- Author: Kauser Akhter, MD; Chief Editor: Michael Stuart Bronze, MD more...
Relapsing fever, as the name implies, is characterized by recurrent acute episodes of fever. These are followed by periods of defervescence of increasing duration. The infection is caused by various spirochete species of the Borrelia genus. Spirochetes are a unique species of bacteria that also cause syphilis, Lyme disease, and leptospirosis. The fever relapses result from spirochetal antigenic variation. Relapsing fever, if untreated, may be fatal.
Relapsing fever is an arthropod-borne infection spread by lice (Pediculus humanus) and ticks (Ornithodoros species). Two main forms of this infection exist: tick-borne relapsing fever (TBRF) and louse-borne relapsing fever (LBRF).
TBRF is caused by 8 or more Borrelia species (eg, Borrelia hermsii, Borrelia turicatae, Borrelia parkeri,Borrelia duttonii), while LBRF is caused solely by Borrelia recurrentis.
TBRF and LBRF vary significantly in terms of epidemiology. A soft-bodied tick (Ornithodoros) transmits multiple Borrelia species that cause endemic relapsing fever, whereas the human body louse transmits B recurrentis, which causes an epidemic form of relapsing fever. Unlike hard ticks, Ornithodoros adult ticks are able to live for many years, feed repeatedly on blood meals, lay eggs, and perpetuate their life cycle. In addition, Ornithodoros ticks may survive long periods in a fasting state. In fact, Ornithodoros turicata ticks have been known to transmit spirochetes in the laboratory setting after 7 years without a blood meal.
Humans are the sole host of B recurrentis, while mammals (eg, cattle, pigs, prairie dogs, ground and tree squirrels, chipmunks) and reptiles (lizards, snakes, gopher tortoises) may serve as a reservoir for tick-borne Borrelia species.
The first reported case of TBRF in the United States was identified in 1905 in New York. The patient had previously traveled to Texas. In the United States, where fewer than 30 cases of TBRF are diagnosed each year, B hermsii and B turicatae cause most outbreaks. A recently discovered Borrelia species, Borrelia miyamotoi, has been found in hard-bodies ticks in regions where Lyme disease is endemic.
TBRF is reported worldwide, except Antarctica, Australia, and the Pacific Southwest.
LBRF is uncommon in the United States but is occasionally observed in travelers returning from endemic regions (see International). The last reported outbreak of LBRF in the United States occurred in 1871.
Spirochetes are wavy filamentous bacteria with one or more flagellae at each end. Most borrelial spirochetes measure 10-30 µm long X 0.2 µm wide. In TBRF, the spirochetes are transmitted via the bite of an infected tick, whereas, in LBRF, contact with hemolymph from the human body louse (eg, from scratching-induced louse crushing) is the mode of spirochete transfer.
Most Ornithodoros tick bites occur at night and go unnoticed in most individuals. Other described modes of transmission in the literature include blood transfusions, a laboratory worker who was bitten by an infected monkey with gingival bleeding, and intravenous drug use. In rare cases, transplacental transmission has been reported. The spirochete is not transmitted via aerosol, saliva, urine, feces, or semen.
The recently discovered B miyamotoi species is transmitted by tick bite and may be transmissible via blood transfusion. Recent data demonstrate that this species resists human complement-mediated killing.
Spirochetes enter breaks in the skin or mucous membranes, gain access to the vasculature, and disseminate to the spleen, bone marrow, liver, lungs, kidneys, and CNS. All it takes is a single spirochete to initiate the infectious process.
Borrelia species are able to induce cycles of disease by varying antigen expression and by displaying new outer-surface proteins during the disease course. The antigenic variants are referred to as serotypes. The proteins are named either variable small proteins or variable large proteins and are encoded within plasmid DNA. Alteration of these proteins prevents elimination of the spirochetes by the immune system, leading to recurrent febrile episodes. In 2008, Thein et al identified and described the first porin of relapsing fever, Oms38, which is present in the outer membranes of B hermsii, B turicatae, B duttonii, and B recurrentis.
