Rocky Mountain spotted fever: What should a hospitalist know?

The absolute number of diagnosed cases per year may be underreported due to the difficulty in diagnostic confirmation and misdiagnosis.


Rocky Mountain spotted fever (RMSF) is a potentially deadly, tickborne disease caused by Rickettsia rickettsii and endemic to most of the Americas and all of the continental United States, with the highest prevalence in the southeastern and south-central states (11. Sexton DJ. Clinical manifestations and diagnosis of Rocky Mountain spotted fever. ). The highest concentration in the U.S. occurs in North Carolina, Tennessee, Oklahoma, Arkansas and Missouri (with those states accounting for 60% of reported cases, according to 2010 data from the CDC) (22. Centers for Disease Control and Prevention. Rocky Mountain spotted fever. Statistics and epidemiology.). But the absolute number of diagnosed cases per year may be underreported due to the difficulty in diagnostic confirmation and misdiagnosis (33. Chen LF, Sexton DJ. What's new in Rocky Mountain spotted fever? Infect Dis Clin North Am. 2008;22:415-32, vii-viii. [PMID: 18755382]).

Definitive diagnosis of RMSF requires serologic or tissue biopsy confirmation; this is costly, time-consuming and may not be done on all infected patients. To save lives, patients who present with suggestive symptoms in the right clinical context should be treated empirically with doxycycline, pending diagnostic confirmation.

Clinical scenario

A colleague brings his 10-year-old daughter to the emergency department because of fever. The child is febrile and flushed and appears to not feel well. She is reporting headache, myalgias, mild nausea and abdominal cramps. No recent travel, no tick bites and no other exposures are elicited. The family has a dog. Tomorrow is the last day of school, and the patient wants to feel well enough to go. Other than fever of 39 °C and tachycardia of 100 beats/min, her vital signs are normal. There are no meningeal signs. She appears mildly jaundiced, but she has a history of Gilbert's disease and the family is used to her being a bit jaundiced, especially when she is ill. Her heart and lungs sound fine, her abdomen is nonacute and there is no evidence of hepatomegaly. No rash or petechiae are found.

Laboratory data show minor abnormalities with a white blood cell (WBC) count of 3.2 × 1000 micro-liter and a platelet count of 148,000/micro-liter. Electrolytes are normal with a sodium level of 135 mEq/L and potassium of 4 mEq/L. Blood urea nitrogen is 25 mg/dL with normal creatinine. Bilirubin is elevated at 4.5 mg/dL, but remaining liver function tests are normal. A rickettsial screen is ordered. What next steps do you recommend?

History

In the late 1800s, Edward E. Maxey reported a disease he called the spotted fever of Idaho (44. Dantas-Torres F. Rocky Mountain spotted fever. Lancet Infect Dis. 2007;7:724-32. [PMID: 17961858]). Shortly after the turn of the century, about 1904, Louis B. Wilson and William M. Chowning identified the wood tick as the vector for this illness (44. Dantas-Torres F. Rocky Mountain spotted fever. Lancet Infect Dis. 2007;7:724-32. [PMID: 17961858]). By 1908, Howard Ricketts had isolated the causative agent in ticks and documented the transmission of disease. The organism was later named for Dr. Ricketts, in honor of his contribution to understanding this illness (44. Dantas-Torres F. Rocky Mountain spotted fever. Lancet Infect Dis. 2007;7:724-32. [PMID: 17961858]). There was no treatment for the disease until the late 1940s.

Microbiology

Rickettsia rickettsii is a gram-negative coccobacillus, obligate intracellular bacteria, with a propensity to infect endothelial cells, resulting in clinical vasculitis (55. Sexton DJ, Kaye KS. Rocky mountain spotted fever. Med Clin North Am. 2002;86:351-60, vii-viii. [PMID: 11982306]). The organism is transmitted by the bite of the American dog tick, Rocky Mountain wood tick and, less commonly, other ticks. The organism is transmitted vertically from the infected female tick to her offspring or horizontally by feeding on an infected host mammal (44. Dantas-Torres F. Rocky Mountain spotted fever. Lancet Infect Dis. 2007;7:724-32. [PMID: 17961858], 66. Dumler JS, Walker DH. Rocky Mountain spotted fever—changing ecology and persisting virulence. N Engl J Med. 2005;353:551-3. [PMID: 16093463]).

