Infectious Disease and Microbiology – Rocky Mountain Spotted Fever

Rocky Mountain spotted fever (RMSF) is an acute tick-borne infection caused by the intracellular bacterium Rickettsia rickettsii. Despite its name, most cases in the United States occur outside the Rocky Mountain region. The disease can progress rapidly and may be fatal if treatment is delayed.

RMSF is a reportable disease in the United States, with hundreds to a few thousand cases historically reported each year. Although cases have occurred across most states, a large proportion have been concentrated in North Carolina, Oklahoma, Arkansas, Tennessee, and Missouri. RMSF also occurs in Canada, Mexico, Central America, and South America.

The disease is most common during spring and summer, when tick activity is highest. Children younger than 10 years and adults between 40 and 64 years have historically had high incidence rates. Risk increases with residence or activity in wooded areas, tall grass, and places where dogs and ticks are common. Glucose-6-phosphate dehydrogenase deficiency has been associated with more severe disease in some patients.

Prevention depends on reducing tick exposure. People entering wooded or grassy environments should wear protective clothing, perform frequent tick checks, and consider repellents containing DEET on exposed skin and permethrin on clothing where appropriate. Attached ticks should be removed promptly using fine-tipped forceps, grasping the tick close to the skin and pulling steadily upward without twisting.

After a tick bite, R. rickettsii enters vascular endothelial cells and spreads through the vascular system. Infection produces widespread vasculitis, increasing vascular permeability and activating coagulation pathways. The resulting capillary leak, edema, hypovolemia, and tissue ischemia account for many of the systemic manifestations and complications of RMSF.

Rickettsia rickettsii is an obligate intracellular, gram-negative coccobacillus transmitted through the salivary glands of feeding ticks. Important vectors include Dermacentor variabilis, the American dog tick, in much of the eastern United States, and Dermacentor andersoni, the Rocky Mountain wood tick, in western regions. The brown dog tick, Rhipicephalus sanguineus, can transmit infection in parts of Arizona and Mexico, while Amblyomma species have been important vectors in Central and South America.

The incubation period is generally 2–14 days, averaging about 7 days. Illness usually begins abruptly with fever, severe headache, myalgias, and marked malaise. Nausea, vomiting, and abdominal pain are also common. Neurologic involvement may range from mild confusion to seizures and encephalitis. Importantly, many patients do not recall a tick bite.

The classic triad of fever, rash, and known tick exposure is uncommon early in the disease and should not be required for diagnosis. The rash typically appears 2–5 days after fever begins. It usually starts as small blanching erythematous macules on the wrists and ankles, then spreads to the palms, soles, arms, legs, and trunk. As disease progresses, the lesions may become petechial.

The rash may appear late or may never develop. A minority of patients have so-called spotless RMSF. In addition, the rash may be difficult to recognize in people with darker skin tones. Therefore, absence of rash does not exclude the diagnosis.

Ocular abnormalities may include conjunctivitis, retinal vascular changes, hemorrhages, arterial occlusion, and papilledema. Neurologic findings may include lethargy, photophobia, meningismus, transient hearing loss, amnesia, behavioral changes, seizures, or encephalopathy. Hepatomegaly and pulmonary findings resembling pneumonia can also occur.

Diagnosis requires a high degree of clinical suspicion because laboratory confirmation is often unavailable during the early phase when treatment is most important. Antibodies against R. rickettsii are generally not detectable until approximately 7–10 days after illness begins.

Indirect immunofluorescence antibody testing is the traditional reference serologic method. Diagnosis is supported by a fourfold rise in antibody titer between acute and convalescent specimens. A single positive result may be difficult to interpret because antibodies to other spotted-fever rickettsiae may cross-react and background seropositivity can occur.

Thrombocytopenia is one of the most common laboratory abnormalities. The white blood cell count may be normal, decreased, or elevated and is not sufficiently reliable to exclude the disease. Other abnormalities may include hyponatremia, elevated creatinine, azotemia, increased serum transaminases, bilirubin elevation, and increased creatine kinase.

Chest radiographs may demonstrate focal pulmonary infiltrates or interstitial edema. In patients with encephalopathy, CT or MRI may reveal generalized cerebral edema. Cerebrospinal fluid may show a mild lymphocytic pleocytosis. Electrocardiographic abnormalities may range from nonspecific ST-wave changes to atrial arrhythmias.

Direct immunofluorescence staining of a skin biopsy for R. rickettsii antigens can provide early diagnostic evidence, although it is not routinely available and is generally less practical than clinical diagnosis and serology.

The differential diagnosis is broad and includes viral syndromes, bacterial sepsis, meningococcemia, disseminated gonococcal infection, secondary syphilis, typhoid fever, leptospirosis, ehrlichiosis, anaplasmosis, toxic shock syndrome, drug hypersensitivity reactions, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, and bacterial or viral meningoencephalitis.

Treatment should begin immediately when RMSF is suspected and must not be delayed while awaiting laboratory confirmation. Doxycycline is the treatment of choice for both adults and children. Adults are generally treated with doxycycline 100 mg twice daily, while children weighing less than 45 kg receive approximately 2.2 mg/kg per dose twice daily.

Therapy is typically continued for at least 5–7 days and for at least 48 hours after the patient becomes afebrile and shows clear clinical improvement. Oral or intravenous therapy may be used depending on severity and the patient’s ability to tolerate oral medications.

Doxycycline is also recommended for young children despite historical concerns about tooth staining because short courses have not shown the same risk associated with prolonged tetracycline exposure, and delayed effective therapy can be life-threatening.

Chloramphenicol has historically been used as an alternative, particularly when tetracyclines were considered contraindicated. However, outcomes have generally been less favorable than with doxycycline, and treatment decisions in pregnancy or other special circumstances require individualized risk-benefit assessment.

Severely ill patients may require hospitalization and intensive supportive care. Intravenous antibiotics are appropriate for patients with persistent vomiting, unstable vital signs, altered mental status, or other signs of severe disease. Shock, renal failure, respiratory compromise, and neurologic deterioration may require intensive care, hemodynamic support, mechanical ventilation, or renal replacement therapy.

Patients with neurologic symptoms, elevated creatinine, significant vomiting, hypotension, or other unstable vital signs should generally be admitted to the hospital. Approximately one-fourth of suspected cases historically required hospitalization.

The prognosis is strongly influenced by how quickly effective treatment is started. Delay beyond the first several days of illness substantially increases the risk of death and severe complications. Older age, neurologic involvement, renal dysfunction, and failure to receive doxycycline are associated with poorer outcomes.

Most survivors recover fully, but severe disease may produce permanent neurologic deficits, hearing impairment, or tissue ischemia severe enough to cause gangrene and require amputation.

Major complications include meningitis, encephalitis, seizures, acute kidney injury, acute respiratory distress syndrome, shock, disseminated vascular injury, myocarditis, tissue necrosis, and multiorgan failure.