Tick-Borne Diseases, Relapsing Fever

Background: Relapsing fever is an acute febrile illness caused by spirochetes of the genus Borrelia. The high fevers of presenting patients spontaneously abate and then recur. This characteristic pattern of remission and relapse not only gives relapsing fever its name, but also allows it to be differentiated clinically from other febrile illnesses as it has since the 1840s.

Large outbreaks of louse-borne relapsing fever have occurred throughout the past century. These outbreaks usually occur following man-made breakdowns in public health, as typified by the epidemic following World War II that involved about 10 million people.

Pathophysiology: Relapsing fever is transmitted to humans by 2 vectors, ticks and lice. The human body louse, Pediculus humanus, is the specific vector (Pediculus pubis is not a vector). Louse-borne relapsing fever is more severe than the tick-borne variety.

Louse-borne relapsing fever is caused by Borrelia recurrentis. No animal reservoir exists. Lice that feed on infected humans acquire the Borrelia that then multiplies in the gut of the louse. When an infected louse feeds on an uninfected human, the organism gains access when the victim crushes the louse or scratches the area where the louse is feeding. Borrelia recurrentis infects the patient via either abraded or intact skin (or mucous membranes) and then invades the bloodstream.

Soft ticks of the genus Ornithodoros spread the tick-borne variety. The responsible Borrelia species are identified closely with its tick vector and they share parallel nomenclature. (For example, Borrelia parkeri infects Ornithodoros parkeri; Borrelia hermsii is the agent transmitted by tick bite by Ornithodoros hermsii.) Soft ticks feed for short periods of time (an hour or so) and the Borrelia are inoculated within minutes. This is an important distinction from other tick-borne diseases, such as Lyme disease.

Regardless of the mode of transmission, a spirochetemia develops. The Borrelia then invade the endothelium. This can produce a low-grade disseminated intravascular coagulation and thrombocytopenia. The relapse phenomenon occurs because of genetically programmed shifting of outer surface proteins of the Borrelia that allows a new clone to avoid destruction by antibodies directed against the majority of the original infecting organisms. Thus, the patient clinically improves until the new clone multiplies sufficiently to cause another relapse. Tick-borne disease tends to have more relapses (average of 3) compared to the louse-borne variety (often just 1).

The recent resurgence of interest in Borrelia because of Lyme disease and especially the recent publication of the genomic sequence of B burgdorferi has led to advances in the understanding of the host-parasite interactions of the relapsing fever Borrelia too.

Frequency:

• In the US: Louse-borne relapsing fever is not endemic in the United States, although an occasional traveler will present with an imported case.

  Few cases of tick-borne relapsing fever are reported in the United States; however, sporadic cases continue to occur. It is highly focal, with 13 counties producing 50% of cases. Most of these are found in the late spring and summer in the western mountainous states, south into Texas, and northwest into Washington.

  Undoubtedly, many cases occur that either are misdiagnosed or go unreported.

  Clusters of cases are reported; often groups of campers share a rustic facility infested with rodents on which the ticks feed.

• Internationally: Endemic foci of louse-borne relapsing fever occur in much of the world where war, poverty, and overcrowding exist; all of which are conditions that favor louse infestation. Civil wars, which result in large refugee camps, are also fertile ground for lice and relapsing fever.

Mortality/Morbidity:

• Mortality rates from 30-70% are reported in untreated patients during epidemics of the louse-borne variety; the mortality rate falls to about 5% with treatment. This striking figure probably reflects the underlying malnutrition and coexisting infections that exist in these situations.

• The mortality rate of patients with tick-borne relapsing fever who are treated is less than 1%.

Sex: A slight preponderance of female patients exists in louse-borne epidemics (60%); tick-borne relapsing fever occurs more often in males (60%). The latter figure probably reflects the greater likelihood of males being exposed to ticks through recreational and occupational activities.

Age: A trend towards pediatric cases of both forms of relapsing fever exists. In the case of the louse-borne variety, this may reflect the general state of health in populations where relapsing fever is endemic. Regarding the tick-borne disease, this may reflect activities that lead to tick exposure.
History: Relapsing fever develops abruptly 3-18 days (average 7-8) after exposure to the spirochete.

As with all the tick-borne diseases, the season of onset and epidemiologic history suggesting possible tick exposure are important clues. Ornithodoros ticks often frequent caves and decaying woodpiles. Many patients report a history of having spent time in rustic cabins in which the ticks gain access by hitching a ride on a rodent.

