1418 PART 5 Infectious Diseases

Outbreaks may result from exposure to floodwaters contaminated

by urine from infected animals, as has been reported from several

countries. However, it is also true that outbreaks may occur without

floods, and floods often occur without outbreaks.

The vast majority of infections

with Leptospira cause no or only mild

disease in humans. A small percentage of infections (~1%) lead to severe,

potentially fatal complications. The

proportion of leptospirosis cases that

are mild is unknown because patients

either do not seek or do not have

access to medical care or because

the nonspecific symptoms are interpreted as an influenza-like illness.

Reported cases surely represent a

significant underestimation of the

total number. Certain occupational

groups are at especially high risk,

including veterinarians, agricultural

workers, sewage workers, slaughterhouse employees, and workers in the

fishing industry. Risk factors include

direct or indirect contact with animals, including exposure to water

and soil contaminated with animal

urine. Leptospirosis has also been

recognized in deteriorating inner cities

and suburban areas where rat and

mouse populations are expanding.

Recreational exposure and

domestic-animal contact are prominent sources of leptospirosis. Recreational freshwater activities, such as

canoeing, windsurfing, swimming,

and waterskiing, place persons at risk

FIGURE 184-2 Transmission electron microscopic image of Leptospira interrogans

invading equine conjunctival tissue. (Image kindly provided by Dr. JE Nally, National

Animal Disease Center, U.S. Department of Agriculture, Ames, IA.)

Approximate time scale

Incubation period

Incubation

Leptospires present in

Antibody titers

Laboratory investigations

Culture/PCR

PCR

Serology

Phases

High

Low

“Negative”

Blood

CSF

Urine

2-30 days

4 Months-years Years

Uveitis

? Interstitial nephritis

Convalescent shedder

Reservoir host

Titers decline at

varying rates Delayed

Normal response

Early treatment

Anamnestic

Convalescent

stage

Acute

stage

Fever

Blood

Urine

Urine

1 2 3 4 5

CSF

Week 1 2 3

Leptospiremia Leptospiruria and immunity

FIGURE 184-3 Biphasic nature of leptospirosis and relevant investigations at different stages of disease. Specimens

1 and 2 for serology are acute-phase serum samples; specimen 3 is a convalescent-phase serum sample that may

facilitate detection of a delayed immune response; and specimens 4 and 5 are follow-up serum samples that can provide

epidemiologic information, such as the presumptive infecting serogroup. CSF, cerebrospinal fluid. (Republished with

permission of American Society for Microbiology, from Leptospirosis, PN Levett, 14:296, 2001; permission conveyed through

Copyright Clearance Center, Inc.)

for infection. Several outbreaks have followed sporting events. For

example, an outbreak took place in 1998 among athletes after a triathlon in Springfield, Illinois. Ingestion of one or more swallows of

lake water during the swimming leg of the triathlon was a prominent

risk factor for illness. Heavy rains that preceded the triathlon, with

consequent agricultural runoff, are likely to have increased the level of

leptospiral contamination in the lake water. In another outbreak, 42%

of participants contracted leptospirosis during the 2000 Eco-Challenge-Sabah multisport endurance race in Malaysian Borneo. Swimming in the Segama River was shown to be an independent risk factor.

Furthermore, outbreaks among athletes participating in the recently

popular mud-runs are increasingly reported.

In addition, leptospirosis is a traveler’s disease. Large proportions

of patients acquire the infection while traveling in tropical countries,

usually during adventurous activities such as whitewater rafting, jungle

trekking, and caving. Recent data from the GeoSentinel Global Surveillance Network described in detail 180 returned travelers (mostly male;

74%) with leptospirosis from January 1997 through December 2016.

Infection was predominantly acquired in Southeast Asia (52% [n=93];

mainly [n=52] from Thailand); overall 110 patients (59%) were hospitalized, and one patient died. Transmission via laboratory accidents

has been reported but is rare. New data indicate that leptospirosis may

develop after unanticipated immersion in contaminated water (e.g.,

in an automobile accident) more frequently than has generally been

thought and can also result from an animal bite.

■ PATHOGENESIS

Transmission occurs through cuts, abraded skin, or mucous membranes, especially the conjunctival and oral mucosa. After entry, the

highly motile organisms proliferate, cross tissue barriers, and disseminate hematogenously to all organs (leptospiremic phase). During

this initial incubation period, leptospires can be isolated from the

bloodstream (Fig. 184-3). Clearly, Leptospira are able to survive in

the nonimmune host by evading parts of the innate immune response

such as complement-mediated killing and phagocytosis; however,

1419CHAPTER 184 Leptospirosis

earlier studies have highlighted the relation between an exaggerated

proinflammatory immune response and mortality. During the immune

phase, the appearance of antibodies coincides with the disappearance

of leptospires from the blood. However, the bacteria persist in various

organs, including liver, lung, kidney, heart, and brain. Autopsy findings

illustrate the involvement of multiple organ systems in severe disease.

