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April 2007 An Evidence-Based Approach To The Diagnosis And Treatment Of Rocky Mountain Spotted Fever In The Emergency Department Volume 9, Number 4 Authors Benjamin P. Davis, MD Attending Physician, Carle Foundation Hospital, Urbana IL; Clinical Instructor, College of Medicine, University of Illinois at Urbana-Champaign, Champaign, IL John A. Marx, MD Chair, Department of Emergency Medicine, Carolinas Medical Center; Adjunct Professor of Emergency Medicine, University of North Carolina at Chapel Hill, Charlotte, NC A 21-year-old man presents with headache, fever, myalgias, and vomiting for two days. You think to yourself that it is unusual for a young man to have the flu in the summertime. Being the ever-astute clinician, you discover that he has not traveled outside of the country, but did spend last weekend camping with some friends in a nearby state park. You think that he probably didn’t get much sleep on the trip and caught a virus. He feels much better after a liter of normal saline so you discharge him home with NSAIDs and instructions to drink plenty of fluids. One week later, as you go to sign out, your partner says,”Remember that guy with the viral illness that you saw last week…” F ever. Muscles aches. Vomiting. Headache. Each is a nonspecific complaint that may imply a diagnosis in isolation, but taken together often lead to the general diagnosis of viral syndrome. Only rarely does a constellation of nonspecific complaints lead to a specific diagnosis. Rocky Mountain Spotted Fever (RMSF) is a disease with protean manifestations. The classic presentation is a patient complaining of fever, headache, myalgias, nausea, and a petechial rash involving the palms and soles. Although RMSF, among the tick-borne illnesses, has taken a back seat to Lyme disease in terms of national attention due to its relatively low prevalence, it has a high incidence of mortality and substantive associated morbidity. Failure to diagnose RMSF in a timely manner is the primary explanation for this. RMSF must be in the front of the Editor-in-Chief Andy Jagoda, MD, FACEP, Professor and Vice-Chair of Academic Affairs, Department of Emergency Medicine; Mount Sinai School of Medicine; Medical Director, Mount Sinai Hospital, New York, NY. Associate Editor Health Science Center, New Orleans, LA. Wyatt W. Decker, MD, Chair and Associate Professor of Emergency Medicine, Mayo Clinic College of Medicine, Rochester, MN. Francis M. Fesmire, MD, FACEP, Director, Heart-Stroke Center, Erlanger Medical Center; Assistant Professor, UT College of Medicine, Chattanooga, TN. HSC/Jacksonville, FL. Gregory L. Henry, MD, FACEP, CEO, Medical Practice Risk Assessment, Inc; Clinical Professor of Emergency Medicine, University of Michigan, Ann Arbor. Keith A. Marill, MD, Instructor, Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA. John M. Howell, MD, FACEP, Clinical Charles V. Pollack, Jr, MA, MD, FACEP, Professor of Emergency Medicine, Michael J. Gerardi, MD, FAAP, FACEP, Professor and Chair, Department of George Washington University, Director, Pediatric Emergency Emergency Medicine, Pennsylvania Washington, DC; Director of Academic Medicine, Children’s Medical Center, Hospital, University of Pennsylvania Affairs, Best Practices, Inc, Inova Atlantic Health System; Department of Health System, Philadelphia, PA. Fairfax Hospital, Falls Church, VA. Emergency Medicine, Morristown Memorial Hospital, NJ. Michael S. Radeos, MD, MPH, Editorial Board Assistant Professor of Emergency Michael A. Gibbs, MD, FACEP, Chief, Medicine, Lincoln Health Center, William J. Brady, MD, Associate Department of Emergency Medicine, Bronx, NY. Professor and Vice Chair, Department Maine Medical Center, Portland, ME. of Emergency Medicine, University of Robert L. Rogers, MD, FAAEM, Steven A. Godwin, MD, FACEP, Virginia, Charlottesville, VA. Assistant Professor and Residency Assistant Professor and Emergency Director, Combined EM/IM Program, Peter DeBlieux, MD Medicine Residency Director, University of Maryland, Baltimore, Professor of Clinical Medicine, LSU University of Florida MD. Peer Reviewers Peter DeBlieux, MD Professor of Clinical Medicine, LSU Health Science Center, New Orleans, LA. Denis Pauze, MD, FACEP Inova Faifax Hospital, Falls Church, Virginia; Clinical Assistant Professor of Emergency Medicine, The George Washington University School of Medicine, Washington, DC CME Objectives Upon completion of this article, you should be able to: 1. Understand the epidemiologic and historical features of RMSF. 2. Understand the utility and limitations of diagnostic testing for RMSF. 3. Describe the clinical features of RMSF. 4. Discuss the appropriate treatment for patients with suspected RMSF. Date of original release: April 1, 2007 Date of most recent review: March 1, 2007 See “Physician CME Information” on back page. Alfred Sacchetti, MD, FACEP, Assistant Clinical Professor, Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA. Corey M. Slovis, MD, FACP, FACEP, Professor and Chair, Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN. Jenny Walker, MD, MPH, MSW, Assistant Professor; Division Chief, Family Medicine, Department of Community and Preventive Medicine, Mount Sinai Medical Center, New York, NY. Ron M. Walls, MD, Professor and Chair, Department of Emergency Medicine, Brigham & Women’s Hospital, Boston, MA. Research Editors Nicholas Genes, MD, PhD, Mount Sinai Emergency Medicine Residency. Beth Wicklund, MD, Regions Hospital Emergency Medicine Residency, EMRA Representative. International Editors Valerio Gai, MD, Senior Editor, Professor and Chair, Dept of EM, University of Turin, Italy. Peter Cameron, MD, Chair, Emergency Medicine, Monash University; Alfred Hospital, Melbourne, Australia. Amin Antoine Kazzi, MD, FAAEM, Associate Professor and Vice Chair, Department of Emergency Medicine, University of California, Irvine; American University, Beirut, Lebanon. Hugo Peralta, MD, Chair of Emergency Services, Hospital Italiano, Buenos Aires, Argentina. Maarten Simons, MD, PhD, Emergency Medicine Residency Director, OLVG Hospital, Amsterdam, The Netherlands. Commercial Support: Emergency Medicine Practice does not accept any commercial support. All faculty participating in this activity report no significant financial interest or other relationship with the manfacturer(s) of any commercial product(s) discussed in this educational presentation. minds of clinicians, even those who do not practice in endemic regions. This issue of Emergency Medicine Practice will provide a systematic approach to the diagnosis and treatment of RMSF. zoan pathogen as the infecting microorganism and demonstrated that the wood tick (Dermacentor andersoni) was the vector for the disease.3,4 The reported annual incidence of RMSF in the United States is extremely low, approximately 2.2 cases per million. This number appears to be increasing. In 2004, 1514 cases of RMSF were reported, compared to only 365 cases in 1998.5 However, the reported numbers may still be artificially low for several reasons. First, most confirmed diagnoses are based on serologic tests that are typically not positive until the second or third week of the disease and may never be positive in patients treated early in the course of disease.6,7 Second, several patients may have mild disease and recover without proper diagnosis or treatment, as demonstrated by a recent study by Marshall which showed that 12% of a random sample of children were found positive for serum antibodies reactive to Rickettsia rickettsii.8 Third, cases may be drastically underreported. Paddock et al compared cases reported to the CDC on standard forms to national mortality statistics from death certificates. They found that an estimated 400 cases of fatal RMSF went unreported from 1983 - 1998. The nature of passive surveillance makes it difficult to improve the quantity and quality of national reported RMSF data.9,10 Critical Appraisal Of The Literature RMSF has been referenced in the medical literature for over 100 years. Unfortunately, there is still a paucity of robust studies to assist clinical decision making. Most reports are retrospective analyses. While some of these contain large patient cohorts, such as those from the Centers for Disease Control and Prevention (CDC), there are very few high grade evidence-based studies. While the National Guideline Clearinghouse provides a link to Infectious Disease Society of America recommendations for the diagnosis and treatment of Lyme Disease, no such guidelines exist for RMSF in adults. The American Academy of Pediatric Committee on Infectious Diseases, however, does publish guidelines for the treatment of RMSF in children.1 A search of the Cochrane Database of Systematic Reviews, Cochrane Central Register of Clinical Trials, ACP Journal Club, and Database of Abstracts of Reviews and Effects revealed only three articles relevant to RMSF and these are of marginal significance to emergency practitioners. This paper will attempt to tease out reasonably evidence-based recommendations from groundless and traditional dogma. We will endeavor to provide recommendations based upon the strongest evidence, and to dispel any myths that may remain. Table 1. Incidence of RMSF Epidemiology RMSF was first described by physicians during the 1880s in the Snake River Valley of Idaho. The disease was called the “black measles” in reference to the petechial rash seen later in the course of the disease. In the nearby Bitter Root Valley in Western Montana, Native Americans told stories of the “evil spirits” that occupied the Bitter Root Valley during the spring.2 In the early 1900s, much controversy surrounded the etiological agent of RMSF. Several scientists believed that ticks were a possible vector and protozoa were the infecting agent. Others saw no evidence of protozoa, and concluded that ticks could not be the vector. In 1909, Howard Ricketts, a microbiologist at the University of Chicago, published a series of landmark epidemiologic studies that elucidated a non-proto- Emergency Medicine Practice© Incidence of RMSF in the US since 1920 from Dumler “Rocky Mountain Spotted Fever—Changing Ecology and Persisting Virulence” NEJM 2005. 353;6:551-553] Geography plays a major role in the epidemiology of RMSF. Although originally described in the Rocky Mountains, the name Rocky Mountain Spotted Fever is something of a misnomer and a potential source of confusion. The majority of reported cases actually occur in the Southeast and Midwest, while the disease is only sporadically reported in the Rocky Mountain region. Furthermore, RMSF has been reported in all the contiguous United States, with the 2 April 2007 • EBMedicine.net exception of Maine and Vermont.7 North Carolina and Oklahoma consistently have the highest reported incidence.11 In one surveillance report from two highly endemic counties in North Carolina, the mean annual incidence was nearly 20 cases per 100,000.12 The disease also occurs in South and Central America, where it goes largely unrecognized. Table 2. Seasonal Variation Figure 1. Incidence Within US reported a case of a man from Tennessee who died of RMSF. After his funeral, his wife, brother, sister, and son all developed symptoms compatible with RMSF and were seropositive for the disease.17 Similarly, in 2003, the CDC reported three separate fatal cases of RMSF in which family members developed similar illness.18 The phenomenon of familial clustering is probably the result of shared exposure to R. rickettsii. Some epidemiologists have proposed that there may be “foci of disease hyperendemicity” (areas in which R. rickettsii-infected ticks are especially prevalent) which are responsible for the clusters.17 Around the turn of the 20th Century, R. rickettsii killed up to 75% of infected patients.5 Case fatality ratios for RMSF in the pre-antibiotic era of the 1920s and 30s ranged from 18 - 28%.19 This number was cut in half by the discovery of tetracycline and chloramphenicol in the late 1940s. Despite the improved use of antibiotics and improvements in supportive care, approximately 5% of infected individuals will die from the disease and many more suffer from its sequelae.20,21 Exposure to the outdoors, particularly woody areas, increases the risk of contracting RMSF. In one study, 95 of 96 subjects reported exposure to woody areas in the 14 days prior to symptom onset.12 Although RMSF may occur at any age, historically, children ages five to nine have the highest incidence of disease, presumably because they are more likely to be playing outdoors. This may be changing, however, as surveillance data from 2003 demonstrated that patients in the 40 - 65 year age range had the highest incidence of disease.13 One report demonstrated that men greater than 60 years of age have a high risk of disease as well. The case fatality rate is highest for those greater than age 40.14 Persons ages 20 - 29 have the lowest incidence. Seasonal variation is important in the epidemiology of RMSF. Not surprisingly, seasonal peaks in RMSF occur when people are more likely to be in the outdoors, i.e., the summer months. This also corresponds to the period of highest tick activity. Ticks are usually dormant during the winter, unless they are disturbed.15 According to CDC data from 