Borrelia species (Relapsing Fever)

Authors: Peter J. Krause, M.D.

Authors, Second Edition: Teshale Seboxa, MD, M.SC (CTM); Daniel Fekade, M.D.


Relapsing fever is a group of infections caused by spirochetes in the genus Borrelia that are characterized by recurrent fever and found throughout the world (1151619242731323338424752,56596169707176788286). These Borrelia are transmitted either by lice (louse-borne relapsing fever or LBRF), soft-bodied ticks (soft tick-borne relapsing fever or STBRF), or hard bodied ticks (hard tick-borne relapsing fever or HTBRF). Distinct febrile episodes are accompanied by non-specific symptoms separated by periods of very mild symptoms or wellness (11516192427313233384247,5256596169707176788286). Relapse of fever and associated symptoms are caused by cycles of rising spirochetemia and an associated immune response characterized by diminution in the number of spirochetes, immune evasion by a subset of spirochetes, and a resurgence in spirochetemia.

Relapsing  fever borrelia are spirochetal bacteria whose spiral shape enhances their motility (Figure 1). They contain a linear chromosome and several linear and circular plasmids. Inner and outer cell membranes are separated by a periplasmic space that contains a bundle of flagella, which  are not surface exposed (8364991). Flagella  emerge from each end of the organism and overlap in the middle. They  are responsible for shape and motility. The most abundant surface lipoproteins of the outer membrane are variable major proteins (Vmps) that determine serotype identity (4568).  A change in the expression of variable major proteins enables relapsing fever borrelia to survive in vertebrate hosts and during transmission between a vertebrate host and arthropod vector (56877).  Alteration in variable major proteins allow escape from adaptive immune attack and sustained spirochetemia in mammalian reservoir hosts that helps perpetuate vector-host transmission (28-36).  Relapsing fever borreliarequire nutrients found in the extracellular environment in reservoir hosts and tick vectors to survive. These environments can be recreated using in vitro culture for propagation of Borrelia for research studies.


Louse-Borne Relapsing Fever

Lice transmit a single species of relapsing fever borrelia (Borrelia recurrentis) from person to person without an intermediate host. Episodic outbreaks of LBRF have been widely reported in Africa, Asia, Europe, and South America (15192752,  5970718286).  Louse-borne relapsing fever has caused massive epidemics in times of war and social disruption.  The most recent consisted of an estimated 13 million cases and 5 million deaths in Eastern Europe and Russia between 1919 and 1923 and more than a million cases and 50,000 thousand deaths in Europe and North Africa during World War II (5282).   Louse-borne relapsing fever is currently endemic only in Eritrea, Ethiopia, Somalia, and Sudan (152759707186).

Soft Tick-Borne Relapsing Fever

Soft bodied ticks (Argasidae) transmit several species of Borrelia including Borrelia hermsii and Borrelia turicatae in the US, Borrelia duttonii and Borrelia crocidurae in sub Saharan Africa, and Borrelia persicaBorrelia latyshevi, and Borrelia hispanica in Asia, Africa, and the Middle East (11624313233384759617678). These Borrelia are maintained in rodents and other mammals, including domestic farm animals. Birds also might serve as reservoir hosts. Transovarial transmission from female adults to their eggs allows survival of the Borrelia when reservoir hosts are scarce.  Soft ticks feed for less than an hour, usually at night when people are asleep, and are almost never detected.   Soft tick-borne relapsing fever is widespread and is found in North, Central and South America and in Africa, Asia, and Europe. STBRF cases have a focal distribution in the United States and occur throughout western North America and northern Mexico (Figure 2) (163132384778).Borrelia hermsii cases are predominantly associated with staying overnight in rustic cabins or other habitats where rodents have gotten into the walls or ceilings, rather than from camping in tents in the outdoors. B. turicatae is found primarily in the southwestern and south-central United States in desert or plains environments.  Most cases are acquired from entering caves or sleeping in caves.

Hard Tick-Borne Relapsing Fever

Hard-bodied ticks transmit the relapsing fever spirochete Borrelia miyamotoi   (132325303440424344485056576369737475808385)These same tick species also transmit Borrelia burgdorferi (the Lyme disease agent) and several other pathogens including Babesia microti and human granulocytic anaplasmosis. B. miyamotoi has been found in Ixodes scapularis in the northeastern and midwestern United States, Ixodes pacificus in the western United States, Ixodes ricinus in Europe, and Ixodes ovatusIxodes pavlovskyi, and Ixodes persulcatus in Asia. Human cases were first described in Russia in 2011 but have since been described in the United States, Europe, and Japan , (23424856576975).   Ixodes ticks feed over the course of several days, usually in the daytime, and are more easily detected than soft bodied ticks.