Virulence is variable and can be altered by the feeding status of the tick (77. Sexton DJ. Biology of Rickettsia rickettsii infection. ). Dr. Ricketts noted a hundred years ago that the mortality rate for patients in the Montana Bitterroot Valley was over 80% compared with mortality of less than 5% in the nearby Snake River Valley, although his study of the organisms in each area did not reveal any difference between the two (33. Chen LF, Sexton DJ. What's new in Rocky Mountain spotted fever? Infect Dis Clin North Am. 2008;22:415-32, vii-viii. [PMID: 18755382]). Other factors may also contribute to the virulence of a particular organism.

Pathophysiology

R. rickettsii is tropic for endothelial cells, causing necrosis and cell death. The organism does not secrete exotoxins (77. Sexton DJ. Biology of Rickettsia rickettsii infection. ). The infected and injured endothelial cells stimulate a host immune response, resulting in lymphohistiocytic vasculitis (77. Sexton DJ. Biology of Rickettsia rickettsii infection. ). This leads to increased vascular permeability and thereby may result in acute respiratory distress syndrome or central nervous system complications. Autopsy reports on patients with RMSF show vasculitic damage to the brain, spinal cord, lungs, kidneys, spleen and heart (myocarditis) (55. Sexton DJ, Kaye KS. Rocky mountain spotted fever. Med Clin North Am. 2002;86:351-60, vii-viii. [PMID: 11982306]).

Clinical presentation

The classic triad of fever, headache and rash, particularly with a history of tick bite, should warrant antibiotic treatment under most circumstances. Even if the presentation (as in the case described above) is only fever and headache with no history of tick bite, one must still have a low threshold for empiric treatment. If the fever duration is less than 24 hours and the patient looks well, one could make a case to observe for another 24 to 48 hours, but if symptoms persist, empiric treatment is often the better part of valor. Most case presentations are not textbook; therefore, one must maintain a high index of suspicion.

At presentation, fever is nearly universally present, followed by headache (67%). Half of affected patients will provide a history of tick exposure, but nearly 85% have exposure to dogs (88. Kirk JL, Fine DP, Sexton DJ, Muchmore HG. Rocky Mountain spotted fever. A clinical review based on 48 confirmed cases, 1943-1986. Medicine (Baltimore). 1990;69:35-45. [PMID: 2299975]). Rash is common, but the onset of rash ranges from day 1 to 14 and is therefore not reliable at the time of diagnosis. The rash is described as maculopapular and/or petechial rash, with 90% of patients eventually showing a petechial rash (88. Kirk JL, Fine DP, Sexton DJ, Muchmore HG. Rocky Mountain spotted fever. A clinical review based on 48 confirmed cases, 1943-1986. Medicine (Baltimore). 1990;69:35-45. [PMID: 2299975]). Patients who are treated with antibiotics in the first 3 days of illness usually have complete cure (33. Chen LF, Sexton DJ. What's new in Rocky Mountain spotted fever? Infect Dis Clin North Am. 2008;22:415-32, vii-viii. [PMID: 18755382], 99. Helmick CG, Bernard KW, D’Angelo LJ. Rocky Mountain spotted fever: clinical, laboratory, and epidemiological features of 262 cases. J Infect Dis. 1984;150:480-8. [PMID: 6491365]).