1981 to 1992, 90% of confirmed cases had symptom onset between April 1 and September 30.11 Wilfert et al corroborated these findings.16 However, sporadic cases are still reported throughout the year, even in colder climates.11 Rocky Mountain Spotted Fever is not contagious and is generally a sporadic illness. However, familial clustering of RMSF has been reported. Jones et al EBMedicine.net • April 2007 Etiology And Pathophysiology R. rickettsii are small, obligate intracellular bacteria, and are the etiologic agents of RMSF. The species has evolved through a symbiotic relationship with ticks. The primary tick vectors are the Rocky Mountain wood tick (Dermacentor andersonii) in the western U.S. and the American dog tick (D. variabilis) in the Midwestern and Eastern U.S. However, a recent investigation reported the presence of RMSF in Arizona, with the brown dog tick (Rhipicephalus sanguineus) as the vector.22 Ticks infected with R. rickettsii transmit the infection to humans through salivary secretions during a blood meal. The ticks also transmit the infection to their progeny, maintaining R. rickettsii in nature.23 Interestingly, more than 90% of infected tick larvae die 3 Emergency Medicine Practice© from the infection prior to becoming adults.24 Some studies estimate that less than 1% of ticks carry pathogenic R. rickettsii, even in endemic areas.17 Because the tick bite is painless, many persons never know that a tick was attached. After at least 6 - 10 hours of attachment, rickettsiae begin to be injected from the salivary glands. In some cases, transmission may not occur for 24 hours or longer.25 According to unpublished case reports, humans can also be infected when removing ticks from another person or from an animal.26 Dogs are at risk for clinical infection with RMSF, and concurrent rickettsial infection in a dog and its owner has been reported.27 Other small mammals, and even birds, may also be infected with rickettsiae.23 Once a human is infected, the rickettsiae initiate a devastating pathogenic sequence; the hallmark is a vasculitis that may occur anywhere in the body. The bacteria spread via the lymphatics into the circulation. Once in the circulation, they establish numerous foci of infection within the vascular endothelium of small vessels. This leads to endothelial cell injury and a profound inflammatory response.28 The net result is increased vascular permeability causing edema and hypovolemia. In addition, this setting promotes a hypercoagulable state, which may play a role in the end organ damage that may include the skin, CNS, myocardium, lungs, liver, and kidneys.29,30 The mean incubation period from tick bite to symptoms is seven days.31 gitis. Some authors have argued that any patient hospitalized for suspected RMSF should also receive coverage for meningococcal meningitis until the diagnosis of RMSF is secure and that of meningococcal disease is eliminated.35,36,37 Gastroenteritis Nausea and vomiting may be present in more than 50% of RMSF patients. Diarrhea may be present in 20 - 30%.31,32 Without careful history taking, it is easy to dismiss a patient with RMSF as having gastroenteritis. One should approach the diagnosis of gastroenteritis in children with extreme caution, as the enteroviral season overlaps with that of RMSF.38 Acute Abdomen Abdominal pain may be a significant feature of RMSF. Davis and Bradford reported two patients with severe RLQ pain who had appendectomies with pathologically normal appendices and were later diagnosed with RMSF; one of whom died postoperatively.39 Walker et al reported two similar cases of elderly patients with fever and abdominal pain, one of whom underwent a cholecystectomy and one of whom underwent appendectomy. Pathology demonstrated infection with R. rickettsii in the respective organs.40 Toxic Shock Syndrome Toxic shock syndrome (TSS) also overlaps significantly with RMSF. The defining characteristics of TSS are fever, rash, hypotension, and multisystem involvement. The classic rash for TSS is diffuse, blanching, macular erythroderma and may involve desquamation of the palms and soles. As with RMSF, the rash may also be faint and not noticed on initial exam.41 Barson reported a case of confluent macular rash in the setting of headache and fever that was ultimately diagnosed clinically with RMSF.42 Similarly, TSS may affect any organ system and cause GI symptoms, myalgias, CNS abnormalities, hepatic, and renal abnormalities. Although hypotension is a requirement for a diagnosis of TSS, it may also be seen in severe RMSF. In a patient who presents with fever, rash, and hypotension, it is prudent for the emergency physician to treat for both toxic shock and severe RMSF until the true etiology is discovered. Differential Diagnosis Given the often nonspecific presentation of patients with RMSF, the differential is vast. The emergency physician should consider life-threatening as well as benign presentations as potential harbingers of RMSF. Meningitis It is difficult, if not impossible, to differentiate bacterial or viral meningitis from RMSF by history and physical exam alone. Fever and headache are the two most prevalent symptoms in RMSF; meningismus can also be present.31,32 Furthermore, the rash of RMSF is classically petechial, as is the rash of meningococcal meningitis. A history of tick bite or recollection that the rash began on the wrists and ankles, spreading to the trunk, palms, and soles may point towards RMSF, though these findings are absent in up to 20% of confirmed RMSF cases.33,34 Emergency physicians should perform a lumbar puncture if there is any clinical suspicion for meninEmergency Medicine Practice© Measles Measles generally occurs during the winter and spring, while RMSF is more common in the summer 4 April 2007 • EBMedicine.net syphilis (VDRL and RPR) are readily available to help rule out this diagnosis. months. The rash of measles typically appears after three to five days of fever, coryza, cough, and conjunctival injection. It is typically maculopapular and coalesces, spreading from the face to the trunk and extremities. Koplik spots are small white spots on the buccal surface of the oropharynx and are pathognomonic for measles. It is important to ask about immunization history and any possible exposure to measles. Nieburg et al reported positive measles antibodies in the sera of 6 of 46 children originally suspected to have RMSF but who, in fact, had measles.43 Allergic Reaction The rash of RMSF may be indistinguishable from a drug reaction. However, urticaria and pruritis are uncommon with RMSF. Some patients will inevitably present after being prescribed antibiotics in the preceding days, such that it is important to keep RMSF in the differential diagnosis. Other Tick-borne Illnesses The signs and symptoms of several other tick-borne illnesses may overlap with RMSF, including ehrlichiosis, anaplasmosis (formerly human granulocytic ehrlichiosis), and Lyme Disease. Headache, myalgias, and fever are particularly nonspecific findings in these disorders. Like RMSF, each of these exhibits a seasonal predisposition for the summer months. Ehrlichiosis and anaplasmosis are increasingly recognized disease entities in the United States. Headache, fever, myalgias, and malaise are the main presenting symptoms of these disorders.44 Rash may be present in children with ehrlichiosis, although it does not follow the typical pattern of RMSF. Adults with ehrlichiosis are unlikely to have a rash.45,46 Some authors have suggested that some cases presumed to be RMSF were, in fact, ehrlichiosis.47 Sexton et al even reported a case of simultaneous infection with rickettsia and ehrlichial agents.48 Fortunately for emergency physicians, these diseases are treated with the same antibiotic as RMSF: doxycycline. Lyme disease is the most common tick-borne disease in the United States. Caused by Borrelia burgdorferi, Lyme disease classically presents with the rash of erythema migrans, an expanding erythematous lesion surrounding the tick bite. The majority of patients present with a solitary lesion, but up to 20% may present with secondary lesions which may raise suspicion for RMSF. Additional symptoms are similar to RMSF and include fatigue, chills, fever, headache, myalgias, and arthralgias.49 Unlike RMSF, untreated Lyme Disease is rarely fatal. Long term morbidity is high; 60% of patients develope arthritis, 10% have a neurologic manifestation (most commonly facial nerve palsy), and approximately 5% develop a cardiac complication (usually AV block).50 Hughes reported an interesting case of RMSF in which the patient presented with an erythematous rash at the site of the tick bite consistent with erythema migrans, but serology suggested that the offending Carbon Monoxide Poisoning CO poisoning is generally a winter malady. However, it is always important to consider in a patient with headache and flu-like symptoms. You must obtain a thorough exposure history, and consider a carboxyhemoglobin level by co-oximetry if there is any doubt. Viral Illness One must consider RMSF in ANY patient presenting with a constellation of symptoms consistent with viral illness. Several viruses may present with a maculopapular rash and similar symptoms to RMSF. Enteroviruses, such as coxsackie virus and echovirus, may cause symptoms which may be impossible to distinguish from RMSF. Human herpes virus 6 infections (roseola infantum) may have a similar presentation to RMSF with two to three days of febrile illness followed by rash. However, the child typically defervesces and symptoms improve soon after appearance of the rash. Parvovirus B19 (erythema infectiosum) may also present with a prodrome of fever and nonspecific symptoms followed by a rash. Kawasaki Disease Kawasaki Disease may be confused with RMSF, particularly because of a rash and changes in the extremities. However, several of the classic criteria for Kawasaki Disease, such as cracked or fissured lips, conjunctivitis, and cervical lymphadenopathy, are not common with RMSF. Nonetheless, both diseases are diagnosed clinically and should not be excluded prematurely. Syphilis Secondary syphilis should be considered in the differential of any rash that involves the palms and soles. Like RMSF, symptoms of secondary syphilis may be nonspecific. Fortunately, blood tests for EBMedicine.net • April 2007 5 Emergency Medicine Practice© agent was R. rickettsii.51 Babesiosis is another emerging tick borne illness. Like Lyme disease, babesiosis is endemic to the northeastern United States; it is transmitted by the Ixodes tick. Babesiosis usually presents as a nonspecific flu-like illness. Unlike RMSF, rash is extremely uncommon in babesiosis.52 A final consideration in the patient with suspected RMSF and neurological findings is tick paralysis. Tick paralysis typically presents with neurologic symptoms as a result of a neurotoxin released by an attached tick. These symptoms include flaccid paralysis and ataxia, although ataxia may be seen in isolation. Although Dermacentor species are known to secrete the toxin responsible for this disease, it is a completely separate disease from RMSF. Unlike RMSF, tick paralysis is treated not with antibiotics, but by removing the tick. Symptoms will typically resolve within 48 hours of tick removal. Any patient presenting with suspected RMSF and neurologic findings should be thoroughly searched for the continued presence of a tick.53 Prehospital Care Prehospital care of the patient with suspected RMSF is primarily supportive. In stable patients with a febrile illness and rash, IV access may not be necessary. In contrast, patients may present with respiratory compromise, hypotension, or even cardiac arrest.54 In these situations, EPs should pay careful attention to the ABCs, and initiate ACLS protocols if indicated. Because ill patients with petechial rash may in fact have meningococcal disease, it is imperative to observe universal precautions in the provision of care to these patients.55 If a tick is present, it should be removed promptly. Timely removal of the tick may limit infectivity..26 There are several anecdotal reports of prehospital providers responding to calls for “emergent” tick removal. There is no evidence that prophylactic treatment of an asymptomatic tick bite victim is helpful in preventing RMSF. Some experts suggest that prophylactic treatment may prolong the incubation period. However, practical circumstances in the backcountry setting, such as long distance from a health care facility, may require prophylaxis rather than waiting for symptoms to develop. Table 3. Differential Features of Common Tickborne Infections* Clinical/Laboratory Finding Symptom Headache Meningismus Abdominal pain Myalgias Signs Temperature >38.9°C (>102°F) Relative bradycardia Ankle/wrist rash Periorbital edema Conjunctival suffusion Edema of dorsum of the hands/feet Calf tenderness RMSF HME/ HGE Lyme Disease Babesiosis + + + + + + + + + + + - + + + + + + + - - - + - - - ED Evaluation Initial Assessment There are several important considerations when a patient with a syndrome consistent with RMSF presents to the ED. First and foremost, the ABCs must be addressed. Because of multisystem involvement, RMSF patients may present in extremis and should be managed with airway measures including