Relapsing Fever in Emergency Medicine

Background

Relapsing fever is a bacterial infection caused by spirochetes of the genus Borrelia. It is characterized by recurring episodes of high fever, headache, and muscle and joint aches. 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.

There are two types of relapsing fever: tick-borne relapsing fever (TBRF) and louse-borne relapsing fever (LBRF).

Tick-borne relapsing fever

The two main Borrelia species in North America include Borrelia hermsii (in the west), and Borrelia turicatae (southwest and south central). Relapsing fever caused by these species is usually associated with sleeping in rustic, rodent-infested settings, especially in mountainous areas.

Louse-borne relapsing fever

Louse-borne relapsing fever is caused by Borrelia recurrentis, which is usually transmitted by the human body louse. Thus, louse-borne relapsing fever is generally restricted to refugee settings in developing countries.

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.

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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 B recurrentis, which is transmitted from human to human via the body louse. No animal reservoir exists. Lice that feed on infected humans acquire the Borrelia organisms that then multiply 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. B recurrentis infects the person 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 differ in two important ways from the more familiar hard ticks (eg, dog tick and deer tick). First, soft ticks feed for short periods (< 30 minutes), and the Borrelia organisms are inoculated within minutes. This is an important distinction from other tick-borne diseases such as Lyme disease. Second, soft ticks do not search for a prey in tall grass or bush; instead, they live within rodent burrows, feeding as needed on the rodent as it sleeps.^[1]

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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. ....

Regardless of the mode of transmission, a spirochetemia develops. Borrelia organisms 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 person clinically improves until the new clone multiplies sufficiently to cause another relapse. Tick-borne disease tends to have more relapses (average of 3) compared with 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.

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Epidemiology

Frequency

United States

Louse-borne relapsing fever is not endemic in the United States, although an occasional traveler presents 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 California and Colorado and northwest into Washington. Undoubtedly, many cases occur that either are misdiagnosed or unreported.

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Cases of Tick-borne Relapsing Fever - United States, 1990-2011. Courtesy of the Centers for Disease Control and Prevention (CDC).

International

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.^{[2, 3, 4, 5, 6]}

Louse-borne relapsing fever epidemics were common in Europe during the 20th century. Between 1919 and 1923, 13 million cases, resulting in 5 million deaths, occurred in social upheaval that overtook Russia and Eastern Europe. During World War II, a million cases occurred in North Africa. Today, louse-borne relapsing fever causes sporadic illness and outbreaks in sub-Saharan Africa, particularly in regions affected by war and in refugee camps.^{[7, 8, 9, 10]}

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%) than in females. The latter figure probably reflects the greater likelihood of males being exposed to ticks through recreational and occupational activities.

Age

A trend toward 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.

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Prognosis

The mortality rates of untreated louse-borne relapsing fever and tick-borne relapsing fever are range from 10%-70% and 4%-10%, respectively.

With prompt antibiotic treatment, the mortality rate of louse-borne relapsing fever and tick-borne relapsing fever decreases to 2%-5% and less than 2%, respectively.^[11]

The following features are associated with a poor prognosis:

• Stupor or coma on admission
• Diffuse bleeding
• Myocarditis
• Poor hepatic function
• Bronchopneumonia
• Coinfection with malaria, typhoid, or typhus

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Patient Education

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

For excellent patient education resources, see eMedicineHealth's patient education article Ticks.

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History

Relapsing fever develops abruptly, 3-18 days (average, 7-8 days) after exposure to the spirochete. The incubation period is approximately 7 days.

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.

High fever is typical.

Onset of symptoms generally is abrupt.

Two or more episodes of high fever occur, usually higher than 39°C.

Symptoms can recur, producing a telltale pattern of fever lasting roughly 3 days, followed by 7 days without fever, followed by another 3 days of fever. Without antibiotic treatment, this can repeat several times. In louse-borne relapsing fever, the first febrile episode is usually unremitting, lasting 3-6 days, and it is typically followed by a single milder episode. In tick-borne relapsing fever, multiple febrile periods last 1-3 days each. In both forms, the interval between febrile episodes ranges from 4-14 days.

The first fever episode usually ends with “crisis,” such as rigors, and is associated with labile blood pressures and pulse, lasting 15-30 minutes, followed by profuse diaphoresis, falling temperatures, and hypotension, typically over a few hours.^[12] Louse-borne relapsing fever normally produces fewer relapses (usually one relapse). Tick-borne relapsing fever produces an average of 3 relapses; however, in some cases more than 10 relapses occur.

Other symptoms are nonspecific. Headache is a very common symptom, occurring in nearly 95% of cases. Patients also complain of nausea, vomiting, and upper abdominal pain (due to liver and spleen involvement) during febrile episodes.

Myalgia and chills also occur in approximately 90% of cases.

