare sequelae of RMSF (Linnemann & Janson, 1978).
    J) ENCEPHALITIS
    1) WITH POISONING/EXPOSURE
    a) In one case series (n=89), 15% (n=13) of children surviving RMSF developed residual neurologic deficits including ataxia, global encephalopathy, speech and/or swallowing dysfunction and cortical blindness (Buckingham et al, 2007).
    b) Clinically evident encephalitis occurs in 25% to 30% of patients and is associated with a high risk of fatal outcome (Scully, 1997) (Walker, 1989; Horney & Walker, 1988).
    1) Manifestations may include confusion, stupor or delirium, ataxia, coma, and seizures. The clinical picture may suggest a diagnosis of viral encephalitis, meningitis, or meningococcemia with early meningitis (Walker, 1989).
    2) Coma occurs more frequently in fatal cases (86%) than in nonfatal cases (6%).
    c) Most survivors who experience neurologic symptoms and receive proper antibiotic treatment regain all or most neurologic function, although in some cases, neurologic recovery is not complete for weeks to months after the resolution of fever and other clinical signs and symptoms.
    d) Persistence of symptoms is more likely in patients in coma, than those with other severe neurologic signs, and patients not treated (Horney & Walker, 1988).
    K) CSF CELL CONTENT: RAISED
    1) WITH POISONING/EXPOSURE
    a) Pleocytosis (mainly lymphocytes and monocytes) is a common finding (Linnemann & Janson, 1978), although polymorphonuclear leukocytes may predominate (Kirk, 1990). The usual CSF WBC count (both PMNs and lymphocytes) ranges from 8 to 35/mm(3).
    b) Eosinophilia was reported in a single case of RMSF; 60% of 112 WBCs in CSF were eosinophils (Crennan & Van Scoy, 1986).
    c) An elevated protein level with normal glucose level is a common finding (Massey, 1985).
    L) GUILLAIN-BARRé SYNDROME
    1) WITH POISONING/EXPOSURE
    a) A case of Guillain-Barre Syndrome following RMSF has been reported (Toerner et al, 1996).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH POISONING/EXPOSURE
    a) Gastrointestinal complaints, including nausea, vomiting, abdominal pain, and diarrhea, have been reported in about 30% of patients with fatal RMSF, as compared with 4% of patients with nonfatal cases (Hattwick, 1978). The majority of fatal cases show evidence of vasculitis of the pancreas and large and small intestines at autopsy (Randall & Walker, 1984).
    b) NAUSEA: Overall, up to two-thirds of patients experience nausea and vomiting (Linnemann, 1987).
    c) DIARRHEA: About 5% of patients experience diarrhea (Linnemann, 1987).
    d) ABDOMINAL PAIN: Overall, about one-third of patients complain of abdominal pain, which may lead to the misdiagnosis of an acute abdomen (Linnemann, 1987). Nonspecific abdominal tenderness is present in 8% patients (Linnemann & Janson, 1978) and may mimic appendicitis (Davis & Bradford, 1982) or cholecystitis (Spach, 1993). Abdominal distention is a common finding, as is some degree of ileus.
    e) Cases of fever and abdominal pain in elderly patients that lead to cholecystectomy have been reported; Rickettsia were demonstrated in blood vessels of the gallbladder in both cases (Walker, 1985). Acalculus cholecystitis also has been described in a younger patient (Verne & Myers, 1994).
    f) SPLENOMEGALY: An enlarged spleen is present in up to 50% of patients.