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The term “relapsing fever” denotes the clinical manifestation that distinguish louse-born relapsing fever (LBRF), soft tick-borne relapsing fever (STBRF), and hard-tick borne relapsing fever (HTBRF) from most other infectious diseases, namely episodes of high fever separated by periods of wellness (Figure 3). Up to 10 relapses may occur over several weeks or months if the diagnosis is missed and no antibiotic therapy is given (2732596978).  Alternatively, there may be only one relapse or no relapse in some patients, especially with LBRF and HTBRF. In the initial report of human B. miyamotoi infection where the diagnosis was confirmed in 46 patients with febrile illness, only five experienced relapsing fever (69).  It is possible that a greater number of these patients would have developed fever relapse had they not been treated early in the course of illness with antibiotics. In other respects, the clinical presentation of relapsing fever is highly variable. Although most patients experience a viral-like illness, some may have gastrointestinal symptoms and a few may develop central nervous system symptoms such as meningoencephalitis (223242485259).  The characteristic recurring episodes of fever are accompanied by non-specific symptoms, including headache, shaking chills, myalgia, arthralgia, and abdominal distress that last from 3 to 5 days with relapses that occur after 5 to 14 days of apparent recovery (Table 1) (1,161924273132333842475256596169717882). In the original case series of hard-tick borne relapsing fever, 10% of patients presented with an erythema migrans rash (69).  It is unclear whether the erythema migrans rash was due to coinfecting Lyme borreliosis or to B. miyamotoi, although no other relapsing fever Borrelia have been shown to cause erythema migrans. B. miyamotoi and B. burgdorferi coinfection have been documented in reports from the United States and Japan (5675).   B. burgdorferi and Babesia microti coinfection or B. burgdorferi and Anaplasma phagocytophilumcoinfection cause more severe acute disease than B. burgdorferi infection alone (115558). Further studies are needed to determine whether B. miyamotoi and B. burgdorferi coinfection increases relapsing fever disease severity.

Louse-born relapsing fever, soft tick-borne relapsing fever, and hard-tick borne relapsing fever borrelia infections are associated with a variety of possible complications because these pathogens can invade many different tissues and cause inflammation. Neurologic impairment is one of the most common complications of relapsing fever (2236424852). Both the central and peripheral nervous systems may be involved. Meningitis or meningoencephalitis are a result of direct invasion of the cerebrospinal fluid and brain tissue. Patients may have an acute episode of meningitis or a progressive deterioration in consciousness. Cranial neuritis may occur, especially the seventh or eighth cranial nerves that result in Bells’ palsy and decreased hearing. Infection and inflammation of the anterior portion of the eye (iridocyclitis) or more generalized eye involvement (panoptholmitis) have been reported (22).  Involvement of the nerves of the spinal cord (radiculopathy or myelitis) may occur. Cardiac manifestations of relapsing fever include myocarditis and cardiomegaly. Pulmonary complications consist of pneumonia and pulmonary edema. Hepatic impairment may result in hepatitis and hepatomegaly and can proceed to liver failure.  Bleeding may occur with epistaxis, petechiae, and ecchymosis due to thrombocytopenia, decreased clotting factors, or capillary obstruction by aggregation of Borrelia. Louse-born relapsing fever and soft tick-borne relapsing fever can be especially severe during pregnancy, resulting in abortion, stillbirth, and/or neonatal infection (1739576087).

Relapsing fever may cause death and is most commonly associated with LBRF. Fatality rates may exceed 40% in large epidemics among nutritionally and immunosuppressed populations during war or famine (19375982).  In contrast, the fatality rate of STBRF is 5% or less (31).

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The diagnosis of relapsing fever should be considered in any patient who develops a febrile illness, especially if recurrent; lives or travels in an endemic area; and/or has had recent exposure to body lice or soft-bodied or hard-bodied (Ixodes) ticks. Confirmation of the diagnosis can be made by identification of Borrelia on thin blood or CSF smear, amplification of relapsing fever Borrelia DNA using polymerase chain reaction (PCR), inoculation of blood into immunodeficient mice with subsequent identification of the organism as outlined above, or a four-fold rise in specific antibody in acute and convalescent sera (37425657697591). Giemsa or Wright stained thick or thin blood smears are most likely to be positive during a febrile episode. Amplification and identification of relapsing fever Borrelia DNA using PCR in blood or CSF samples is at least equal to or often more sensitive and specific than smear, however, PCR is less available, less rapid, and more labor intensive to perform than smear. The most reliable antibody test currently available is that based on B. miyamotoi GLPQ antigen (5679).   Like PCR, animal inoculation and antibody testing are not yet widely available.