Recent experiments in mice have shown that interleukin-10 (IL-10) may play a protective role in down-regulating inflammation and spirochete load.[11, 12] Extraordinarily high serum IL-10 levels have been found in patients with LBRF in whom the disease course is relatively mild. Hemorrhage and thrombosis were more commonly observed in IL-10–deficient mice.
TBRF has been reported in 14 states west of the Mississippi river, including Arizona, California, Colorado, Idaho, Kansas, Montana, Nevada, New Mexico, Oklahoma, Oregon, Texas, Utah, Washington, and Wyoming. It has also been reported in Ohio. TBRF usually occurs during the summer in people who are on vacation and/or who are traveling to mountainous regions (elevation >8000 ft). Cases of TBRF have been reported in persons inhabiting seasonally occupied lake areas and cabins infested with rodents and/or their ticks. During winter, the ticks are attracted to heat and carbon dioxide generated from indoor fires.
TBRF is endemic in Canada (southern portion of British Columbia), Mexico, Central and South America, central Asia, Africa, the Mediterranean region, and Russia.
LBRF is endemic in Ethiopia and Sudan, especially during the rainy season. The disease typically occurs in areas of war, famine, mass migrations, or overcrowding. Homeless people in crowded shelters are also at risk of LBRF. In a study of 930 homeless people in Marseilles, France, body lice were found in 22%, and immunoglobulin G (IgG) to B recurrentis was found in 15 individuals.
In the United States, TBRF carries a low mortality rate. Overall, TBRF carries a mortality rate of less than 2% (in treated patients) to 4-10% (in untreated individuals). LBRF carries a higher mortality rate, with a case-fatality rate of 4% (in treated patients) to 40% (in untreated individuals). Two species of Borrelia associated with a relatively high rate of relapsing fever–related fatality include B recurrentis (causes LBRF; found in Africa, South America, Europe, and Asia) and B duttoni (causes TBRF; found in East Africa and transmitted by the soft tick Ornithodoros moubata).
Natives of areas with LBRF endemicity usually experience a milder form of the disease than visitors.
Antibiotic treatment of relapsing fever commonly results in Jarisch-Herxheimer reaction (JHR; see Complications). This reaction tends to be more severe in patients with LBRF treated with penicillin. Pretreatment with steroids does not seem to alter this reaction.
Relapsing fever has no racial predilection.
Relapsing fever has no sexual predilection.
Barbour AG, Hayes SF. Biology of Borrelia species. Microbiol Rev. 1986 Dec. 50(4):381-400. [Medline].
Dworkin MS, Schwan TG, Anderson DE Jr, Borchardt SM. Tick-borne relapsing fever. Infect Dis Clin North Am. 2008 Sep. 22(3):449-68, viii. [Medline].
Wynns HL. The epidemiology of relapsing fever. Moulton FR. A Symposium on Relapsing Fever in the Americas. American Association for the Advancement of Science. Washington, DC: 1942. 100-5.
Blevins SM, Greenfield RA, Bronze MS. Blood smear analysis in babesiosis, ehrlichiosis, relapsing fever, malaria, and Chagas disease. Cleve Clin J Med. 2008 Jul. 75(7):521-30. [Medline].
Moursund WH. Historical introduction to the symposium on relapsing fever. Moulton FR. A Symposium on Relapsing Fever in the Americas. American Association for the Advancement of Science. Washington, DC: 1942. 1-6.
Barbour AG. Microbiology, pathogenesis, and epidemiology of relapsing fever. UpToDate. Available at http://www.uptodate.com/online/content/topic.do?topicKey=tickflea/11713&selectedTitle=2~15&source=search_result#references. Accessed: November 25, 2008.
Fuchs PC, Oyama AA. Neonatal relapsing fever due to transplacental transmission of Borrelia. JAMA. 1969 Apr 28. 208(4):690-2. [Medline].
Krause PJ, Hendrickson JE, Steeves TK, Fish D. Blood transfusion transmission of the tick-borne relapsing fever spirochete Borrelia miyamotoi in mice. Transfusion. 2014 Sep 23. [Medline].
