Microbiology, pathogenesis, and epidemiology of relapsing fever

INTRODUCTION — Relapsing fever, which is caused by spirochetes of the genus Borrelia, is characterized by recurrent episodes of fever that accompany spirochetemia. It is an arthropod-borne infection that occurs in two major forms: tick-borne and louse-borne [1,2].

●Tick-borne relapsing fever is a zoonosis (ie, an animal disease that is transmissible to humans). The two main Borrelia spp involved in North America are Borrelia hermsii (in the mountainous West) and Borrelia turicatae (in the Southwest and South Central region), although rare cases of human infection with Borrelia parkeri have also been reported in the United States. Other tick-borne species cause relapsing fever on other continents.

●Louse-borne relapsing fever is caused by Borrelia recurrentis. It is principally a disease seen in the developing world. It is most commonly spread from person to person by the body louse and can result in large epidemics.

The microbiology, pathogenesis, and epidemiology of relapsing fever will be reviewed here. The clinical manifestations, diagnosis, treatment, and prevention of this disorder, as well as a related spirochete, Borrelia miyamotoi, are discussed separately. (See "Borrelia miyamotoi infection" and "Clinical features, diagnosis, and management of relapsing fever".)

MICROBIOLOGY

Taxonomy — The agents of relapsing fever are spirochetes, a morphologically unique group of bacteria that differ substantially from both gram-negative and gram-positive organisms [3]. Spirochetes can cause a diverse group of diseases, including syphilis, leptospirosis, Lyme disease, and B. miyamotoi infection. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV" and "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Epidemiology of Lyme disease".)

The agents that cause relapsing fever belong to the genus Borrelia, which is in the family Borreliaceae [4-6]. The other genus in the family Borreliaceae is Borreliella (previously known as "Borrelia burgdorferi sensu lato complex"), which includes several species that cause Lyme disease. (See "Microbiology of Lyme disease".)

The genus Borrelia comprises two major clusters classified on the basis of genome relatedness and vector associations:

●The first cluster includes Borrelia spp that are transmitted by soft (or argasid) ticks. Several species can cause tick-borne relapsing fever (TBRF). These species are divided into Old World (or Paleartic and Afrotropical) species, such as B. duttonii, B. crocidurae, and B. hispanica; and New World (or Neartic and Neotropical) species, such as B. hermsii and B. turicatae (table 1). It is also likely that additional species exist [7]. (See 'Tick-borne relapsing fever' below.)

A distinctive member of the first cluster is B. recurrentis, the sole louse-borne agent of relapsing fever. B. recurrentis is closely related to B. duttonii and B. crocidurae [4,6,8]. (See 'Louse-borne relapsing fever' below.)

●The second cluster includes Borrelia spp that are transmitted by hard (or ixodid) ticks, such as those in the genus Amblyomma. They cause an infection of the blood in the vector tick's vertebrate host, including mammals, birds, and reptiles. Only one, B. miyamotoi, is known to cause disease in humans. (See "Borrelia miyamotoi infection".)

Structure and biochemistry of the organisms — Spirochetes are wavy or helical in shape and are approximately 0.2 microns in width and 10 to 30 microns in length [9]. Their inner and outer cell membranes are separated by a periplasmic space. One or more flagella are inserted at each end and run the length of the organism through the periplasmic space [10].

The spirochetes are too thin to be seen in wet mounts by light microscopy, but can be visualized by phase microscopy or dark field microscopy [1,11]. For fixed blood smears, the spirochetes are detected by Wright or Giemsa stain. Borrelias have fewer and larger amplitude waves than the tightly-coiled treponemes and leptospires. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Microbiology' and "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Microbiology'.)

Borrelias lack a lipopolysaccharide-type endotoxin [12,13]. However, they have an abundance of bacterial lipoproteins that are potent stimulators of proinflammatory cytokines (eg, tumor necrosis factor and interleukin-6) through specific recognition by Toll-like receptors (TLRs), mainly TLR2 [14,15]. These lipoproteins are anchored by fatty acids at their amino-terminal ends, which are embedded in the membrane of the spirochetes.