Relapsing fever borrelia are transmitted by lice or ticks but also can be transmitted across the placenta or transmitted through accidental contact with infected blood. At least one case each of blood transfusion transmission with B. recurrentis and B. duttoni have been reported (4689). A recent study in mice suggests that B. miyamotoi also may be transmitted through blood transfusion (54).

Following initial transmission and proliferation of relapsing fever borrelia in the blood, antibody and other immune factors greatly decrease spirochetemia. A few remaining Borrelia are able to alter certain surface variable membrane lipoproteins, evade immune attack, and begin to proliferate. The new variant (serotype) elicits an altered immune response and the recrudescence of symptoms (45676572). A single strain of B. hermsii can produce up to 40 anitigenically distinct variable small (Vsp) and large (Vlp) membrane proteins. Certain strain variants are more efficient in their ability to invade neural tissue.


Relapsing fever Borrelia are microaerophilic and can be cultivated in cell free media but have complex nutritional requirements for growth (891).  In general, relapsing fever Borrelia are very susceptible to tetracyclines and penicillins and most cephalosporins and less susceptible to macrolids.   Minimum inhibitory concentrations of penicillin and tetracycline for Borrelia spp. generally are less than 0.1 µg/ml (2,9).  B. recurrentis was cultivated in the laboratory for the first time in 1997 and was found to be highly susceptible to tetracycline (MIC and MBC 0.006µg/ml); penicillin (MIC 0.2µg/ml and MBC 0.75µg/ml); and erythromycin (MIC 0.04µg/ml and MBC < 0.02µg/ml). The recently discovered B. miyamotoi has been cultured in vitro from isolates in Japan and the United States but information about in vitroantimicrobial susceptibility is not yet available.

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Doxycycline/tetracyclinepenicillin, most cephalosporins, and erythromycin are effective for the treatment of relapsing fevers (101314212829415362666781).  Borrelia species are susceptible tochloramphenicol and vancomycin but side effects of chloramphenicol and the poor CNS penetration of vancomycin limit their use. Azithromycin is likely to be effective but therapeutic trials have not been carried out.  Borrelia species are not susceptible to rifampin, metronidazole and sulfa drugs, and are relatively resistant to most quinolones and aminoglycosides. 

For louse-borne relapsing fever, single dose doxycycline (100 mg) or tetracycline (500 mg), or erythromycin stearate or ethyl succinate (500 mg), by mouth provide effective therapy and clear spirochetes from the circulation in 2-4 hrs (Table 2) (216267).  Doxycyclines/tetracyclines are preferred but should not be used in pregnant and nursing women and in children less than 9 years old. For all children, erythromycin (12.5 mg/kg up to 500 mg) by mouth is effective. For children older than 8 years old, doxycycline  (2 mg/kg up to 100 mg) or tetracycline (12.5 mg/kg up to 500 mg) can be used. If oral therapy cannot be given, parenteral treatment with intramuscular penicillin G procaine (600,000-800,000 units for adults and 400,000 units for children) can be given. The overall recurrence rate is less than 5% following antimicrobial therapy. 

For soft tick-borne relapsing fever or hard tick-borne relapsing fever, doxycycline or tetracycline given for 7 to 10 days are preferred treatments for patients who are non-pregnant, non-lactating, and older than 9 years. Although single dose therapy can be used (100 mg doxycycline or 500 mg tetracycline), there is some evidence that the recurrence rate may be unacceptably high for soft tick-borne relapsing fever (324782).  Doxycycline (100 mg or 4 mg/kg) twice daily or tetracycline (500 mg or 12.5 mg/kg) every 6 hours are given by mouth. Erythromycin (500 mg or 12.5 mg/kg) given orally every 6 hours is an alternative choice. For children less than 8 years of age, erythromycin is the drug of choice. For patients experiencing central nervous system involvement, parenteral beta-lactam antibiotics are administered. Patients with meningoencephalitis due to B. miyamotoi were successfully treated either with intravenous penicillin G 24 million units daily for 30 days of ceftriaxone 2 grams per day for 2 weeks (4248). 