• Onset of symptoms generally is abrupt.

• Pulse is rapid in proportion to the fever, a point of differential value with typhoid fever with which louse-borne relapsing fever can be confused.

• Headache is a very common symptom, occurring in nearly 95% of cases.

• Myalgias and chills also occur in approximately 90% of cases.

• Arthralgias

• Weakness

• Anorexia

• Weight loss

• Cough

• Systemic symptoms

• Patients commonly complain of nausea, vomiting, and upper abdominal pain due to liver and spleen involvement.

• Hepatic and splenic involvement is more common in louse-borne relapsing fever.

• A dry cough frequently is observed, a feature that is in common with typhoid fever.

• Relapses

• The primary febrile episode typically ends after 3-6 days by crisis that can culminate in fatal shock. About 7-10 days later, the first relapse occurs abruptly. Subsequent relapses tend to be less severe.

• The primary febrile episode, usually only 1-2.

• Louse-borne relapsing fever normally produces fewer relapses.

• In tick-borne disease, relapses average 3, and there can be more than 10.

Physical: Physical findings are not diagnostic.

• Fever (most common finding)

• Tachypnea

• Tachycardia

• Hypotension

• Abdominal tenderness with hepatosplenomegaly

• Petechial or maculopapular rash

• Rales

• Rhonchi

• Nuchal rigidity

• Lymphadenopathy

• Jaundice

• Iritis and iridocyclitis

• Neurologic findings are more common in louse-borne disease and include coma, cranial neuropathy (especially Bell palsy), hemiplegia, meningitis, and seizures.

Lab Studies:

• Hematologic studies occasionally reveal anemia and thrombocytopenia.

• The white blood cell (WBC) count usually is normal.

• The prothrombin time (PT) and partial thromboplastin time (PTT) frequently are elevated.

• The hepatic transaminases and serum bilirubin can be elevated.

• In louse-borne relapsing fever, azotemia can occur.

• Definitive diagnosis is established by visualizing spirochetes in smears of peripheral blood during a febrile episode.

• Multiple smears (both thick and thin, using Wright and Giemsa stains) may need to be examined.

• This is the best way to secure the diagnosis in the ED.

• Organisms are not found between relapses.

• Injection of blood into laboratory animals followed by examination of their blood sometimes is useful.

Imaging Studies:

• Imaging studies are not routinely useful, although chest x-ray and hepatobiliary ultrasound might be indicated in isolated cases in which pulmonary or hepatic manifestations predominate.

• CT scanning of the brain may be indicated in cases with predominant central nervous system (CNS) manifestations.

Other Tests:

• The electrocardiogram (ECG) may show a prolonged QTc interval.

• Nonspecific antibody response to Proteus OXK antigens is elevated in about one third of tick-borne cases and most louse-borne cases.

The JH reaction produces apprehension, diaphoresis, fever, tachycardia, and tachypnea with an initial pressor response followed rapidly by hypotension. The JH reaction can be fatal. Recent studies have shown that tumor necrosis factor-a (TNF-a) may be partly responsible for the reaction. Preadministration of glucocorticoids does little to limit the JH reaction, but antibodies to TNF-a do help.

Note that the regimens listed below are for tick-borne disease. Adults with louse-borne relapsing fever can be treated with a single 500 mg dose PO/IV of tetracycline, chloramphenicol, or erythromycin or 100 mg of doxycycline. Penicillin also can be used for louse-borne disease.

Antipyretics are indicated to reduce fever.