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) JAUNDICE
    1) WITH POISONING/EXPOSURE
    a) Jaundice is present in 2% of patients (Linnemann & Janson, 1978). In one series, it was noted in 3 of 8 fatal cases (Jackson, 1986).
    B) LARGE LIVER
    1) WITH POISONING/EXPOSURE
    a) Hepatomegaly is found in 25% of patients (Linnemann & Janson, 1978).
    C) ABNORMAL LIVER FUNCTION
    1) WITH POISONING/EXPOSURE
    a) Elevated AST and LDH levels are found in the majority of patients with RMSF. Less than 50% of patients have elevated bilirubin levels (Linnemann & Janson, 1978).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) OLIGURIA
    1) WITH POISONING/EXPOSURE
    a) Oliguria may initially reflect simple dehydration or reduced intravascular volume secondary to altered systemic vascular permeability; however, persistent oliguria is indicative of acute tubular necrosis secondary to prolonged hypotension (Dumler & Walker, 1994).
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Acute renal failure is a frequent complication of RMSF (19% in one series) and contributes to a fatal outcome (Conlon, 1996). This involves several simultaneous pathogenic mechanisms, including hypotension, prerenal insufficiency, intravascular thrombosis, and direct rickettsial infection of the kidneys (Conlon, 1996).
    b) Prolonged hypotension may result in acute tubular necrosis. In one study, dip stick and microscopic examinations were negative despite postmortem documentation of multifocal perivascular interstitial nephritis in all 10 cases (Walker & Mattern, 1979).
    c) Reversible acute renal failure due to glomerulonephritis in a patient with RMSF has been reported and is associated with severe disease (Quigg, 1991).
    d) Clinical and biochemical markers on presentation that are useful in predicting development of acute renal failure include increased bilirubin, increasing age, thrombocytopenia, and presence of neurologic involvement (Conlon, 1996).
    C) BLOOD UREA ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) BUN concentration may be slightly elevated secondary to dehydration (Linnemann & Janson, 1978).
    b) A markedly elevated BUN level occurs in acute renal failure due to hypotension-induced acute tubular necrosis (Walker & Mattern, 1979).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLOOD COAGULATION PATHWAY FINDING
    1) WITH POISONING/EXPOSURE
    a) Coagulation abnormalities indicating DIC (prolonged PT, PTT, decreased fibrinogen, positive fibrin split products) are found in nearly all patients seriously ill with RMSF (Linnemann & Janson, 1978). DIC may produce gastrointestinal, pulmonary, or cerebral hemorrhage (Walker, 1995).
    B) LEUKOPENIA
    1) WITH POISONING/EXPOSURE
    a) Leukopenia occurs initially and may persist for the first week of illness. It may be followed by a mild leukocytosis, although a normal white count is most common (Linnemann, 1987).
    C) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) Mild leukocytosis may occur during the second week of illness. Moderate to severe leukocytosis should prompt a search for secondary infections (Linnemann, 1987).
    D) LYMPHOCYTOPENIA
    1) WITH POISONING/EXPOSURE
    a) An increased percentage of polymorphonuclear neutrophils is common (Linnemann & Janson, 1978); profound reversible lymphopenia with CD4 cell lymphocytopenia has been described (Turett, 1995). Two thirds of patients have increased immature forms or bands (10% to 50%) (Weber & Walker, 1991).
    E) THROMBOCYTOPENIC DISORDER
    1) WITH POISONING/EXPOSURE
    a) Platelet count <150,000/mm(3) may be present in 30% to 50% of patients; platelet counts <20,000 may be seen in 10% (Weber & Walker, 1991).
    F) ANEMIA
    1) WITH POISONING/EXPOSURE
    a) Most patients develop anemia during their illness (usually mild) (Kirk, 1990).
    b) Hemolysis may occur in some patients, with up to 11% requiring transfusion (Walker, 1995).