The following are other potential symptoms:

• Arthralgia
• Joint aches
• Weakness
• Anorexia
• Weight loss
• Non-productive cough (more common in louse-borne relapsing fever)

Localizing neurologic symptoms (eg, flaccid paralysis, myelitis, radiculopathy, hemiplegia) are more common in tick-borne relapsing. There has been a case report of meningoencephalitis. Delirium can be seen in both tick-borne relapsing and louse-borne relapsing.^[13]

Over the last several years, acute respiratory distress syndrome (ARDS) has been reported in several patients with relapsing fever in North America.^[14]

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

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Physical

Physical findings are not diagnostic but may include the following:

• Fever (most common finding)
• Abdominal tenderness with hepatosplenomegaly
• Petechial, ecchymosis (more common in patients with louse-borne relapsing^[15] )
• Epistaxis (common in louse-borne disease)
• Abnormal lung findings (rales, rhonchi)
• Nuchal rigidity (more common in louse-borne relapsing): Neurological manifestations are believed to be secondary to spirochetemia rather than direct invasion of central nervous system.
• Lymphadenopathy^[16]
• Jaundice
• Iritis and iridocyclitis
• Gallop reflecting heart disease/myocarditis: Myocarditis appears to be common in both louse-borne relapsing and tick-borne relapsing and has been prominent in fatal cases.
• Neurologic findings are more common in tick-borne disease and include coma, cranial neuropathy (especially Bell palsy), hemiplegia, meningitis, and seizures. In louse-borne relapsing, neurological findings include nuchal rigidity, mental status changes, and neck stiffness.
• Rash is more common in tick-borne relapsing.

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Causes

Relapsing fever is caused by infection with the causative Borrelia species.

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Complications

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

JH reaction may occur.

ARDS may occur.

In pregnant women, premature labor, spontaneous abortion, and transplacental spread with neonatal death have all been reported.

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Approach Considerations

A diagnosis of relapsing fever in the emergency department should be considered in patients with a characteristic fever pattern (especially if accompanied with the crisis) and history of exposure to lice or ticks in geographic areas where tick-borne relapsing fever and louse-borne relapsing fever are endemic. 

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Laboratory Studies

The emergency department workup of relapsing fever focuses on ruling out other potential diagnoses. Basic laboratory studies such as complete blood cell (CBC) count, chemistry panel, and coagulation studies can be performed; however, most laboratory studies are nonspecific.

CBC count

CBC count usually reveals mild to moderate normocytic anemia and thrombocytopenia. The WBC count is usually within the reference range.

Coagulation studies

Coagulation studies usually show prolonged prothrombin time (PT) and partial thromboplastin time (PTT).

Chemistry panel

Chemistry panel can show increased liver function test (LFTs) and elevated bilirubin levels. In louse-borne relapsing fever, azotemia can occur.

In patients with CNS involvement, CSF studies show mononuclear pleocytosis and mildly elevated protein levels.^[17]

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Photomicrograph of a patient who presented to the ED with cyclical fevers and chills, which she developed while traveling in one of the recently forme....

Animal inoculation

Animal inoculation, which involves injection of blood into laboratory animals followed by examination of their blood, can be used when relapsing fever is suspected and spirochetes are not visually detected via smear. Inoculation of blood into weanling mice or mice with severe combined immunodeficiency (SCID) may yield Borrelia species in the blood or, less commonly, in cerebral spinal fluid (CSF), even between fever episodes.

For suspected tick-borne relapsing fever, blood, plasma, buffy coat, or CSF is injected intraperitoneally into the mouse. Infection of the mouse is enhanced by the SCID phenotype or by splenectomy. Blood of the inoculated mice should be examined daily for the presence of the spirochetes for seven days.^[18]

Peripheral blood smears

Relapsing fever is definitively diagnosed based on visualization of spirochetes in peripheral blood smears during fever episodes. Thus, thin and thick smears are the first tests performed for suspected relapsing fever. Peripheral smears yield a sensitivity of 70% (more sensitive in tick-borne relapsing fever than in louse-borne relapsing fever).^[14]

Both thick and thin smears using Wright and Giemsa stains may need to be examined.

The optimal time to obtain samples is during the onset of fever spikes.

This is the best way to secure the diagnosis in the emergency department.

Organisms are not found between relapses.

As many as 200 oil immersion fields should be viewed before judging the smear to be negative.

Thick smear is more sensitive.

Other tests

When relapsing fever is suspected but spirochetes are not directly visualized, laboratory confirmation requires techniques that are not available in most laboratories. Such techniques include animal inoculation, in vitro cultivation, wet mount, cultures, and polymerase chain reaction (PCR). 

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Imaging Studies

Imaging studies are not routinely useful, although chest radiography and hepatobiliary ultrasonography 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.

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Other Tests

Electrocardiography (ECG) may show a prolonged QTc interval.

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

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Histologic Findings

Spirochetes may be detected in tissue using silver stain. They may also be visualized using immunofluorescence.

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Approach Considerations

The antibiotics of choice in the treatment of relapsing fever penicillin and tetracyclines. There has been no evidence of acquired resistance to antibiotics.