A feature of Borreliaceae that distinguishes the family from other spirochetes and most other bacteria is a largely linear genome [16,17]. Each genome consists of a linear chromosome of about 1000 kilobases and different types of linear and circular plasmids.

A gene that differentiates Borrelia from Borreliella species is glycerophosphodiester phosphodiesterase, or GlpQ [18]. GlpQ is immunogenic and serves as the basis for a subunit immunoassay that serologically discriminates the Borrelia infection relapsing fever and B. miyamotoi disease from the Borreliella infection Lyme disease [19]. (See "Borrelia miyamotoi infection", section on 'Serology' and "Clinical features, diagnosis, and management of relapsing fever", section on 'Serologies'.)

Variable major proteins — The antigens that determine serotype identity of relapsing fever Borrelia spp are abundant outer membrane lipoproteins called variable major proteins (VMPs) [20,21]. In B. hermsii, for example, there are approximately 30 different VMPs [22]. There can be as little as 30 percent identity in amino acid sequences between two different VMPs of the same strain of a relapsing fever Borrelia spp [23]. This explains the lack of cross-reactivity between antisera raised against different serotypes [24]. (See 'Significance of serotypes' below.)

Genetics — In B. hermsii, there is a complete or near-complete gene for each VMP [22]. Only one VMP gene is expressed at a time in a cell. Expression of this gene occurs at a site near the end of a linear plasmid [23,25]. The other 30 or so VMP genes in the genome are also located on linear plasmids, but they are silent (ie, not expressed in this storage or archival form) [26]. The expression site, unlike the silent sites, has a promoter adjacent to the VMP gene [27].

During expansion of the population, a different VMP gene replaces the one at the expression site at a frequency of approximately 10^-4 per cell generation [24,28]. In other words, by the time the population size in an infection reaches around 10,000 organisms, a new serotype has probably appeared. The new serotype is still infrequent at the time the host responds to the infecting serotype with an outpouring of IgM antibodies. But the new serotype continues to proliferate while the original infecting serotype is cleared from the blood. Once the second serotype reaches a population size of 10,000 or so organisms in the animal, another one or two serotypes have spontaneously appeared. The antibodies do not cause the change in serotype; they merely select against the majority of cells in the population, allowing new serotypes to predominate.

Mechanisms of gene replacement — In B. hermsii, the most common way for a VMP gene at the expression site to be replaced by another VMP gene (thereby switching the serotype of the organism) is recombination between two linear plasmids [22,25,26]. A simplified representation of such a switch in VMP genes is shown in the figure (figure 1). The boundaries for this recombination are regions of sequence identity between silent and expression sites around and flanking the 5' and 3' ends of the expressed and silent VMP genes [22,28].

B. hermsii also has another type of VMP, known as the Variable Tick Protein (Vtp); its expression is specifically associated with the tick stage of its life cycle [29,30]. The Vtp gene with its own promoter is located on a different plasmid from those with other VMP genes [27,31]. Sequences of Vtp genes differ between strains and are used to distinguish between B. hermsii strains for epidemiologic purposes [32].

Cultivation — Borrelias are microaerophilic microorganisms with complex nutritional requirements for growth in cell-free medium [9]. The medium contains serum, glucose, albumin, peptides, amino acids, vitamins, a thickening agent such as gelatin, and, critically, N-acetylglucosamine [33,34]. A commonly used medium is Barbour-Stoenner-Kelly ("BSK") [35], or one its modifications [36]. The generation time is between 5 and 12 hours in BSK media. Otherwise, uncultivable organisms may be isolated and then propagated in immunodeficient mice.