Renal pathology shows both acute tubular damage and interstitial

nephritis. Acute tubular lesions progress in time to interstitial edema

and acute tubular necrosis. Severe nephritis is observed in patients

who survive long enough to develop it and seems to be a secondary

response to acute epithelial damage. The reported deregulation of the

expression of several transporters along the nephron contributes to

impaired sodium absorption, tubular potassium wasting, and polyuria. Histopathology of the liver shows focal necrosis (widespread

hepatocellular necrosis is usually not found), foci of inflammation,

and plugging of bile canaliculi. Hepatocyte apoptosis has also been

documented. Experimental work showed infiltration of Leptospira in

Disse space (perisinusoidal space) and migration between hepatocytes with detachment of the intercellular junctions and disruption

of bile canaliculi leading to bile leakage. Petechiae and hemorrhages

are observed in the heart, lungs (Fig. 184-4), kidneys (and adrenals),

pancreas, liver, gastrointestinal tract (including retroperitoneal fat,

mesentery, and omentum), muscles, prostate, testes, and brain (subarachnoid bleeding). Several studies show an association between hemorrhage and thrombocytopenia. Although the underlying mechanisms

of thrombocytopenia have not been elucidated, it seems likely that

platelet consumption plays an important role. A consumptive coagulopathy may occur, with elevated markers of coagulation activation

(thrombin–antithrombin complexes, prothrombin fragments 1 and 2,

d-dimer), diminished anticoagulant markers (antithrombin, protein

C), and deregulated fibrinolytic activity. Overt disseminated intravascular coagulation (DIC) has been documented in several studies.

Elevated plasma levels of soluble E-selectin and von Willebrand

factor in patients with leptospirosis reflect endothelial cell activation.

Experimental models show that pathogenic leptospires or leptospiral

proteins are able to activate endothelial cells in vitro and to disrupt

endothelial-cell barrier function, promoting dissemination. Platelets

have been shown to aggregate on activated endothelium in the human

lung, whereas histology reveals swelling of activated endothelial cells

but no evident vasculitis or necrosis. Immunoglobulin and complement deposition have been demonstrated in lung tissue involved in

pulmonary hemorrhage.

Leptospira species have a typical double-membrane cell wall structure harboring a variety of membrane-associated proteins, including

an unusually high number of lipoproteins. The peptidoglycan layer is

located close to the cytoplasmic membrane. The lipopolysaccharide

(LPS) in the outer membrane has an unusual structure with relatively low endotoxic potency. However, host immunity depends on

the production of circulating antibodies to serovar-specific LPS. It is

unclear whether other antigens play a significant role in protective

humoral immunity.

Pathogenic Leptospira contain a variety of genes coding for proteins

involved in motility and in cell and tissue adhesion and invasion that

represent (potential) virulence factors. Many of these are surfaceexposed outer-membrane proteins (OMPs). It is likely that several

surface-exposed proteins mediate pathogen–host cell interactions, and

these proteins may represent candidate vaccine components. Although

animal-model studies have shown various degrees of vaccine efficacy

for various putative virulence-associated OMPs, it is not yet clear

whether such proteins elicit acceptable levels of sterilizing immunity.

Ongoing breakthroughs in genetic manipulation of Leptospira and

whole-genome sequencing will undoubtedly provide more insight into

the biology and virulence of this pathogen.

■ CLINICAL MANIFESTATIONS

Although leptospirosis is a potentially fatal disease with bleeding and

multiorgan failure as its clinical hallmarks, the majority of cases are

thought to be relatively mild, presenting as the sudden onset of a febrile

illness. The incubation period is usually 1–2 weeks but ranges from 2 to

30 days. Leptospirosis is classically described as biphasic. The acute leptospiremic phase is characterized by fever of 3–10 days’ duration, during

which time the organism can be cultured from blood and detected by

polymerase chain reaction (PCR). During the immune phase, resolution of symptoms may coincide with the appearance of antibodies, and

leptospires can be cultured from the urine. The distinction between the

first and second phases is not always clear: milder cases do not always

include the second phase, and severe disease may be monophasic and

fulminant. The idea that distinct clinical syndromes are associated with

specific serogroups has been refuted, although some serovars tend to

cause more severe disease than others.

Mild Leptospirosis Most patients are asymptomatic or only

mildly ill and do not seek medical attention. Serologic evidence of

past inapparent infection is frequently found in persons who have

been exposed but have not become ill. Mild symptomatic leptospirosis

usually presents as a flulike illness of sudden onset, with fever, chills,

headache, nausea, vomiting, abdominal pain, conjunctival suffusion

(redness without exudate), and myalgia. Muscle pain is intense and

especially affects the calves, back, and abdomen. The headache is

intense, localized to the frontal or retroorbital region (resembling that

occurring in dengue), and sometimes accompanied by photophobia.

Aseptic meningitis may be present and is more common among children than among adults. Although Leptospira can be cultured from

the cerebrospinal fluid (CSF) in the early phase, the majority of cases

follow a benign course with regard to the central nervous system;

symptoms disappear within a few days but may persist for weeks.