The initial clinical presentation may be confused with many other illnesses, including a viral syndrome. Rash will occur in 90% of cases but is often delayed until the third to fifth day of illness. Fewer than 15% of patients have a rash on the first day. Only half of patients have a rash by day 3 (11. Sexton DJ. Clinical manifestations and diagnosis of Rocky Mountain spotted fever. ). The rash often begins on the wrists and ankles and then generalizes to the torso, sparing the face (1010. American College of Physicians. MKSAP 16. Infectious diseases.). Up to 10% of patients never develop rash (11. Sexton DJ. Clinical manifestations and diagnosis of Rocky Mountain spotted fever. ).

Major neurological complications such as encephalitis, seizures or psychiatric symptoms may be prominent at presentation; this often denotes severe disease (88. Kirk JL, Fine DP, Sexton DJ, Muchmore HG. Rocky Mountain spotted fever. A clinical review based on 48 confirmed cases, 1943-1986. Medicine (Baltimore). 1990;69:35-45. [PMID: 2299975]). Other serious complications may also require intensive care, including adult respiratory distress syndrome, renal failure, coagulopathy and acral gangrene (88. Kirk JL, Fine DP, Sexton DJ, Muchmore HG. Rocky Mountain spotted fever. A clinical review based on 48 confirmed cases, 1943-1986. Medicine (Baltimore). 1990;69:35-45. [PMID: 2299975]). Neurological symptoms are associated with a worse prognosis and increased risk of permanent morbidity such as stroke, neuropathy, cranial nerve palsies, blindness, paresis and ataxia (11. Sexton DJ. Clinical manifestations and diagnosis of Rocky Mountain spotted fever. ). There is at least one case report of RMSF presenting with Guillain-Barré syndrome (55. Sexton DJ, Kaye KS. Rocky mountain spotted fever. Med Clin North Am. 2002;86:351-60, vii-viii. [PMID: 11982306]).

Most cases of RMSF occur when ticks are active in the spring and summer. Physicians practicing in endemic areas should be highly vigilant. Eugene Furth, MD, chairman of the department of medicine at East Carolina University in the 1980s, repeatedly instructed the housestaff, “Any fever of more than 48 hours' duration without an obvious source, between the months of March and September, should get doxycycline. Ask questions later.”

There was good reason for this dictum. Mortality for untreated RMSF has been reported as 5% to 10% in one review (66. Dumler JS, Walker DH. Rocky Mountain spotted fever—changing ecology and persisting virulence. N Engl J Med. 2005;353:551-3. [PMID: 16093463]) and was even estimated at 20% by a CDC report in 2006 (77. Sexton DJ. Biology of Rickettsia rickettsii infection. ). The same report concluded that among treated patients, mortality rate was highest among older persons (>60 years, 4% to 9%) or the very young (<4 years, 3% to 4%) (11. Sexton DJ. Clinical manifestations and diagnosis of Rocky Mountain spotted fever. , 1111. Chapman AS, Bakken JS, Folk SM, Paddock CD, Bloch KC, Krusell A, et al; Tickborne Rickettsial Diseases Working Group. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and anaplasmosis—United States: a practical guide for physicians and other health-care and public health professionals. MMWR Recomm Rep. 2006;55(RR-4):1-27. [PMID: 16572105]). These data are based on cases that were eventually diagnosed as RMSF. Twenty percent is a high mortality rate, but these were clinically ill patients and they were not treated with appropriate antibiotics. If one included patients with subclinical or mild disease that resolved undiagnosed and without treatment, then the overall mortality would be lower (55. Sexton DJ, Kaye KS. Rocky mountain spotted fever. Med Clin North Am. 2002;86:351-60, vii-viii. [PMID: 11982306]). Nonetheless, this is a sobering mortality figure for untreated patients who present with clinical illness (99. Helmick CG, Bernard KW, D’Angelo LJ. Rocky Mountain spotted fever: clinical, laboratory, and epidemiological features of 262 cases. J Infect Dis. 1984;150:480-8. [PMID: 6491365]).

