Rocky Mountain Spotted Fever

Ascent
Didn't play the corresponding interactive case or want to try it again? Click here to do so.

Diagnosis and reasoning

This 26 year old man initially presented with mild, flu like symptoms for 3 days. Following admission, he rapidly deteriorated within the span of a few hours, becoming dyspneic and diaphoretic. Examination reveals a blood pressure of 77/52 mmHg indicating that he is in shock; further assessment demonstrates the presence of tachycardia, tachypnea, and a temperature > 38 °C indicating the presence of systemic inflammatory distress syndrome (SIRS). Due to his critical condition, the initial focus should be on the acute management; diagnostic measures should follow only once the patient has been stabilized. The cause of shock is still uncertain, although those most likely are either septic shock (in view of the fever), and hypovolemic shock (which can occur secondary to capillary leakage induced by certain viral infections); in both cases, fluid resuscitation via the intravenous route is the urgent first step. This patient shows signs of distributive and hypovolemic shock. Note that the sepsis is the most likely form of distributive shock (in view of the fever), where the mechanism of shock is capillary leakage induced by microbial infections; in both cases, fluid resuscitation via intravenous route is the urgent first step. Note also the presence of respiratory distress and bilateral coarse crackles; this is suggestive of acute respiratory distress syndrome (ARDS) and confirmed by the inward chest x-ray. Given the risk of impending respiratory failure, intubation and mechanical ventilation is mandatory. Following stabilization, further evaluation to determine the likely causative etiology is essential; note that a complete septic screen including blood cultures and lactic acid levels should be performed in patients who present with SIRS. Though blood cultures will be of limited value in the immediate management, lactic acid levels may guide volume resuscitation. The history of a 2 week hike in Florida suggests the possibility of a zoonotic etiology. Based on the severity of presentation, diagnosis to include in the differential are, tick borne diseases such as human granulocytic anaplasmosis (HGA); previously known as human granulocytic ehrlichiosis), and rocky mountain spotted fever (RMSF). A bacterial or viral etiology should also be included in the differential. Examination reveals the presence of tenderness in right upper quadrant; however, a follow up ultrasound scan is normal, while the elevation of liver enzymes is a nonspecific finding which could be caused by many different diseases, including those considered above. Note that the indirect fluorescent antibody test (IFA) for identification of R. rickettsii becomes positive only 5 to 10 days following the tick bite; thus, the negative result here does not rule out the disease; the test should be repeated several days later. Doxycycline is the drug of choice in treatment of common tick-borne diseases including RMSF, and thus empirical therapy is probably justified in this setting; antibacterial therapy with a 3rd generation cephalosporin could also be considered. Sulfasalazine is not indicated in his current management; if the disease is indeed tick-borne in etiology, it might in fact result in worsening of the patient. Considering the patient in this case, on day 4 of admission, the IFA test became positive with a titer of 1:128, establishing the diagnosis of RMSF.


Discussion

Rocky Mountain spotted fever (RMSF) is a systemic, small-vessel vasculitis caused by Rickettsia rickettsii, an obligate intracellular bacterium; the disease can have a potentially fatal outcome if left untreated. Despite the name, RMSF is distributed throughout the United States, primarily along the southeast coast, and occurs far north as Canada and as far south as Central America and parts of South America. The overall incidence in the United States has increased over the past few decades with an incidence rate of 8 per million individuals (2563 cases) in 2008. While much of existing literature on RMSF is in children, it is important to appreciate that adults are also frequently affected. Humans are an accidental host, and acquire the disease following a bite from an infected tick. In the US, the american dog tick, the rocky mountain wood tick and the brown dog tick are the most common vectors. Subsequently, Rickettsial infection of endothelial cells induces production of interleukin (IL)-1β, IL- 6 and IL-8 and tumor necrosis factor-α (TNF-α); these inflammatory markers activate natural killer cells early in infection and produce interferon-γ, which inhibits Rickettsial growth. RMSF has an incubation period of approximately 2 to 14 days, an abrupt or insidious onset of symptoms with a wide spectrum of severity ranging from a mild to moderate, self-limiting febrile illness, to a severe life-threatening infection. The classical triad of symptoms consists of fever, rash and a headache; however this is of poor diagnostic sensitivity, with 58% or less of patients presenting with all 3 symptoms. The most characteristic feature of RMSF is the centripetal rash, which begins in the ankles and wrists and spreads to the trunk. Note that appearance of the rash on the palms and soles implies that the disease is at a later stage. Typically the rash appears 2 to 5 days following the onset of the fever. While morphologically variable, it typically starts as erythematous, blanchable macules that progress to a petechial or purpuric rash in a few days. In 97% of affected children, fever often exceeding 38.9°C (102 °F) is the earliest presentation observed. A cough and sore throat are often present as prodromal respiratory symptoms; in severe cases, pulmonary edema may occur. Headache, if present, is likely due to circulating pro-inflammatory cytokines and a vasculitis-related increase in intracranial pressure. Meningism and an altered level of consciousness are common complications of RMSF involving the central nervous system (CNS); they are observed mostly in children. Other rare CNS complications include seizures, cranial nerve palsies, coma, hearing loss and cerebral herniation resulting in death. Currently, RMSF remains the only tick-borne disease which have been shown to directly cause congestive heart failure secondary to myocarditis; this is due to subsequent lymphocytic infiltration secondary to infection. Malaise, myalgia, abdominal pain, nausea, vomiting and diarrhea also commonly appear during the initial stages of the disease. The differential diagnosis of RMSF includes both other tick-borne diseases, as well as non tick-borne diseases such as meningitis, pneumonia, thrombotic thrombocytopenic purpura, leptospirosis, dengue fever, infectious mononucleosis, bacterial sepsis, toxic shock syndrome, syphilis, enteroviral infections, viral hepatitis and malaria. The diagnosis of RMSF depends on the presence of suggestive physical symptoms (i.e. the clinical triad) along with the epidemiological possibility of tick exposure. Laboratory abnormalities including anemia, elevated liver enzymes, increased bilirubin and hyponatremia may also be seen. Serologic testing and skin biopsy remain the gold standard diagnostic tests; Immunofluorescent antibody assays (IFA) are considered the best serologic tests, with a titer greater than or equal to 1:64 being suggestive of RMSF in patients with a compatible clinical presentation. Doxycycline is the drug of choice in treating RMSF in suspected patients of all ages. The Centers for Disease Control and Prevention (CDC) recommend that treatment of these patients should never be delayed pending laboratory confirmation of the diagnosis. Minimally ill patients with epidemiological risk can be observed in an outpatient setting for about 3 days; severely ill patients in shock will require intravascular volume and inotropic support with intensive care monitoring. Mechanical ventilation may be needed for the management of pulmonary edema and increased intracranial pressure, while dialysis may be required for renal insufficiency. It is essential to appreciate that RMSF may mimic meningococcemia in children; thus, in this age group, a 3rd generation cephalosporin active against N. Meningitidis is often administered simultaneously. Note also that β-Lactam antimicrobials have proven to be ineffective in the management of RMSF; in addition, several animal studies have shown increased severity of illness following administration of Sulfonamides. Patients with RMSF usually recover completely following prompt antimicrobial therapy; however, several studies have revealed a high mortality and morbidity rate in patients in whom therapy is delayed. For prevention, individuals traveling to endemic regions should be advised to use permethrin treated clothing and/or skin repellents containing 20% to 30% diethyltoluamide; these repel the tick carriers of the disease.


