# 75 - 189 Leptospirosis

### 189 Leptospirosis

A
B
FIGURE 188-3  Clinical manifestations of bejel and pinta. A. Mucous patches of 
early bejel. B. Pigmented macules of early pinta. (Photos reprinted with permission 
from the Handbook of Endemic Treponematoses, PL Perine et al, Geneva, World 
Health Organization, Color Plates 54, 60; 1984.)
Pinta 
Pinta (mal del pinto, carate, azul, purupuru) is the most 
benign of the treponemal infections. This disease has three stages 
that are characterized by marked changes in skin color (Fig. 188-3B), 
but pinta does not appear to cause destructive lesions or to involve 
tissues other than the skin. The initial papule is most often located 
on the extremities or face and is pruritic. After 1 to many months of 
infection, numerous disseminated secondary lesions (pintides) appear. 
These lesions are initially red but become deeply pigmented, ultimately 
turning a dark slate blue. The secondary lesions are infectious and 
highly pruritic and may persist for years. Late pigmented lesions are 
called dyschromic macules and contain treponemes. Over time, most 
pigmented lesions show varying degrees of depigmentation, becoming 
brown and eventually white and giving the skin a mottled appearance. 
White achromic lesions are characteristic of the late stage.
■
■DIAGNOSIS
Diagnosis of the endemic treponematoses is based on clinical manifes­
tations and, when available, dark-field microscopy and serologic test­
ing. The same serologic tests—detecting antibodies to either lipoidal or 
treponemal antigens—that are used for syphilis (Chap. 187) become 
reactive during all treponemal infections. To date there is no antibody 
test that can discriminate among the treponemal infections. The nonsyphilis treponemal infections should also be considered in the evalu­
ation of a reactive syphilis serology in any person who has emigrated 
from an endemic area. Sensitive nucleic acid amplification–based 
assays can be used to confirm treponemal infection and to identify the 
etiologic agent in research and selected clinical laboratories.
TREATMENT
Endemic Treponematoses
The current WHO-recommended therapy for patients and their con­
tacts includes either azithromycin (30 mg/kg, up to a maximum of 

2 g) or benzathine penicillin G (1.2 million units IM for adults; 
600,000 units for children <10 years old); these two drugs have been 
shown to be equivalent for early yaws. The recommended dose of 
benzathine penicillin G is half of that recommended for early syphi­
lis, yet no controlled efficacy studies have been conducted. Evidence 
of genetic resistance to penicillin is lacking, although relapsing lesions 
have been reported after penicillin treatment in Papua New Guinea.
The efficacy of single-dose azithromycin provided the WHO’s 
revitalized yaws eradication program with a much easier regimen for 
use in mass treatment. Macrolide resistance has become common in 
circulating strains of T. pallidum subspecies pallidum in many parts 
of the world (Chap. 187), and analyses of yaws samples from Papua 
New Guinea and elsewhere have yielded evidence of mutations con­
ferring resistance to macrolide antibiotics, including azithromycin, 

in a small number of treated patients. Careful molecular surveil­
lance is essential to monitor developing resistance in yaws-endemic 
areas. Limited data suggest the efficacy of tetracycline for treatment 
of yaws, but no data exist for other endemic treponematoses. Based 
solely on experience with syphilis, it is likely that doxycycline, tetra­
cycline (at doses appropriate for syphilis; Chap. 187), or ceftriaxone 
are alternatives, in addition to azithromycin, for patients allergic to 
penicillin. A Jarisch-Herxheimer reaction (Chap. 187) may follow 
treatment of endemic treponematoses. Lipoidal serologic titers (in 
the Venereal Disease Research Laboratory [VDRL] slide test or the 

rapid plasma reagin [RPR] test) usually decline after effective 
therapy, but patients may not become seronegative.