Note that there is no recommendation for prophylactic antibiotic treatment after a tick bite without associated symptoms.

CDC data from 2010 suggest increasing cases of RMSF in recent years. This may also be related to increased reporting of documented cases of RMSF; fortunately, this has also been associated with a concomitant decrease in mortality (22. Centers for Disease Control and Prevention. Rocky Mountain spotted fever. Statistics and epidemiology.). The falling mortality rate probably has multiple causes, but the use of doxycycline in suspected cases is likely an important component.

In addition to age, other patient factors have been associated with poorer clinical outcomes, including chronic alcoholism, G6PD deficiency and male sex (11. Sexton DJ. Clinical manifestations and diagnosis of Rocky Mountain spotted fever. ). Some authors have mentioned racial differences, suggesting poorer prognosis for Native-American or African-American patients, but there are some confounders with these data.

Laboratory data

Routine laboratory data are nondiagnostic but may be suggestive. Hyponatremia was noted at some point during hospitalization in more than 90% of patients (88. Kirk JL, Fine DP, Sexton DJ, Muchmore HG. Rocky Mountain spotted fever. A clinical review based on 48 confirmed cases, 1943-1986. Medicine (Baltimore). 1990;69:35-45. [PMID: 2299975]). More than half had some abnormality of liver function tests or jaundice, but this may not be noted at presentation (88. Kirk JL, Fine DP, Sexton DJ, Muchmore HG. Rocky Mountain spotted fever. A clinical review based on 48 confirmed cases, 1943-1986. Medicine (Baltimore). 1990;69:35-45. [PMID: 2299975]). The peripheral WBC count may be high, normal or low. Platelet count may be normal but tends to be low. Cerebrospinal fluid (CSF) may show monocytic pleocytosis and in some cases may also show mildly elevated protein (55. Sexton DJ, Kaye KS. Rocky mountain spotted fever. Med Clin North Am. 2002;86:351-60, vii-viii. [PMID: 11982306], 88. Kirk JL, Fine DP, Sexton DJ, Muchmore HG. Rocky Mountain spotted fever. A clinical review based on 48 confirmed cases, 1943-1986. Medicine (Baltimore). 1990;69:35-45. [PMID: 2299975]).

RMSF is a clinical diagnosis. It is unlikely that confirmatory laboratory data will be available when the decision to treat must be made. R. rickettsii is not readily cultured, and diagnosis is made by acute and convalescent antibody titers (11. Sexton DJ. Clinical manifestations and diagnosis of Rocky Mountain spotted fever. ). In suspected cases, acute titers for RMSF should be sent for analysis, including IgM antibody levels, at the start of antibiotic therapy. Convalescent titers require an average of 4 weeks for conversion (1010. American College of Physicians. MKSAP 16. Infectious diseases.) and may be blunted secondary to antibiotic treatment, which may cloud the final diagnosis in some cases, but this is unavoidable.

Quicker laboratory diagnosis may be achieved by immunohistochemical studies of skin biopsy samples if a vasculitic skin rash is present. Even then, getting biopsy result confirmation will take some time, and if the index of suspicion is high, antibiotic treatment should not be withheld (1010. American College of Physicians. MKSAP 16. Infectious diseases.). Adverse clinical outcomes are associated with delayed antibiotic treatment (11. Sexton DJ. Clinical manifestations and diagnosis of Rocky Mountain spotted fever. ). Individual immunity after recovery from RMSF is lifelong (11. Sexton DJ. Clinical manifestations and diagnosis of Rocky Mountain spotted fever. ).

Differential diagnosis

If a sick patient presents to the emergency department with fever, headache, altered mental status and meningismus, he or she should clearly be treated empirically for bacterial meningitis, but RMSF may also need to be considered. This is particularly true if it is spring or summer, if the CSF findings are not classic for meningococcal meningitis, or if a history of tick exposure is elicited. In these cases, adding doxycycline to the therapeutic regimen is important. The key component in these scenarios for a hospitalist, or any clinician in an acute care setting, is to think about RMSF. It should be in the differential diagnosis.

