Rocky Mountain Spotted Fever: a Clinician's Dilemma

REVIEW ARTICLE Rocky Mountain Spotted Fever A Clinician’s Dilemma

Edwin J. Masters, MD; Gary S. Olson, MD; Scott J. Weiner, MD, PhD; Christopher D. Paddock, MD

ocky Mountain spotted fever is still the most lethal tick-vectored illness in the United States. We examine the dilemmas facing the clinician who is evaluating the patient with possible Rocky Mountain spotted fever, with particular attention to the following 8 pitfalls in diagnosis and treatment: (1) waiting for a petechial rash to develop before diag- Rnosis; (2) misdiagnosing as gastroenteritis; (3) discounting a diagnosis when there is no history of a tick bite; (4) using an inappropriate geographic exclusion; (5) using an inappropriate seasonal exclusion; (6) failing to treat on clinical suspicion; (7) failing to elicit an appropriate history; and (8) failing to treat with doxycycline. Early diagnosis and proper treatment save lives. Arch Intern Med. 2003;163:769-774

Rocky Mountain spotted fever (RMSF), a For older clinicians, RMSF was per- tick-vectored disease that was first de- haps the primary, if not only, tick-borne scribed in the Rocky Mountain region of illness emphasized in medical school cur- the United States in the late 1800s, is ricula before the early 1980s. Within the caused by the obligate, intracellular coc- last 20 years, RMSF has been relatively cobacillus Rickettsia rickettsii.1,2 Rickett- overshadowed by the discoveries of, and sia rickettsii elicits a moderately severe to subsequent attentions devoted to, an ex- life-threatening systemic illness in its host panding and diverse collection of other by infecting endothelial cells lining small tick-transmitted diseases in the United vessels of all major tissues and organ sys- States, including Lyme disease,4-6 Lyme- tems. Lethal and irreversible damage to en- like illnesses in the South (Masters dis- dothelium in the dermis, lungs, heart, kid- ease or southern tick-associated rash neys, gastrointestinal tract, brain, skeletal illness),7-22 the ehrlichioses (human mono- muscle, and other sites results in the pro- cytic ehrlichiosis, human granulocytic tean and often severe clinical manifesta- ehrlichiosis, and Ehrlichia ewingii ehrli- tions associated with untreated disease. chiosis),23-29 and several distinct babesio- These pathophysiologic events are respon- ses.30,31 Despite the recent recognition of sible for the rash, headache, myalgias, and these various novel illnesses, RMSF re- gastrointestinal symptoms that are com- mains the most lethal tick-borne infec- monly associated with RMSF, and can lead tion in the United States. The case- to more devastating manifestations, in- fatality ratio of untreated RMSF across all cluding gangrene, pulmonary hemor- age groups combined approaches 25%,32 rhage and edema, acute respiratory dis- and the disease continues to kill patients tress syndrome, myocarditis, acute renal throughout the United States each year: failure, meningoencephalitis, and cere- 224 deaths caused by RMSF were re- bral edema.3 ported to the Centers for Disease Control and Prevention during 1983 through 1998,33 although this number underesti- From the Department of Pediatrics, St Francis Medical Center and Southeast Missouri mates the true magnitude of mortality at- Hospital, Cape Girardeau, Mo (Dr Weiner), and the Viral and Rickettsial Zoonoses 34 Branch, Centers for Disease Control and Prevention, Atlanta, Ga (Dr Paddock). Drs tributable to this infection. Masters and Olson are in private practice, Cape Girardeau. Dr Weiner is now with the Rocky Mountain spotted fever is some- Department of Pediatrics, Austin Medical Education Programs and Children’s Hospital thing of a misnomer, as the disease has been of Austin, Austin, Tex. reported in all the contiguous United States

