Microbiology, pathogenesis, and epidemiology of relapsing fever

Microbiology, pathogenesis, and epidemiology of relapsing fever

Author
Alan G Barbour, MD
Section Editor
Daniel J Sexton, MD
Deputy Editor
Anna R Thorner, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Oct 2012. | This topic last updated: Aug 15, 2012.
INTRODUCTION 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) [1]. As the name implies, relapsing fever is characterized by recurrent episodes of fever
that accompanies spirochetemia.
The microbiology, pathogenesis, and epidemiology of relapsing fever will be reviewed here. The
clinical manifestations, diagnosis, treatment, and prevention of this disorder are discussed
separately. (See "Clinical features and management of relapsing fever".)
MICROBIOLOGY Tick-borne relapsing fever is caused by eight or more Borrelia species,
whereas louse-borne relapsing fever is caused only by B. recurrentis [2,3].
The agents of relapsing fever are spirochetes, a morphologically unique group of bacteria
species, which cause syphilis, leptospirosis, and Lyme disease [3]. As their own phylum of
bacteria, spirochetes differ substantially from both gram-negative and gram-positive organisms
[4]. (See "Pathophysiology, transmission, and natural history of syphilis" and "Microbiology,
epidemiology, clinical manifestations, and diagnosis of leptospirosis" and "Epidemiology of
Lyme disease".)
The agents of relapsing fever and Lyme disease are in the genus Borrelia [1]. Every known
species of Borrelia is host-associated; free-living forms have not been found. Borrelias are
usually extracellular in location within the host, but they pass through endothelial cell layers to
enter and leave the blood. Borrelia spp are susceptible to drying, hypotonic or hypertonic
conditions, dilute detergents, and temperatures above 40C.
Structure of the organisms Spirochetes are wavy or helical filaments in shape, with both inner
and outer cell membranes 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 [3]. Most members of
the genus Borrelia are approximately 0.2 microns in width and 10 to 30 microns in length. 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]. 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.
Borrelias lack classical endotoxin [5], but they do have outer membrane lipoproteins that are
potent B cell mitogens and stimulators of the release of pro-inflammatory cytokines, such as
tumor necrosis factor [6-9]. The lipoproteins are anchored at their amino-terminal ends by fatty
acids embedded in the fluid membrane of the spirochetes.
Cultivation Borrelias are microaerophilic microorganisms with complex nutritional
requirements for growth in cell-free medium [10,11]. The medium contains serum, glucose,
albumin, peptides, amino acids, vitamins, a thickening agent such as gelatin, and, critically, Nacetylglucosamine, the building block for an arthropod's chitin exoskeleton [12,13]. A
commonly used medium is Barbour-Stoenner-Kelly, or "BSK" [14]. B. recurrentis was only
successfully cultivated in the laboratory for the first time in 1997 [15], and some Borrelia species
have yet to be cultivated in serial passage outside of a natural or experimental host animal.
Genome and taxonomy A unique feature of the genus Borrelia is a largely linear genome
[16,17]. Each genome consists of a linear chromosome of about 1000 kilobases and one copy
each of different types of linear and circular plasmids [16-19]. All Borrelia species studied to
date have GC contents of approximately 30 percent [20].
The species of Borrelia causing relapsing fever and Lyme disease form two related but distinct
groups by DNA sequences of their ribosomal RNA genes and their genomes [4,15]. A phylogeny
of relapsing fever agents based upon DNA sequences has generally confirmed a taxonomy based
upon biological considerations [21] (table 1).
In the past, the different species of tick-borne relapsing fever agents were categorized according
to the species of tick that carried them in nature and their host range among ticks and
experimental animals in the laboratory [21]. The several tick-borne species are generally divided
between Old World (or Paleartic and Afrotropical) species, such as B. duttonii and B. crocidurae,
and New World (or Neartic and neotropical) species, such as B. hermsii and B. turicatae. It is
likely that additional species exist: in a study of patients with relapsing fever in Tanzania, 11 of
17 isolates were B. duttonii, but six were a new species [22]. The louse-borne B. recurrentis is
closely related to B. duttonii [15].
PATHOLOGY The spirochetes can be detected in tissue sections with silver stains, such as
Warthin-Starry or modified Dieterle, or by immunofluorescence with conjugated antibodies [2325]. Borrelias move through or between endothelial cells as they leave the blood to enter the
tissues, but they do not appear to proliferate in endothelial or phagocytic cells [26]. Spirochetes
have been found in the spleen, liver, brain, eye, and kidney in autopsy cases and experimentally
infected animals [27,28]. The severity of relapsing fever generally correlates directly with the
numbers of spirochetes in the blood [24].
In fatal cases of relapsing fever, the usual gross findings were widespread petechial
hemorrhages, enlarged spleen and liver, and an edematous, congested brain [27,28]. The most
common general findings on histologic examination of autopsy cases 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