Teegler A, Herzberger P, Margos G, Fingerle V, Kraiczy P. The relapsing fever spirochete Borrelia miyamotoi resists complement-mediated killing by human serum. Ticks Tick Borne Dis. 2014 Oct. 5(6):898-901. [Medline].
Thein M, Bunikis I, Denker K, Larsson C, Cutler S, Drancourt M, et al. Oms38 is the first identified pore-forming protein in the outer membrane of relapsing fever spirochetes. J Bacteriol. 2008 Nov. 190(21):7035-42. [Medline].
Gelderblom H, Schmidt J, Londoño D, Bai Y, Quandt J, Hornung R, et al. Role of interleukin 10 during persistent infection with the relapsing fever Spirochete Borrelia turicatae. Am J Pathol. 2007 Jan. 170(1):251-62. [Medline].
Londoño D, Marques A, Hornung RL, Cadavid D. Relapsing fever borreliosis in interleukin-10-deficient mice. Infect Immun. 2008 Dec. 76(12):5508-13. [Medline].
Centers for Disease Control and Prevention (CDC). Acute respiratory distress syndrome in persons with tickborne relapsing fever--three states, 2004-2005. MMWR Morb Mortal Wkly Rep. 2007 Oct 19. 56(41):1073-6. [Medline].
Platonov AE, Karan LS, Kolyasnikova NM, Makhneva NA, Toporkova MG, Maleev VV, et al. Humans infected with relapsing fever spirochete Borrelia miyamotoi, Russia. Emerg Infect Dis. 2011 Oct. 17(10):1816-23. [Medline].
Brouqui P, Stein A, Dupont HT, Gallian P, Badiaga S, Rolain JM, et al. Ectoparasitism and vector-borne diseases in 930 homeless people from Marseilles. Medicine (Baltimore). 2005 Jan. 84(1):61-8. [Medline].
Barbour AG. Clinical features and management of relapsing fever. UpToDate. Available at http://www.uptodate.com/online/content/topic.do?topicKey=tickflea/11413#1. Accessed: November 25, 2008.
Rhee KY, Johnson WD Jr. Borrelia species (relapsing fever). Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, PA: Churchill Livingstone; 2005. Vol 2: 2795-8.
Ramos JM, Reyes F, Tesfamariam A, Malmierca E. Louse-borne relapsing fever and malaria co-infection in Ethiopia. Trop Doct. 2007 Apr. 37(2):121-2. [Medline].
Nordstrand A, Bunikis I, Larsson C, Tsogbe K, Schwan TG, Nilsson M, et al. Tickborne relapsing fever diagnosis obscured by malaria, Togo. Emerg Infect Dis. 2007 Jan. 13(1):117-23. [Medline]. [Full Text].
ANDERSON TR, ZIMMERMAN LE. Relapsing fever in Korea; a clinicopathologic study of eleven fatal cases with special attention to association with Salmonella infections. Am J Pathol. 1955 Nov-Dec. 31(6):1083-109. [Medline].
Goubau PF. Relapsing fevers. A review. Ann Soc Belg Med Trop. 1984. 64(4):335-64. [Medline].
Southern PM, Sanford JP. Relapsing fever: a clinical and microbiological review. Medicine. 1969. 48:129-49.
Hovius JW, de Wever B, Sohne M, Brouwer MC, Coumou J, Wagemakers A, et al. A case of meningoencephalitis by the relapsing fever spirochaete Borrelia miyamotoi in Europe. Lancet. 2013 Aug 17. 382(9892):658. [Medline]. [Full Text].
Perine PL, Parry EH, Vukotich D, Warrell DA, Bryceson AD. Bleeding in louse-borne relapsing fever. I. Clinical studies in 37 patients. Trans R Soc Trop Med Hyg. 1971. 65(6):776-81. [Medline].
Dennis DT, Awoke S, Doberstyn EB, Fresh JW. Bleeding in louse-borne relapsing fever in Ethiopia; clinical and laboratory features in 29 patients. East Afr Med J. 1976 Apr. 53(4):220-5. [Medline].