Drug Category: Antibiotics -- Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Drug Name	Tetracycline (Sumycin) -- Useful for louse- and tick-borne cases. DOC for the latter. Treats susceptible bacterial infections of both gram-positive and gram-negative organisms as well as infections caused by Mycoplasma, Chlamydia, and Rickettsia species. Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s) of susceptible bacteria.
Adult Dose	500 mg PO qid for 7-14 d
Pediatric Dose	<8 years: Not recommended >8 years: 10-20 mg/lb/d (25-50 mg/kg) PO qid; 25-50 mg/kg/d divided q6h
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants
Pregnancy	D - Unsafe in pregnancy
Precautions	JH reaction may develop with use of antimicrobials; photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Doxycycline (Doryx, Bio-Tab) -- Has advantage of covering other tick-borne diseases and ease of bid dosing. Interferes with bacterial cell wall synthesis during active multiplication, causing cell wall death and resultant bactericidal activity against susceptible bacteria.
Adult Dose	Acute infection: 200 mg, PO/IV, immediately and 100 mg hs followed by 100 mg bid for 3 d; alternatively, 300 mg immediately followed by 300 mg in 1 h or 100 mg PO/IV bid for 7 d
Pediatric Dose	<8 years: Not recommended >8 years: 2-5 mg/kg/d in 1-2 divided doses; not to exceed 200 mg/d
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D - Unsafe in pregnancy
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Erythromycin (Erythrocin, Ery-Tab) -- DOC for patients who are allergic to or cannot tolerate tetracyclines. Is also safe in pregnant patients although estolate salt should be avoided. In children, age, weight, and severity of infection determine proper dosage. When twice-a-day dosing is desired, half-total daily dose may be taken q12h. For more severe infections, dosage may be doubled.
Adult Dose	250 mg erythromycin stearate/base (or 400 mg ethylsuccinate) PO q6h 1 h ac, or 500 mg q12h for 10 d; alternatively, 333 mg PO q8h; increase up to 4 g/d depending on severity of infection for 10 d
Pediatric Dose	30-50 mg/kg/d (15-25 mg/lb/d) PO in divided doses; for severe infections, double the dose
Contraindications	Documented hypersensitivity; hepatic impairment
Interactions	Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin, increases risk of rhabdomyolysis
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in liver disease; estolate formulation may cause cholestatic jaundice; GI side effects are common (give doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

Drug Name	Chloramphenicol (Chloromycetin) -- Is also useful for patients allergic to tetracycline. If a question of Rocky Mountain spotted fever exists, this is a useful drug. Binds to 50 S bacterial-ribosomal subunits and interferes with or inhibits protein synthesis. Is effective against gram-negative and gram-positive bacteria.
Adult Dose	50-100 mg/kg/d PO/IV divided q6h for 10 d; not to exceed 4 g/d
Pediatric Dose	50-75 mg/kg/d PO/IV divided q6h
Contraindications	Documented hypersensitivity
Interactions	Concurrently with barbiturates, chloramphenicol serum levels may decrease while barbiturate levels may increase causing toxicity; manifestations of hypoglycemia may occur with sulfonylureas; rifampin may reduce serum chloramphenicol levels, presumably through hepatic enzyme induction; may increase effects of anticoagulants; may increase serum hydantoin levels, possibly resulting in toxicity; chloramphenicol levels may be increased or decreased
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use only for indicated infections, or as prophylaxis for bacterial infections; serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) can occur; evaluate baseline and perform periodic blood studies approximately every 2 d while in therapy; discontinue upon appearance of reticulocytopenia, leukopenia, thrombocytopenia, anemia or findings attributable to chloramphenicol; adjust dose in liver or kidney dysfunction; caution in pregnancy at term or during labor because of potential toxic effects on fetus (gray syndrome)

Drug Category: Antipyretics -- In treating relapsing fever, bed rest and mild analgesic-antipyretic therapy are often helpful in relieving the associated lethargy, malaise, and fever associated with the disease.

Drug Name	Aspirin (Bayer Aspirin, Bufferin, Ascriptin) -- Lowers elevated body temperature through vasodilation of peripheral vessels, thus enhancing dissipation of excess heat. Also acts on hypothalamus heat-regulating center to reduce fever.
Adult Dose	325-650 mg PO q4-6h; not to exceed 4 g/d
Pediatric Dose	10-15 mg/kg/dose PO q4-6h; not to exceed 60-80 mg/kg/d
Contraindications	Documented hypersensitivity; liver damage, hypoprothrombinemia, vitamin K deficiency, bleeding disorders, asthma; due to association of aspirin with Reye syndrome, do not use in children (<16 y) with flu
Interactions	Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses >2 g/d may potentiate glucose lowering effect of sulfonylurea drugs
Pregnancy	D - Unsafe in pregnancy
Precautions	May cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients with severe anemia, with history of blood coagulation defects, or taking anticoagulants