intubation, aggressive intravenous fluids, and careful monitoring. In these acutely ill patients, meningococcal disease will often be a consideration and universal precautions and isolation should be considered. Triage nurses must be careful to not be dismissive of a febrile illness with a rash. Abnormal laboratory finding Leukocytosis + Anemia + Thrombocytopenia + + + + + + ÇAST/ALT + ÇLDH + WBC inclusions + (morulae) RBC inclusions + (Maltese crosses) Confirmation ÇlgM ÇlgM ÇlgM Strained diagnostic test serology serology serology peripheral smear History In an emergency department evaluation of possible RMSF, the greatest challenge is first considering the diagnosis. In a waiting room full of patients with headaches and vague complaints or children with a suspected summer virus, looking for RMSF may seem akin to searching for a needle in a haystack. Knowing the suggestive history and the frequency of physical findings is essential. In a survey by Abreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; HGE, human granulocytic ehrlichiosis; HME, human monocytic ehrlichiosis; LDH, lactate dehydrogenase; RBC, red blood cell; RMSF, Rocky Mountain Spotted Fever; WBC, white blood cell; +, usually present; -, may be present; Ç, increased levels. * Table adapted from Woodward and Cunha and Cunha. Emergency Medicine Practice© 6 April 2007 • EBMedicine.net O’Reilly et al assessing physician knowledge of RMSF, less than 50% of physicians surveyed knew that most patients with RMSF do not present with the classic constellation of tick bite, fever, and rash.56 When taking a history, several key elements can help to keep RMSF in the differential. should remain in the minds of practitioners in all parts of the country. When did symptoms begin? Traditional dogma is that RMSF has an abrupt onset of symptoms. However, up to one-third of patients will describe a gradual onset.31 If a definite tick bite or exposure took place, symptoms usually begin within seven days, although the incubation period may range from 2 to 14 days.25 The incubation period tends to be shorter in those with more severe disease.59 Is there a history of tick bite or tick exposure? Every patient presenting with a febrile illness should be asked about recent tick bite. If there has not been known tick bite, inquire about occupational or recreational exposure to ticks. Young children often do not give a thorough history. If the weather is nice, assume that they have been playing outside and have been exposed to ticks. Ticks may also be found inside the home, particularly on dogs and other pets.31 Unfortunately, many patients will not report a history of tick bite. There are several possible reasons for this: ticks are very small, they attach in places on the body that are difficult to observe, and they usually inflict a painless bite.35 In a CDC report from 1981 to 1992, only 66% of over 4000 confirmed cases of RMSF reported tick attachment in the 14 days prior to illness.11 In a review by Kirk et al, only 56% confirmed cases reported tick bite.32 In a retrospective study by Helmick et al, 80% of confirmed cases reported tick bite or attachment. They compared those 158 patients with 31 persons without tick exposure. Patients without a history of tick exposure had significant delays in diagnosis and prolonged hospitalization.31 Physical Constitutional signs and symptoms As the name Rocky Mountain Spotted Fever implies, fever is a nearly ubiquitous symptom in RMSF. Approximately 94 - 100% of patients will experience a fever at some time in their illness.11,32,33 Fever is reported by 73% during the first three days of illness. Similarly, headache is found in 60 - 80% of cases. The reported severity of headache varies among patients, though more reported mild to moderate pain than severe. The symptoms at presentation are most commonly fever, headache, or both.31 Skin Findings The rash of RMSF is classically described as blanching erythematous macules, beginning on the ankles and wrists, eventually including involvement of the palms and soles, and spreading rapidly to the trunk and face. The rash is believed to result from the diffuse vasculitis and is usually observed two to five days after symptom onset. The rash then becomes petechial over days six to nine.60,61 Although these are the most characteristic findings in RMSF, the rash may occur in myriad ways, or be completely absent, or the patient may present prior to developing the rash. National surveillance studies indicate that up to 20% of confirmed cases may never have a rash during the course of their illness.11 Sexton and Corey reported that 10% of 90 cases of RMSF had no rash or had fleeting rash. They urge clinicians to beware of the “wolf in sheep’s clothing.”33 In a retrospective cohort study, Kirkland et al reported only 39% of patients presented with rash. They found that the absence of the typical rash was associated with delays in therapy.57 Still, it is imperative that the emergency physician diligently search for the presence of any rash. A rash appearing after three days of fever should strongly suggest RMSF. Some authors have suggested that the slightly higher case Is the season right for RMSF? Not surprisingly, the majority of tick bites occur in warmer months, when humans venture into the outdoors with greater frequency and ticks are active. While 90% of cases occur between April 1 and September 30, it is imperative that the emergency physician be cognizant of the fact that cases present year round. In Kirkland’s retrospective cohort study, 28% of RMSF cases presented during the “off-season,” though they defined the season as May 1 through July 31.57 Is this an endemic area for RMSF? Dorland’s Medical Dictionary defines endemic as “present or usually present in a population or geographical area at all times.”58 Cases of RMSF have been reported in every state in the continental U.S. except for Vermont and Maine. You must know the prevalence in your local area. However, RMSF EBMedicine.net • April 2007 7 Emergency Medicine Practice© fatality ratio in African-Americans is due to dark skin color causing a delay in the detection of a rash.7 The skin findings of RMSF can also progress beyond the rash. Skin necrosis has been noted to occur, and the literature contains several cases of gangrene. Though limited by small sample size, there do not appear to be any features to distinguish the patients who developed gangrene from other the course of the disease, and 30% will have abdominal pain during the first three days of the disease.31 Febrile patients in whom abdominal pain is the chief complaint present a clinical challenge. RMSF may be misdiagnosed as appendicitis or cholecystitis.39,40 It is unclear if this is secondary to inflammation of the abdominal wall or vasculitic involvement of a specific organ. Similarly, nausea, vomiting, and diarrhea may all occur in 20 - 60% of cases, leading to a misdiagnosis of gastroenteritis.31 Hepatobiliary involvement may occur, ranging from mild elevations in LFTs to frank jaundice.34 Figure 2. RMSF Rash Neurologic Findings Neurologic manifestations of RMSF are numerous. These are generally attributed to the effects of the vasculitis on brain tissue.64 Common findings are headache and meningismus. Seizure may occur in up to 10% of cases.31 Many will present with altered mental status, even progressing to coma. Other common neurologic manifestations include ataxia, cranial nerve findings, peripheral neuropathy, and hearing loss.64 In a retrospective review, neurological involvement was associated with an odds ratio of 8.3 for mortality.65 However, the authors’ definition of neurological involvement was very broad, such that the majority of critical patients would be considered to have “neurological involvement.” Furthermore, this finding was limited by a very large confidence interval (4.6 - 28). Recent case reports have suggested a relation between rickettsial infection and demyelinating diseases, such as Guillain-Barre and Acute Disseminated Encephalomyelitis.66,67 In any patient presenting with suspected RMSF and neurological findings, perform a careful search for any attached ticks. These should be removed promptly to exclude tick paralysis as the etiology of the neurologic symptoms.53 As a result of the neurotoxin released by an attached tick, tick paralysis typically presents with flaccid paralysis, acute ataxia, or a combination. Symptoms improve within hours of tick removal, and usually resolve within 48 hours.68 Dumler JS NEJM 2005 patients with RMSF.62 Musculoskeletal Findings Myalgias are the third most prevalent symptom after fever and headache, occurring in up to 83% of cases.31 Arthralgias were reported by patients in one series, occurring 10% of the time.32 An acute, monoarticular arthritis may also be observed.63 Cardiovascular Findings Clinically obvious rickettsial myocardial involvement is an unusual complication of RMSF. These patients may present with classic signs and symptoms of left ventricular dysfunction, i.e., dyspnea, orthopnea, chest pain, jugular venous distension, and crackles on lung exam. According to one case report, the symptoms may even mimic acute MI.69 Gastrointestinal Findings Abdominal pain may be a prominent finding in RMSF. Up to 50% will have abdominal pain during Emergency Medicine Practice© 8 April 2007 • EBMedicine.net Cardiac involvement may not be readily apparent on examining the patient with suspected RMSF. In a classic pathological study, Bradford described 16 children who died of RMSF; all had some evidence of myocardial involvement.70 However, because these patients had widespread multisystem involvement, it is difficult to determine the significance of these findings. In a small study, Feltes et al performed echocardiograms on nine children admitted with a diagnosis of RMSF. Seven of the nine had varying degrees of left ventricular dysfunction, though not all were symptomatic. When Feltes performed repeat echocardiograms 10 months after resolution of the disease, all patients had regained normal ventricular function.71 In a similar small cohort of children, Marin-Garcia found that nine of thirteen patients have various abnormalities on echocardiogram. In contrast to Feltes’ study, half of these patients had persistent LV dysfunction at five month follow up.72 However, symptoms of left ventricular dysfunction are not commonly observed in the acute setting.73 The long term clinical significance is unknown. Patients with RMSF should be considered at risk for cardiac decompensation. Diagnostic Studies Laboratory Tests Complete Blood Count A CBC with differential is necessary in any patient with moderate to severe RMSF, and may be helpful in the diagnosis. Thrombocytopenia is present in more severe cases, but may be seen in those with mild disease.74 In the majority of cases, the thrombocytopenia is mild to moderate, with typical ranges from 21,000 – 150,000.75 The etiology of thrombocytopenia is not entirely clear. Most experts have postulated that it is due to peripheral platelet aggregation and adherence to Rickettsia-infected endothelial cells, rather than a direct injury to bone marrow.36,74 However, a recent dog study by Grindem et al found elevated levels of anti-platelet antibodies; this suggests a possible immunological component for thrombocytopenia.76 To the authors’ knowledge, no study has attempted to correlate the appearance of the rash with the platelet count. Classic teaching is that RMSF is associated with a low or normal white blood cell count (WBC). This is largely based upon a single retrospective study of 78 cases by Haynes et al in 1970.77 Unlike the elevated WBC (greater than 10,000) typically seen with infectious processes, RMSF is associated with a low to normal WBC with a predominance of immature forms. Hall and Schwartz reported 27 confirmed cases of RMSF in which 78% had a WBC less than 10,000, 89% had at least 10% bands, and 67% had greater than 20% bands.75 They proposed that using the WBC may help distinguish between RMSF and meningitis, i.e., patients with a WBC greater than 10,000 should be suspected to have meningococcemia while patients with a WBC less than 10,000 are more likely to have RMSF. In their study, the calculated sensitivity would be 78%. The specificity for RMSF would be horrendous given that most “healthy” patients would be expected to have a WBC less than 10,000. One must remember that the WBC is a nonspecific test and its utility in the ED setting is debatable. Pulmonary Findings Pulmonary edema may be observed, and is present in many cases of fatal RMSF. In an autopsy study by Roggli et al, 15 of 16 children with RMSF had histopatholgic changes identified.29 Pulmonary edema is non-cardiogenic and multifactorial, resulting from the diffuse vasculitic process. Renal Findings Severe RMSF is also associated with acute renal failure (ARF). In a retrospective review of 114 patients with RMSF by Conlon et al, nearly 20% developed ARF, defined as a serum creatinine greater than 2 mg/dL. Of these patients, 52% died. The mechanism of renal failure is probably due to intravascular thrombosis, hypotension, and possibly rhabdomyolysis, in addition to direct infection of kidney endothelial cells with R. rickettsii. This study’s findings are undermined by a mortality rate of 14%, which is two to three times higher than is typically reported. Thus, the patients who developed ARF were probably much sicker than the typical patient admitted with RMSF.65 EBMedicine.net • April 2007 Coagulation Studies Abnormalities of coagulation times are unusual in RMSF and are usually clinically insignificant. Fibrinogen and fibrin split product levels should be ordered in patients suspected of disseminated intravascular coagulation, although this is also a rare complication.30 9 Emergency Medicine Practice© Chemistries Blood chemistries are often abnormal in RMSF patients. Hyponatremia is a common finding, occurring in an estimated 20% of cases.36 Reported mean sodium values for two retrospective studies were 124 and 129.32,65 The etiology of hyponatremia is probably multifactorial, although SIADH may play a role in some cases.78 Derangements of liver function tests are often reported with RMSF. This is likely due to rickettsial infection of the hepatic vasculature, as pathology studies have shown microscopic involvement of the liver in up to 75% of cases. 