OVERVIEW: What every practitioner needs to know

Relapsing Fever is an arthropod-borne spirochetal infection characterized by recurring febrile episodes of a remitting nature. There are two forms: Tick-borne relapsing fever (TBRF), sometimes called endemic, and Louse-borne relapsing fever (LBRF) or epidemic. Both forms are caused by Borrelia species. This chapter will primarily address TBRF (with comments on LBRF).

Are you sure your patient has Relapsing Fever? What are the typical findings for this disease?

The most common symptoms: Sudden onset of fever, chills, malaise, with intervening afebrile periods
Other common symptoms: Headache, myalgias, arthralgias, nausea, vomiting, abdominal pain, confusion, dizziness

Crisis and relapse

After 3-6 days, fever terminates abruptly (crisis). Initially there may be a chill phase with high fever, delirium, confusion, tachycardia, and tachypnea (for 10-30 minutes). It is followed by flushing with abrupt decrease in temperature and drenching sweats. This may be associated with hypotension and shock. Rarely, there is a primarily truncal rash for 1-2 days.
Remission occurs for 4-14 days with little or no fever. There may be debilitating weakness.
Related Content
Relapse – often only one for LBRF; may be several for TBRF

Less common manifestations

Acute respiratory distress syndrome (TBRF)
Non-productive cough (LBRF)
Localizing neurologic signs/symptoms- hemiplegia, facial palsy, myelitis, radiculopathy, delirium, coma
Myocarditis
Deafness and ocular abnormalities such as uveitis

Physical Findings

Most physical findings are non-specific. Temperature is usually at least 39⁰C and may reach as high as 43°C. Other findings may include;

Epistaxis, petechiae, ecchymoses (LBRF)
Splenomegaly; less commonly hepatomegaly
Myocarditis – gallop on exam
Neurologic findings – unilateral or bilateral VII nerve palsies, deafness (often not with first episode)
Eye involvement – iridocyclitis to panophthalmitis

What other disease/condition shares some of these symptoms?

Epidemiologic features should help with differentiation from the following:

Malaria (may be concurrent in LBRF)

Typhoid fever

Hepatitis

Leptospirosis

Infectious mononucleosis

Rat-bite fever

Colorado tick fever

Dengue fever

Lyme disease

Brucellosis

Enteric cytopathic human orphan (ECHO) 9 infection

Bartonella infection

Ascending (intermittent) cholangitis

Chronic meningococcemia

African hemorrhagic fevers

Yellow fever

What caused this disease to develop at this time?

TBRF develops when Ornithodoros ticks infected with Borrelia species feed on humans. Most soft-bodied ticks usually feed on one type of animal, such as squirrels, during their lifetime. Humans are incidental hosts. These ticks remain near or close to the habitation of animals and humans; they are not found on vegetation. They are found on every continent except Antarctica, Australia, and the southwest Pacific.
LBRF is a disease of the developing world. The only host for the infected louse is human. The louse can live on clothing. LBRF is endemic in Ethiopia and the Sudan. Famine, war, and movement and congregation of refugees are risk factors.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Awareness of the epidemiology of the illness and recognition of the pattern of recurring fevers are crucial to the diagnosis of Relapsing Fever.
Confirmation of the diagnosis requires demonstration of spirochetes in the blood during an episode of fever. The organism can be seen using Wright’s stain or Giemsa stain. Examination of dehemoglobinized thick smears or buffy coat smears may increase yield. Use of acridine orange may also be helpful.
Intraperitoneal injection of infective blood into young mice or rats, with demonstration of the organism in 1-14 days, may be used to confirm the diagnosis (consult the Division of Vector-Borne Diseases, Centers for Disease Control and Prevention).
Serologic testing is not valuable for immediate diagnosis but is available through public health laboratories and the CDC. Patients with TBRF may have false positive tests for syphilis and Lyme disease.
Nonspecific laboratory abnormalities include elevated (or normal) white blood cell count with immature forms, mild to moderate thrombocytopenia, increased bilirubin, proteinuria, microhematuria, and prolongation of the prothrombin time (PT) and partial thromboplastin time (PTT).

Would imaging studies be helpful? If so, which ones?

Imaging studies are not helpful for diagnosis.

Confirming the diagnosis

There is no clinical algorithm available.