■
■CONTROL
Buoyed by the successful elimination of yaws in India and the avail­
ability of an inexpensive, single-dose oral drug for treatment, in 2012, 
the WHO renewed its efforts to eradicate yaws globally by 2020. Based 
on the results of several pilot programs of MDA, however, the target 
year for eradication was extended to 2030. Initial enthusiasm has been 
dampened by several factors: (1) Pilot studies have indicated that a very 
high level of MDA coverage must be achieved and that multiple rounds 
of MDA are needed in the affected areas. Treatment must be followed 
by careful case detection and targeted treatment of cases and contacts. 
(2) Azithromycin resistance has emerged during MDA studies in 
Papua New Guinea. Although subsequent treatment with benzathine 
penicillin G was able to contain the spread of resistant organisms, such 
evidence suggests that there may be only a short window of time during 
which countries can successfully use azithromycin for yaws eradica­
tion. Antibiotic resistance is of particular concern because multiple 
rounds of MDA are likely to be required. Further, given the ongoing 
campaigns against trachoma using low-dose azithromycin MDA, often 
in populations also at high risk for yaws, more widespread macrolide 
resistance seems inevitable. (3) Lastly, the possible animal reservoir 
needs to be evaluated, particularly in Africa. Yaws elimination will 
require rapid implementation and scale-up of high-level drug coverage 
in endemic areas, and continued careful surveillance by local health 
centers will be essential for success of this timely and important effort.
CHAPTER 189
Leptospirosis
■
■FURTHER READING
Giacani L, Lukehart SA: The endemic treponematoses. Clin Micro­
biol Rev 27:89, 2014.
Janecková K et al: The genomes of the yaws bacterium, Treponema 
pallidum subsp. pertenue, of nonhuman primate and human origin 
are not genomically distinct. PLoS Negl Trop Dis 17:e0011602, 2023.
John LN et al: Trial of three rounds of mass azithromycin administra­
tion for yaws eradication. N Engl J Med 386:47, 2022.
Marco Goeijenbier, Jiři F. P. Wagenaar

Leptospirosis
Leptospirosis is a globally important zoonotic disease whose appar­
ent reemergence is illustrated by recent outbreaks on virtually all 
continents. The disease is caused by pathogenic Leptospira species 
and is characterized by a broad spectrum of clinical manifestations, 
varying from asymptomatic infection to fulminant, fatal disease. In its 
mild form, leptospirosis may present as nonspecific symptoms such 
as fever, headache, and myalgia. Severe leptospirosis, characterized by 
the triad of jaundice, renal dysfunction, and hemorrhagic diathesis, is 
often referred to as Weil’s syndrome. With or without jaundice, severe 
pulmonary hemorrhage is increasingly recognized as an important 
presentation of severe disease.