Physical examination may include any of the

following findings, none of which is pathognomonic for leptospirosis: fever, conjunctival suffusion, pharyngeal injection, muscle tenderness,

lymphadenopathy, rash, meningismus, hepatomegaly, and splenomegaly. If present, the rash is often

transient; may be macular, maculopapular, erythematous, or hemorrhagic (petechial or ecchymotic);

and may be misdiagnosed as due to scrub typhus

or viral infection. Lung auscultation may reveal

crackles. Mild jaundice may be present.

The natural course of mild leptospirosis usually

involves spontaneous resolution within 7–10 days,

but persistent symptoms have been documented.

In the absence of a clinical diagnosis and antimicrobial therapy, the mortality rate in mild leptospirosis is low.

Severe Leptospirosis Although the onset of

severe leptospirosis may be no different from that

of mild leptospirosis, severe disease is often rapidly

FIGURE 184-4 Severe pulmonary hemorrhage in leptospirosis. Left panel: Chest x-ray. Right panel:

Gross appearance of right lower lobes of lung at autopsy. This patient, a 15-year-old from the Peruvian

Amazonian city of Iquitos, died several days after presentation with acute illness, jaundice, and hemoptysis.

Blood culture yielded Leptospira interrogans serovar Copenhageni/Icterohaemorrhagiae. (Adapted with

permission from E Segura et al: Clin Infect Dis 40:343, 2005. © 2005 by the Infectious Diseases Society of

America.)

1420 PART 5 Infectious Diseases

progressive and is associated with a case–fatality rate ranging from 1%

to 50%. Higher mortality rates are associated with an age >40 years,

altered mental status, acute renal failure, respiratory insufficiency,

hypotension, and arrhythmias. The classic presentation, often referred

to as Weil’s syndrome, encompasses the triad of hemorrhage, jaundice,

and acute kidney injury.

Patients die of septic shock with multiorgan failure and/or severe

bleeding complications that most commonly involve the lungs (pulmonary hemorrhage), gastrointestinal tract (melena, hemoptysis),

urogenital tract (hematuria), and skin (petechiae, ecchymosis, and

bleeding from venipuncture sites). Pulmonary hemorrhage (with or

without jaundice) is now recognized as a widespread public health

problem, presenting with cough, chest pain, respiratory distress, and

hemoptysis that may not be apparent until patients are intubated.

Jaundice occurs in 5–10% of all patients with leptospirosis; it can be

profound and give an orange cast to the skin but usually is not associated with fulminant hepatic necrosis. Physical examination may reveal

an enlarged and tender liver.

Acute kidney injury is common in severe disease, presenting after

several days of illness, and can be either nonoliguric or oliguric. Typical electrolyte abnormalities include hypokalemia and hyponatremia.

Loss of magnesium in the urine is uniquely associated with leptospiral

nephropathy. Hypotension is associated with acute tubular necrosis,

oliguria, or anuria, requiring fluid resuscitation and sometimes vasopressor therapy. Hemodialysis can be lifesaving, with renal function

typically returning to normal in survivors.

In severe leptospirosis, an altered mental status may reflect leptospiral meningitis. The diagnosis of leptospirosis meningitis may be

challenging since patients may be anicteric, or lack other diagnostic

hallmarks of severe leptospirosis. Without proper antibiotic treatment,

a mortality rate of 13% has been reported; in contrast, among patients

treated with antibiotics, the mortality rate is 2%. Neurologic sequelae

are described until months after acute illness.

Other syndromes include (necrotizing) pancreatitis, cholecystitis,

skeletal muscle involvement, and rhabdomyolysis with moderately elevated serum creatine kinase levels. Cardiac involvement is commonly

reflected on the electrocardiogram as nonspecific ST- and T-wave

changes. Repolarization abnormalities and arrhythmias are considered

poor prognostic factors. Myocarditis has been described. Rare hematologic complications include hemolysis, thrombotic thrombocytopenic

purpura, and hemolytic-uremic syndrome.

Long-term symptoms following severe leptospirosis include fatigue,

myalgia, malaise, and headache and may persist for years. Autoimmuneassociated uveitis, a potentially chronic condition, is a recognized sequela

of leptospirosis.

■ DIAGNOSIS

The clinical diagnosis of leptospirosis should be based on an appropriate exposure history combined with any of the protean manifestations

of the disease. Returning travelers from endemic areas usually have

a history of recreational freshwater activities or other mucosal or

percutaneous contact with contaminated surface waters or soil. For

nontravelers, recreational or accidental water/soil contact and occupational hazards that involve direct or indirect animal contact should be

explored (see “Epidemiology,” above).

Although biochemical, hematologic, and urinalysis findings in

acute leptospirosis are nonspecific, certain patterns may suggest the

diagnosis. Laboratory results usually show signs of a bacterial infection, including leukocytosis with a left shift and elevated markers of

inflammation (C-reactive protein level, procalcitonin, and erythrocyte

sedimentation rate). Thrombocytopenia (platelet count ≤100 × 109

/L)

is common and is associated with bleeding and renal failure. In severe

disease, signs of coagulation activation may be present, varying from

borderline abnormalities to a serious derangement compatible with

DIC as defined by international criteria. The kidneys are invariably

involved in leptospirosis. Related findings range from urinary sediment changes (leukocytes, erythrocytes, and hyaline or granular casts)

and mild proteinuria in mild disease to renal failure and azotemia in

severe leptospirosis. Nonoliguric hypokalemic renal insufficiency (see

“Clinical Manifestations,” above) is characteristic of early leptospirosis.