If you are able to confirm that the patient has Relapsing Fever, what treatment should be initiated?

RF has been treated successfully with tetracyclines, chloramphenicol, penicillin, and erythromycin. Resistance has not been reported. Treatment for TBRF is usually for 7 days, although duration of treatment is not well-studied. Before starting any regimen, the possibility of causing the Jarisch-Herxheimer reaction needs to be considered. For TBRF: Oral treatment is preferred.

Adolescents and children >8 years of age:

Tetracycline 500 mg four times a day

Doxycycline 100 mg twice a day (or 2 mg/kg/day in two divided doses up to 100 mg each)

Erythromycin 500 mg three times a day

Children < 8 years of age:

Erythromycin 30-50 mg/kg/day in four divided doses (preferred)

Azithromycin 20 mg/kg day 1, then 10 mg/kg days 2-5

Penicillin V 25-50 mg/kg/day in four divided doses

Severe cases (CNS involvement) or severe vomiting:

Ceftriaxone 75-100 mg/kg/day (max: 2 grams/day) IV for 1-2 weeks

Penicillin G parenteral aqueous 300,000 U/kg/day (max: 24 million units/day) in divided doses q4h for 1-2 weeks

Longer therapy up to 2 weeks for complicated patients; has not been studied

For LBRF: Single-dose treatment with tetracycline 500 mg is recommended except in pregnant women for whom the alternative is erythromycin 500 mg. Single-dose treatment for children has not been standardized.

Other considerations:

Evaluate and correct hydration status

Administer antipyretics as needed

Monitor for Jarisch-Herxheimer reaction

What are the adverse effects associated with each treatment option?

Treatment with doxycycline may be associated with a photosensitivity reaction (skin or, rarely, nails) and GI complaints. Macrolide treatment is most commonly associated with GI complaints. Allergy is the most common adverse reaction to the beta-lactam antibiotics. See Jarisch-Herxheimer reaction below.

Jarisch-Herxheimer Reaction

The Jarisch-Herxheimer reaction is commonly induced when treating relapsing fever. It is generally less severe in children. It is associated with severe rigors, leukopenia, increase in temperature, and hypotension. It appears to be an exaggeration of the crisis observed in untreated patients and is most severe in LBRF treated with penicillin. It is associated with the release of cytokines including TNFα, interleukins 6 and 8, as well as others. The first symptoms usually appear within 1-4 hours of the first dose of antibiotic.

Suggestions:

If possible, start treatment with antibiotics during an afebrile period when there is a lower load of organisms in the blood. However, treatment should not be inordinately delayed.

Monitor in an intensive care unit, if possible, with close attention to fluid status, blood pressure, and cardiac function for the first 6-12 hours.

Pretreatment with corticosteroids is ineffective.

Use of nonsteroidal antiinflammatory medications has been tried and may be helpful.

What are the possible outcomes of Relapsing Fever?

The mortality rate for treated relapsing fever (TBRF) is <5%. Most patients recover without sequelae. Rare patients have had ophthalmic scarring, renal problems, or neurologic abnormalities such as sensorineural hearing loss.

What causes this disease and how frequent is it?

TBRF is found throughout the world. It is endemic in the western US, British Columbia, the plateau regions of Mexico, Central and South America, the Mediterranean, Central Asia and much of Africa. The incidence is unknown in most countries. It is not a nationally reportable disease in the United States, although it is reportable in several states where it is endemic.
In the United States, exposure sites are typically in forested, mountainous regions in the West and in limestone caves in central Texas. Cases in western states mainly are associated with rustic cabins or vacation homes at higher elevations.
It usually occurs in summer months when people are vacationing in the mountains. It can occur in winter in rodent-infested cabins when people start fires, producing carbon dioxide and warmth that attract the ticks.
The organism is transmitted to humans through the bite of infected soft-bodied ticks of the genus Ornithodoros, which are distributed worldwide. These ticks take a brief blood meal lasting less than 30 minutes, usually at night. The bites are usually painless, and persons who are bitten while asleep are often unaware of a bite. Between meals, the ticks live in the nesting materials in their host burrows, often for many years. Individual ticks may take many blood meals during each stage in their life cycles, including the development of eggs by the adult females.
The individual Borrelia species are usually associated with a specific tick vector. Each tick has a preferred environment and set of hosts.
The incubation period from bite to symptoms is about 6 days.
LBRF occurs in epidemics, often associated with typhus. It is not seen in the western hemisphere. Epidemics have been associated with war, poverty, famine, and poor hygiene. With increased movement of refugees, many developed countries, particularly in Europe, are seeing patients with LBRF. It occurs commonly in winter. The disease is endemic in Ethiopia and is caused by B. recurrentis. It is transmitted from person to person by the human body louse, Pediculus humanus. After ingestion of an infective blood meal by the louse, the spirochetes penetrate the midgut and migrate to and multiply within the hemolymph. They remain viable throughout the life of the louse, for several weeks. Human infection occurs as a result of crushing the louse during scratching, allowing entry of the infected hemolymph through the abraded skin.