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CASE 1 A 5-year-old female resident of Cape Girardeau County, Missouri, presented to an emergency department and was evaluated by one of us (S.J.W.) on June 1, 2001, with a 1-week history of intermittent fever, with temperatures as high as 40°C. Three days after the onset of fever, she developed a maculopapular erythematous rash on her extremities, including her palms and soles, that moved centripetally to involve her trunk. Her parents reported tick Cases per 1 Million Population exposure around their rural resi- 0-5 15-30 dence, but no definite antecedent tick 5-15 ≥30 bite. The family did not own a dog. The patient’s additional symptoms at Figure 1. Cases of Rocky Mountain spotted fever by county per 1 million population, 1993 to 1996 (from presentation included mild nausea Treadwell et al35). the previous week, headache, and a “scratchy” sore throat. Other than except for Maine and Vermont35 Although a history of recent rash, the findings of the physical ex- (Figure 1). During the last several tick bite can be extremely helpful in amination were unremarkable. The decades, relatively few reports of establishing a presumptive diagno- patient’s temperature was 40.6°C. RMSF have originated from the sis of RMSF, the absence of this fea- Significant laboratory results in- Rocky Mountain states. The great- ture should not dissuade a clini- cluded a white blood cell count of est number of cases are reported from cian from considering this diagnosis 8800ϫ103/µL, with 5% band cells, southeastern and midwestern states, if clinical or epidemiologic suspi- 70% neutrophils, 17% lympho- with North Carolina, Oklahoma, cion for the disease is otherwise high. cytes, and 8% monocytes. The plate- Tennessee, Arkansas, South Caro- In this context, a definite recollec- let count was 192ϫ103/µL. The se- lina, Maryland, and Virginia consis- tion of a tick bite within the 14 days rum glutamic pyruvic transaminase tently among the top 10 states in con- before the occurrence of symptoms and glutamic oxaloacetic transami- temporary national surveillance has been reported in approxi- nase levels were elevated (60 µL and summaries of RMSF.35,36 During 1996 mately 60% of confirmed cases in 80 µL, respectively). Serologic tests through 2000, approximately 2700 several patient series.35,36 An early di- were negative for Ehrlichia chaffeen- cases of RMSF were reported to the agnosis of RMSF remains a clinical sis. A 2-week course of oral doxycy- Centers for Disease Control and Pre- dilemma and represents an often dif- cline was prescribed. vention (cases per year: mean, 536; ficult challenge, even to physicians The patient’s fever abated on range, 365-831).37,38 The disease is who are acquainted with the dis- June 3, and she reported feeling much transmitted by the American dog tick ease. The broad yet sporadic distri- better the following day. Her fading (Dermacentor variabilis), a rela- bution of RMSF, coupled with the rash was still visible (Figure 2 and tively common and broadly distrib- relatively nonspecific signs and Figure 3). She had an increased ap- uted tick in the eastern United States, symptoms early in the illness, com- petite and, according to her mother, and by the wood tick (Dermacentor pounds the diagnostic difficulty for was again becoming playful. Serum andersoni) in the Rocky Mountain physicians who are unfamiliar with samples collected on days 7 and 35 states.35,39,40 A clear spring-summer the epidemiological and clinical fea- of the illness were tested with an in- distribution of cases is an immu- tures of this disease. Periodic rein- direct immunofluorescence assay, table feature of this illness and at- forcement of RMSF in the differen- which demonstrated rising IgG anti- tests to the association of RMSF with tial diagnoses of tick-borne illnesses body titers that were reactive with R peak occurrences of Dermacentor tick is important because a delayed or rickettsii at dilutions of 1:32 and bites. During 1993 through 1996, missed diagnosis can be cata- 1:2048, respectively). 92% of confirmed cases of RMSF strophic.41-45 occurred from April through Sep- We report 2 cases of RMSF to CASE 2 tember, with 43% occurring in May illustrate the diagnosis. The second and June. Confirmed cases may oc- case, which was diagnosed later in An 11-year-old white female resi- cur during every month of the year, the course of the illness, demon- dent of Cape Girardeau County pre- but episodes of RMSF are unusual strates the difficulties that can be en- sented in late May with a low-grade during fall and winter, and these gen- countered in reaching the correct fever at home (in-office tempera- erally originate from southern states.35 diagnosis. ture, 38.3°C), frontal headache,