Physicians need to be aware of the potential for a Jarisch-Herxheimer reaction when treating patients for relapsing fever because it occurs in 80-90% of patients with louse-borne relapsing fever and 30-40% of patients with soft tick-borne  relapsing fever, and can be life-threatening or fatal in some cases. Patients with this reaction experience an acute exacerbation of symptoms within 1 to 2 hours following the first dose of antibiotic (121820263564848890).  These include fever and chills followed by drenching sweats, hypotension, and exhaustion. It is thought that large numbers of bacteria are abruptly fragmented and killed with antibiotic therapy, exposing lipoprotein antigen that bind to macrophages and other cytokine producing cells, which in turn elicit an intense cytokine response. Circulating levels of tumor necrosis factor, interleukin-6 and interleukin-8 were increased by six and four fold, respectively from admission levels in patients with the Jarisch-Herxheimer reaction and there was a correlation between peak cytokine concentrations and the severity of the reaction (64). Most reactions are self-limited and can be managed using supportive therapy that consists of bed rest, antipyretics, and volume expansion for hypotension. Measures to kill Borrelia gradually will decrease the severity of the reaction, although they may prolong symptoms.  The use of penicillin in low dose is less likely to rapidly kill Borrelia than tetracyclines and results in less severe but more prolonged symptoms (2090). Treatment to block the reaction is more problematic. Meptazinol is an opiod with agonist properties that has been shown to lessen the severity of the reaction in louse-borne relapsing fever but the drug is not available in the United States (84).  Pretreatment with sheep anti–tumor necrosis factor (TNF), Fab antibody fragments suppresses Jarisch-Herxheimer reactions in louse-borne relapsing fever patients (35). Corticosteroids do not work very well, although prednisone and prednisolone have shown some beneficial effects in patients experiencing the reactions associated with treatment for syphilis (12). Regardless of the management approach, patients who experience evidence of this reaction should be monitored closely for the first 12 hours after the initial dose of antibiotic in the emergency room or hospital with IV access in place.

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Mortality rates for LBRF range from 10-70% and for STBRF range from 4-10% without treatment. These rates decrease with treatment to 2-5% and less than 2%, respectively (3259).  Spirochetes usually are cleared from the circulation by 24 hours following administration of antibiotics. Relapsing fever patients who are immunocompromised and those with CNS, cardiac, pulmonary or liver complications have a poorer prognosis and need to be followed more closely and for a longer duration.


There are no vaccines available for relapsing fever.


Preventive measures for louse-borne relapsing fever include avoiding contact with human body lice, good personal hygiene, delousing procedures, cutting hair short, laundering clothing and bedding material at 60°C with soap followed by ironing, and applying residual insecticides to clothing and bedding.  

Preventive measures for soft tick-borne relapsing fever include rodent-proof construction for dwellings in endemic areas. For unsatisfactory dwellings, removal of rodent nesting materials and liberal spraying of insecticides are useful. People traveling in endemic areas should be advised to avoid cabins or caves and natural areas inhabited by ticks and rodents and should use tick repellents. Sleeping on the floor or in a bed adjacent to walls should be avoided. People who are bitten by a soft-bodied tick in an area that is endemic for soft tick-borne relapsing fever may be protected if they take prophylactic antibiotic within 2 days of the exposure. For non-pregnant individuals over 9 years of age, doxycycline (200 mg orally the first day and then 100 mg a day for four days) or tetracycline (500 mg orally four times daily for 3 days) will decrease the risk of infection (45).

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Table 1. Manifestations of tick-borne relapsing fever acquired in the northwestern United States and southwestern British Columbia. (Adapted from Dworkin MS, Schwan TG, Anderson DE, Borchardt SM. Tick-borne relapsing fever. Inf Dis N Am 2008;22:449-468.13).

Sign or symptom % Sign or symptom %
Headache 94 Photophobia 25
Myalgia 92 Neck pain 24
Chills 88 Rash 18
Nausea 76 Dysuria 13
Arthralgia 73 Jaundice 10
Vomiting 71 Hepatomegaly 10
Abdominal pain 44 Splenomegaly 6
Confusion 38 Conjunctival injection 5
Dry cough 27 Eschar 2
Eye pain 26 Meningitis 2
Diarrhea 25 Nuchal rigidity 2
Dizziness 25    

Table 2. Antibiotic treatment of tick-borne and louse-borne relapsing fever in adults. (Adapted from Dennis DT, Hayes EB. Relapsing fever. In: Braunwald E, Hauser SL, Fauci AS, Longo DL, Kasper DL, Jameson JL, editors. Harrison’s principles of internal medicine. 16th edition. New York: McGraw-Hill; 2005).

Medication Tick-borne relapsing fever (7-day adult dosage schedule) Louse-borne relapsing fever (single dose)
Doxycycline 100 mg every 12 hours 100 mg
Erythromycin 500 mg every 6 hours 500 mg
Tetracycline 500 mg every 6 hours 500 mg
Doxycycline 100 mg every 12 hours 100 mg
Erythromycin 500 mg every 6 hours 500 mg
Penicillin G (procaine) 600,000 IU daily 600,000 IU
Tetracycline 250 mg every 6 hours 250 mg

* Parenteral medication should be continued until oral medication is tolerated. If oral medication is tolerated at the time of diagnosis, parenteral medication may not be necessary.

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