49 Transaminase elevations are generally mild, with mean AST around 200 - 300. However, in Conlon’s retrospective review, higher elevations (greater than 500) were associated with an odds ratio of 2.3 having a fatal outcome. This study is limited by its small size.65 Hyperbilirubinemia is also generally mild, with mean elevation to a level of 1.6 mg/dL, and rarely high enough to cause jaundice.34 BUN and creatinine may also be abnormal. In Conlon’s study creatinine greater than 2 mg/dL was associated with an increased risk of mortality.65 meningitis.”32,64 The CSF in meningococcal disease typically demonstrates a neutrophilic pleocytosis (often greater than 100 wbc/microliter), very low glucose (less than 20 - 30 mg/dL), and gram-negative diplococci on gram stain.80 RMSF Serology Serology is the usual method for confirmation of the diagnosis of RMSF. However, serology is unlikely to be helpful in the emergency department, as serologic tests may take several days to return and are typically not positive until the convalescent phase of illness. The Weil-Felix agglutination test, the original serologic test for R. rickettsii, is insensitive and nonspecific. This test is based on the principle that serum antibodies agglutinate antigens which are shared by Proteus vulgaris, R. rickettsii, and various other Rickettsiae. The sensitivity of Weil-Felix for RMSF is, at best, 70%.81 In addition, the specificity is very low as many healthy persons have the antibodies and will have false positive results. The WeilFelix test should not be ordered for suspected RMSF cases. Newer methods of serological diagnosis include indirect fluorescent antibody (IFA), latex agglutination (LA), complement fixation (CF), enzyme immunoassay (EIA), indirect hemagglutination (IHA), polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay (ELISA).82-85 LA can be performed as a rapid screening test in some labs with a turnaround time of one to two hours.86 Unfortunately, it is severely limited by a sensitivity of only 50 - 70%.82,83 IFA is the most sensitive, specific, and widely used test. Sensitivities for IFA are reported to be approximately 94%.83,84,87 However, the turnaround time for IFA is several days in most centers.86 There are several drawbacks to the use of serological tests in the emergency department. Most importantly, all the tests, including IFA, have very poor sensitivities if drawn during the first one to two weeks of symptoms. Second, it is difficult to distinguish between active or past infection when convalescent titers are positive.88 Finally, the tests require long turnaround times, and are unlikely to affect emergent management. The routine use of serological tests for RMSF is not recommended unless performed in coordination with a consultant who can follow up on the results and the condition of the patient. Table 4. Factors Associated With Need For ICU Admission • Age greater than 40 • Symptoms for five days or more • Neurological involvement • AST greater than 500 • Bilirubin greater than 3.0 • Creatinine greater than 2.0 • Sodium less than 130 Cerebrospinal Fluid Because of the overlap of clinical presentation with bacterial meningitis, lumbar puncture is commonly performed in patients with RMSF. Kirk et al found that 21 of 32 patients with RMSF who underwent lumbar puncture had abnormalities. Unfortunately, the indication for lumbar puncture is not explicitly stated. The most commonly noted was an elevated CSF white blood count (usually less than 100 wbc/microliter) with a predominance of mononuclear cells.32 Massey et al reported a similar CSF pleocytosis.64 The CSF protein is often mildly elevated (100 - 200 mg/dL) and the CSF glucose is usually normal. Gram stain will typically not show any organisms as Rickettsia are not well differentiated by gram stain.79 Thus, the CSF composition in RMSF is usually either negative or compatible with “aseptic Emergency Medicine Practice© 10 April 2007 • EBMedicine.net EBMedicine.net • April 2007 11 Emergency Medicine Practice© Biopsy Skin biopsy in patients with a rash is recommended by some authors.87 Immunohistochemistry staining of tissue samples may be a valuable technique for making an early diagnosis of RMSF, even during the acute phase of the illness.19 Again, this should be performed in coordination with a consulting physician. old male with fever, headache, myalgias, and vomiting in mid-June after being bit by a tick), “possible RMSF” (e.g., 20-year-old with fever and myalgias in August), or “probably not RMSF” (e.g., 35-year-old in mid-December, in non-endemic location, with fever, chills, myalgias). Patients in the “probable” or “possible” groups should be treated with antibiotics. Patients in the “probably not” group can be managed expectantly. A recent report from Chapman and the Tickborne Rickettsial Disease Working Group with the CDC introduced the idea of a “watch and wait” strategy for 24 hours in a patient with an acute febrile illness, who appears well, and has an unrevealing history and physical examination.80 Emergency physicians should be very cautious about using this approach. Perhaps the highest risk for mortality in RMSF is delay in initiating treatment. Multiple studies have reported a much higher risk of death for those patients in whom antibiotics were not started until more than five days of symptoms.11,31,92 Emergency physicians must focus on recognizing the possibility of RMSF, and initiating early antibiotic treatment. Many commonly prescribed antibiotics lack activity against the intracellular rickettsiae. Although multiple drugs may have activity against R. rickettsiae, doxycycline is considered the drug of choice in suspected cases of RMSF. Imaging Chest X-ray Chest x-ray may be useful in suspected RMSF cases with pulmonary symptoms. In a retrospective study of 70 confirmed RMSF cases, McCook et al found that 27% had abnormalities on chest x-ray. Of these abnormalities, more than 50% showed a pulmonary edema pattern.89 This study is limited by small sample size and selection bias. Routine radiographs are not necessary in suspected RMSF cases without objective evidence of pulmonary involvement. Neuroimaging Given the multitude of neurological manifestations of RMSF, one would suspect that imaging of the brain, either by computed tomography (CT) or by magnetic resonance imaging (MRI), may be useful. However, Bonawitz et al reviewed 44 CT scans and six MRIs in confirmed RMSF cases and found abnormalities on only 4 of 44 CTs and four of six MRIs. The abnormalities included infarctions, cerebral edema, meningeal enhancement, and prominent perivascular spaces. All abnormalities were considered “subtle.” In addition, none of the abnormal findings altered clinical treatment.90 Although there is a case report suggesting that MRI may be useful in patients with RMSF, routine neuroimaging in the emergency department is unnecessary. However, in cases where there are significant neurological findings, other diagnoses are under consideration, or both, CT or MRI may provide useful information.91 Doxycycline Doxycycline is the drug of choice for the treatment of RMSF in adults AND children. Historically, chloramphenicol and doxycycline were felt to be equally efficacious in treating RMSF. However, several recent large epidemiologic studies suggest that patients treated only with chloramphenicol have a higher mortality rate than those treated with either doxycycline alone or both drugs concurrently.11,31,92 Holman et al conducted a large analysis (6388 patients) of confirmed cases of RMSF reported to the CDC from 1981 to 1998 and found that chloramphenicol was associated with a three-fold risk of death, compared to treatment with tetracyclines.92 Results were similar for patients from 1981 to 1989, when chloramphenicol use was much more common, and for patients from 1990 to 1998. Similar older studies by Dalton et al and Fishbein et al produced similar results.11,93 Unfortunately, inherent in these study designs is an inability to control for severity of illness. Therefore, sicker patients may be more likely to be treated with chloramphenicol. Treatment The decision of whom to treat for RMSF is a difficult one. Because of the varied symptoms and signs, RMSF is not amenable to the simple algorithms often used by emergency physicians. We recommend a conservative approach to the use of antibiotics for RMSF. Although it is impossible to list the possible combinations of variables that may be present in an individual case, most patients can be divided into these categories: “probable RMSF” (e.g., nine-yearEmergency Medicine Practice© 12 April 2007 • EBMedicine.net break, and many physicians continue to be unaware of the recommendations.56 In one case series, only one of 35 children was given a tetracycline class antibiotic as initial therapy despite the fact that rickettsial infection was a diagnostic consideration.95 There have been no controlled studies on dosage or duration of treatment in RMSF. Recommendations for dosage are 100 mg every 12 hours for adults and 2 - 4 mg/kg/day divided every 12 hours for children.60,87 Duration is typically 7 to 10 days, or until the patient has been afebrile for at least three days.1 Given the dose-dependent relation to side effects, some authors have proposed shorter courses of doxycycline. Yagupsky et al showed efficacy of a much shorter course of doxycycline in a randomized trial of children with rickettsial spotted fever.101 However, there was no blinding in this trial and no placebo used to equalize the two treatment groups. Furthermore, they studied Mediterranean spotted fever, a related but much less severe rickettsial disease caused by Rickettsia conorii. Thus, these results can not be generalized to patients with RMSF. Nevertheless, if close follow up with a primary care physician is assured, it may be reasonable to stop the antibiotic in a low risk patient prior to finishing the full 7 to 10 day course. Moreover, chloramphenicol has a poor safety profile in comparison with doxycycline.94 Previously, the use of tetracyclines was contraindicated in children. In the 2003 edition of Red Book, the American Academy of Pediatrics Committee on Infectious Diseases unequivocally stateed that doxycycline is the drug of choice.1 Tetracycline antibiotics have several adverse effects that have limited their use, including phototoxic eruptions, hypersensitivity reactions, esophagitis, and staining of teeth and fingernails.95,96 Although these adverse reactions rarely occur, the risk of teeth staining is commonly cited as a reason not to prescribe tetracyclines to children. Recent data suggest that the risk of teeth staining may be exaggerated.97,98 In a study by Lochary et al, there was no statistically significant difference in teeth staining between controls and patients less than nine years of age who received doxycycline for treatment of RMSF.98 This study is limited by a very small sample size and its retrospective nature. However, it is the only study of its kind and certainly suggests that doxycycline may not cause significant staining. Data from Grossman and colleagues suggest that the risk of teeth staining is directly proportional to the frequency of tetracycline exposure. In their study of 160 children, a single six-day course of tetracycline caused an exceedingly small amount of teeth darkening. Even those children who received five courses of tetracycline had a difference in shading that was nearly imperceptible. However, children who received eight or more courses were more likely to have moderate darkening. These authors also suggest that, after age five, the risk of staining can be ignored because the “cosmetically important anterior teeth” have already been formed. Moreover, they suggest that doxycycline may cause less staining than other tetracyclines because of less calcium binding.97 This study is well-designed, but lacks any calculation of inter-observer reliability. In addition, the number of patients with tetracycline exposure is hinted at, but never clearly stated. The concern of teeth staining can be further repudiated when one considers the advances of modern cosmetic dentistry. Dentists can now use bleaching to improve mild cases of tetracycline-related