PART 5
Infectious Diseases
workers in the fishing industry. Risk factors include direct or indirect 
contact with animals, including exposure to water and soil contami­
nated with animal urine. Leptospirosis has also been recognized in 
deteriorating inner cities and suburban areas where rat and mouse 
populations are expanding.
FIGURE 189-1  Differentiation of pathogenic, intermediate, and nonpathogenic 
(saprophytic) Leptospira species by molecular phylogenetic analysis using core 
genomes comparison (CgMLST). (Reproduced with permission from Dr. A Ahmed, 
Leptospirosis Reference Center, Academic Medical Center, Medical Microbiology, 
Amsterdam, The Netherlands.)
■
■ETIOLOGIC AGENT
Leptospira species are spirochetes belonging to the order Spirochaetales 
and the family Leptospiraceae. Traditionally, the genus Leptospira com­
prised two species: the pathogenic L. interrogans and the free-living 
L. biflexa, now designated L. interrogans sensu lato and L. biflexa sensu 
lato, respectively. Sixty-four Leptospira species with pathogenic (17 spe­
cies), intermediate (21 species), and nonpathogenic (26 species) status 
have now been described based on phylogenetic analyses (Fig. 189-1). 
Genome sequences of all Leptospira species have been published, and 
this will undoubtedly lead to a better understanding of the pathogen­
esis of leptospirosis. However, classification based on serologic differ­
ences better serves clinical, diagnostic, and epidemiologic purposes. 
Pathogenic Leptospira species are divided into serovars according to 
their antigenic composition. There are more than 260 known patho­
genic serovars, which are arranged in 26 serogroups.
Leptospires are coiled, thin, highly motile organisms that have 
hooked ends and two periplasmic flagella, with polar extrusions from 
the cytoplasmic membrane that are responsible for motility (Fig. 189-2). 
These organisms are 6–20 μm long and ~0.1 μm in diameter; they stain 
poorly but can be seen microscopically by dark-field examination and 
after silver impregnation staining of tissues. Leptospires require special 
media and conditions for growth; it may take weeks to months for 
cultures to become positive.
■
■EPIDEMIOLOGY
Leptospirosis has a worldwide distribution. Infection occurs most 
commonly in the tropics and subtropics because the climate and occa­
sionally poor hygienic conditions favor the pathogen’s survival and 
distribution. In most countries, leptospirosis is an underappreciated 
problem. Most cases occur in men, with a peak incidence during the 
summer and fall in both the Northern and Southern Hemispheres and 
during the rainy season in the tropics.
Reliable data on morbidity and mortality from leptospirosis have 
gradually started to appear. Current information on global human 
leptospirosis varies but indicates that ~1 million severe cases occur per 
year, with a mean case–fatality rate of nearly 10%.
As a zoonosis, leptospirosis affects almost all mammalian species 
and represents a significant veterinary burden. Rodents, especially 
rats, are the most important reservoir, although other wild mammals 
as well as domestic and farm animals may also harbor these microor­
ganisms. Leptospires establish a symbiotic relationship with their host 
and can persist in the urogenital tract for years. Some serovars are 
generally associated with specific animals—e.g., Icterohaemorrhagiae 
and Copenhageni with rats, Grippotyphosa with voles, Hardjo with 
cattle, Canicola with dogs, and Pomona with pigs—but may occur in 
other animals as well.
Leptospirosis presents as both an endemic and an epidemic disease. 
Transmission of leptospires may follow direct contact with urine, 
blood, or tissue from an infected animal or, more commonly, exposure 
to environmental contamination. The dogma that human-to-human 
transmission is very rare is challenged by recent findings on household 
clustering, asymptomatic renal colonization, and prolonged excretion 
of leptospires. Both of the latter features could imply human infection 
sources that are not recognized. Because leptospires can survive in a 
humid environment for many months, water is an important vehicle in 
their transmission. Epidemics of leptospirosis are not well understood. 
Outbreaks may result from exposure to floodwaters contaminated by 
urine from infected animals, as has been reported from several coun­
tries. 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 symp­
toms 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

FIGURE 189-2  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.)
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 for infection. Also, several out­
breaks have followed sporting events. 
For example, an outbreak took place 
in 1998 among athletes after a triath­
lon in Springfield, Illinois. Ingestion 
of one or more swallows of lake water 
during the swimming leg of the tri­
athlon was a prominent risk factor 
for illness. Heavy rains that preceded 
the triathlon, with consequent agri­
cultural runoff, are likely to have 
increased the level of leptospiral 
contamination in the lake water. In 
another outbreak, 42% of partici­
pants contracted leptospirosis during 
the 2000 Eco-Challenge-Sabah mul­
tisport endurance race in Malaysian 
Borneo. Swimming in the Segama 
River was shown to be an indepen­
dent risk factor. Furthermore, out­
breaks among athletes participating 
in the recently popular mud-runs are 
increasingly reported.
Approximate time scale
Incubation period
Incubation
Leptospires present in
Blood
CSF
Urine
Antibody titers
High
Low
“Negative”
Laboratory investigations
Culture/PCR
PCR
In addition, leptospirosis is a trav­
eler’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 or spelunking. Recent data 
from the GeoSentinel Global Surveil­
lance Network described in detail 180 
returned travelers (mostly male; 74%) 
with leptospirosis from January 1997 
Serology
Phases
FIGURE 189-3  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. (Used with permission of [ASM], from Leptospirosis, PN 
Levett, 14:296, 2001; permission conveyed through Copyright Clearance Center, Inc. and Turner, Leptospirosis I, Transactions of 
the Royal Society of Tropical Medicine & Hygiene, 61:842, 1967. Permission is granted as per the terms of the STM Permissions 
Guidelines. Reproduced by permission of Oxford University Press on behalf of the Royal Society of Tropical Medicine & Hygiene.)