Other tickborne illnesses, such as monocytic ehrlichiosis (Ehrlichia chaffeensis with tropism for monocytes) or granulocytic anaplasmosis (Anaplasma phagocytophilum with tropism for polymorphonuclear leukocytes) may present in spring and summer with fever, headache, myalgia and maculopapular and/or petechial rash. Both have similar laboratory profiles as RMSF, except that these organisms may occasionally be visualized as a morulae within the WBCs on a buffy coat smear (1010. American College of Physicians. MKSAP 16. Infectious diseases.). From a clinical standpoint, these illnesses are nearly indistinguishable from RMSF, but the good news is they are both also treated with doxycycline (11. Sexton DJ. Clinical manifestations and diagnosis of Rocky Mountain spotted fever. , 1010. American College of Physicians. MKSAP 16. Infectious diseases.).

Another common tickborne disease is Lyme disease. The geographical distribution of Lyme disease is different from RMSF, although the regions do overlap. Lyme disease is usually clinically distinct from RMSF, with erythema migrans as the hallmark for diagnosis. Less commonly, Lyme disease presents with fever, headache and history of tick exposure, with variable symptoms of rash, making the differential diagnosis blurred. A more recently described tickborne disease called Southern tick-associated rash illness (STARI) presents much like Lyme disease with erythema migrans. STARI may also have associated fever and headache but is not associated with disease progression like Lyme disease (1010. American College of Physicians. MKSAP 16. Infectious diseases.). Both of these illnesses respond to doxycycline therapy.

Treatment

As noted, early antibiotic treatment of RMSF results in improved outcomes; delayed treatment (defined as the fifth day of illness or later) is associated with significant increased mortality (33. Chen LF, Sexton DJ. What's new in Rocky Mountain spotted fever? Infect Dis Clin North Am. 2008;22:415-32, vii-viii. [PMID: 18755382], 1212. Sexton DJ. Treatment of Rocky Mountain spotted fever. ). Causes of delayed treatment include failure to consider the diagnosis, failure to make the diagnosis before development of a rash, and reluctance to use tetracycline in children even when the diagnosis is entertained because of the risk of dental staining (1212. Sexton DJ. Treatment of Rocky Mountain spotted fever. ). However, the risk of dental staining is low, especially for a short course of therapy. In balance, considering the risk of aplastic anemia with chloramphenicol and the bulk of data using tetracycline to treat RMSF, the safest course is doxycycline, even in children (1212. Sexton DJ. Treatment of Rocky Mountain spotted fever. ).

Doxycycline, 100 mg twice a day, is the drug of choice for both adults and children over 45 kg. Children under 45 kg should be treated with doxycycline, 2.2 mg/kg, every 12 hours (1212. Sexton DJ. Treatment of Rocky Mountain spotted fever. ). The exception is pregnant women, who should be treated with chloramphenicol, the only alternate drug available (1212. Sexton DJ. Treatment of Rocky Mountain spotted fever. ). Tetracycline in pregnant women has been associated with hepatotoxicity.

Clinical scenario conclusion

Returning to the child in the emergency department, she should be treated with doxycycline and RMSF titers should be sent for diagnosis.

The child in the scenario was actually my daughter. She was very sick when she was seen, but her clinicians were wary of using empiric doxycycline in a child, so titers were sent and we were instructed to watch her over the next few days. She remained ill for the next 48 hours, and then she started getting better. At 6 days into the illness she had improved greatly, but then I noted a petechial rash on her wrists and ankles. I called the infectious disease doctor for recommendations. He suggested that we should not treat since she was clinically improving and, indeed, she continued to do so. Final titers supported the diagnosis of acute RMSF. We were very lucky.

Acknowledgment: The author thanks Daniel Sexton, MD, for his review and recommendations on this article.