teeth staining.99 Ayaslioglu even describes four adults with tooth discoloration secondary to doxycycline in whom abrasive dental cleaning led to complete recovery of original tooth color.100 Despite the evidence, old habits are hard to EBMedicine.net • April 2007 Chloramphenicol Chloramphenicol was the first antibiotic used to treat rickettsial diseases.102 However, due to its safety profile, lack of availability, and evidence that it is less efficacious than RMSF, use of chloramphenicol for RMSF has markedly declined.11,94 Major side effects include aplastic anemia, other hematologic abnormalities, and cardiovascular collapse, known as “gray baby syndrome” in neonates. Aplastic anemia is idiopathic, irreversible, non-dose-related, and occurs in approximately one in 40,000. Other hematologic abnormalities which are dose-related and reversible include isolated thrombocytopenia, anemia, and leucopenia.103 The only current recommended indications for chloramphenicol are in pregnant patients and in those with documented hypersensitivity to doxycycline.87 The recommended dose of chloramphenicol is 50 mg/kg/day divided every six hours.104 Duration is 7 to 10 days. The oral form of chloramphenicol is no longer manufactured in the United States. The parenteral formulation may be administered orally, but its efficacy has not been thoroughly studied.103 13 Emergency Medicine Practice© Corticosteroids The use of steroids in the treatment of RMSF is controversial. Some authors have advocated their use in critically ill patients with widespread vasculitis or encephalitis.112 In a case series from the 1950s, cortisone added to chloramphenicol subjectively improved the clinical course.113 A canine study showed no improvement with prednisolone used in conjunction with doxycycline.114 Until more studies are performed, steroids are not recommended in the routine management of RMSF. Other Antibiotics In addition to tetracyclines and chloramphenicol, other antibiotics, such as fluoroquinolones, macrolides, and rifampin, have shown some promise in the treatment of RMSF. The fluoroquinolones trovafloxacin and enrofloxacin have proven efficacious in treating RMSF in dogs.105,106 In addition, ciprofloxacin is commonly used to treat Mediterranean spotted fever.107 Though R. rickettsii is susceptible to clarithromycin in vitro, azithromycin was less efficacious than doxycycline and trovafloxacin in one dog study.87,106 Finally, in vitro studies suggest that new antimicrobials that target the methods by which rickettsia spread throughout the body may be on the horizon.108 These studies show promise, but until further analyses are performed, there is no clinical role for these antibiotics in the usual treatment of RMSF. Prophylaxis Patients may present to the emergency department requesting antibiotics after tick exposure, even if they are asymptomatic. Some studies have demonstrated success in preventing Lyme Disease when prophylactic treatment is initiated after tick exposure in an endemic area.115,116 In contrast, prophylactic treatment for RMSF of patients sustaining a tick bite is believed to prolong the incubation period without mitigating the disease course.25 Data are scarce, and one guineapig study suggested that single-dose prophylaxis may be useful if given in the first 24 - 48 hours after the tick bite.117 Until further studies are performed, prophylactic treatment is not recommended for patients with tick exposure who are asymptomatic. Antibiotics To Avoid (Sulfonamides) It has been reported for over 50 years that sulfonamides may increase the severity of RMSF.109 Recently, reports have emerged showing similar severe cases of ehrlichiosis treated with sulfonamides.109,110 One theory is that sulfa drugs have an enhancing effect on the multiplication of rickettsia.111 Unfortunately, this concept is largely anecdotal. Poor outcomes in patients treated with sulfonamides may be due to delay in treatment with doxycycline rather than an effect of the sulfonamides. Despite any compelling evidence, use caution when prescribing sulfonamides to any patient with a syndrome consistent with RMSF. Avoidance The best prophylaxis against RMSF is avoidance and early tick removal. Patients should be educated on avoidance strategies. The first and most obvious is keeping away from wooded areas. If time must be spent in wooded areas, thoroughly inspect the head, body, and clothes for ticks after exposure.118,119 Table 5. Recommended Antibiotics For Rocky Mountain Spotted Fever Emergency Medicine Practice© 14 April 2007 • EBMedicine.net Finally, the use of clothing that thoroughly covers the entire body and the use of tick repellents, such as DEET (N,N-diethyl-m-toluamide), will help prevent tick bites.31 severe RMSF may be mistaken for preeclampsia, HELLP syndrome, thrombotic thrombocytopenic purpura (TTP), or sepsis.123 RMSF must also be differentiated from several diseases transmitted from mother to fetus, such as measles, rubella, toxoplasmosis, leptospirosis, enteroviruses, Epstein-Barr virus, and syphilis. It is not known if R. rickettsii can cross the placenta and infect the fetus. In one case of serologically proven RMSF at 28 weeks gestation treated with chloramphenicol, the patient delivered a full-term healthy infant and pathologic evaluation of the placenta revealed no evidence of rickettsial infection.124 As in non-pregnant adults, RMSF is a clinical diagnosis. In addition to a high false negative rate in the early stages of the disease, serologic tests may have a high rate of false-positive results in pregnancy.125 The cause of the high false-positive rate is unclear, but it appears to only occur with latex agglutination and not with indirect fluorescent antibody testing. Treat the pregnant patient with RMSF as soon as the diagnosis is suspected. Tetracyclines are contraindicated during pregnancy in the first and second trimesters due to concerns about limb hypoplasia and growth abnormalities, and in the third trimester due to concerns about hepatotoxicity. However, while tetracyclines as a class are associated with the aforementioned concerns, doxycycline has not been linked to specific problems during pregnancy, and short courses are considered unlikely to cause harm. Nevertheless, at this time, chloramphenicol remains the drug of choice for rickettsial infection during pregnancy.124,126 The side effects are essentially the same as in the adult patient, the most untoward being aplastic anemia. “Gray baby syndrome” has not been reported in newborns of mothers treated for RMSF, though this theoretically could occur.126 Tick Removal At least 6 to 10 hours of tick attachment are required before rickettsiae are transferred to a human host. Furthermore, in the laboratory setting, dormant ticks attached for more than 10 hours have shown a tendency to revert to a more virulent state.120 Therefore, an attached tick should be removed as soon as possible to minimize the risk of infection. Several methods have been proposed for the removal of an attached tick. Some of these include petroleum jelly, burning the tick with a match, fingernail polish, isopropyl alcohol, forceps, and even commercial removal devices. Needham et al compared several of these techniques and found that grasping the tick with curved forceps as close to the skin as possible and pulling straight up achieved the best results.26 Three commercially available tick removal tools compared favorably with forceps in a study by Stewart et al.121 In a systematic review of the topic, Teece confirmed that straight slow pressure was best for removal.122 Table 6. Recommended Procedure For Tick Removal26 1. Use blunt curved forceps or tweezers. 2. Grasp the tick as close to the skin surface as possible and pull upward with steady even pressure. Do not twist or jerk the tick. 3. Do not squeeze or crush the body of the tick as its fluids may also be infective. 4. Do not handle the tick with bare hands. 5.Thoroughly irrigate the bite site after tick removal, and wash with soap and water. 6. Ticks may be safely disposed of by placing in a container of alcohol or flushing them down the toilet. Elderly Elderly patients are much more likely to present with atypical features of RMSF.11,127 In addition, the elderly have a higher risk of other infections, making arrival at the correct diagnosis even more difficult. In patients who are untreated because the diagnosis was missed, mortality is greater than 50%. Maintain a very low threshold for treating patients greater than age 60 who present with a flu-like illness without another definite source. Special Populations Pregnancy The diagnosis and treatment of RMSF in pregnancy is especially difficult. The nonspecific symptoms of early RMSF are easily dismissed as the common ailments that accompany pregnancy. In addition, EBMedicine.net • April 2007 15 Emergency Medicine Practice© related rickettsiae which may share antigens.129,130 However, there is no commercially available vaccine against R. rickettsii at this time. Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD) Fulminant RMSF is more commonly reported in African-American males with G6PD deficiency. Presumably, this is due to more severe hemolysis than usually occurs with Rickettsial infection.59 Since these patients may present with severe illness, or even in extremis, the clinician must remember that African Americans are less likely to have a rash on presentation.7 Bioterrorism Rickettsial pathogens have been used in the past as bioweapons. The USSR and Japan developed Rickettsia prowazekii, the agent of epidemic typhus, as a biologic weapon in the 1930s and 1940s. The danger in rickettsial agents is that they may achieve high infectivity as stable, small particle aerosols. In addition, it would theoretically be simple to confer resistance to tetracyclines and chloramphenicol to any Rickettsiae in a laboratory environment, rendering the antibiotics of choice useless. Furthermore, the low level of immunity and the absence of an effective vaccine make a high attack rate likely after exposure to an infectious aerosol.131 Emergency physicians must be aware of the potential malicious use of rickettsial pathogens. Controversies And Cutting Edge Immunization Vaccination of high risk groups for RMSF, such as children in endemic areas, is not a novel concept. History of infection with R. rickettsii provides strong protective immunity, but studies evaluating killed R. rickettsii vaccines have demonstrated incomplete immunity on reexposure.128 Recently, immunization with rickettsial surface antigens has shown promise as well as the possibility of vaccines using distantly Ten Pitfalls To Avoid in RMSF. Beware of patients with severe abdominal pain and multiple other symptoms. 1. “He had no history of a tick bite, so it must have just been the flu.” Approximately half of confirmed RMSF cases recall a history of tick bite. Patients without such a history are at risk for delays in diagnosis and worse outcomes. 7. “I didn’t want to stain his teeth, so I held off on writing for any antibiotics.” Doxycycline is the drug of choice for treatment of suspected RMSF in children of all ages. There is reasonable evidence that a short course will not cause permanent staining of teeth. 2. “I sent a RMSF test to lab, which came back negative. So I sent the patient home.” RMSF serologies are commonly falsely negative during the first one to two weeks of illness. In addition, there is significant turnaround time associated with the more sensitive tests. 8. “I treated one child with doxycycline, but now his brother is in the ICU with fulminant RMSF. Why are they blaming me?” Familial clustering of RMSF cases has been reported multiple times, probably as a result of natural foci of ticks infected with R. rickettsia. Although RMSF is not a contagious disease, family members need to be warned about the symptoms and the need to seek early treatment. 3. “I considered RMSF, but she didn’t have a rash.” Over half of patients with RMSF present without a rash, and 10 - 20% will never develop a rash during the course of their disease. 4. “Sure I would have thought about Rocky Mountain Spotted Fever, if I lived in Montana or Colorado.” RMSF has been reported in all contiguous United States except Vermont and Maine. Physicians in all states must consider this diagnosis. 9. “I covered him with ceftriaxone for his meningitis, but the internist says his CSF culture was negative and he’s getting worse.” There is significant overlap in symptoms of bacterial meningitis and RMSF. Furthermore, RMSF may show increased WBC on CSF analysis. Thus, it is important to consider treatment with doxycycline for any patient in whom the clinical diagnosis of bacterial meningitis is in doubt. 5. “It’s April, ticks aren’t even around yet.” Cases of RMSF have been reported in every month of the year. The diagnosis should strongly be considered between April 1 and September 30. 10. “I knew that she could have RMSF, but nobody dies from that anymore.” Despite efforts to increase physician education about the appropriate use of doxycycline for RMSF, the mortality rate remains around 5%. 