Drug Name	Ibuprofen (Motrin, Nuprin) -- One of the few NSAIDs indicated for reduction of fever.
Adult Dose	200-400 mg PO q4-6h while symptoms persist; not to exceed 3.2 g/d
Pediatric Dose	6 months to 12 years: 20-40 mg/kg/d PO divided tid/qid; start at lower end of dosing range and titrate upward; not to exceed 2.4 g/d >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; peptic ulcer disease, recent GI bleeding or perforation, renal insufficiency, or high risk of bleeding
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related side effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; monitor PT closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category D in third trimester of pregnancy; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy

Drug Name	Acetaminophen (Tylenol, Anacin Free Aspirin, Feverall) -- DOC for treatment of pain in patients with documented hypersensitivity to aspirin, NSAIDs, diagnosed with upper GI disease, or taking oral anticoagulants. Inhibits action of endogenous pyrogens on heat regulating centers.
Adult Dose	325-650 mg PO q4-6h or 1000 mg tid/qid; not to exceed 4 g/d
Pediatric Dose	<12 years: 10-15 mg/kg/dose PO q4-6h prn; not to exceed 2.6 g/d >12 years: 325-650 mg PO q4h; not to exceed 5 doses in 24 h
Contraindications	Documented hypersensitivity; known G-6-PD deficiency
Interactions	Rifampin can reduce analgesic effects of acetaminophen; coadministration with barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Hepatotoxicity possible in chronic alcoholics following various dose levels; severe or recurrent pain or high or continued fever may indicate a serious illness; APAP is contained in many OTC products and combined use with these products may result in cumulative APAP doses exceeding recommended maximum dose

Further Inpatient Care:

• Many patients with louse-borne relapsing fever are malnourished and will require inpatient care to correct their hypovolemia, coagulation abnormalities, and nutritional status.

• Patients with abnormal mental status also require close observation with airway protection, as indicated.

• Those with prolonged QTc intervals are best monitored by telemetry.

• Be especially vigilant in monitoring for a JH reaction.

Further Outpatient Care:

• Refer patients to follow up with their primary care physician to address complete recovery, any malnutrition issues, and any lab or ECG abnormalities.

Deterrence/Prevention:

• See Tick-borne Diseases, Introduction.

• For the louse-borne variety, maintaining personal hygiene to avoid lice prevents the disease.

• In many situations (eg, a refugee camp) maintenance of personal hygiene is difficult or impossible.

• Chemical delousing may be required in epidemic situations.

Complications:

• Bleeding is a common complication with both forms of the disease. Bleeding in the skin, nose, eyes, lungs, urinary tract, GI tract, and brain can occur. The latter two can be fatal.

• JH reaction

Prognosis:

• In untreated epidemics of louse-borne disease, mortality rate is 30-70%. This is lowered to less than 1% with appropriate antibiotic therapy.

• Poor prognostic signs include severe jaundice, severe change in mental status, severe bleeding, and prolonged QTc interval.

Patient Education:

• Educate patients about the vectors and how they can be avoided.

• For excellent patient education resources, visit eMedicine's Bites and Stings Center. Also, see eMedicine's patient education article Ticks.

Medical/Legal Pitfalls:

• Because physicians, especially in developed countries, almost never see (or diagnose) relapsing fever, they tend not to include the diagnosis in the differential. In all patients with a febrile illness, an appropriate epidemiological history must be taken, to include tick and other insect exposure, travel, and lifestyle. Simply asking these questions may suggest a diagnosis that might have been overlooked otherwise.

• Taking a detailed history of the pattern of fever may suggest this diagnosis. While physicians are more likely to consider malaria in the setting of intermittent, recurring fevers, a careful examination of a blood smear will be likely to diagnose both diseases.

Special Concerns:

• The JH reaction can be severe. At a minimum, patients ought to be counseled that it might occur (so they do not mistake it for an allergic reaction). Patients who are ill should probably be observed for this reaction in a monitored setting.

	PICTURES	Section 10 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Caption: Picture 1. Relapsing fever can be tick- or louse-borne. Soft-bodied ticks of the genus Ornithodoros transmit tick-borne cases. Below is an image of such a tick. Unlike the hard-bodied ticks, the Ornithodoros feed briefly and can transmit disease within minutes. (Photo courtesy of Julie Rawlings, MPH, Texas Department of Health)
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Caption: Picture 2. This is a photomicrograph of a patient who presented to the ED with cyclical fevers and chills, which she developed while traveling in one of the recently formed Soviet republics in 1990. A blood smear for malaria was ordered and this is what the lab technician saw.
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