Reproductive

    3.20.1) SUMMARY
    A) It is not known whether R rickettsii can cross the placenta and adversely affect the fetus.
    3.20.3) EFFECTS IN PREGNANCY
    A) PLACENTAL BARRIER
    1) It is not known whether R rickettsii can cross the placenta and adversely affect the fetus. In one case report, RMSF in pregnancy was treated successfully with chloramphenicol, with no apparent adverse maternal or neonatal effects (Markley et al, 1998).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Early laboratory data only lend nonspecific support to the diagnosis of RMSF. Antibodies to R rickettsii are not detectable until 7 to 10 days after disease onset and should not be relied upon to initiate treatment. Confirmation should be obtained by testing for rickettsial antibody in paired sera.
    B) Monitor ECG, complete blood count, electrolytes, ABGs, creatine kinase, renal and hepatic function. Thrombocytopenia, hyponatremia, elevated aminotransferase levels and depressed or normal leukocyte counts have been reported.
    C) Diagnosis is confirmed by immunofluorescent antibody (IFA) tests or enzyme immunoassay with a 4-fold rise in titer in paired testing or convalescence titer greater than 1:64. Immunofluorescence or immunoenzyme demonstration of R rickettsii in a biopsy specimen of skin or organ tissue is both sensitive (50% to 70%) and specific (100%); however, a rash must be present for the skin biopsy to be useful, and test availability is limited. PCR amplification of rickettsial DNA may be specific for the causative agent but lacks sensitivity and; therefore, has limited utility in the diagnosis of RMSF.
    D) PCR for the diagnosis of RMSF is limited because of its poor sensitivity in detecting R rickettsii DNA in blood specimens.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor complete blood count, electrolytes and hepatic function. Thrombocytopenia, hyponatremia, elevated aminotransferase levels and depressed or normal leukocyte counts have been reported (Centers for Disease Control and Prevention, 2014; Spach et al, 1993).
    4.1.3) URINE
    A) URINALYSIS
    1) Urinalysis is useful to detect associated renal or skeletal muscle damage (Linnemann, 1987).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) ECG abnormalities are usually nonspecific but may indicate myocardial or conduction system involvement (Weber & Walker, 1991; Marin-Garcia et al, 1981; Linnemann & Janson, 1978).
    2) CEREBROSPINAL FLUID
    a) WHITE BLOOD CELLS, INCREASED
    1) Pleocytosis (mainly lymphocytes and monocytes) is a common finding (Linnemann & Janson, 1978), although polymorphonuclear leukocytes may predominate (Kirk, 1990). The usual CSF WBC count (both PMNs and lymphocytes) ranges from 8 to 35/mm(3).
    2) Eosinophilia was reported in a single case of RMSF; 60% of 112 WBCs in CSF were eosinophils (Crennan & Van Scoy, 1986).
    b) PROTEIN, INCREASED
    1) An elevated protein level with normal glucose level is a common finding (Massey, 1985).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) INDICATIONS: Baseline and repeated chest films are indicated to identify RMSF-related cardiorespiratory dysfunction (Linnemann, 1987).
    2) FINDINGS: Abnormal in about 25% of cases; findings may include cardiomegaly with pulmonary edema, interstitial or patchy alveolar infiltrates, and pleural effusions (Donohue, 1980; Linnemann & Janson, 1978; Marin-Garcia et al, 1981).
    B) CT RADIOGRAPH
    1) COMPUTED TOMOGRAPHY, HEAD
    a) INDICATIONS: Head CT is indicated in patients with neurologic symptoms and may reveal cerebral edema, focal thrombosis, or hemorrhage.
    b) FINDINGS: Often subtle; abnormalities may include infarctions, cerebral edema, meningeal enhancement, prominent perivascular spaces (Bonawitz et al, 1997).
    c) PROGNOSTIC INDICATORS: Although abnormalities on neuroimaging studies are not common in RMSF, when present, they are associated with unfavorable outcome (Bonawitz et al, 1997).
    C) ULTRASOUND
    1) ECHOCARDIOGRAPHY
    a) Evidence of myocardial dysfunction may be detected by echocardiography before it is detectable clinically; the most consistent abnormality in RMSF is decreased left ventricular contractility, occurring most often in severely affected patients (Marin-Garcia & Barrett, 1983).
    D) MAGNETIC RESONANCE IMAGING
    1) IMAGING, MAGNETIC RESONANCE, HEAD
    a) INDICATIONS: May be useful in diagnosis and follow-up of patients with neurologic findings suggesting encephalitis (Baganz et al, 1995).
    b) FINDINGS: Often subtle; abnormalities may include infarctions, cerebral edema, meningeal enhancement, prominent perivascular spaces (Bonawitz et al, 1997).
    1) In one case report, abnormal signal intensity in perivascular spaces on T2 weighted images reflected vasculitis due to RMSF; improvement in these abnormalities paralleled clinical improvement (Baganz et al, 1995).
    c) PROGNOSTIC INDICATORS: Although abnormalities on neuroimaging studies are not common in RMSF, when present, they are associated with unfavorable outcome (Bonawitz et al, 1997).
    E) ELECTROENCEPHALOGRAPHY
    1) In one study, all 6 patients who underwent EEG demonstrated abnormal diffusely slow activity (Massey, 1985).