6. “At first I thought it was the flu, but because of the severe right lower quadrant pain, I called the surgeon.” Abdominal pain may be a prominent symptom Emergency Medicine Practice© 16 April 2007 • EBMedicine.net independently. Other clear reasons for admission include altered mental status, immunocompromised state, pain management, inability to tolerate oral antibiotics, and evidence of multi-organ-system involvement. Patients greater than 60 years of age should be strongly considered for admission for observation. All probable cases of RMSF should be reported to the state health department for follow up. Patients who are discharged home must have close follow up within the next two to three days. If a “watch and wait” approach is used, those patients should be reevaluated within the next 24 - 48 hours. The first dose of doxycycline should be given in the emergency department, and arrangements should be made to ensure that patients are compliant with therapy. Patients should receive detailed information regarding the disease, the reason for the antibiotics, and the importance of taking the entire course. The patient’s family members should be educated on the early symptoms of the disease and seek medical care if symptoms occur. Medicolegal Concerns In 1993, a case before the Tennessee Supreme Court brought forth the issue of physicians’ duty to warn third parties (i.e., family members and close contacts) of the risk of contracting RMSF. In Bradshaw v. Daniel, the court ruled that a physician treating a patient with documented or suspected RMSF has a legal duty to “act to protect identifiable third persons from foreseeable risks emanating from a patient’s disease.” Physicians are generally aware of their medical and legal duty to warn and sometimes treat family members of patients with contagious diseases, such as meningococcemia or tuberculosis.132 However, RMSF is not transmitted from one person to the other, and rarely has RMSF been transmitted via blood transfusion or transplantation.133,134 It is counterintuitive that emergency physicians be required to warn family members in close contact. However, because of the Bradshaw Case, it is important that physicians be aware of this statute as it establishes a legal duty to warn third parties about the risk of non-contagious diseases, such as RMSF.135 Summary Disposition Rocky Mountain Spotted Fever remains the leading killer among the tick-borne diseases in the United States. Delay in the diagnosis and failure to initiate treatment with antibiotics lead to significant morbidity and mortality. It is a difficult diagnosis to make as it may present in a variety of ways, in nearly any geographic location, and at any time of year. Many patients will not remember a tick bite, and several will not present with any classic findings. Despite advances in laboratory and radiographic tests, the preliminary diagnosis of RMSF remains clinical. Therapy should be initiated as soon as the diagnosis is considered, with doxycycline as the treatment of choice for both adults and children, and chloram- The decision to admit a patient with suspected RMSF is largely based on “clinical gestalt.” In general, any patient with a probable case of RMSF should strongly be considered for admission. Similarly, patients with more severe symptoms (e.g., intractable vomiting) or abnormal vital signs should be admitted, even if they are considered to “possibly” vs. “probably” have RMSF. However, the majority of cases of possible RMSF can be treated as outpatients with oral doxycycline. The line between a possible and probable case is difficult to draw, and each case must be examined Cost Effective Care Key Points • Diagnostic tests should be used judiciously in patients with suspected RMSF. The main indication for testing is to rule out other potential conditions. For the emergency physician, the diagnosis of RMSF is made on clinical grounds. • The incidence of RMSF peaks between April and September and it primarily occurs in specific regions of the country; however, it can occur at any time of the year. • Treating all possible and probable cases of RMSF with doxycycline will limit morbidity and mortality. A "watch and wait" approach in low-suspicion cases can be used only if close 24-hour follow up is ensured. EBMedicine.net • April 2007 • RMSF is a disease with protean manifestations that compel the emergency physician to consider RMSF in the differential diagnosis. • Helpful and specific findings from the history and physical examination, such as tick bite and rash, are often absent in patients with RMSF. • Despite advances in testing for RMSF, the diagnosis remains a clinical one based on history and physical examination. • Doxycycline is the treatment of choice for RMSF in both adults and children. If RMSF is a possibility, it is appropriate to initiate treatment with doxycycline. 17 Emergency Medicine Practice© phenicol reserved for pregnant patients and those with known hypersensitivity. 6. 7. Case Conclusions The 21-year-old man returned two days after your initial encounter. This time, he was brought by his girlfriend for fever and altered mental status. Your partner was very concerned for meningitis and immediately initiated ceftriaxone prior to performing a lumbar puncture. CSF showed a 65 WBC/microliter, 2 RBC/microliter, protein of 75 mg/deciliter, and glucose of 60 mg/dL. Upon receiving the results and reviewing your note, your partner astutely initiated empiric doxycycline prior to consulting the critical care team for admission. The patient’s mental status improved over the next two days and he was discharged home on oral doxycycline after four days in the hospital. Two weeks later, results from IFA and PCR testing confirmed the diagnosis of Rocky Mountain Spotted Fever. 8. 9. 10. 11. References Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report. To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study, will be included in bold type following the reference, where available. 1. 2. 3. 4. 5. 12. 13. 14. 15. American Academy of Pediatrics. Rocky Mountain Spotted Fever. In: Pickering LK, ed. 2003 Red Book: Report of the Committee on Infectious Disease. Elk Grove Village, IL: American Academy of Pediatrics; 2005:532-533. (Textbook chapter) Heyneman D. The blight of the Bitterroot, the mysterious Rocky Mountain spotted fever, and the significant role of Wilson and Chowning—a commentary. Wilderness and Environmental Medicine 2001;12:118-120. (Commentary) Centers for Disease Control. Rocky Mountain Spotted Fever. 20 May 2005. Available at: http://www.cdc.gov/ncidod/dvrd/rmsf/index.htm. Accessed 3 March 2006. Ricketts, HT. Some Aspects of Rocky Mountain Spotted Fever as Shown by Recent Investigations. Medical Record 1909;76: 843-55. (Review Article, reprinted in Reviews of Infectious Diseases 1991;13:1227-1240.) Dumler JS, Walker DH. Rocky Mountain Spotted Fever—Changing Ecology and Persisting Virulence. N Engl J Med 2005;353:551-553. (Commentary) Emergency Medicine Practice© 16. 17. 18. 19. 20. 21. 18 Kostman JR. Laboratory Diagnosis of Rickettsial Diseases. Clin Dermatol 1996;14:301-306. (Review Article, 58 references) Treadwell TA, Holman RC, Clarke MJ, et al. Rocky Mountain Spotted Fever in the United States, 19931996. Am J Trop Med Hyg 2000;63:21-26. (Retrospective epidemiologic, 2313 cases) Marshall GS, Gordon G, Stout BS, et al. Antibodies Reactive to Rickettsia rickettsii Among Children Living in the Southeast and South Central Regions of the United States. Arch Pediatr Adolesc Med 2003;157:443448. (Retrospective, 300 patients) Paddock CD, Holman RC, Krebs JW, et al. Assessing the Magnitude of Fatal Rocky Mountain Spotted Fever in the United States: Comparison of Two National Data Sources. Am J Trop Med Hyg 2002;67:349-354. (Retrospective epidemiologic ) Childs JE, Paddock CD. Passive Surveillance as an Instrument to Identify Risk Factors for Fatal Rocky Mountain Spotted Fever: Is There More to Learn? Am J Trop Med Hyg 2002;66:450-457. (Review Article) Dalton MJ, Clarke MJ, Holman RC, et al. National Surveillance for Rocky Mountain Spotted Fever, 19811991: Epidemiologic Summary and Evaluation of Risk Factors for Fatal Outcome. Am J Trop Med Hyg 1995;52:405-413. (Retrospecitive epidemiologic, 9223 cases) Wilfert CM, MacCormack JN, Kleeman K. Epidemiology of Rocky Mountain Spotted Fever as Determined by Active Surveillance. J Infect Dis 1984;150:469-479. (Prospective epidemiologic) CDC. Summary of Notifiable Diseases—United States, 2003. MMWR Morbid Mortal Wkly Rep 2005;52. Current Trends Rocky Moutain Spotted Fever—United States, 1990. MMWR Morb Mortal Wkly Rep 1991;40:451453. (Epidemiologic) Sonenshine DE. Zoogeography of the American dog tick, Demacentor variabilis. Recent Adv Acarol 1979;2:123-134. Wilfert CM, MacCormack JN, Kleeman K. Epidemiology of Rocky Mountain Spotted Fever as Determined by Active Surveillance. J Infect Dis 1984;150:469-479. (Prospective epidemiologic) Jones TF, Allen SC, Paddock CD, et al. Family Cluster of Rocky Mountain Spotted Fever. Clin Infect Dis 1999;28:853-859. (Case Series) Fatal Cases of Rocky Mountain Spotted Fever in Family Clusters—Three States, 2003. MMWR Morb Mortal Wkly Rep 2004;53:407-410. (Case Series) Paddock CD, Greer PW, Ferebee TL, et al. Hidden Mortality Attributable to Rocky Mountain Spotted Fever: Immunohistochemical Detection of Fatal, Serologically Unconfirmed Disease. J Infect Dis 1999;179:1469-1478. (Retrospective, 16 patients) Archibald LK, Sexton DJ. Long-Term Sequelae of Rocky Mountain Spotted Fever. Clin Infect Dis 1995;20:1122-1125. (Retrospective, 25 patients) Bergeron JW, Braddom RL, Kaelin DL. Persisting Impairment Following Rocky Mountain Spotted Fever: April 2007 • EBMedicine.net 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. A Case Report. Arch Phys Med Rehabil 1997;78:12771280. (Case Report) Demma LJ, Traeger MS, Nicholson WL, et al. Rocky Moutain Spotted Fever from an Unexpected Tick Vector in Arizona. N Engl J Med 2005;353:587-594. (Retrospective) Azad AF, Beard CF. Rickettsial Pathogens and their Arthropod Vectors. Emerg Infect Dis 1998;4:179-185. (Review Article, 31 references) Niebylski ML, Peacock MG, Schwan TG. Lethal Effect of Rickettsia ricketsii on Its Tick Vector. Appl Environ Microbiol 1999;65:773-778. (Epidemiologic) Thorner AR, Walker DH, Petri WA. Rocky Mountain Spotted Fever. Clin Infect Dis 1998;27:1353-1360. (Review Article, 50 references) Needham GR. Evaluation of Five Popular Methods for Tick Removal. Pediatrics 1985;75:997-1002. Paddock CD, Brenner O, Vaid C, et al. Short Report:Concurrent Rocky Mountain Spotted Fever in A Dog and Its Owner. Am J Trop Med Hyg 2002;66:197199. Walker DH, Valbuena GA, Olano JP. Pathogenic Mechanisms of Diseases Caused by Rickettsia. Ann NY Acad Sci 2003;990:1-11. (Basic Science Review Article, 63 references) Roggli VL, Keener S, Bradford WD et al. Pulmonary Pathology of Rocky Mountain Spotted Fever in Children. Pediatr Pathol 1985;4:47-57. (Case Control) Elghetany MT, Walker DH. Hemostatic Changes in Rocky Mountain Spotted Fever and Mediterranean Spotted Fever. Am J Clin Pathol 1999;112:159-168. (Basic Science Review Article, 91 references) Helmick CG, Bernard KW, D’Angelo LJ. Rocky Mountain Spotted Fever: Clinical, Laboratory, and Epidemiological Features of 262 Cases. J Infect Dis 1984;150:480-488. (Retrospective) Kirk JL, Fine DP, Sexton DJ, et al. Rocky Mountain Spotted Fever A Clinical Review Based on 48 Confirmed Cases, 1943-1986. Medicine 1990;69:35-45. (Retrospective) Sexton DJ, Corey GR. Rocky Mountain “Spotless” and “Almost Spotless” Fever: A Wolf in Sheep’s Clothing. Clin Infect Dis 1992;15:439-448. (Retrospective, 93 patients) Verne GN, Myers BM. Jaundice in Rocky Mountain Spotted Fever. Am J Gastroenterol 1994;89:446-448. (Case Report) Masters EJ, Olson GS, Weiner SJ, et al. Rocky Mountain Spotted Fever—A Clinician’s Dilemma. Arch Intern Med 2003;163:769-773. (Review Article, 73 references) Razzaq S, Schurtze GE. Rocky Mountain Spotted Fever: A Physicians’ Challenge. Pediatr Rev 2005;26:125129. (Review Article) Benson P. Rocky Mountain Spotted Fever, Another Important Cause of Fever and Rash. J Emerg Med 2004;27:415-418. (Letter) Cunha BA. Rocky Mountain Spotted Fever Revisited. Arch Intern Med 2004;164:221-222. (Letter) Davis AE, Bradford WD. Abdominal Pain Resembling EBMedicine.net • April 2007 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 19 Acute Appendicitis in Rocky Mountain Spotted Fever. JAMA 1982;247:2811-2812. (Case Report) Walker DH, Lesesne HR, Varma VA, et al. Rocky Mountain Spotted Fever Mimicking Acute Cholecystitis. Arch Intern Med 1985;145:2194-2196. (Case Report) Stevens DL. Streptococcal Toxic-Shock Syndrome: Spectrum of Disease, Pathogenesis, and New Concepts in Treatment. Emerg Infect Dis 1995;1:69-78. (Review Article) Nieburg PI. D’Angelo LJ, Herrmann KL. Measles in Patients Susptected of Having Rocky Mountain Spotted Fever. JAMA 1980;244:808-809. (Case Control Study) Nieburg PI. D’Angelo LJ, Herrmann KL. Measles in Patients Susptected of Having Rocky Mountain Spotted Fever. JAMA 1980;244:808-809. (Case Control Study) Current Trends Rocky Mountain Spotted Fever and Human Ehrlichiosis—United States, 1989. MMWR Morb Mortal Wkly Rep 1990;39:281-284. (Retrospective, 603 patients) Centers for Disease Control. Human Ehrlichiosis in the United States. 