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SAVE THE DATE!
2014 Lyme & Tick-Borne Diseases:
Medical, Neuropsychiatric & Public Health Implications

Providence Downtown Marriott

Providence, RI

May 3-4, 2014



Relapsing Fever

Overview

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Bright-field microscopy image of Borrelia hermsii spirochetes in mouse blood smear. Photo courtesy of the Centers for Disease Control.

Relapsing fever, as its name implies, is an illness characterized primarily by recurrent episodes of fever, often accompanied by fatigue, malaise and other constitutional symptoms. It is caused by at least 15 spirochete species belonging to the genus Borrelia, and can be vectored to humans by either lice or ticks.

Louse-borne relapsing fever (LBRF) is caused by Borrelia recurrentis and is transmitted from human to human by the body louse, Pediculus humanus humanus. The pathogen multiplies in the gut of the louse and is transmitted when an infected louse is crushed or scratched while feeding on a human host. No human skin wound or scratch is necessary for inoculation to occur. Uninfected lice acquire the bacterium when feeding on infected humans; no other animal serves as a reservoir for B. recurrentis.

LBRF tends to occur in epidemic waves, usually in times of human crisis such as war, deep poverty and/or overcrowding. Epidemics of LBRF followed both World War I and World War II, resulting in over a million deaths. It is now primarily a disease of the developing world, with foci in East Africa, South America and parts of China. It is not endemic in the United States.

More than a dozen species of Borrelia have been implicated in tick-borne relapsing fever (TBRF), which is transmitted by soft-bodied ticks from the genus Ornithodoros. Each TBRF Borrelia species is adapted to a specific tick vector; in turn, each tick species has a preferred set of hosts, mostly small mammals such as mice, squirrels or chipmunks, which serve as natural reservoirs for the spirochetes. Ornithodoros ticks feed for short periods, on the order of half an hour at most, and tend to take their meals at night. Their bites are painless; thus, most humans are infected while asleep and have no recollection of being bitten.

Tick-borne relapsing fever is endemic primarily in Africa, Central Asia, the Mediterranean, and Central and South America, but cases occur in western parts of the United States and southern British Columbia as well. Only 450 cases were reported in the US from 1977 to 2000, but national reporting is passive rather than mandatory and the true incidence of the disease is probably higher. The states with the largest number of reported cases during this period were California, Colorado, Washington, Idaho and Oregon. Most cases occurred in the summer months, from June through September.

Signs and Symptoms

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Reported cases of tick-borne relapsing fever by county in the United States, 1990-2002. Figure courtesy of the Centers for Disease Control.

The incubation period for relapsing fever is usually around a week. Symptom onset is abrupt, and consists primarily of episodic febrile events, commonly lasting a few days, followed by slightly longer periods of resolution. If untreated, the cycle usually reoccurs; more than 10 cycles have been reported in untreated patients. (TBRF generally involves more relapses than the louse-borne variant of the disease.) Additional signs and symptoms are non-specific but numerous, and include headache, myalgias, arthralgias, nausea, vomiting, anorexia, conjunctivitis and dry cough.

Fever cycles often conclude in a classic pattern commonly referred to as a “crisis.” First the patient experiences a spike in fever, sometimes up to 106ºF or more, and an increased metabolic rate (such as rapid breathing and tachycardia) is seen. Shortly thereafter, body temperature falls dramatically and the patient endures drenching sweats. Severe drops in blood pressure can occur during this second stage. These cycles are caused by the ability of Borrelia spirochetes to shift their outer surface protein coat in order to evade the human immune response; once a new clone is created and the organism multiplies in sufficient numbers, clinical relapses occur.

Liver and spleen involvement are not uncommon in relapsing fever, but seem to occur more frequently in LBRF. Neurologic complications can also occur – again, more commonly in LBRF – and include meningitis, seizures, cranial neuropathies (especially facial palsy) and even coma. Myocarditis can be a fatal complication of either LBRF or TBRF. Relapsing fever can also cause complications in pregnant women, resulting in spontaneous abortion, premature birth or neonatal death.

Diagnosis

A pattern of recurrent fevers in a patient from an endemic area should prompt an evaluation for relapsing fever. Conventional blood tests may show an increased white blood cell count, low platelets, mildly increased bilirubin, elevated erythrocyte sedimentation rate, and an increase in prothrombin time (PT) and partial thromboplastin time (PTT) coagulation tests, but none of these are diagnostic. Serologic tests (direct and indirect immunofluorescent assays) for relapsing fever can be performed, but they are not standardized across laboratories and not useful for timely diagnosis in any case. Cross reaction with antibodies to Lyme disease and syphilis have also been reported.

PCR tests exist but are not widely available.

The gold standard for relapsing fever diagnosis is the visualization of spirochetes in smears of peripheral blood or cerebrospinal fluid. Dark field microscopy is the preferred method, but various stains (such as Wright-Giemsa or acridine orange) are also frequently employed. The number of circulating spirochetes tends to decrease with each febrile episode.

Treatment

Louse-borne relapsing fever is usually treated with a single dose of antibiotic. Antipyretics (aspirin, NSAIDs or acetaminophen) are usually administered concomitantly. First line antibiotic agents are doxycycline and erythromycin, but chloramphenicol and parenteral penicillin G are also used. Treatment for tick-borne relapsing fever utilizes the same antibiotics, but lasts longer, typically one week. A common regimen is 100 mg of doxycycline every 12 hours, or 500 mg of erythromycin every 6 hours, for one week. Intravenous penicillin is recommended in cases of suspected or proven central nervous system involvement.

A common and potentially serious complication of relapsing fever treatment is the Jarisch-Herxheimer reaction, caused by the massive release of cytokines (primarily TNF-alpha, IL-6 and IL-8) during the spirochete die-off. The reaction usually begins 2-4 hours after antibiotic administration and is similar to the crisis stage of the fever cycle. Typical presentations are elevated fever, increased respiration and heart rate, excessive sweating, chills, and sudden changes in blood pressure. Fatalities from the J-H reaction can occur. Research suggests that administration of anti-TNF-alpha antibodies can ameliorate the severity of the J-H reaction, but aspirin, acetaminophen and corticosteroids are ineffective in doing so.

The mortality rate for untreated LBRF ranges widely but can approach 70%. In TBRF it is on the order of 5-10%. Treated properly, the death rate is reduced to around 1%, but TBRF patients often report residual symptoms even after treatment. These symptoms are usually associated with delayed diagnosis and initiation of treatment.

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