How do these pathogens/genes/exposures cause the disease?

The Borrelia species that cause relapsing fever are helical organisms that are motile. They are normally 0.2 microns in width and 10-30 microns in length. The three most common in the United States are B.hermsii, B. parkeri, and B. turicatae. Most human disease is caused by B. hermsii. The Borrelia species (TBRF) are named after the tick vector in which they reside.
Borrelias have the ability to generate repetitive cycles of disease through a phenomenon called antigenic variation. The outer membrane lipoproteins of these spirochetes have antigens called variable membrane proteins. The characteristic recurrent febrile episodes interspersed with relatively asymptomatic periods are associated with changes in these proteins that are encoded within the DNA of the linear plasmids. Serotype specific proteins are expressed sequentially one at a time, to which the host has a sequential immunologic response.
Organisms evade eradication by modification of these outer membrane surface antigens, thus facilitating recurrent febrile episodes. The number of relapses in untreated patients is dependent on the number of antigenic variants of the infecting strain.

What complications might you expect from the disease or treatment of the disease?

Most patients recover without sequelae. Poorer prognostic features include: stupor and coma on admission, diffuse bleeding, myocarditis, poor hepatic function, bronchopneumonia, and co-infection with typhus, typhoid, or malaria. Relapsing fever in pregnancy may lead to abortion or stillbirth. Pregnant women and infants tend to have more severe and prolonged illnesses. Rare patients have residual renal, neurologic, or ocular problems.

How can Relapsing Fever be prevented?

Prevention of RF requires avoidance or elimination of the arthropod vectors.

For TBRF:

The varied habitats over vast geographic areas populated by Ornithodoros ticks make total eradication impossible.

Insecticides can be used for dwellings such as log cabins and surrounding areas.

Avoid rodent-infested buildings for sleeping.

Wear long sleeves and long pants while sleeping in endemic areas.

Use permethrins on clothing.

Use insect repellent such as DEET on skin may further decrease exposure risks.

Report cases immediately, particularly if they can be traced to public recreational settings.

Prophylactic use of doxycycline for 5 days has been studied with positive results in Israel (B. persica). No prophylactic treatment studies have been done in children or in North America.

No vaccine is available.

For LBRF:

Decrease crowding and promote personal hygiene.

What is the evidence?

Dworkin, MS, Schwan, TG, Anderson, DE, Borchardt, SM. “Tick-borne relapsing fever”. Infect Dis Clin North Am. vol. 22. 2008. pp. 449-68.

Melkert, PW, Stel, HV. “Neonatal Borrelia infections (relapsing fever): report of 5 cases and review of the literature”. East Afr Med J. vol. 68. 1991. pp. 999-1005.

Guerrier, G, Doherty, T. “Comparison of antibiotic regimens for treating Louse-borne relapsing fever: a meta-analysis”. Trans R Soc Trop Med Hyg. vol. 105. 2011. pp. 483-490.

Moran-Gilad, J, Levine, H, Schwartz, E, Bartal, C. “Postexposure prophylaxis of tick-borne relapsing fever: lessons learned from recent outbreaks in Israel”. Vector Borne Zoonotic Dis. 2013. pp. 791-7.

Ongoing controversies regarding etiology, diagnosis, treatment

Because TBRF tends to be a sporadic disease, there are no well-controlled studies of diagnostic or treatment options. Because of the antigenic variation in the organism, vaccine development has been difficult.

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