Serum bilirubin levels may be high, whereas rises in aminotransferase

and alkaline phosphatase levels are usually moderate. Although clinical

symptoms of pancreatitis are not a common finding, amylase levels are

often elevated. When symptoms of meningitis develop, examination

of the CSF shows pleocytosis that can range from a few cells to >1000

cells/μL, with a predominance of lymphocytes. Predominant polymorphonuclear pleocytosis has been reported. This phenomenon may be

related to the timing of the lumbar puncture: polymorphonuclear cells

are thought to be found in early disease and are later replaced by lymphocytes. Although protein and glucose levels in the CSF are usually

normal, protein levels may be slightly elevated.

In severe leptospirosis, pulmonary radiographic abnormalities are

more common than would be expected on the basis of physical examination (Fig. 184-4). The most common radiographic finding is a patchy

bilateral alveolar pattern that corresponds to scattered alveolar hemorrhage. These abnormalities predominantly affect the lower lobes. Other

findings include pleura-based densities (representing areas of hemorrhage) and diffuse ground-glass attenuation typical of acute respiratory

distress syndrome (ARDS).

A definitive diagnosis of leptospirosis is based on isolation of the

organism from the patient, on a positive result in the PCR, or on seroconversion or a rise in antibody titer. In cases with strong clinical evidence of infection, a single antibody titer of 1:200–1:800 (depending on

whether the case occurs in a low- or high-endemic area) in the microscopic agglutination test (MAT) is required. Preferably, a fourfold or

greater rise in titer is detected between acute- and convalescent-phase

serum specimens. Antibodies generally do not reach detectable levels

until the second week of illness. The antibody response can be affected

by early treatment with antibiotics.

The MAT, which uses a battery of live leptospiral strains, and the

enzyme-linked immunosorbent assay (ELISA), which uses a broadly

reacting antigen, are the standard serologic procedures. The MAT usually is available only in specialized laboratories and is used for determination of the antibody titer and for tentative identification of the

involved leptospiral serogroup—and, when epidemiologic background

information is available, the putative serovar. This point underscores

the importance of testing antigens representative of the serovars prevalent in the particular geographic area. However, cross-reactions occur

frequently, and thus definitive identification of the infecting serovar or

serogroup is not possible without isolation of the causative organism.

Because serologic testing lacks sensitivity in the early acute phase of the

disease (up to day 5), it cannot be used as the basis for a timely decision

about whether to start treatment.

In addition to the MAT and the ELISA, various rapid tests with

diagnostic value have been developed, and some of these are commercially available. These rapid tests mainly apply lateral flow, (latex)

agglutination, or ELISA methodology and are reasonably sensitive

and specific, although results reported in the literature vary, probably

as a consequence of differences in test interpretation, (re)exposure

risks, serovar distribution, and the use of biased serum panels. These

methods do not require culture or MAT facilities and are useful in

settings that lack a strong medical infrastructure. PCR methodologies,

notably real-time PCR, have become increasingly widely implemented.

Compared with serology, PCR offers a great advantage: the capacity to

confirm the diagnosis of leptospirosis with a high degree of accuracy

during the first 5 days of illness.

■ DIFFERENTIAL DIAGNOSIS

The differential diagnosis of leptospirosis is broad, reflecting the

diverse clinical presentations of the disease. Although leptospirosis

transmission is more common in tropical and subtropical regions, the

absence of a travel history does not exclude the diagnosis. When fever,

headache, and myalgia predominate, influenza and other common

and less common (e.g., dengue and chikungunya) viral infections

should be considered. Malaria, typhoid fever, ehrlichiosis, viral hepatitis, and acute HIV infection may mimic the early stages of leptospirosis and are important to recognize. Rickettsial diseases, dengue,

and hantavirus infections (hemorrhagic fever with renal syndrome

1421CHAPTER 185 Relapsing Fever and Borrelia miyamotoi Disease

or hantavirus cardiopulmonary syndrome) share epidemiologic and

clinical features with leptospirosis. Dual infections have been reported.

In this light, it is advisable to conduct serologic testing for rickettsiae,

dengue virus, and hantavirus when leptospirosis is suspected. When

bleeding is detected, dengue hemorrhagic fever and other viral hemorrhagic fevers, including hantavirus infection, yellow fever, Rift Valley

fever, filovirus infections, and Lassa fever, should be considered.

TREATMENT

Leptospirosis

Severe leptospirosis should be treated with IV penicillin

(Table 184-1) as soon as the diagnosis is considered. Leptospira

are highly susceptible to a broad range of antibiotics, including the

β-lactam antibiotics, cephalosporins, aminoglycosides, and macrolides, but are not susceptible to vancomycin, rifampicin, metronidazole, and chloramphenicol. Early intervention may prevent the

development of major organ-system failure or lessen its severity.