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 stomachache, and an erythematous maculopapular rash on her arms, legs, and trunk that had spread to her palms and soles. There were no oral lesions. The diagnosis of Coxsack- ievirus hand-foot-and-mouth disease was made, and the patient was sent home. Her fever, rash, and headache persisted. Two days later, nausea and vomiting developed. The patient was evaluated in the emergency department, diagnosed as having viral gastroenteritis, treated with in- travenous fluids, and discharged with promethazine suppositories. Four days later, she was treated by a chiropractor for neck and back Figure 2. Fading centripetal Rocky Mountain spotted fever rash on left foot of a 5-year-old girl on day 11 pain, without relief. The next day she of illness. was hospitalized for further evaluation and treatment. On admis- was treated with ceftriaxone pend- sion, she had petechiae in some areas ing culture results. and blanching erythematous pap- Two days into her hospitaliza- ules in others, but no palpable pur- tion, one of the authors (S.J.W.) was pura. It was unclear when her rash consulted, and a prophylactic regi- had developed petechial character- men of doxycyline was initiated istics. She was hemodynamically pending titer results. The patient’s stable throughout her illness, and the fever abated less than 2 days later, headache, vomiting, fever (tempera- with resolution of her headache and tures as high as 40°C), and rash were vomiting. Two days later, she was her predominant complaints. There discharged, with the rash begin- was no recollection of a tick bite. The ning to fade on her extremities. At family did own a healthy dog. The discharge, her RMSF IgG serology patient denied photophobia on ad- drawn during hospitalization was mission, but developed it later in the negative, with the IgM positive at hospitalization. She had no menin- Ͼ1:2048. She was treated with doxy- gismus. She had been treated for at- cycline for 14 days and had no re- tention deficit disorder and gave a ported sequelae. Figure 3. Fading centripetal Rocky Mountain history of having had migrainelike spotted fever rash on a 5-year-old girl. headaches. A review of systems re- COMMENT vealed no other abnormalities. quent, and the rash, which in the ini- On admission, the patient DIAGNOSIS tial phases is macular rather than pe- underwent a spinal fluid examina- techial, with the macules blanching tion (negative results) because of Rocky Mountain spotted fever has with pressure, is generally not ap- the fever, neck pain, vomiting, and a mean incubation time of 7 days af- parent until 3 to 4 days after the on- petechial rash. A complete blood ter the bite of an infecting tick.41 We set of the disease. Occasionally, cell count demontrated a white need to remember that ticks can be RMSF may be “spotless” or “almost blood cell count of 12ϫ 103/µL very small; can attach on the body spotless.”46 Of importance, early in (5% band cells, 43% segmented in places that are difficult to ob- the illness, more than 50% of the pa- neutrophils, 40% lymphocytes, serve, such as the scalp, back, axil- tients have nausea or vomiting, and 10% monocytes, and 1% reactive lae, and inguinal regions; usually infection of the gastrointestinal tract lymphocytes). The hemoglobin have a painless bite; and com- is a common misdiagnosis.23 Pho- level was 12.1 g/dL, and the plate- monly go unnoticed. Diagnosis of tophobia and myalgias, especially bi- let count was 379ϫ103/µL. A com- RMSF can be difficult, particularly lateral calf pain, can also be pre- prehensive metabolic profile in the early stages of the illness. In sent.47,48 In addition, IgM and IgG showed a normal sodium level a recent series of approximately 1000 antibodies reactive with R rickettsii (138 mEq/L) and elevated levels of cases of confirmed RMSF that oc- may be undetectable during the first aspartate aminotransferase (51 curred during 1993 to 1996, the triad week of the illness.42 Tick-borne ill- U/L) and alanine aminotransferase of rash, fever, and headache was pre- nesses need to be considered by phy- (95 U/L). Other laboratory test sent in only 44% of the cases at any sicians during the evaluation of fe- results were normal. The leading time during the illness. The occur- ver of unknown origin, especially in diagnosis at this time was still a rence of this classic triad at initial the spring and summer. However, viral syndrome, and the patient presentation, however, is less fre- cases have been reported in all 12

