Rocky Mountain spotted fever and other rickettsial infections

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Rocky Mountain spotted fever and other rickettsial infections

Sean C. McElligott, George G. Kihiczak and Robert A. Schwartz

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

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The Rickettsiae are a family of obligate intracellular Gram-negative bacteria that cause infections with a diverse array of clinical presentations. They may be divided into the spotted fevers, including Rocky Mountain spotted fever, the typhus group, rickettsialpox, Q fever, and erhlichiosis.

Rickettsial spotted fevers

These include African tick bite fever (Rickettsia africae), Astrakhan fever (R. conorii), Flinders Island spotted fever (R. honei), Indian tick typhus (R. conorii), Israeli spotted fever (R. conorii), Japanese spotted fever (R. japonica), Mediterranean spotted fever (R. conorii), Queensland tick typhus (R. australis), Rocky Mountain spotted fever (R. rickettsii), and Siberian tick typhus (R. sibirica).

Rocky Mountain spotted fever

Rocky Mountain spotted fever (RMSF) is caused by R. rickettsia and is endemic to almost all areas of the USA with a high degree of prevalence in North Carolina, Tennessee, and Oklahoma. RMSF is a tick-borne disease. The classic triad seen early on in the course of the disease consists of tick bite, rash, and fever. The characteristic rash is pink macules that appear on the wrists and ankles, become petechial and purpuric, and then progress to the palms, soles, extremities, and trunk, sparing the face. The rash does not appear until the third day and is absent in nearly 10% of patients. Atypical rashes, confined to one region of the body, may be seen. Fever, myalgias, and severe headaches are present in most cases; bilateral calf pain is the most common presenting complaint. Gastrointestinal symptoms such as abdominal pains, diarrhea, nausea, and vomiting occur in nearly half of patients, usually early in the course of the illness. This often leads to misdiagnosis or delay in therapy. Vascular injury to the appendix, gallbladder, and small intestine has been reported, in some cases mimicking acute cholecystitis.

Prognosis is related to the timely diagnosis and initiation of effective treatment.

Prevention is achieved by avoiding areas with ticks. Covering skin with long protective clothing reduces the risk of exposure. Clothing may be impregnated with acaricidal compounds for added protection. Any uncovered skin should be treated with topical insect repellants prior to activities in high-risk areas. Unfortunately, most insect repellants are effective for only short periods and need to be reapplied frequently. Thorough skin examinations should be conducted on a regular basis, at least twice daily in endemic areas, and any ticks removed. The scalp, axillary, and pubic hair requires particularly careful examination. There is currently no effective vaccine, although immunogenic surface protein antigens have been cloned and sequenced.

Management strategy

Doxycycline is the best first-line agent for treating RMSF and other spotted fevers, as shown by extensive research data and clinical experience. In pregnant patients chloramphenicol is the therapy of choice as an alternative to tetracyclines (although serious side effects such as agranulocytosis may occur). Supportive care is also an important component in successful treatment. A high-protein diet, adequate hydration, and continuous monitoring of blood volume are critical. In cases in which renal, pulmonary, or cardiac complications occur, other specialized therapies may be required.

Clinical suspicion of a spotted fever is sufficient to warrant treatment. Serologic confirmation should not delay the initiation of appropriate therapy. Diagnosis is difficult, as the characteristic rash is not a reliable sign of disease and the classic triad is often not evident. The spotted fevers progress rapidly and therefore immediate treatment is required initially (ideally in the first 3 to 4 days). Doxycycline is the medication of choice, administered at a dose of 100 mg twice daily orally in adults. Children under 45.4 kg should receive doxycycline 2.2 mg/kg per dose twice daily orally. The therapeutic benefit provided by doxycycline in the treatment of RMSF is thought to outweigh the potential risk for tooth discoloration in children receiving doxycycline. These oral antibiotics are taken for a minimum of 7 days and are continued until the patient is afebrile for a minimum of 48–72 hours. Within 24 hours of the initiation of treatment a response may be observed. Within the first 36–48 hours considerable clinical improvement is seen, and apyrexia is often achieved by 72 hours. Death occurs at a higher rate in those untreated beyond 5 days of illness onset. Of note, early discontinuation of therapy may result in relapse. RMSF has a case-fatality rate as high as 30% in certain untreated patients. Even with treatment, hospitalization rates of 72% and case-fatality rates of 4% are seen.

Tetracycline (500 mg every 6 hours, maximum dose 2 g) is efficacious but is contraindicated in patients with renal failure, during pregnancy, and in children under 8 years of age. Chloramphenicol (50–75 mg/kg daily, divided into four doses, for 7 days) is the recommended treatment for pregnant women. When using chloramphenicol, close monitoring is prudent due to the limited data on treatment as well as the increased risk of gray baby syndrome in pregnant women and aplastic anemia in children.

In severe cases requiring hospitalization, intravenous doxycycline every 12 hours is the recommended treatment. Supportive measures including fluid maintenance, intravenous hydration, nutritional support, and oxygen supplementation are essential in severe cases. In some cases anuria, oliguria, or renal failure may necessitate hemodialysis.