Take home messages

  1. RMSF is considered the most severe tick-borne disease in the United States.
  2. The classical triad of symptoms includes fever, headache and rash; this is however of poor diagnostic sensitivity.
  3. The immunofluorescent antibody assay (IFA) is the gold standard diagnostic test for RMSF; however, a negative result in the early stages does not exclude the disease, owing to the delay in immune response.
  4. Doxycycline is the drug of choice, and should be started empirically following clinical suspicion.

Insightful, fun cases to improve your diagnostic skills

Use your detective skills, strengthen fundamentals faster, and access a wealth of knowledge.

  1. Consequences of delayed diagnosis of Rocky Mountain spotted fever in children--West Virginia, Michigan, Tennessee, and Oklahoma, May-July 2000. Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2000 Oct 6;49(39):885-8.
  2. Emerging and re-emerging rickettsioses: endothelial cell infection and early disease events. Walker DH, Ismail N. Nat Rev Microbiol. 2008 May;6(5):375-86.
  3. Emerging and re-emerging tick-transmitted rickettsial and ehrlichial infections. Walker DH, Paddock CD, Dumler JS. Med Clin North Am. 2008 Nov;92(6):1345-61
  4. Hitch-hiker taken for a ride: an unusual cause of myocarditis, septic shock and adult respiratory distress syndrome. Kushawaha A, Brown M, Martin I, Evenhuis W. BMJ Case Rep. 2013 Jan 11;2013.
  5. Rickettsial and other tick-borne infections. Flicek BF. Crit Care Nurs Clin North Am. 2007 Mar;19(1):27-38.
  6. Rocky Mountain spotted fever in children. Woods CR. Pediatr Clin North Am. 2013 Apr;60(2):455-70.
  7. Rocky Mountain spotted fever. Dantas-Torres F. Lancet Infect Dis. 2007 Nov;7(11):724-32.
  8. Rocky Mountain spotted fever: a physician's challenge. Razzaq S, Schutze GE. Pediatr Rev. 2005 Apr;26(4):125-30.
  9. Sepsis and septic shock. Maloney PJ. Emerg Med Clin North Am. 2013 Aug;31(3):583-600.
  10. Tick-borne bacterial, rickettsial, spirochetal, and protozoal infectious diseases in the United States: a comprehensive review. Amsden JR, Warmack S, Gubbins PO. Pharmacotherapy. 2005 Feb;25(2):191-210.
  11. Tick-borne illnesses: a CME update. Graham J, Stockley K, Goldman RD. Pediatr Emerg Care. 2011 Feb;27(2):141-7; quiz 148-50.
  12. Tickborne infections in the southern United States. Salinas LJ, Greenfield RA, Little SE, Voskuhl GW. Am J Med Sci. 2010 Sep;340(3):194-201.
  13. What's new in Rocky Mountain spotted fever? Chen LF, Sexton DJ. Infect Dis Clin North Am. 2008 Sep;22(3):415-32, vii-viii.