Although studies supporting antibiotic therapy have produced

conflicting results, clinical trials are difficult to perform in settings

where patients frequently present for medical care with late stages

of disease. Antibiotics are less likely to benefit patients in whom

organ damage has already occurred. Two open-label randomized

studies comparing penicillin with parenteral cefotaxime, parenteral

ceftriaxone, and doxycycline showed no significant differences

among the antibiotics with regard to complications and mortality

risk. Thus ceftriaxone, cefotaxime, or doxycycline is a satisfactory

alternative to penicillin for the treatment of severe leptospirosis.

Antimicrobial susceptibility testing is not routine practice in individual cases of leptospirosis; to date, however, antibiotic resistance

has not been reported in isolates from patients or the environment.

In mild cases, oral treatment with doxycycline, azithromycin,

ampicillin, or amoxicillin is recommended. In regions where rickettsial diseases are coendemic, doxycycline or azithromycin is the

drug of choice. In rare instances, a Jarisch-Herxheimer reaction

develops within hours after the initiation of antimicrobial therapy.

Aggressive supportive care for leptospirosis is essential and can

be life-saving. Patients with nonoliguric renal dysfunction require

aggressive fluid and electrolyte resuscitation to prevent dehydration

and precipitation of oliguric renal failure. Peritoneal dialysis or

hemodialysis should be provided to patients with oliguric renal

failure. Rapid initiation of hemodialysis has been shown to reduce

mortality risk and typically is necessary only for short periods.

Patients with pulmonary hemorrhage may have reduced pulmonary

compliance (as seen in ARDS) and may benefit from mechanical

TABLE 184-1 Treatment and Chemoprophylaxis of Leptospirosis in

Adultsa

INDICATION REGIMEN

Treatment

Mild leptospirosis Doxycyclineb

 (100 mg PO bid) or

Amoxicillin (500 mg PO tid) or

Ampicillin (500 mg PO tid)

Moderate/severe

leptospirosis

Penicillin (1.5 million units IV or IM q6h) or

Ceftriaxone (2 g/d IV) or

Cefotaxime (1 g IV q6h) or

Doxycyclineb

 (loading dose of 200 mg IV, then

100 mg IV q12h)

Chemoprophylaxis

Doxycyclineb

 (200 mg PO once a week) or

Azithromycin (250 mg PO once or twice a week)

a

All regimens are given for 7 days. b

Doxycycline should not be given to pregnant

women or children. c

The efficacy of doxycycline prophylaxis in endemic or epidemic

settings remains unclear. Experiments in animal models and a cost-effectiveness

model indicate that azithromycin has a number of characteristics that may make it

efficacious in treatment and prophylaxis.

ventilation with low tidal volumes to avoid high ventilation pressures. Evidence is contradictory for the use of glucocorticoids and

desmopressin as adjunct therapy for pulmonary involvement associated with severe leptospirosis.

■ PROGNOSIS

Most patients with leptospirosis recover. However, post-leptospirosis

symptoms, mainly of a depression-like nature, may occur and persist

for years after the acute disease. Mortality rates are highest among

patients who are elderly and those who have severe disease (pulmonary hemorrhage, Weil’s syndrome). Leptospirosis during pregnancy

is associated with high fetal mortality rates. Long-term follow-up of

patients with renal failure and hepatic dysfunction has documented

good recovery of renal and hepatic function.

■ PREVENTION

Individuals who may be exposed to Leptospira through their occupations or their involvement in recreational freshwater activities should

be informed about the risks. Measures for controlling leptospirosis

include avoidance of exposure to urine and tissues from infected

animals through proper eyewear, footwear, and other protective equipment. Targeted rodent control strategies could be considered.

Vaccines for agricultural and companion animals are generally available, and their use should be encouraged. The veterinary vaccine used

in a given area should contain the serovars known to be present in that

area. Unfortunately, some vaccinated animals still excrete leptospires in

their urine. Vaccination of humans against a specific serovar prevalent in

an area has been undertaken in some European and Asian countries and

has proved effective. Although a large-scale trial of vaccine in humans

has been reported from Cuba, no conclusions can be drawn about

efficacy and adverse reactions because of insufficient details on study

design. The efficacy of chemoprophylaxis with doxycycline (200 mg

once a week) or azithromycin (in pregnant women and children) is being

disputed, but focused pre- and postexposure administration is indicated

in instances of well-defined short-term exposure (Table 184-1).

■ FURTHER READING

Adler A: Leptospira and Leptospirosis, 1st ed. Berlin Heidelberg,

Springer-Verlag, 2015.

de Vries SG et al: Leptospirosis among returned travelers: A GeoSentinel

Site Survey and Multicenter Analysis−1997−2016. Am J Trop Med

Hyg 99:127, 2018.

Haake DA, Levett PN: Leptospirosis in humans. Curr Top Microbiol

Immunol 387:65, 2015.

van Samkar A et al: Suspected leptospiral meningitis in adults: Report

of four cases and review of the literature. Neth J Med 73:464, 2015.