EPIDEMIOLOGY — Tick-borne relapsing fever (TBRF) is usually characterized by sporadic cases or small outbreaks that are restricted in their geographic distribution. The risk of infection within a single country or state varies greatly. Travelers returning from endemic areas may develop the disease after return to their homes in other states, provinces, or countries, where physicians may be unfamiliar with the disease [37]. Louse-borne relapsing fever (LBRF) typically occurs as epidemics, and has been seen among refugees and migrants from Africa after their arrival in Europe [38,39].

Tick-borne relapsing fever — Tick-borne relapsing fever (TBRF) occurs on every continent except Antarctica, Australia, and the southwest Pacific (table 1). However, it is generally not found in tropical regions or in heavily urban areas.

●North America – TBRF has been reported in western Canada [40], northern Mexico [2], and the United States. In the United States, TBRF occurs almost exclusively west of the Mississippi River, particularly in the mountainous West and the high deserts and plains of the Southwest (figure 2) [41]. In the mountainous western United States, the onset of TBRF is most frequent during the summer, while in the Southwest, more cases occur in the late fall or winter. In a survey of 504 cases in the US from 1990 to 2011, TBRF was more common in males (57 percent), and there were peaks in the incidence among persons aged 10 to 14 and 40 to 44 years [41].

The Borrelia species that causes TBRF can vary depending upon the geographic location. As examples:

•B. hermsii typically causes infection in the mountains and foothills of California, Utah, Arizona, New Mexico, Nevada, Colorado, Oregon, and Washington. Infection is often acquired from exposure to cabins in pine forests at altitudes of 1000 to 3100 meters.

•B. turicatae is the usual agent of relapsing fever in the nonmountainous regions of the Southwest (eg, west, north, and central Texas [42,43]) and parts of New Mexico. Common exposures in this region include entering caves and crawling under houses [2,40].

●Africa – In Africa, TBRF is caused by B. crocidurae, which is transmitted by Ornithodoros erraticus [44-46], or by B. duttonii, which is transmitted by Ornithodoros moubata [47]. B. crocidurae is more common in western and northern Africa, and B. duttonii is more common in eastern, central, and southern Africa.

The incidence of TBRF in Senegal, Mali, and Mauritania of West Africa was evaluated through clinical surveillance and blood testing of individuals with fever from 1990 to 2003 [48]. The average incidence was 11 per 100 person-years, with a range of 4 in 1990 to 25 in 1997. Twenty-six of the 30 studied villages (87 percent) were colonized with the tick vector; the B. crocidurae infection rate of the vector was 31 percent.

●Other areas – TBRF has been reported on the Eurasian continent [49]. B. hispanica is present on the Iberian Peninsula and across the Strait of Gibraltar in Morocco [50-52]. Borrelia persica is transmitted by Ornithodoros tholozani ticks in the Middle East (including Israel), Iran, and Central Asia [53-55]. There has been comparatively little study of the epidemiology of Borrelia latyschewii infection in Russia and the former Soviet republics for over three decades. While TBRF from Borrelia venezuelensis has been described in South America [2], there have been few reports of it on that continent.

Louse-borne relapsing fever — B. recurrentis remains endemic in Ethiopia and probably exists in the Sudan and Somalia as well [56,57]. The highlands region of Ethiopia has many cases of louse-borne relapsing fever (LBRF) annually; the highest incidence is during the cold rainy season, when individuals with limited resources gather together for shelter and wear more layers of clothes. Lice move from one person to another, thus spreading the infection to new hosts. When LBRF spreads outside the Horn of Africa (eg, to Europe), true epidemics can occur [58].

Famine, war, and the movements and congregations of refugees are common predisposing factors for epidemics of LBRF. Under these conditions there is crowding, poor hygiene, few changes of clothing, and lack of access to washing. As an example, the large epidemics of LBRF during the 20^th century occurred around the two world wars, and millions of people were infected [2]. More recently, LBRF has been identified in refugees from northeast Africa who recently arrived in Europe [38,39,59,60].