5 April 2000. Available at: http://www.cdc.gov/ncidod/dvrd/ehrlichia/Signs/S igns.htm. Accessed 18 April 2006. Jacobs RF. Human Monocytic Ehrlichiosis: Similar to Rocky Mountain Spotted Fever But Different. Pediatric Annals 2002;31:181-184. (Review article, 24 references) Carpenter CF, Gandhi TK, Kong LK, et al. The Incidence of Ehrlichial and Rickettsial Infection in Patients with Unexplained Fever and Recent History of Tick Bite in Central North Carolina. J Infect Dis 1999;180:900-903. (Prospective, 35 patients) Sexton DJ, Corey GR, Carpenter C, et al. Dual Infection with Ehrlichia chaffeensis and a Spotted Fever Group Rickettsia: A Case Report. Emerg Infect Dis 1998;4:311316. (Case Report) Centers for Disease Control. Lyme Disease Symptoms. 13 October 2005. Available at: http://www.cdc.gov/ncidod/dvbid/lyme/ld_humandisease_symptoms.htm Accessed 20 April 2006. Wormser GP. Early Lyme Disease. N Engl J Med 2006;354:2794-801. (Review article, 51 references) Hughes C. Rocky Mountain “Spotless” Fever with an Erythema Migrans-Like Skin Lesion. Clin Infect Dis 1995;21:1328-1329. (Case Report) Krause PJ. Babesiosis. Med Clin North Am 2002;86:36173. (Review Article) Zhongzeng L, Turner RP. Pediatric Tick Paralysis: Discussion of Two Cases and Literature Review. Pediatr Neurol 2004;31:304-307. (Case Report) Hattwick MAW, Retailliau H, O’Brien RJ, et al. Fatal Rocky Mountain spotted fever. JAMA 1978;240:14991503. (Retrospective, 44 patients) Centers for Disease Control. Meningococcal Disease. 12 October 2005. Available at: http://www.cdc.gov/ncidod/dbmd/diseaseinfo/meningococcal_g.htm Accessed 20 April 2006. Emergency Medicine Practice© 56. O’Reilly M, Paddock C, Elchos B, et al. Physician Knowledge of the Diagnosis and Management of Rocky Mountain Spotted Fever. Ann NY Acad Sci 2003;990:295-301. (Survey, 148 physicians) 57. Kirkland KB, Wilkinson WE, Sexton DJ. Therapeutic Delay and Mortality in Cases of Rocky Mountain Spotted Fever. Clin Infect Dis 1995;20:1118-1121. (Retrospective, 148 patients) 58. Dorland’s Illustrated Medical Dictionary. Philadelphia: W.B. Saunders; 2000:591-592. 59. Walker DH, Hawkins HK, Hudson P. Fulminant Rocky Mountain Spotted Fever. Arch Pathol Lab Med 1983;107:121-125. (Retrospective, 3 patients) 60. Buckingham SC. Rocky Mountain Spotted Fever: A Review for the Pediatrician. Pediatric Annals 2002;31:163-168. (Review article, 24 references) 61. Harrell GT. Rocky Mountain Spotted Fever. Medicine. 1949;28:333-370. (Review article) 62. Kirkland KB, Marcom PK, Sexton DJ, et al. Rocky Mountain Spotted Fever Complicate by Gangrene: Report of Six Cases and Review. Clin Infect Dis 1993;16:629-634. (Case Series, 6 patients) 63. Sundy JS, Allen NB, Sexton DJ. Rocky Mountain Spotted Fever presenting with Acute Monartciular Arthritis. Arthritis Rheum 1996;39:175-176. (Case Report) 64. Massey EW, Thames T, Coffey CE, et al. Neurologic Complications of Rocky Mountain Spotted Fever. South Med J 1985;78:1288-1290. (Retrospective, 16 patients) 65. Conlon PJ, Procop GW, Fowler V, et al. Predictors of Prognosis and Risk of Acute Renal Failure in Patients with Rocky mountain Spotted Fever. Am J Med 1996;101:621-626. (Retrospective, 114 cases) 66. Toerner JG, Kumar PN, Garagusi WF. Guillain-Barre Syndrome Associated with Rocky Mountain Spotted Fever: Case Report and Review. Clin Infect Dis 1996;22:1090-1091. (Case Report) 67. Wei TY, Baumann RJ. Acute Disseminated Encephalomyelitis After Rocky Mountain Spotted Fever. Pediatr Neurol 1999;21:503-505. (Case Report) 68. Bolgiano EB, Sexton J. Tick-Borne Illnesses. In: Marx JA, Hockberger RS, Walls RM, eds. Rosen’s Emergency Medicine: Concepts and Clinical Practice. St. Louis: Mosby; 2002:1879-1902. (Textbook chapter) 69. Doyle A, Bhalla KS, Jones JM, et al. Myocardial Involvement in Rocky Mountain Spotted Fever: A Case Report and Review. Am J Med Sci 2006;332:208-210. (Case Report) 70. Bradford WD, Hackel DB. Myocardial Involvement in Rocky Mountain Spotted Fever. Arch Pathol Lab Med 1978;102:357-9. (Case Series, 16 patients) 71. Feltes TF, Wilcox WD, Feldman WE, et al. M-mode Echocardiographic Abnormalities in Rocky Mountain Spotted Fever. South Med J 1984;77:1130-2. (Case Series, 9 patients) 72. Marin-Garcia J. Left ventricular dysfunction in Rocky Mountain Spotted Fever. Clin Cardiol 1983;6:501-6. 73. Marin-Garcia J, Mirvis DM. Myocardial Disease in Rocky Mountain Spotted Fever: Clinical, Functional, Emergency Medicine Practice© 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 20 and Pathologic Findings. Pediatr Cardiol 1984;5:149-154. (Review Article, 34 references) Woodard BH, Farnham R, Bradford WD. Fatal Rocky Mountain Spotted Fever. Arch Pathol Lab Med 1981;105:452-453. Hall GW, Schwartz RP. White Blood Cell Count and differential in Rocky Mountain Spotted Fever. NC Med J 1979;40:212-214. (Retrospective, 27 patients) Grindem CB, Breitschwerdt EB, Perkins PC, et al. Platelet-associated Immunoglobulin (antiplatelet antibody) in Canine Rocky Mountain Spotted Fever and Ehrlichiosis. J Am Anim Hosp Assoc 1999;35:56-61. Haynes RE. Rocky Mountain Spotted Fever in Children. J Pediatr 1970;76:685. Sexton DJ, Clapp J. Inappropriate antidiuretic hormone secretion. Occurence in a patient with Rocky Mountain Spotted Fever. Arch Intern Med 1977;137:362363. (Case Report) Abedon ST. Eubacterial Classification. 14 May 1998. Available at: http://www.mansfield.ohiostate.edu/~sabedon/biol3018.htm Accessed 22 October 2006. Chapman AS, Bakken JS, Folk SM, et al. Diagnosis and Management of Tickborne Rickettsial Disease: Rocky Mountain Spotted Fever, Ehrlichioses, and Anaplasmosis—United States. MMWR Morbid Mortal Wkly Rep 2006;55(RR04):1-27. Walker DH. Rocky Mountain Spotted Fever:A Disease in Need of Microbiological Concern. Clin Microbiol Rev 1989;2:227-40. Greene CE, Marks MA, Lappin MR. Comparison of Latex Agglutination, Indirect Immunofluorescent Antibody, and Enzyme Immunoassay Methods for Serodiagnosis of Rocky Mountain Spotted Fever in Dogs. Am J Vet Res 1993;54:20-28. (Basic Science) Kaplan JE, Schonberger LB. The Sensitivity of Various Serologic Tests in the Diagnosis of Rocky Mountain Spotted Fever. Am J Trop Med Hyg 1986;35:840-844. (Basic Science) Kostman JR. Laboratory Diagnosis of Rickettsial Diseases. Clin Dermatol 1996;14:301-306. (Review article, 58 references) Eremeeva ME, Dasch GA, Silverman DJ. Evaluation of a PCR Assay for Quantitation of Rickettsia ricketsii and Closely Related Spotted Fever Group Rickettsiae. J Clin Microbiol 2003;41:5466-5472. (Basic Science) University of North Carolina. Rocky Mountain Spotted Fever Serologies. 24 September 2004. Available at: http://www.pathology.unc.edu/labs/test/r/rmsf_ifa. htm Accessed 26 October 2006. Walker DH, Raoult D. Rickettsia rickettsii and Other Spotted Fever Group Rickettsiae. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. Philadelphia: Elsevier; 2005:22872295. (Textbook chapter) Hechemy KA. Correspondence. Am J Trop Med Hyg 1987;37:205-207. (Letter) McCook TA, Briley C, Ravin CE. Roentgenographic Abnormalities in Rocky Mountain Spotted Fever. South April 2007 • EBMedicine.net Mountain Spotted Fever in Dogs. Antimicrob Agents Chemother 1991;35:2375-2381. (Prospective) 106.Breitschwerdt EB Papich MG, Hegarty, et al. Efficacy of Doxycycline, Azithromycin, or Trovafloxacin for Treatment of Experimental Rocky Mountain Spotted Fever in dogs. Antimicrob Agents Chemother 1999;43:813821. (Prospective) 107.Tsai TF, Olson JG. Rickettsial Spotted Fever Infections: Another Pediatric Indication for Fluoroquinolones? Pedatr Infect Dis J 1995;14:635. (Letter) 108.Walker DH. Targetting Rickettsia. N Engl J Med 2006;354:1418-1420. (Commentary) 109.Peters TR, Edwards KM, Standaert SM. Severe Ehrlichiosis in an Adolescent Taking TrimethoprimSulfamethoxazole. Pediatr Infect Dis J 2000;19:170-71. (Case Report) 110.Brantley RK. Trimethoprim-Sulfamethoxazole and Fulminant Ehrlichiosis. Pediatr Infect Dis J 2001;20:231233. (Letter) 111. Steigman AJ. Rocky Mountain Spotted Fever and the Avoidance of Sulfonamides. J Pediatr 1977;91:163-164. (Letter) 112.Woodward TE. Rocky Mountain Spotted Fever: Epidemiological and Early clinical Signs are Keys to Treatment and Reduced Mortality. J Infect Dis 1984;150:465-468. (Editorial) 113.Workman JB, Hightower JA, Borges FJ, et al. Cortisone as an adjunct to chloramphenicol in the treatment of Rocky Mountain Spotted Fever. New Engl J Med 1952;246:962-966. 114.Breitschwerdt EB, Davidson MG, Hegarty BC, et al. Prednisolone at Anti-Inflammatory of Immunosuppressive Dosages in Conjunction with Doxycycline Does Not Potentiate the Severity of Rickettsia ricketsii Infection in Dogs. Antimicrob Agents Chemother 1997;41:141-147. (Prospective) 115.Donovan BJ, Weber DJ, Rublein JC, et al. Treatment of Tick-Borne Diseases. Ann Pharmacother 2002;36:15901597. (Review article, 72 references) 116.Nadelman RB, Nowakowski J, Fish D, et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med 2001;345:79-84. (Prospective Double-blind RCT, 482 patients) 117.Kenyon RH, Williams RG, Oster CN, et al. Prophylactic Treatment of Rocky Mountain Spotted Fever. J Clin Microbiol 1978;8:102-104. (Prospective) 118.Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 2000;49:885-888. (Case Report) 119.Rotz L, Callejas L, McKechnie D, et al. An epidemiologic and Entomologic Investigation of a Cluster of Rocky Mountain Spotted Fever Cases in Delaware. Del Med Jrl 1998;70:285-291. (Retrospective, 7 patients) 120.Hayes SF, Burgdorfer W. Reactivation of Rickettsia rickettsii in Dermacentor andersoni Ticks: an Ultrastructural Analysis. Infect Immun 1982;37:779-785. 121.Stewart RL, Burgdorger W, Needham GR. Evaluation of Three Commerical Tick Removal Tools. Wilderness and Environmental Medicine 1998;9:137-142. Med J 1982;75:156-160. (Retrospective, 70 cases) 90. Bonawitz C, Castillo M, Mukherji SK. Comparison of CT and MR Features with Clinical Outcome in Patients with Rocky Mountain Spotted Fever. Am J Neuroradiol 1997;18:459-464. (Retrospective, 54 patients) 91. Baganz MD, Dross PE, Reinhardt JA. Rocky Mountain Spotted Fever Encephalitis: MR Findings. Am J Neuroradiol 1996;16:919-922. 92. Holman RC, Paddock CD, Curns AT, et al. Analysis of Risk Factors for Fatal Rocky Mountain Spotted Fever: Evidence for Superiority of Tetracyclines for Therapy. J Infect Dis 2001;184:1437-1444. (Retrospective 213 patients) 93. Fishbein DB, Frontini MG, Giles R, Vernon LL. Fatal Cases of Rocky Mountain Spotted Fever in the United States, 1981-1988. Ann NY Acad Sci 1990;590:246-247. (Retrospective) 94. Marks MI, LaFerriere C. Chloramphenicol: Recent Developments and Clinical Indications. Clin Pharm 1982;1:315-320. (Review article, 29 references) 95. Purvis JJ, Edwards MS. Doxycycline Use for Rickettsial Disease in Pediatric Patients. Pediatr Infect Dis J 2000;19:871-874. (Retrospective, 35 patients) 96. Akcam M, Artan R, Akcam FZ, et al. Nail Discoloration Induced by Doxycycline. Pediatr Infect Dis J 2005;24:845. (Case Report) 97. Grossman ER, Walchek A, Freeman H. Tetracyclines and Permanent Teeth: The Relation Between Dose and Tooth Color. Pediatrics 1971;47:567-570. (Retrospective, 160 patients) 98. Lochary ME, Lockhart PB, Williams WT. Doxycycline and Staining of Permanent Teeth. Pediatr Infect Dis J 1998;17:429-431. (Retrospective, 10 patients) 99. Ship JA. Tooth Discoloration. 27 October 2005. Available at: http://www.emedicine.com/derm/topic646.htm Accessed 15 May 2006. 100.Ayaslioglu E, Erkek E, Oba AA, et al. Doxycyclineinduced Staining of Permanent Adult Dentition. Aust Dent J 2005;50:273-275. (Case Series) 101.Yagupsky P, Gross EM, Alkan M, et al. Comparison of Two Dosage Schedules of Doxycycline in Children with Rickettsial Spotted Fever. J Infect Dis 1987;155:1215-1219. (Prospective Randomized, 60 patients) 102.DuPont HL, Hornick RB, Weiss CF. Evaluation of Chloramphenicol Acid Succinate Therapy of Induced Typhoid Feer and Rocky Mountain Spotted Fever. N Engl J Med 1970;282:53-58. (Prospective, 8 patients) 103.Cale DF, McCarthy MW. Treatment of Rocky Mountain Spotted Fever in Children. Ann Pharmacother 1997;31:492-494. (Review article, 23 references) 104.American Society of Health-System Pharmacists. Chloramphenicol. Available at: http://www.ashp.org/emergency/chloramphenicol.p df Accessed 3 March 2006. 