Vincent AT et al: Revisiting the taxonomy and evolution of pathogenicity of the genus Leptospira through the prism of genomics. PLoS

Negl Trop Dis 13:e0007270, 2019.

Relapsing fever is caused by infection with any of several species

of Borrelia spirochetes. Physicians in ancient Greece distinguished

relapsing fever from other febrile disorders by its characteristic clinical

presentation: two or more fever episodes separated by varying periods

of well-being. In the nineteenth century, relapsing fever was one of

the first diseases to be associated with a specific microbe by virtue

of its characteristic laboratory finding: the presence of large numbers of

spirochetes of the genus Borrelia in the blood.

185 Relapsing Fever and

Borrelia miyamotoi Disease

Alan G. Barbour

1422 PART 5 Infectious Diseases

transmission is currently limited to Ethiopia, Eritrea, and Somalia,

the disease has had a global distribution in the past, and that potential

remains. Epidemics of LBRF, often in association with typhus, can

occur under circumstances of famine, refugee migration, war, and

pervasive homelessness. Transmission of LBRF can occur in camps of

migrants at a distance from their home countries.

All other known species of relapsing fever agents are tick-borne—in

most cases, by soft ticks of the genus Ornithodoros (Fig. 185-1). Tickborne relapsing fever (TBRF) is found on most continents but is absent

in tropical or arctic environments. For most species, the reservoirs of

infection are small to medium-sized mammals, usually rodents but

sometimes pigs and other domestic animals living around human

habitats. However, one species, Borrelia duttonii in sub-Saharan Africa,

is largely maintained by tick transmission between human hosts. In

North America, TBRF occurs as single cases or small case clusters

through transient exposure of persons to infested buildings or caves

where mammals have nests or sleep in less populated areas. The two

main Borrelia species involved in North America are Borrelia hermsii in

the mountainous west and Borrelia turicatae in arid southwestern and

south-central regions. The soft tick vectors typically feed for no more

than 30 min, usually while the victim is sleeping. Transovarial transmission from one generation of ticks to the next means that infection

risk may persist in an area long after incriminated mammalian reservoirs have been removed.

Borrelia miyamotoi belongs to the same clade as relapsing fever

species but instead is transmitted to humans from other mammals by

hard ticks (e.g., Ixodes scapularis in the eastern United States) that also

transmit Lyme disease, babesiosis, anaplasmosis, and a viral encephalitis. B. miyamotoi is acquired through outdoor activities and through

contact with ticks in forested and shrubby areas during recreation,

work, or activities around the home, similarly to Lyme disease (Chap. 186).

Among residents of most areas where B. miyamotoi and Borreliella

(also called Borrelia) burgdorferi coexist, the prevalence of antibodies

to the former is about one-third of that to the latter. In contrast to B.

burgdorferi, the transmission of B. miyamotoi to the host begins soon

after the tick begins to feed.

■ PATHOGENESIS AND IMMUNITY

TBRF spirochetes enter the body in the tick’s saliva with the onset of

feeding. From an inoculum of a few cells, the spirochetes proliferate

TABLE 185-1 Relapsing Fever Borrelia Species, by Geographic Region, Vector, and Primary Reservoir

SPECIES REGION(S) ARTHROPOD VECTOR(S) PRIMARY RESERVOIR

B. crocidurae Africa Ornithodoros erraticus, Ornithodoros sonrai (soft

ticks)

Mammals

B. duttonii Africa O. moubata Humans

B. hermsii North America O. hermsi Mammals

B. hispanica Europe, North Africa O. erraticus Mammals

B. johnsonii North America Carios kellyi (soft ticks) Bats

B. kalaharica Africa O. savignyi Mammals

B. mazzottii Mexico, Central America O. talaje Mammals

B. miyamotoi Eurasia, North America Ixodes species (hard ticks) Mammals

B. persica Eurasia O. tholozani Mammals

B. recurrentis Africa, globala Pediculus humanus corporis (human body louse) Humans

B. turicatae North America O. turicata Mammals

B. venezuelensis Central and South America O. rudis Mammals

a

Although transmission is currently limited to Ethiopia and adjacent countries, B. recurrentis infection has had a global distribution in the past, and that potential remains.

FIGURE 185-1 Ornithodoros turicata soft ticks of different ages.

The host responds with systemic inflammation that results in an

illness ranging from a flulike syndrome to sepsis. Other manifestations

are the consequences of central nervous system (CNS) involvement

and disordered hemostasis. Antigenic variation of the spirochetes’

surface proteins accounts for the infection’s relapsing course. Acquired

immunity follows the serial development of antibodies to each of

the several variants appearing during an infection. Treatment with

antibiotics results in rapid cure but at the risk of a moderate to severe

Jarisch-Herxheimer reaction.

Louse-borne relapsing fever (LBRF) caused large epidemics well

into the twentieth century and currently occurs in northeastern Africa

and among migrants from that area. At present, however, most cases of

relapsing fever are tick-borne in origin. Sporadic cases and small outbreaks are focally distributed on most continents, with Africa and Central Asia most affected. In North America, the majority of reports of

relapsing fever have been from the western United States and Canada.