Homeless people are also highly exposed to body lice in crowded shelters. A prospective study of 930 homeless people in Marseilles, France detected body lice in 22 percent and IgG antibodies to B. recurrentis in 15 (1.6 percent) [61].

TRANSMISSION — Borrelia infection most commonly begins after contact with a tick or louse bearing the spirochetes. Transplacental transmission from mother to fetus also occurs [62-64]. Rarely, relapsing fever is acquired through transfusion, accidental inoculation of infected blood, or contact of blood with abraded or lacerated skin, mucous membranes, or the conjunctiva [65]. The incubation period between the exposure and the first fever is between 3 and 12 days.

Transmission to humans by aerosol, fomites, human saliva, urine, feces, or sexual contact does not occur. In addition, Borrelia spp are susceptible to drying, hypotonic or hypertonic conditions, dilute detergents, and temperatures above 42°C.

Every known species of Borrelia is host associated; free-living forms have not been found [9]. However, some relapsing fever agents are transmitted vertically in the eggs of the female tick [66,67] and, thereby, may persist in an environment for several years without need for passage through a vertebrate host.

Tick-borne

Tick vector — The usual vectors of tick-borne relapsing fever (TBRF) are argasid ticks (soft ticks), usually of the Ornithodoros genus (figure 3) [68]. Ornithodoros ticks may live for up to 15 to 20 years and can survive without a blood meal for several years. (See 'Risk of acquiring infection' below.)

Ornithodoros ticks usually remain close to or near the habitations of animals (eg, rodents or domestic pigs) and humans [69]. Unlike the tick vectors of Lyme disease and Rocky Mountain spotted fever, they are not found on vegetation, in the forest, or on brush. (See "Epidemiology of Lyme disease", section on 'Tick vectors' and "Biology of Rickettsia rickettsii infection", section on 'Tick feeding status'.)

Ornithodoros ticks usually attach to humans residing in or visiting an infested house or other dwelling, or a cave. As an example, in western North America and southwestern United States, relapsing fever has been acquired entering caves, crawling under a building, or sleeping in or near rustic cabins, particularly those built of logs [41,70-73]. They can also attach to individuals sleeping near rodent nests at a campsite. In Africa, the Middle East, and parts of Asia, the ticks live in thatched roofs or in the cracks of mud walls or floors [44,53,74]. (See 'Epidemiology' above.)

Risk of acquiring infection — The risk of relapsing fever after a bite of an infected tick is approximately 50 percent. TBRF is acquired directly through the tick bite and from saliva secreted by the tick into the skin as it feeds.

For Ornithodoros ticks, the blood feeding itself takes 30 minutes or less and usually occurs at night. Consequently, most people are not aware of being exposed to or bitten by a soft tick. The only sign of an Ornithodoros tick bite may be a small red or violaceous papule with a central eschar that appears within a few days of the exposure. This is in contrast to the ixodid tick vectors, such as those that transmit Lyme disease, which feed for days at a time and attach to people during the day as they move through forested areas or bushy vegetation.

Vertebrate reservoirs — TBRF is maintained in the environment by vertebrate reservoirs, which harbor the spirochetes for weeks to months at a time [1]. These are usually rodents, such as chipmunks and tree and ground squirrels in North America [75]; other animal reservoirs include wild and domestic pigs, insectivores, and bats. In some areas of Africa, the natural reservoir for tick-borne B. duttonii includes humans. Ornithodoros ticks usually feed on just one type of animal during their lifetimes [68].

Louse-borne — Pediculus humanus corporis, the human body louse, was first recognized as the vector of B. recurrentis in the 19^th century [2]. It lives on clothing, not on the skin or hair [76,77]. The body louse coevolved with hominids and feeds only on humans. Lice must have frequent blood meals since they have a lifespan measured in weeks (unlike ticks that can live for years). B. recurrentis has also been found in Pediculus humanus capitus (the head louse), but its role in transmission has not been determined [78].