Parola P, Raoult D. Ticks and tickborne bacterial diseases in humans: an emerging infectious threat. Clin Infect Dis. 2001 Mar 15. 32(6):897-928. [Medline].
van Dam AP, van Gool T, Wetsteyn JC. Tick-borne relapsing fever imported from West Africa: diagnosis by quantitative buffy coat analysis and in vitro culture of Borrelia crocidurae. J Clin Microbiol. 1999 Jun. 37(6):2027-30. [Medline].
Kelly R. Cultivation of Borrelia hermsi. Science. 1971 Jul 30. 173(995):443-4. [Medline].
Schwan TG, Gage KL, Karstens RH, Schrumpf ME, Hayes SF, Barbour AG. Identification of the tick-borne relapsing fever spirochete Borrelia hermsii by using a species-specific monoclonal antibody. J Clin Microbiol. 1992 Apr. 30(4):790-5. [Medline].
Fukunaga M, Okada K, Nakao M, Konishi T, Sato Y. Phylogenetic analysis of Borrelia species based on flagellin gene sequences and its application for molecular typing of Lyme disease borreliae. Int J Syst Bacteriol. 1996 Oct. 46(4):898-905. [Medline].
Jiang J, Temenak JJ, Richards AL. Real-time PCR duplex assay for Rickettsia prowazekii and Borrelia recurrentis. Ann N Y Acad Sci. 2003 Jun. 990:302-10. [Medline].
Uhlmann EJ, Seed PC, Schwan TG, Storch GA. Tick-borne relapsing fever polymerase chain reaction of tick-borne relapsing fever caused by Borrelia hermsii. Pediatr Infect Dis J. 2007 Mar. 26(3):267-9. [Medline].
Magnarelli LA, Anderson JF, Johnson RC. Cross-reactivity in serological tests for Lyme disease and other spirochetal infections. J Infect Dis. 1987 Jul. 156(1):183-8. [Medline].
Magnarelli LA, Meegan JM, Anderson JF, Chappell WA. Comparison of an indirect fluorescent-antibody test with an enzyme-linked immunosorbent assay for serological studies of Lyme disease. J Clin Microbiol. 1984 Aug. 20(2):181-4. [Medline].
Bryceson AD, Parry EH, Perine PL, Warrell DA, Vukotich D, Leithead CS. Louse-borne relapsing fever. Q J Med. 1970 Jan. 39(153):129-70. [Medline].
Pennington PM, Allred CD, West CS, Alvarez R, Barbour AG. Arthritis severity and spirochete burden are determined by serotype in the Borrelia turicatae-mouse model of Lyme disease. Infect Immun. 1997 Jan. 65(1):285-92. [Medline]. [Full Text].
Guerrier G, Doherty T. Comparison of antibiotic regimens for treating louse-borne relapsing fever: a meta-analysis. Trans R Soc Trop Med Hyg. 2011 Sep. 105(9):483-90. [Medline].
Horton JM, Blaser MJ. The spectrum of relapsing fever in the Rocky Mountains. Arch Intern Med. 1985 May. 145(5):871-5. [Medline].
CHERRY JK. The prevention and treatment of tick-borne relapsing fever with special reference to aureomycin and terramycin. Trans R Soc Trop Med Hyg. 1955 Nov. 49(6):563-73. [Medline].
Hasin T, Davidovitch N, Cohen R, Dagan T, Romem A, Orr N, et al. Postexposure treatment with doxycycline for the prevention of tick-borne relapsing fever. N Engl J Med. 2006 Jul 13. 355(2):148-55. [Medline].
Dworkin MS, Anderson DE Jr, Schwan TG. Tick-borne relapsing fever in the northwestern United States and southwestern Canada. Clin Infect Dis. 1998 Jan. 26(1):122-31. [Medline].
Scott R. Neurological complications of relapsing fever. Lancet. 1944. 247:436-8.
Cadavid D, Barbour AG. Neuroborreliosis during relapsing fever: review of the clinical manifestations, pathology, and treatment of infections in humans and experimental animals. Clin Infect Dis. 1998 Jan. 26(1):151-64. [Medline].
Wengrower D, Knobler H, Gillis S, Chajek-Shaul T. Myocarditis in tick-borne relapsing fever. J Infect Dis. 1984 Jun. 149(6):1033. [Medline].