Methods

    A) SUMMARY
    1) Confirmation of RMSF is based on laboratory testing, but antibiotic therapy should not be delayed (Centers for Disease Control and Prevention, 2014).
    B) BIOASSAY
    1) ANTIBODY STAIN, IMMUNOHISTOLOGIC, RICKETTSIA
    a) Best rapid diagnostic test available.
    b) Immunofluorescent or immunoenzyme demonstration of R rickettsii in a biopsy specimen of skin or organ tissue is both sensitive (50% to 70%) and specific (100%) and may be useful during the acute stage of RMSF (Dantas-Torres, 2007); however, a rash must be present for the skin biopsy to be useful, and test availability is limited (Walker, 1995; Dumler & Walker, 1994). More frequently, the test appears more useful for detecting rickettsiae in necropsy tissue (Dantas-Torres, 2007).
    2) CULTURE, TISSUE
    a) Centrifugation of infected blood samples into shell-vial tissue culture cells may allow detection of rickettsial growth by immunostaining within several days; this test is not widely available (Dumler & Walker, 1994; Walker, 1995).
    3) BIOPSY, SKIN
    a) Immunofluorescent or immunoenzyme demonstration of R rickettsii in a biopsy specimen of skin or organ tissue is both sensitive (70%) and specific (100%); however, a rash must be present for the skin biopsy to be useful.
    1) Best rapid diagnostic test available; diagnostic confirmation can be made within 4 hours using this technique to visualize Rickettsia within vascular endothelium.
    4) POLYMERASE CHAIN REACTION ASSAY
    a) LIMITED UTILITY: Detection of DNA in a skin biopsy of rash by polymerase chain reaction assay is usually unreliable for acute blood samples (Centers for Disease Control and Prevention, 2014).
    b) PCR for the diagnosis of RMSF is limited because of its poor sensitivity in detecting R rickettsii DNA in blood specimens (Dantas-Torres, 2007). However, this test is NOT widely available, and in one study reamplification was required in 3 of 4 positive patients, suggesting lack of sensitivity (Sexton, 1994).
    5) LUMBAR PUNCTURE
    a) INDICATIONS: Not indicated routinely but is important to exclude meningeal inflammation in some cases of suspected RMSF or other infectious etiologies, particularly if the patient presents with a predominantly meningitis-like syndrome (Linnemann, 1987).
    6) SEROLOGY
    a) OVERVIEW
    1) Serology has limited usefulness in the diagnosis of RMSF in the acute care setting because of the limited ability of such tests to yield diagnostic results in the first 2 weeks of illness.
    2) Initiation of antibiotic therapy should not await confirmation of the diagnosis.
    3) Most sensitive and specific tests are indirect fluorescent antibody (IFA), and indirect hemagglutination (IHA) tests. Complement fixation, latex agglutination, and microagglutination tests are specific but lack sensitivity. Weil-Felix titer lacks sensitivity and specificity.
    b) ANTIBODY TITER, FLUORESCENT
    1) Immunofluorescence assay (IFA) is the GOLD standard serologic test (Dantas-Torres, 2007). Antibodies to R rickettsii are detectable 7 to 10 day after the onset of illness. The test looks for a 4-fold change in antibody titers using IFA. Ideally, the sample should be collected within the first week of illness and the second test obtained 2 to 4 weeks later (Centers for Disease Control and Prevention, 2014).
    2) FALSE NEGATIVE: Antibody titers are often negative during the first 7 to 10 days of illness, thus serologic tests may produce a false negative result during this period (Centers for Disease Control and Prevention, 2014).
    3) A serum indirect immunofluorescent antibody titer of greater than 1:64 or paired sera demonstrating a 4-fold rise in titer is considered diagnostic (Dantas-Torres, 2007). Sensitivity is 94% and specificity is 100% for RMSF (Walker, 1995).
    c) HEMAGGLUTINATION, INDIRECT
    1) Useful to confirm diagnosis; 96% sensitivity (Walker, 1995).
    d) AGGLUTINATION TEST, RICKETTSIA
    1) FALSE POSITIVE results are common in pregnancy and increase with the duration of pregnancy (first trimester, 4%, third trimester, 12%); must rely on clinical picture to direct therapy during pregnancy (Welch et al, 1991).
    e) WEIL-FELIX TEST
    1) NOT RECOMMENDED: One of the older serological assays which lacks sensitivity and specificity; it is not often used (Dantas-Torres, 2007).
    f) COMPLEMENT FIXATION TEST
    1) NOT RECOMMENDED: Specific but insensitive test; requires acute and convalescent sera. Does not show positive results for 3 to 6 weeks after infection (Walker, 1995). This test is no longer recommended (Walker, 1989).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.6) DISPOSITION/BITE-STING EXPOSURE
    6.3.6.1) ADMISSION CRITERIA/BITE-STING
    A) All patients with RMSF in whom the diagnosis is uncertain or with moderate to severe RMSF should be hospitalized.
    6.3.6.2) HOME CRITERIA/BITE-STING
    A) Patients with early, mild illness may be treated on an outpatient basis with oral antibiotics if they are reliable and close follow-up observation can be arranged.
    B) Family clustering of RMSF has been reported; family members of a patient with suspected RMSF should be warned that they have an increased risk of contracting the disease (Gelfand et al, 1995).
    6.3.6.3) CONSULT CRITERIA/BITE-STING
    A) Consultation with an infectious disease specialist may be helpful, particularly for those patients who have not yet developed a rash. Consultation with a dermatologist to obtain skin biopsy specimen for early pathologic confirmation of diagnosis is indicated as soon as RMSF is suspected.
    6.3.6.4) PATIENT TRANSFER/BITE-STING
    A) Transport is necessary when facilities for intensive care and invasive monitoring of the critically ill patient are not available.
    6.3.6.5) OBSERVATION CRITERIA/BITE-STING
    A) Early, mild illness may be observed if either the patient is unreliable or outpatient follow up is not available.