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. Transmis­
sion 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 mem­
branes, especially the conjunctival and oral mucosa. After entry, the 
highly motile organisms proliferate, cross tissue barriers, and dis­
seminate hematogenously to all organs (leptospiremic phase). During 
this initial incubation period, leptospires can be isolated from the 
bloodstream (Fig. 189-3). Clearly, Leptospira can survive in the non­
immune host by evading parts of the innate immune response such as 
complement-mediated killing and phagocytosis; however, earlier stud­
ies have highlighted the relation between an exaggerated proinflamma­
tory immune response and mortality. During the immune phase, the 
appearance of antibodies coincides with the disappearance of lepto­
spires from the blood. However, the bacteria persist in various organs, 
including liver, lung, kidney, heart, and brain. Autopsy findings illus­
trate 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 cana­
liculi. 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 
CHAPTER 189
Leptospirosis
Months-years

Years
Week 1

Acute
stage
Convalescent
stage
Uveitis
? Interstitial nephritis
2-30 days
Fever
Reservoir host
Convalescent shedder
Normal response
Titers decline at
varying rates
Delayed
Early treatment
Anamnestic
Blood
CSF
Urine
Urine

Leptospiremia
Leptospiruria and immunity

FIGURE 189-4  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.)
intercellular junctions and disruption of bile canaliculi leading to bile 
leakage. Petechiae and hemorrhages are observed in the heart, lungs 
(Fig. 189-4), kidneys (and adrenals), pancreas, liver, gastrointesti­
nal tract (including retroperitoneal fat, mesentery, and omentum), 
muscles, prostate, testes, and brain (subarachnoid bleeding). Several 
studies show an association between hemorrhage and thrombocytope­
nia. 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 activ­
ity. Overt disseminated intravascular coagulation (DIC) has been doc­
umented in several clinical studies. Elevated plasma levels of soluble 
E-selectin and von Willebrand factor in patients with leptospirosis 
reflect endothelial cell activation. More specifically, markers of endo­
thelial cell activation correlate to disease severity in patients with severe 
leptospirosis. Experimental models show that pathogenic leptospires or 
leptospiral proteins are able to activate endothelial cells in vitro and to 
disrupt endothelial-cell barrier function, thus increasing permeability 
and promoting dissemination. Platelets have been shown to aggre­
gate 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.
PART 5
Infectious Diseases
Leptospira species have a typical double-membrane cell wall struc­
ture 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 pro­
duction 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 char­
acterized 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 associ­
ated 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 cere­
brospinal 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 spontane­
ous 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 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 hemor­
rhage, jaundice, and acute kidney injury.
Patients die of multiorgan failure after septic shock and/or severe 
bleeding complications that most commonly involve the lungs (pul­
monary hemorrhage), gastrointestinal tract (melena, hematemesis), 
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 associ­
ated 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 vaso­
pressor therapy. Hemodialysis can be lifesaving, with renal function 
typically returning to normal in survivors.
In severe leptospirosis, an altered mental status may reflect lepto­
spiral 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 ele­
vated 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 hemato­
logic 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. Autoim­
mune-associated uveitis, a potentially chronic condition, is a recog­
nized sequela of leptospirosis.
■
■DIAGNOSIS
The clinical diagnosis of leptospirosis should be based on an appropri­
ate 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 per­
cutaneous contact with contaminated surface waters or soil. For non­
travelers, recreational or accidental water/soil contact and especially 
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 infec­
tion, 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. The absence of renal involvement does not 
rule out leptospirosis. However, when the kidneys are involved, related 
findings range from urinary sediment changes (leukocytes, erythro­
cytes, and hyaline or granular casts) and mild proteinuria in mild dis­
ease 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 symp­
toms 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 based on physical examination 
(Fig. 189-4). The most common radiographic finding is a patchy bilat­
eral alveolar pattern that corresponds to scattered alveolar hemorrhage. 
These abnormalities predominantly affect the lower lobes. Other find­
ings include pleura-based densities (representing areas of hemorrhage) 

and diffuse ground-glass attenuation typical of acute respiratory dis­
tress 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 (depend­
ing 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 convalescentphase 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 usu­
ally is available only in specialized laboratories and is used for deter­
mination 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 preva­
lent 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 com­
mercially 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.
CHAPTER 189
Leptospirosis
■
■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, SARS-CoV-2, 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, den­
gue, and hantavirus infections (hemorrhagic fever with renal syndrome 
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 hemor­
rhagic 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 
189-1) 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