B. recurrentis grows in the body cavity of the louse but does not appear in the saliva or feces. When people crush a louse with their fingers, the organism is introduced at the bite site, into the skin of the crushing fingers, or into the conjunctivae when they rub their eyes. Nonhuman primates can also be infected with B. recurrentis; however, humans are probably the only reservoir of B. recurrentis.

PATHOGENESIS — Relapsing fever is primarily an extracellular infection of the bloodstream. Involvement of other organs, such as the central nervous system, the eye, and the liver, are the consequence of the large numbers of intravascular organisms migrating into tissues.

Initiation of infection and mechanism of relapse — A single spirochete may be sufficient to initiate an infection [79]. Once in the blood, the borrelias divide every 6 to 12 hours until they number 10⁶ to 10⁸ per mL of blood. The spirochetes move through or between endothelial cells as they leave the blood to invade the brain, eye, inner ear, liver, heart, testes, and other organs [80-82]. Although blood is the main site of replication during the acute illness, borrelias do not proliferate inside of endothelial or phagocytic cells [83].

During recurrence of fever, spirochetes can be easily seen by microscopic examination of the blood. They may be as numerous as erythrocytes on blood smears. Between febrile periods, borrelias do not completely disappear from the blood, but their numbers diminish to the point at which they are undetectable by microscopic examination of blood smears [24].

Antigenic variation accounts for the reappearance of spirochetes in the blood and the relapses of illness [83]. By changing a major antigen on its surface, the Borrelia population is able to stay one step ahead of the host adaptive immune response. Other vector-borne pathogens that use the strategy of multiphasic antigenic variation as a strategy to evade specific immunity are trypanosomes that cause African trypanosomiasis and Plasmodium species that cause malaria. (See "Human African trypanosomiasis: Treatment and prevention" and "Pathogenesis of malaria".)

Significance of serotypes — The antigens that determine serotype identity of relapsing fever Borrelia spp are abundant outer membrane lipoproteins called variable major proteins (VMPs). A detailed discussion of VMPs is found above. (See 'Variable major proteins' above.)

A single strain of a relapsing fever Borrelia species is able to produce several antigenically distinct variants called serotypes [22]. As an example, a mouse or human infected with one strain of relapsing fever Borrelia species may initially have serotype A in the blood, then have serotype B during the first relapse, and finally serotype C during a second relapse [84]. The order of serotype appearance is not rigidly fixed and is reversible. For instance, it may be A to B to C in one host, and B to A to C in another [28]. In passive transfer experiments, antiserum raised to a specific serotype (eg, A) protects mice against challenges with the homologous serotype but not against other serotypes (eg, B or C) [24,85].

Other pathogenetic mechanisms — During relapsing fever, there may be adherence of the spirochetes in the blood to erythrocytes or platelets [86,87]. This produces microaggregates that accumulate in small vessels, leading to organ dysfunction and splenomegaly. In addition, complement-mediated killing may be thwarted by different bacterial surface proteins that bind and tie up complement factors or regulators [88-90].

PATHOLOGY — Spirochetes have been found in the spleen, liver, brain, eye, and kidney at the time of autopsy in patients with relapsing fever and at the time of necropsy in experimentally infected animals [58,91,92]. Borrelia spp can be detected in tissue sections with silver stains, such as Warthin-Starry or modified Dieterle, by immunofluorescence with conjugated antibodies [93-95], or with polymerase chain reaction [11,96,97]. (See "Clinical features, diagnosis, and management of relapsing fever", section on 'Diagnostic methods'.)

The severity of relapsing fever generally correlates directly with the numbers (concentration) of spirochetes in the blood [94]. Gross findings in fatal cases of relapsing fever usually include widespread petechial hemorrhages, enlarged spleen and liver, and an edematous, congested brain [58,91]. The most common histologic findings at autopsy are swelling of endothelial cells, microvascular leakage, perivascular mononuclear cell infiltrates, microabscesses, and hemorrhages.