Monitoring

    A) Early laboratory data only lend nonspecific support to the diagnosis of RMSF. Antibodies to R rickettsii are not detectable until 7 to 10 days after disease onset and should not be relied upon to initiate treatment. Confirmation should be obtained by testing for rickettsial antibody in paired sera.
    B) Monitor ECG, complete blood count, electrolytes, ABGs, creatine kinase, renal and hepatic function. Thrombocytopenia, hyponatremia, elevated aminotransferase levels and depressed or normal leukocyte counts have been reported.
    C) Diagnosis is confirmed by immunofluorescent antibody (IFA) tests or enzyme immunoassay with a 4-fold rise in titer in paired testing or convalescence titer greater than 1:64. Immunofluorescence or immunoenzyme demonstration of R rickettsii in a biopsy specimen of skin or organ tissue is both sensitive (50% to 70%) and specific (100%); however, a rash must be present for the skin biopsy to be useful, and test availability is limited. PCR amplification of rickettsial DNA may be specific for the causative agent but lacks sensitivity and; therefore, has limited utility in the diagnosis of RMSF.
    D) PCR for the diagnosis of RMSF is limited because of its poor sensitivity in detecting R rickettsii DNA in blood specimens.

Range Of Toxicity

Summary

    A) TOXIC DOSE: The mean infectious dose is 23 organisms, but as few as one bacillus of R rickettsii may be sufficient to cause infection. A single tick may cause infection. Risk increases with tick attachment longer than 48 to 72 hours.

Maximum Tolerated Exposure

    A) SUMMARY
    1) The average 50% infection dose (ID) among individuals that have been exposed is 23 organisms; the ID10 and ID20 are 2.16 and 5, respectively. It is estimated that a single organism has a 5% probability of causing infection in an exposed population (Tamrakar & Haas, 2011).
    2) The mechanism of infection via inhalation (potential biologic weapon/terrorism) and a tick bite (intradermal) are the same. Approximately, 6 hours after inhalation exposure, the pathogens enter the vascular system and then spread to the lumen of pulmonary vessels, spleen, and bone marrow. In the case of a tick bite, the saliva contains numerous organisms that enter through the skin and then enter the blood stream through small blood vessels and lymphatics where it can multiply (Tamrakar & Haas, 2011).
    3) One tick may be enough to cause an infection (Fowler, 1993).

Pharmacology Toxicology

Toxicologic Mechanism

    A) Characterized by rickettsial invasion of small blood vessels throughout the body. After the tick injects the organism through the skin, rickettsia invade the cytoplasm of vascular endothelial cells.
    B) Typical RMSF cases then evolve through two phases: vascular damage due directly to rickettsiae, followed by superimposed vascular damage possibly related to immunologic phenomena (Linnemann, 1987) Sessler, 1995).
    C) A study in healthy volunteers participating in an efficacy study of a vaccine for RMSF found that even in the earliest stages of uncomplicated RMSF, when naturally acquired disease remains undiagnosed, there is activation of platelets, coagulation pathways, and the fibrinolytic system (Rao, 1988).
    D) As rickettsiae multiply in small blood vessels in various tissues and organs, endothelial damage leads to cell necrosis and proliferative hypertrophy of the intima, possible necrosis of the media, and mononuclear and plasma cell infiltration of the adventitia.
    E) The resulting diffuse thrombosis and microinfarction cause partial or total occlusion of the vessel lumen, leading to infarction of skin, heart, kidney, adrenal glands, and brain. Necrosis of arteriolar wall leads to rupture with local areas of hemorrhage.
    F) This widespread vasculitis is responsible for such clinical manifestations as rash, increased extravascular fluid space, hypotension, edema, gangrene, and coagulation abnormalities (Linnemann, 1987).
    G) Manifestations of secondary damage in vital organs may include encephalitis and scattered, discrete microinfarcts with CNS involvement, myocardial inflammation and necrosis, focal areas of fatty degeneration in the liver, focal interstitial vascular lesions in the kidneys, and interstitial pneumonitis or ARDS (primary cause of death) (Linnemann, 1987).

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