Specific investigations

Diagnosis is most often based on clinical presentation, as patients may have a history of a tick bite after spending time in an endemic area. Clinical suspicion requires the rapid initiation of therapy even when confirmatory tests are pending, as mortality increases when treatment is delayed. Direct immunofluorescence or immunoperoxidase staining of skin biopsy specimens is a relatively quick way of diagnosing RMSF. Serologic tests, including indirect immunofluorescence, latex agglutination, and enzyme immunoassay, that detect anti-rickettsial antibodies are available. However, these tests usually yield negative readings in the critical first days of the disease as antibodies are not detectable until 7 to 10 days after the onset of the illness. Confirmation of the diagnosis using acute- and convalescent-phase serum samples is possible with these tests. The indirect hemagglutination antibody and immunofluorescent antibody tests are most useful because of their high sensitivity and specificity. The immunofluorescent test is especially useful because of its capacity to assess IgG and IgM levels.

A highly specific and sensitive polymerase chain reaction (PCR) assay for the detection of spotted fever and typhus group of Rickettsiae was recently developed to provide rapid confirmation of the diagnosis when rickettsial loads are low.

A complete blood count and liver function tests should be obtained. Most patients will have some degree of anemia or leukopenia, though in some cases the white blood count may be elevated. Thrombocytopenia may occur in severe cases. Hepatic enzymes, bilirubin, and lactate dehydrogenase are often elevated.

Blood cultures or skin biopsy specimen may be used to confirm the diagnosis, but are not helpful in the initial diagnosis of spotted fevers owing to the length of time they require for results.

Rickettsiae do not stain well with Gram stain, and instead should be stained with Giemsa, Machiavello or Castaneda stains.

First-line therapies

image Doxycycline or tetracycline C
image Chloramphenicol (in pregnant patients) D

Rickettsia rickettsii is sensitive to tetracyclines, chloramphenicol, and rifampin. Doxycycline is the therapy of choice and should be administered early in the illness. Adults and children weighing 45 kg or more should take 100 doses of doxycycline at 12-hour intervals either orally or intravenously. Children weighing less than 45.4 kg should receive 2.2 mg/kg body weight per dose administered twice daily.

Rocky Mountain spotted fever: a clinician’s dilemma.

Masters EJ, Olson GS, Weiner SJ, Paddock CD. Arch Intern Med 2003; 163: 769–74.

The outcome of RMSF is directly related to the speed of treatment initiation. Failure to diagnose and treat stems from the follow characteristics at presentation: (1) absence of a skin rash; (2) absence of a tick bite by history; (3) inappropriate geographic and seasonal exclusion; (4) misdiagnosis due to non-specific symptoms; and (5) failure to treat with appropriate doses of doxycycline. The mortality rate reported was 6.5% for patients treated within 5 days of disease onset and 22.9% for those treated 5 days or more after onset (Therapeutic delay and mortality in cases of Rocky Mountain spotted fever. Kirkland KB, Wilkinson WE, Sexton, DJ, Clin Infect Dis 1995; 20: 1118–21).

Second-line therapies

image Chloramphenicol (in non-pregnant patients) C
image Azithromycin B
image Clarithromycin B
image Ciprofloxacin B

Analysis of risk factors for fatal Rocky Mountain spotted fever: evidence for superiority of tetracyclines for therapy.

Holman RC, Paddock CD, Curns AT, Krebs JW, McQuiston JH, Childs JE. J Infect Dis 2001; 184: 1437–44.

A study of RMSF derived from reports received by the Centers for Disease Control and Prevention by state health departments and private physicians consisting of 5600 confirmed and probable cases occurring from 1981 to 1998. Age, race, and time of treatment with respect to onset of illness were used to stratify the patient population. Four treatments groups were studied: tetracycline without chloramphenicol; chloramphenicol without tetracycline; chloramphenicol with tetracycline; and neither chloramphenicol nor tetracycline. Patients with RMSF who did not receive tetracycline had an increased risk of death.

Typhus group

Management strategy

Epidemic typhus

Epidemic typhus is caused by R. prowazekii, transmitted via the body louse. Recommended treatment is oral doxycycline (200 mg daily for 5 days) or intravenously in more severe cases. Chloramphenicol is effective also. Prevention is crucial and can be achieved through bathing, washing clothes, and the use of insecticides.

First-line therapies

Epidemic typhus  
image Doxycycline A
image Chloramphenicol D
Murine typhus  
image Doxycycline A
image Chloramphenicol D
Scrub typhus  
image Doxycycline A
image Azithromycin A
image Rifampicin (rifampin) A
image Chloramphenicol D

Q fever

Q fever is caused by Coxiella burnetti. Transmission to humans occurs via aerosolized urine, feces, or birth products of ungulates (hoofed mammals).

Management strategy

Acute Q fever

The primary treatment of choice in adults is doxycycline (100 mg orally twice a day for 14 days). Moxifloxacin (400 mg daily for 14 days) may be used as an alternative. In vitro the disease has been susceptible to fluoroquinolones, chloramphenicol, rifampin, and trimethoprim–sulfamethoxazole.

Specific investigations

Acute Q fever

Chronic Q fever

First-line therapies

Acute Q fever  
image β-Lactams B
image Doxycycline B
image Macrolides B
image Quinolones B
Chronic Q fever  
image Quinolone and doxycycline B
image Doxycycline and hydroxychloroquine B

Ehrlichiosis

The ehrlichioses consists of two tick-borne diseases: human monocytic ehrlichiosis due to Ehrlichia chaffeensis (most common form in United States), and human granulocytic erhlichiosis due to E. equi. Both are found in mammalian reservoirs (deer, dogs, horses) and are transmitted via ticks. Commonly encountered symptoms include fever, headaches, lack of appetite, which, if inappropriately treated, can progress to life-threatening symptoms such as respiratory failure, and meningoencephalitis.

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