Fatal cases of louse-borne relapsing fever frequently have myocarditis with histiocytic infiltrates and microhemorrhages. The spleen and liver, but not the kidneys or adrenals, often have focal areas of necrosis. Although bleeding is a common complication of louse-borne relapsing fever, evidence of intravascular coagulation is not prominent.

IMMUNITY — IgM antibodies alone are sufficient to limit infection in infected animals [85,98]. Because specific antibodies to outer membrane proteins can kill these spirochetes in the absence of complement or phagocytes [99], deficiencies in the latter immune effectors may not be a major handicap to clearing borrelias from the blood. By contrast, absence of a spleen and impaired B-cell function may increase the severity of disease and prolong infection. (See "Primary humoral immunodeficiencies: An overview".)

Humans and other animals produce antibodies to a number of different components of the spirochetes during infection, including the glycerophosphodiester phosphodiesterase (GlpQ) protein [19]. However, only antibodies directed against the variable major proteins appear to be effective in controlling the disease [83]. (See 'Variable major proteins' above.)

Spirochetes are cleared from the blood with increasing concentrations of neutralizing antibodies in the serum. While antibodies alone may be sufficient, lysis of borrelias in the blood or spleen may be more rapid after opsonization and complement fixation [100]. This event is often accompanied by a "crisis," or worsening condition of the patient. This crisis phenomenon with fever and hypotension during relapsing fever is very similar to the Jarisch-Herxheimer reaction, which occurs soon after the start of antibiotic therapy [101,102]. (See "Clinical features, diagnosis, and management of relapsing fever".)

SUMMARY

●Relapsing fever, caused by spirochetes of the Borrelia genus, is an arthropod-borne infection that occurs in two major forms: tick-borne (TBRF) and louse-borne (LBRF). As the name implies, relapsing fever is characterized by recurrent episodes of fever that accompany spirochetemia. (See 'Introduction' above.)

●Borrelia recurrentis is the sole agent of LBRF. In contrast, there are at least 10 species that can cause TBRF; the two main ones in North America are Borrelia hermsii and Borrelia turicatae. (See 'Taxonomy' above.)

●Most members of the Borrelia genus are approximately 0.2 microns in width and 10 to 30 microns in length. They can be visualized by phase microscopy or dark field microscopy. For fixed blood smears, the spirochetes are detected by Wright or Giemsa stain. (See 'Structure and biochemistry of the organisms' above and 'Cultivation' above.)

●TBRF is usually characterized by sporadic cases or small outbreaks that are restricted in their geographic distributions. By contrast, LBRF often occurs as epidemics; famine, war, and the movement and congregation of refugees are common predisposing factors. (See 'Epidemiology' above.)

●The usual vectors of TBRF are argasid ticks of the Ornithodoros genus. The risk of acquiring relapsing fever after a bite from an infected tick is approximately 50 percent. The blood feeding itself takes 30 minutes or less and usually occurs at night. (See 'Tick-borne' above.)

●The vector of B. recurrentis is the body louse, Pediculus humanus corporis, which only feeds on humans. (See 'Louse-borne' above.)

●Borrelia infection begins with contact with a tick or louse bearing the spirochetes. Antigenic variation accounts for the reappearance of spirochetes in the blood, which also correlates with relapses of illness. By changing a major antigen on its surface, the Borrelia population is able to evade the host immune response. (See 'Pathogenesis' above.)

●Humans and other animals produce antibodies to a number of different components of the spirochetes during infection. However, only antibodies directed against the variable membrane proteins appear to be effective in controlling the disease. Spirochetes are cleared from the blood with increasing concentrations of neutralizing antibodies in the serum. (See 'Immunity' above and 'Variable major proteins' above.)