Another member of the genus, Borrelia miyamotoi, causes an acute

febrile illness with nonspecific constitutional symptoms and occasionally meningoencephalitis in the same geographic distribution as Lyme

disease (Chap. 186) in Eurasia and North America.

■ ETIOLOGIC AGENT

Coiled, thin microscopic filaments that swim in one direction and

then coil up before heading in another were first observed in the

blood of patients with relapsing fever in the 1880s. These microbes

were categorized as spirochetes and assigned to the genus Borrelia.

The breakthrough cultivation medium was rich in ingredients, ranging

from simple (e.g., N-acetylglucosamine) to more complex (e.g., serum).

The limited biosynthetic capacity of Borrelia cells is accounted for by a

genome content one-quarter that of Escherichia coli.

Like other spirochetes, the helix-shaped Borrelia cells have two

membranes, the outer of which is more loosely secured than in

other double-membrane bacteria, such as E. coli. As a consequence,

fixed organisms with damaged membranes can assume a variety of

morphologies in smears and histologic preparations. The flagella of

spirochetes run between the two membranes and are not on the cell

surface. Although technically gram-negative, the 10- to 20-μm-long

Borrelia cells, with a diameter of 0.2–0.3 μm, are too narrow to be seen

by microscopy of Gram-stained slides.

■ EPIDEMIOLOGY

The several species of Borrelia that cause relapsing fever have restricted

geographic distributions (Table 185-1). The exception is Borrelia recurrentis, which is also the only species transmitted by an insect. LBRF is

acquired from a body louse (Pediculus humanus corporis), or possibly

a head louse (Pediculus capitis), with humans serving as the reservoir.

Acquisition occurs not from the bite itself but from either rubbing the

insect’s feces into the bite site with the fingers in response to irritation

or inoculation into the conjunctivae or a wound. Although LBRF

1423CHAPTER 185 Relapsing Fever and Borrelia miyamotoi Disease

in the blood, doubling every 6 h to numbers of 106

–107

/mL or more.

Borrelia species are extracellular pathogens; their presence inside cells

connotes dead bacteria after phagocytosis. Binding of the spirochetes

to erythrocytes leads to aggregation of red blood cells, their sequestration in the spleen and liver, and hepatosplenomegaly and anemia. A

bleeding disorder is probably the consequence of thrombocytopenia,

impaired hepatic production of clotting factors, and/or blockage of

small vessels by aggregates of spirochetes, erythrocytes, and platelets.

Some species are neurotropic and enter the brain, where they are comparatively sheltered from host immunity. Relapsing fever spirochetes

can cross the maternal-fetal barrier and cause placental damage and

inflammation, leading to intrauterine growth retardation and congenital infection.

Although Borrelia species do not have potent exotoxins or a

lipopolysaccharide endotoxin, they have abundant lipoproteins that

activate Toll-like receptors on host cells, which leads to a proinflammatory process similar to that in endotoxemia, with elevations of tumor

necrosis factor α, interleukin 6, and interleukin 8 concentrations.

IgM antibodies specific for the serotype-defining surface lipoprotein

appear after a few days of infection and soon reach a concentration that

causes lysis of bacteria in the blood through either direct bactericidal

action or opsonization. The release of lipoproteins and other bacterial

products from dying bacteria provokes a “crisis,” during which there can

be an increase in temperature, hypotension, and other signs of shock. A

similar phenomenon occurring in some patients soon after the initiation

of antibiotic treatment is characterized by an abrupt worsening of the

patient’s condition, which is called a Jarisch-Herxheimer reaction (JHR).

■ CLINICAL MANIFESTATIONS

Relapsing fever presents with the sudden onset of fever. Febrile periods

are punctuated by intervening afebrile periods of a few days; this pattern occurs at least twice. The patient’s temperature is ≥39°C and may

be as high as 43°C. The first fever episode often ends in a crisis lasting

~15–30 min and consisting of rigors, a further elevation in temperature, and increases in pulse and blood pressure. The crisis phase is

followed by profuse diaphoresis, falling temperature, and hypotension,

which usually persist for several hours. In LBRF, the first episode of

fever is unremitting for 3–6 days; it is usually followed by a single

milder episode. In TBRF, multiple febrile periods last 1–3 days each.

In both forms, the interval between fevers ranges from 4 to 14 days,

sometimes with symptoms of malaise and fatigue.

The symptoms that accompany the fevers are usually nonspecific.

Headache, neck stiffness, arthralgia, myalgia, and vomiting may

accompany the first and subsequent febrile episodes. An enlarging

spleen and liver cause abdominal pain. A nonproductive cough is

common during LBRF and—in combination with fever and myalgias—

may suggest influenza. Acute respiratory distress syndrome may occur

during TBRF.

On physical examination, the patient may be delirious or apathetic.

There may be body lice in the patient’s clothes or signs of insect bites.

In regions with B. miyamotoi infection, a hard tick may be embedded

in the skin. Epistaxis, petechiae, and ecchymoses are common during

LBRF but not in TBRF. Splenomegaly or spleen tenderness is common

in both forms of relapsing fever. The majority of patients with LBRF

and ~10% of patients with TBRF have discernible hepatomegaly.

