Background
As the name implies, relapsing fever is a condition characterized by recurrent acute episodes of fever followed by intervening afebrile periods. [1, 2, 3, 4] It is an arthropod-borne infection caused by spirochetes of the Borrelia genus. Spirochetes are a unique species of bacteria that also cause syphilis, Lyme disease, and leptospirosis. [5] 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: tickborne relapsing fever (TBRF) [1, 2, 3] and louse-borne relapsing fever (LBRF). [4]
TBRF is caused by eight or more Borrelia species (eg, Borrelia hermsii, Borrelia turicatae, Borrelia parkeri,Borrelia duttonii), while LBRF is caused solely by Borrelia recurrentis. [1, 5]
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. [6] 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. [6]
Humans are the sole host of B recurrentis, whereas mammals (eg, cattle, pigs, prairie dogs, ground and tree squirrels, chipmunks) and reptiles (lizards, snakes, gopher tortoises) may serve as a reservoir for tickborne Borrelia species. [6]
Relapsing fever is found in the United States in domestic dogs residing in forest cabins. B turicatae [7] and the recently identified B hermsii have also been reported in domesticated dogs.
The first reported case of TBRF in the United States was identified in 1905 in New York. The patient had previously traveled to Texas. [8] In the United States, where fewer than 30 cases of TBRF are diagnosed each year, [9] 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. B miyamotoi may coexist with Borrelia burgdorferi [10, 11, 12] and Babesia. [12]
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. [13]
The pathophysiology, clinical manifestations, differential diagnoses, diagnostic work-up, and treatment of relapsing fever will be discussed here.
Pathophysiology
Spirochetes are wavy filamentous bacteria with one or more flagellae at each end. [5] 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. [1]
Most Ornithodoros tick bites occur at night and go unnoticed in most individuals. [14] 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. [6] In rare cases, transplacental transmission has been reported. [15] 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. [16] Recent data demonstrate that this species resists human complement-mediated killing. [17]
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 phenomenon of antigenic variation contributes to the recurring nature of relapsing fever. [1, 18]
These 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. [6] 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. [19]
The ability of a single spirochete to switch expression among antigenically distinct VSP and VLP genes allows escape from an individual host’s immune response. Allelic polymorphism or genetic variability of VSP and VLP genes within the total spirochete population may help to evade herd immunity. [20]
Recent experiments in mice have shown that interleukin-10 (IL-10) may play a protective role in down-regulating inflammation and spirochete load. [21, 22] Extraordinarily high serum IL-10 levels have been found in patients with LBRF in whom the disease course is relatively mild. [22] Hemorrhage and thrombosis were more commonly observed in IL-10–deficient mice. [22]
Epidemiology
Relapsing fever, caused by various species of Borrelia, is a notable public health concern in both the United States and globally.
United States
In the United States, tick-borne relapsing fever (TBRF) has been documented in numerous states, including Arizona, California, Colorado, Idaho, Kansas, Montana, Nevada, New Mexico, Oklahoma, Oregon, Texas, Utah, Washington, Wyoming, [23] and Ohio. TBRF cases typically peak during the summer months, particularly among individuals vacationing or traveling to mountainous regions at elevations above 8,000 feet. [23] Between 1990 and 2011, approximately 74% of TBRF cases had an onset from June to September, with a significant peak in July and August. In Texas, however, cases were more frequently reported from November to March, with some linked to spelunking activities. [24] During winter, ticks may be drawn indoors by heat and carbon dioxide from fires, [23] increasing the risk of exposure in cabins infested with rodents.
International
Globally, TBRF is endemic in regions such as southern British Columbia in Canada, Mexico, Central and South America, central Asia, Africa, the Mediterranean, and Russia. [25] Louse-borne relapsing fever (LBRF) is particularly prevalent in Ethiopia and Sudan, especially during the rainy season, and is often associated with conditions of war, famine, mass migrations, and overcrowding. [9] Vulnerable populations, including the homeless in crowded shelters, are at heightened risk; for instance, a study in Marseilles, France, found body lice in 22% of homeless individuals, with immunoglobulin G (IgG) to B recurrentis detected in 15 cases. [26] Recent outbreaks of LBRF have also been reported among asylum seekers from Eritrea in the Netherlands, Switzerland, and Germany, as well as among refugees from East Africa residing in Germany. [27, 28, 29, 30, 31]
The prevalence of Borrelia hispanica has been reported at 20.5% among febrile patients in northwestern Morocco, [32] while studies in Europe from 2003 to 2014 indicated that the prevalence of B miyamotoi among Ixodes ricinus ticks was as high as 3.2%. [33] These findings underscore the expanding geographic range and increasing incidence of relapsing fever, highlighting the need for enhanced surveillance and public health measures to effectively address this emerging threat.
Mortality/Morbidity
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). [34] LBRF carries a higher mortality rate, with a case-fatality rate of 4% (in treated patients) to 40% (in untreated individuals). [35] 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). [6]
Poor prognostic indicators include coma on admission, bleeding, myocarditis, hepatic failure, bronchopneumonia, or co-infection with malaria, [36, 37] typhus, or typhoid fever. [38]
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.
TBRF has been linked to complications during pregnancy, resulting in neonatal death (up to 50%), spontaneous abortion, and premature birth (see Complications). [39]
Race
Relapsing fever has no racial predilection.
Sex
Relapsing fever has no sexual predilection.
Prognosis
A mortality rate of 4-10% is associated with untreated tick-borne relapsing fever (TBRF), compared with 10-70% for louse-borne relapsing fever (LBRF). [40] An increased mortality rate is seen in patients who present with stupor or coma on admission, bleeding, myocarditis, poor liver function, malnutrition, bronchopneumonia, coinfection with typhus, typhoid, [41] or malaria. [42, 43] Immediate appropriate management results in a significant decrease in mortality rates, to less than 2% for TBRF, and 2-5% for LBRF. [40]
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Peripheral blood smear in relapsing fever. (Image originally printed in Blevins SM, Greenfield RA, Bronze MS. Blood smear analysis in babesiosis, ehrlichiosis, relapsing fever, malaria, and Chagas disease. Cleve Clin J Med. Jul 2008;75(7):521-30. Reprinted with permission from the Cleveland Clinic.)
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