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 months. Other tick-borne diseases, RMSF or an ehrlichiosis is sus- the first 2 to 3 days of these illnesses. including ehrlichioses, Lyme dis- pected. The risk of tooth staining is The saved initial serum sample can be ease, and babesioses, can also pose not significant for short-term therapy useful when paired with a convales- diagnostic challenges to a clinician and is definitely subordinated to the cent-phase serum sample in proving who is presented with a febrile pa- prospect of a potentially lethal ill- a diagnosis. Polymerase chain reac- tient with nonspecific symptoms ness.5,53,55-59 In one study in which tion technology is being used increas- such as headache, fever, and myal- tooth discoloration in children re- ingly to sort out agents of various tick- gias. Leukopenia, thrombocytope- ceiving tetracycline was evaluated, borne diseases. nia, or elevated liver enzyme levels it was observed that cosmetically In dogs, as in humans, the symp- may occur in patients with RMSF as perceptible staining occurred pri- toms of RMSF and the ehrlichioses well as other tick-borne diseases, marily only in those patients who re- can overlap. While one of the au- such as the ehrlichioses.29,49-52 A good ceived 5 or more multiday courses thors (E.J.M.) was involved in a pro- history is essential to the diagnosis. of this antibiotic.56 Also, doxycy- spective study of human monocyto- cline binds less strongly to calcium trophic ehrlichiosis,28 an experienced TREATMENT than do other tetracyclines.60 The veterinarian called and offered a blood American Academy of Pediatrics and sample for culturing from a dog that The treatment of choice for RMSF is the Centers for Disease Control and he thought had canine monocytic doxycycline therapy for at least 7 Prevention recommend doxycy- ehrlichiosis. The culture yielded R days.49,53 Doxycycline is preferred be- cline as the treatment of choice for rickettsii, the agent of RMSF. Thus, in cause it has a broader spectrum of RMSF and the ehrlichioses in chil- dogs, as in humans, the signs of RMSF coverage for other tick-borne ill- dren of any age.45,53 and the ehrlichioses can be clini- nesses, including the ehrlichioses and In febrile patients with a his- cally similar. There are even reports other rickettsial infections, which are tory of a tick bite in the preceding of concurrent RMSF in dogs and their frequently in the differential diagno- 14 days, we recommend empiric owners.73 sis. These infections collectively have treatment with doxycycline on clini- been described as “doxycycline defi- cal suspicion. For adults, the dos- EIGHT PITFALLS ciency diseases.”51 Chlorampheni- age is 200 mg/d or 3 mg/kg of body IN THE DIAGNOSIS AND col is also active against R rickettsii; weight, whichever is higher. In chil- TREATMENT OF RMSF however, this drug should only be dren who weigh less than 45 kg, the used in situations in which doxycy- dosage of doxycycline is 4.4 mg/ 1. Waiting for a petechial rash cline is contraindicated, such as preg- kg.61 This treatment covers RMSF as on the palms and soles before mak- nancy. Treatment with chlorampheni- well as other tick-borne diseases, ing a diagnosis. Patients usually pre- col is associated with a higher such as the ehrlichioses, relapsing fe- sent for care on day 2 or 3, whereas percentage of fatal outcomes than vers, Lyme disease, Lyme-like ill- the rash usually appears on day 3 treatment with tetracyclines.32,54 ness (also known as Masters dis- or 4. The rash generally begins as a Moreover, gray baby syndrome and ease62,63), and tularemia. At least one macular or maculopapular erup- aplastic anemia that is unrelated of these other diseases is likely to be tion on the wrists or ankles that only to dosage, both rare but potentially in the differential diagnosis. Coin- later involves the palms and soles fatal complications, have been re- fection with more than one of these and becomes