Localizing neurologic findings are more common in TBRF than in

LBRF. In North America, B. turicatae infection has neurologic manifestations more often than B. hermsii infection. Meningoencephalitis

can result in residual hemiplegia or aphasia. Myelitis and radiculopathy

may develop. Unilateral or bilateral Bell’s palsy and deafness from seventh or eighth cranial nerve involvement are the most common forms

of cranial neuritis and typically present in the second or third febrile

episode, not the first. Visual impairment from unilateral or bilateral iridocyclitis or panophthalmitis may be permanent. In LBRF, neurologic

manifestations such as altered mental state or stiff neck are thought to

be secondary to systemic inflammation rather than to direct invasion

of the nervous system.

Myocarditis appears to be common in both forms of relapsing

fever and accounts for some deaths. Most commonly, myocarditis is

evidenced by gallops on cardiac auscultation, a prolonged QTc

 interval,

and cardiomegaly and pulmonary edema on chest radiography.

General laboratory studies are not specific. Mild to moderate normocytic anemia is common, but frank hemolysis and hemoglobinuria

do not develop. Leukocyte counts are usually in the normal range

or only slightly elevated, and leukopenia can occur during the crisis.

Platelet counts can fall below 50,000/μL. C-reactive protein and procalcitonin levels are elevated. Laboratory evidence of hepatitis can be

found, with elevated serum concentrations of unconjugated bilirubin

and aminotransferases; the prothrombin and partial thromboplastin

times may be moderately prolonged.

Analysis of the cerebrospinal fluid (CSF) is indicated in cases of suspected relapsing fever with signs of meningitis or meningoencephalitis.

The presence of mononuclear pleocytosis and mildly to moderately

elevated protein levels justifies intravenous antibiotic therapy in TBRF.

The manifestations and course of B. miyamotoi disease are not as

distinctive as those of relapsing fever. The most common presentation

is fever without respiratory symptoms starting 1–2 weeks after a tick

bite. Patients have been hospitalized with a presumptive diagnosis of

undifferentiated sepsis. Meningoencephalitis with spirochetes in the

CSF was documented in immunodeficient adults but may also occur

in immunocompetent individuals. If the patient has coexisting early

Lyme disease, there may be erythema migrans, the localized skin rash.

■ DIAGNOSIS

Relapsing fever should be considered in a patient with the characteristic

fever pattern and a history of recent exposure—i.e., within 1–2 weeks

before illness onset—to body lice or soft-bodied ticks in geographic

areas with documented current or past transmission. Because of the

longevity of the ticks and the transovarial transmission of the pathogen

in the ticks, a case of relapsing fever may be diagnosed many years after

the last case reported in that locale. The lice may be on the clothes of a

migrant. While the risks for B. miyamotoi disease are similar to those

for Lyme disease, prompt removal of an embedded tick after the exposure may not reduce the risk of infection of this pathogen.

With the exception of B. miyamotoi infection, the bedrock for laboratory diagnosis of LBRF and TBRF remains direct detection of the

spirochetes by microscopy of the blood. Manual differential counts

of white blood cells by Wright stain usually reveal spirochetes in

thin blood smears if their concentration is ≥105

/mL and several oilimmersion fields are examined (Fig. 185-2). But the preferred stains

are Giemsa-Wright or Giemsa alone. The density of B. miyamotoi in the

blood is not high enough for use of a blood smear alone for diagnosis.

For LBRF and TBRF, the preferred time to obtain a blood specimen is

between the fever’s onset and its peak. Lower concentrations of spirochetes may be revealed by a thick blood smear that is treated with 0.5%

acetic acid before staining. An alternative is a wet mount of anticoagulated blood mixed with saline and examined by phase-contrast or

dark-field microscopy for motile spirochetes.

Polymerase chain reaction (PCR) and similar DNA amplification

procedures are increasingly used for examination of blood or CSF in

cases of suspected relapsing fever. PCR may reveal circulating spirochetes between febrile episodes. PCR is the preferred procedure for

direct detection of B. miyamotoi in blood or CSF.

Culture of blood or CSF in Barbour-Stoenner-Kelly broth medium

or equivalent is an option for isolation of Borrelia species. However,

few laboratories offer this service. An alternative for tick-borne Borrelia species, but not B. recurrentis, is inoculation of blood or CSF

into severe combined immunodeficient mice and examination of the

animal’s blood after a few days.

Options for serologic confirmation of infection are limited, and

results may be misleading. Whole cell-based assays, such as enzymelinked immunosorbent assay (ELISA) and immunoblot, and the

C6-peptide ELISA for Lyme disease may be positive in relapsing fever

or B. miyamotoi disease through antigenic cross-reactivities among

these spirochetes. A commercially available assay based on GlpQ, a

protein antigen of all relapsing fever Borrelia species (including B.

miyamotoi) but not of any Lyme disease species, has better specificity,

but commonly is negative at a time when a blood smear or PCR assay