105.Breitschwerdt EB, Davidson MG, Aucoin DP, et al. Efficacy of chloramphenicol, Enrofloxacin, and Tetracycline for Treatment of Experimental Rocky EBMedicine.net • April 2007 21 Emergency Medicine Practice© 122.Teece S, Crawford I. How to Remove a Tick. Emerg Med J 2002;19:323-324. (Systematic review, 2 references) 123.Stallings SP. Rocky Mountain Spotted Fever and Pregnancy: A Case Report and Review of the Literature. Obstet Gynecol Surv 2001;56:37-42. (Review Article, 20 references) 124.Markley KC, Levine AB, Chan Y. Rocky Mountain Spotted Fever in Pregnancy. Obstet Gynecol 1998;91:860. (Case Report) 125.Welch KJ, Rumley RL, Levine JA. False-Positive Results in Serologic Tests for Rocky Mountain Spotted Fever During Pregnancy. South Med J 1991;84:307-311. (Prospective, 195 patients) 126.Gallis HA, Agner RC, Painter CJ. Rocky Mountain Spotted Fever in Pregnancy. N C Med J 1984;45:187-188. (Case Report) 127.Morrison RE, Lancaster L, Lancaster DJ, et al. Rocky Mountain Spotted Fever in the Elderly. J Am Geriatrics Soc 1991;39:205-208. (Case Reports) 128.Dumler JS, Wisseman CL, Fiset P, et al. Cell-mediated Immune Responses of Adults to Vaccination, Challenge with Rickettsia Rickettsii, or Both. Am J Trop Med Hyg 1992;46:105-115. (Prospective) 129.Crosquet-Valdes PA, Diaz-Montero CM, Feng HM, et al. Immunization with a Portion of Rickettsial Outer Membrane Protein A Stimulates Protective Immunity Against Spotted Fever Rickettsiosis. Vaccine 2002;20:979-988. (Basic Science) 130.Feng HM, Walker DH. Cross-protection Between Distantly Related Spotted Fever Group Rickettsiae. Vaccine 2003;21:3901-3905. (Basic Science) 131.Walker DH. Principles of the Malicious Use of Infectious Agents to Create Terror: Reasons for Concern for Organisms of the Genus Rickettsia. Ann NY Acad Sci 2003;990:739-742. (Review Article, 15 references) 132.Bradshaw v Daniel, 854 SW2d 865 (Tenn 1993). (Legal decision) 133.Arguin PM, Singleton J, Rotz LD, et al. An Investigation into the Possibility of Transmission of Tick-borne Pathogens via Blood Transfusion. Transfusion 1999;39:828-833. (Retrospective) 134.Rallis RM, Kriesel JD, Dumler JS, et al. Rocky Mountain Spotted Fever Following Cardiac Transplantation. West J Med 1993;158:625-628. (Case Report) 135.Gelfand MS, Chalmers BD, Killebrew L. Rocky Mountain Spotted Fever: Legal Duty to Warn for Noncontagious Disease. JAMA 1995;274:1586-1587. (Letter) CME Questions 49. Rocky Mountain Spotted Fever most commonly occurs in which of the following seasons? a. Summer b. Spring c. Fall d. Winter 50. The most common symptom of RMSF is: a. Fever b. Headache c. Rash d. Myalgias 51. Which states consistently have the highest reported incidence of RMSF? a. Colorado and Wyoming b. Idaho and Montana c. North Carolina and Oklahoma d. Vermont and Maine e. Wisconsin and Indiana 52. Regarding serologic testing for RMSF: a. Tests are often falsely negative in the first one to two weeks b. Weil-Felix has the greatest sensitivity and specificity c. Turnaround times are rapid d. Antibiotics should be withheld until the test results are known 53. The drug of choice for Rocky Mountain Spotted Fever in children is: a. Doxycycline b. Chloramphenicol c. Amoxicillin d. Azithromycin e. Ciprofloxacin 54. A 15-year-old male presents after a week long camping trip in the Blue Ridge Mountains of North Carolina with complaints of fever, muscle aches, headache, and nausea. He has no rash, vital signs are stable, and he does not appear severely ill. Which is of the following is the best course of action? a. Discharge home with reassurance and return precautions b. Treat empirically with doxycycline c. Treat empirically with chloramphenicol d. Send RMSF serologies and await results prior to initiating treatment Emergency Medicine Practice© 22 April 2007 • EBMedicine.net 60. In regards to its use in the treatment of RMSF, doxycycline: 55. A 22-year-old man presents after a two week hiking trip in the Ouachita Mountains of Arkansas complaining of a tick bite. He denies any complaints, and he removed the tick immediately after finding it. Which of the following is the best course of action? a. Frequently causes severe and irreversible tooth staining b. Is the second line therapy behind chloramphenicol c. May cause severe side effects, such as aplastic anemia and “gray baby syndrome” d. Is often still not used in children despite being the drug of choice according to the American Academy of Pediatrics a. Discharge home with reassurance and return precautions b. Treat empirically with doxycycline c. Treat empirically with chloramphenicol d. Send RMSF serologies and await results prior to initiating treatment 56. The best method of removing a tick is: a. Burning with a match b. Petroleum jelly c. Cyanoacrylate glue d. Steady pressure with forceps 57. The drug of choice for Rocky Mountain Spotted Fever in the pregnant patient is: Jump Ahead of the Class! a. Doxycycline b. Chloramphenicol c. Amoxicillin d. Azithromycin e. Ciprofloxacin EB Medicine's 2007 Lifelong Learning and SelfAssessment is designed exclusively to save you time and money while preparing for this years 58. A 63-year-old man presents with fever, rash, myalgias and shortness of breath. His vital signs are T 102, P 110, R 24, BP 225/120, SaO2 86%. He relates a five day history of progressively worsening orthopnea, pedal edema, and dyspnea on exertion. His wife recalls that he was bitten by a tick while working in the yard a week ago. After initial stabilization and treatment, which of the following is the best course of action? ABEM exam. Order yours today to lock in the low rate of $199---a $50 savings off the regular price of $249! Your study guide includes reprints of the original articles, summaries and in-depth discussions of each article, sample questions with answers and explanations, and 35 CME credits at no extra charge! Your study guide is backed by a a. Discharge home with high dose chloramphenicol b. Empiric IV doxycycline and admission c. Send RMSF titers and admit d. Discharge home with empiric doxycycline 100% money-back guarantee; if you are unsatisfied for any reason, simply call us to receive an immediate refund of the full purchase price. Call 1-800-249-5770 to order yours today! www.empractice.com 59. A 35-year-old woman presents in late summer with fever, headache, and myalgias. You perform a lumbar puncture which shows 65 wbc/microliter, 10 rbc/microliter, glucose 54 milligrams/deciliter, protein 105 milligrams/deciliter. CSF gram stain is negative. Treatment should include: a. Chloramphenicol b. Doxycycline c. Prednisone d. Supportive care as this is aseptic meningitis EBMedicine.net • April 2007 23 Emergency Medicine Practice© Physician CME Information Binders Accreditation: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Mount Sinai School of Medicine and Emergency Medicine Practice. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. Emergency Medicine Practice has handsome binders that are great for storing all your issues. To order your binder for just $15, please email [email protected], call 1-800-249-5770, or go to www.empractice.com, scroll down, and click "Binders" on the left side of the page. Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 48 AMA PRA Category 1 Credit(s)TM per year. Physicians should only claim credit commensurate with the extent of their participation in the activity. Credit may be obtained by reading each issue and completing the printed post-tests administered in June and December or online single-issue post-tests administered at EBMedicine.net. Target Audience: This enduring material is designed for emergency medicine physicians. If you have any questions or comments, please call or email us. Thank you! Needs Assessment: The need for this educational activity was determined by a survey of medical staff, including the editorial board of this publication; review of morbidity and mortality data from the CDC, AHA, NCHS, and ACEP; and evaluation of prior activities for emergency physicians. Date of Original Release: This issue of Emergency Medicine Practice was published April 1, 2007. This activity is eligible for CME credit through April 1, 2010. The latest review of this material was March 1, 2007. Discussion of Investigational Information: As part of the newsletter, faculty may be presenting investigational information about pharmaceutical products that is outside Food and Drug Administration approved labeling. Information presented as part of this activity is intended solely as continuing medical education and is not intended to promote off-label use of any pharmaceutical product. Disclosure of Off-Label Usage: This issue of Emergency Medicine Practice discusses no off-label use of any pharmaceutical product. Coming In Future Issues: Complications in Pregnancy Pediatric Toxicology Faculty Disclosure: It is the policy of Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. Class Of Evidence Definitions Each action in the clinical pathways section of Emergency Medicine Practice receives a score based on the following definitions. Class I • Always acceptable, safe • Definitely useful • Proven in both efficacy and effectiveness Level of Evidence: • One or more large prospective studies are present (with rare exceptions) • High-quality meta-analyses • Study results consistently positive and compelling Class II • Safe, acceptable • Probably useful Level of Evidence: • Generally higher levels of evidence • Non-randomized or retrospective studies: historic, cohort, or casecontrol studies • Less robust RCTs • Results consistently positive Class III • May be acceptable • Possibly useful • Considered optional or alternative treatments Level of Evidence: • Generally lower or intermediate In compliance with all ACCME Essentials, Standards, and Guidelines, all faculty for this CME activity were asked to complete a full disclosure statement. The information received is as follows: Dr. Davis, Dr. Marx, Dr. DeBileux, and Dr. Pauze report no significant financial interest or other relationship with the manufacturer(s) of any commercial product(s) discussed in this educational presentation. levels of evidence • Case series, animal studies, consensus panels • Occasionally positive results For further information, please see The Mount Sinai School of Medicine website at www.mssm.edu/cme. ACEP Accreditation: Emergency Medicine Practice is approved by the American College of Emergency Physicians for 48 hours of ACEP Category 1 credit per annual subscription. Indeterminate • Continuing area of research • No recommendations until further research AAFP Accreditation: Emergency Medicine Practice has been reviewed and is acceptable for up to 48 Prescribed credits per year by the American Academy of Family Physicians. AAFP Accreditation begins August 1, 2006. Term of approval is for two years from this date. Each issue is approved for 4 Prescribed credits. Credits may be claimed for two years from the date of this issue. Level of Evidence: • Evidence not available • Higher studies in progress • Results inconsistent, contradictory • Results not compelling AOA Accreditation: Emergency Medicine Practice has been approved for 48 Category 2B credit hours per year by the American Osteopathic Association. Significantly modified from: The Emergency Cardiovascular Care Committees of the American Heart Association and representatives from the resuscitation councils of ILCOR: How to Develop EvidenceBased Guidelines for Emergency Cardiac Care: Quality of Evidence and Classes of Recommendations; also: Anonymous. Guidelines for cardiopulmonary resuscitation and emergency cardiac care. Emergency Cardiac Care Committee and Subcommittees, American Heart Association. Part IX. Ensuring effectiveness of community-wide emergency cardiac care. JAMA 1992;268(16):2289-2295. Earning Credit: Two Convenient Methods Print Subscription Semester Program: Paid subscribers with current and valid licenses in the United States who read all CME articles during each Emergency Medicine Practice six-month testing period, complete the post-test and the CME Evaluation Form distributed with the December and June issues, and return it according to the published instructions are eligible for up to 4 hours of CME credit for each issue. You must complete both the post test and CME Evaluation Form to receive credit. Results will be kept confidential. CME certificates will be delivered to each participant scoring higher than 70%. Online Single-Issue Program: Current, paid subscribers with current and valid licenses in the United States who read this Emergency Medicine Practice CME article and complete the online post-test and CME Evaluation Form at EBMedicine.net are eligible for up to 4 hours of Category 1 credit toward the AMA Physician’s Recognition Award (PRA). You must complete both the post-test and CME Evaluation Form to receive credit. Results will be kept confidential. CME certificates may be printed directly from the Web site to each participant scoring higher than 70%. Emergency Medicine Practice is not affiliated with any pharmaceutical firm or medical device manufacturer. CEO: Robert Williford President and Publisher: Stephanie Williford Director of Member Services: Liz Alvarez Direct all editorial or subscription-related questions to EB Medicine: 1-800-249-5770 • Fax: 1-770-500-1316 • Non-U.S. subscribers, call: 1-678-366-7933 305 Windlake Court • Alpharetta, GA 30022 E-mail: [email protected] • Web Site: EBMedicine.net Emergency Medicine Practice (ISSN Print: 1524-1971, ISSN Online: 1559-3908) is published monthly (12 times per year) by EB Practice, LLC, 305 Windlake Court, Alpharetta, GA 30022. Opinions expressed are not necessarily those of this publication. Mention of products or services does not constitute endorsement. This publication is intended as a general guide and is intended to supplement, rather than substitute, professional judgment. It covers a highly technical and complex subject and should not be used for making specific medical decisions. The materials contained herein are not intended to establish policy, procedure, or standard of care. Emergency Medicine Practice is a trademark of EB Practice, LLC. Copyright © 20076 EB Practice, LLC. All rights reserved. No part of this publication may be reproduced in any format without written consent of EB Practice, LLC. Subscription price: $299, U.S. funds. (Call for international shipping prices.) Emergency Medicine Practice© 24 April 2007 • EBMedicine.net