petechial.41 Some pa- ported with the use of chlorampheni- pathogens is also a possibility.64-71 An tients have no rash or a very subtle col.23,54 Also, the efficacy of chloram- argument has been made that hos- or focal rash.46,47 phenicol in the treatment of other pitalized patients with suspected 2. Misdiagnosing gastroen- tick-borne illnesses that may mimic RMSF should also receive a third- teritis. Nausea and vomiting early RMSF is uncertain.54 We particu- generation cephalosporin that is ac- in the illness occur in more than larly remember a 2-year-old patient tive against Neisseria meningitidis be- 50% of patients with RMSF.23 Gas- from southern Missouri who was ini- cause of the overlapping signs and trointestinal symptoms can also be tially diagnosed as having RMSF. Ex- symptoms and the disastrous con- a prominent early feature of other amination revealed an extremely ill sequences of missing either diagno- tick-vectored illnesses, such as the child with a petechial centripetal rash sis.61,72 In our evaluations, we rou- ehrlichioses.29 and fever. She did not respond to tinely request a complete blood cell 3. No history of a tick bite. Ap- chloramphenicol therapy but did re- count, measure aspartate amino- proximately 40% of patients with spond to treatment with doxycy- transferase and/or alanine amino- RMSF do not report an antecedent cline. Polymerase chain reaction transferase levels, and obtain extra tick bite.32,35,36,43,47,54 In this con- analysis subsequently led to a diag- serum samples, saving the samples text, absence of tick bite should nosis of infection with E chaffeensis. in a refrigerator for possible future never dissuade a clinician from con- The rash in ehrlichiosis, compared tests. There are no serologic tests that sidering RMSF. with the rash in RMSF, occurs can provide a reliable and accurate 4. Geographic exclusion. less frequently, may be more tran- early diagnosis of any of the tick- Rocky Mountain spotted fever has sient, has a later onset, and is less of- borne illnesses, and treatment deci- been reported in 46 states. It is more ten petechial.29 sions should never hinge on a common in the lower midwestern Doxycycline therapy is indi- confirmatory assay. The greatest and southeastern states, but it does cated, even in children, whenever therapeutic response can be seen in occur elsewhere and should be con-

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 sidered endemic in the contiguous the antibiotic of choice, even for chil- grans–like rashes following Lone Star tick bites. United States.35 dren. Early diagnosis and treat- Arch Dermatol. 1998;134:955-960. 18. Masters EJ. Erythema migrans in the South. Arch 5. Seasonal exclusion. Al- ment can save lives. Intern Med. 1998;158:2162-2165. though 90% of cases occur during 19. Felz MW, Chandler FW Jr, Oliver JH, et al. Soli- April through September, one needs Accepted for publication June 26, 2002. tary erythema migrans in Georgia and South Caro- to have an index of suspicion all We wish to thank David Walker, lina. Arch Dermatol. 1999;135:1317-1326. year. Confirmed cases have been 20. Masters E. Erythema migrans: my point of view. MD, of the University of Texas Medi- J Spirochet Tick-Borne Dis. 2000;7:21-22. reported during every calendar cal Branch at Galveston for his input 21. Goddard J. What’s going on with Lyme disease 35 month. Wintertime cases are more and comments, Charles Cox for pro- in the South? Infect Med. 2001;18:130-133. likely to occur in the southern viding the samples of dog blood that 22. James AM, Liveris D, Wormser GP. Borrelia lon- states.36 yielded Rickettsia rickettsii in cul- estari infection after a bite by an Amblyomma 6. Failure to treat early on americanum tick. J Infect Dis. 2001;183:1810- ture, and Kilja Israel for her assis- 1814. clinical suspicion. Dependent on the tance in researching this article. 23. Walker DH. Tick-transmitted infectious diseases patient’s age, untreated RMSF has a Corresponding author and rein the United States. Annu Rev Public Health. 1998; 10% to 25% case-fatality ratio.32,54 prints: Edwin J. Masters, MD, 8 Doc- 19:237-269. Delayed treatment after day 5 is as- tors Park, Cape Girardeau, MO 63703 24. Parola P, Raoult D. 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