The effectiveness of therapy can be assessed via serial testing of blood smears and observing the clearance of spirochetes from the blood. Most patients have undetectable spirochetes within 8 hours of the first dose of antibiotic.^[11]

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Emergency Department Care

Emergency department care of patients with relapsing fever focuses on establishing the diagnosis and excluding other treatable infections with which it can be confused. As mentioned in Workup, thin and thick smears are usually the first tests performed for suspected relapsing fever.

Louse-borne relapsing fever

Louse-borne relapsing fever is treated with the following:

• Tetracycline 500 mg PO as a single dose (12.5 mg/kg in children)
• Doxycycline 200 mg PO as a single dose (5 mg/kg in children)
• Intramuscular penicillin G procaine (400,000-800,000 units) as a single dose
• If tetracyclines are contraindicated, erythromycin 500 mg as a single dose (12.5 mg/kg in children)^[19]

The recurrence rate in patients receiving the above-mentioned therapy is less than 5%.

If the patient cannot tolerate oral administration, intravenous doxycycline 250 mg or 500 mg can be used.

Tetracycline is contraindicated in pregnant and nursing women and children younger than 9 years.

Tick-borne relapsing fever

Tick-borne relapsing fever is more sporadic than louse-borne relapsing fever.

The relapse rate of tick-borne relapsing fever after single dose of antibiotic is about 20% higher, which might result from probable invasion of the brain by spirochetes. Protected by the blood-brain barrier, spirochetes can reinvade the blood once antibiotic levels have fallen.

Treatment of tick-borne relapsing fever is the same as louse-borne relapsing fever, except the treatment duration is 7-10 days because the relapse rate is 20% after single-dose treatment.

Antibiotic choices for tick-borne relapsing fever include the following:

• Tetracycline 500 mg PO every 6 hours for 7-10 days
• Doxycycline 100 mg PO twice daily for 7-10 days
• If tetracyclines are contraindicated, erythromycin 500 mg PO every 6 hours for 7-10 days
• If CNS involvement is suspected, a beta-lactam antibiotic should be given intravenously: penicillin G (3 million units q4h for 7-10 days) or ceftriaxone 2 g IV once daily for 10-14 days or 1 g IV twice daily (for 10-14 days)

The efficacy of treatment can be measured by clearance of spirochetes in the blood, which usually occurs approximately 8 hours after antibiotic administration.^[11]

For patients in endemic regions, postexposure treatment with doxycycline can be used.

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Consultations

Consultation with an infectious diseases specialist may be appropriate.

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Prevention

No vaccine is available for either louse-borne relapsing fever or tick-borne relapsing fever. Thus, decreasing exposure is the major mean of preventing relapsing fever.

Avoid sleeping in rodent-infested buildings (rodent nests may not be visible).

Use insect repellent containing DEET or permethrin to prevent tick bites.

For patients in endemic regions, postexposure treatment with doxycycline can be used.

In 2006, Hasin et al published a study on postexposure prophylaxis with a 5-day course of doxycycline to prevent tick-borne relapsing fever. A 200-mg dose (day 1) followed by 100 mg daily for 4 more days had 100% efficacy (although the 95% confidence intervals were wide [46-100] because of small numbers of patients).^[20]

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

Chemical delousing may be required in epidemic situations.

For louse-borne relapsing fever, maintaining personal hygiene to avoid lice prevents the disease.

See Tick-borne Diseases, Introduction.

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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 with telemetry.

Be especially vigilant in monitoring for a JH reaction.

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Further Outpatient Care

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

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Medication Summary

In the treatment of relapsing fever, antimicrobials are the drugs of choice. However, following antimicrobial treatment, patients may develop a Jarisch-Herxheimer (JH) reaction, which can be severe, especially in louse-borne relapsing fever, when patients' host defenses may be otherwise compromised. This reaction has been reported to occur in 50% of patients with tick-borne relapsing fever.

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-α (TNF-α) may be partly responsible for the reaction.^[21] Preadministration of glucocorticoids does little to limit the JH reaction, but antibodies to TNF-α do help.

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

Antipyretics are indicated to reduce fever.

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Tetracycline (Sumycin)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Doxycycline (Doryx, Bio-Tab)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Erythromycin (Erythrocin, Ery-Tab)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Chloramphenicol (Chloromycetin)

• Dosing, Interactions, etc.

Clinical Context:  Is also useful for patients allergic to tetracycline. If a question of Rocky Mountain spotted fever exists, this is a useful drug.

Binds to 50S bacterial ribosomal subunits and interferes with or inhibits protein synthesis. Is effective against gram-negative and gram-positive bacteria.

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Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.^[22]

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Aspirin (Bayer Aspirin, Bufferin, Ascriptin)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Ibuprofen (Motrin, Nuprin)

• Dosing, Interactions, etc.

Clinical Context:  One of the few NSAIDs indicated for reduction of fever.

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Acetaminophen (Tylenol, Anacin Free Aspirin, Feverall)

• Dosing, Interactions, etc.

Clinical Context:  DOC for treatment of pain in patients with documented hypersensitivity to aspirin or NSAIDs, those with upper GI disease, or those taking oral anticoagulants.

Inhibits action of endogenous pyrogens on heat-regulating centers.

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Class Summary

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.

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