Leptospirosis

Leptospirosis is an emerging infectious disease, as illustrated by recent large outbreaks in

Asia, Central and South America, and the United States. The disease is caused by pathogenic
leptospires and characterized by a broad spectrum of clinical manifestations, varying from
inapparent infection to fulminant, fatal disease. In its mild form, leptospirosis may present as an
influenza-like illness with headache and myalgias. Severe leptospirosis, characterized by jaundice,
renal dysfunction, and hemorrhagic diathesis, is referred to as Weil’s syndrome.

ETIOLOGIC AGENT
Leptospires are spirochetes belonging to the order Spirochaetales and the family
Leptospiraceae. Traditionally, the genus Leptospira comprised two species: the pathogenic L.
interrogans and the free-living L. biflexa. Although 16 genomospecies of pathogenic leptospires
are now recognized on the basis of their DNA relatedness, it is more practical clinically and
epidemiologically to use a classification based on serologic differences. The pathogenic leptospires
are divided into serovars according to their antigenic composition. More than 200 serovars make
up the 25 serogroups.
Leptospires are coiled, thin, highly motile organisms with hooked ends and two periplasmic
flagella that permit burrowing into tissue. These organisms are 6 to 20µm long and ~0.1µm wide;
one end is often bent, forming a hook. They are actively motile, which is best seen using a
darkfield microscope. Electron micrographs show a thin axial filament and a delicate membrane.
They stain poorly but can be seen microscopically by dark-field examination and after silver
impregnation staining. Leptospires require special media and conditions for growth; it may take
weeks for cultures to become positive.
Leptospirae grow best under aerobic conditions at 28–30 °C in serum-containing semisolid
media (Fletcher's, Stuart's, others). After 1–2 weeks the leptospirae produce a diffuse zone of
growth near the top of the tube and later a ring of growth at a level in the tube corresponding to
the level of the optimal oxygen tension for the organisms. The culture media can be made
selective for leptospirae by addition of neomycin or 5-fluorouracil.
Leptospirae derive energy from oxidation of long-chain fatty acids and cannot use amino
acids or carbohydrates as major energy sources. Ammonium salts are a main source of nitrogen.
Leptospirae can survive for weeks in water, particularly at alkaline pH.
Antigenic Structure
The main strains ("serovars") of L interrogans isolated from humans or animals in different
parts of the world are all serologically related and exhibit cross-reactivity in serologic tests. This
indicates considerable overlapping in antigenic structure, and quantitative tests and antibody
absorption studies are necessary for a specific serologic diagnosis. The outer envelope contains
large amounts of lipopolysaccharide (LPS) of antigenic structure that is variable from one strain
to another. This variation forms the basis for the serologic classification of the Leptospira species.
It also determines the specificity of the human immune response to leptospirae.

Leptospira Source of Disease in Clinical Findings Distribution

interrogans Infection Humans
Serovar
autumnalis ? Pretibial or Ft. Fever, rash over tibia USA, Japan
Bragg fever
ballum Mice — Fever, rash, jaundice USA, Europe,
Israel
Bovis Cattle, voles — Fever, prostration USA, Israel,
Australia
canicola Dog urine Infectious Influenza-like illness, Worldwide
jaundice aseptic meningitis
grippotyphosa Rodents, Marsh fever Fever, prostration, aseptic Europe, USA,
water meningitis Africa
hebdomadis Rats, mice 7-day fever Fever, jaundice Japan, Europe
icterohae- Rat urine, Weil's Jaundice, hemorrhages, Worldwide
morrhagiae water disease aseptic meningitis
mitis Swine Swineherd's Aseptic meningitis Australia
disease
pomona Swine, cattle Swineherd's Fever, prostration, aseptic Europe, USA,
disease meningitis Australia

PATHOGENESIS
The pathogenesis of leptospirosis is incompletely understood. Leptospires may enter the host
through abrasions in the skin or through intact mucous membranes, especially the
conjunctiva and the lining of the oro- and nasopharynx. Drinking of contaminated water may
introduce leptospires through the mouth, throat, or esophagus. After entry of the organisms,
leptospiremia develops, with subsequent spread to all organs. Multiplication takes place in
blood and in tissues, and leptospires can be isolated from blood and cerebrospinal fluid (CSF)
during the first 4 to 10 days of illness. CSF examination during this period documents pleocytosis
in the majority of instances, but only a minority of patients develop symptoms and signs of
meningitis at this point. All forms of leptospires can damage the wall of small blood vessels; this
damage leads to vasculitis with leakage and extravasation of cells, including hemorrhages. The
most important known pathogenic properties of leptospires are adhesion to cell surfaces and
cellular toxicity.
Vasculitis is responsible for the most important manifestations of the disease. Although
leptospires mainly infect the kidneys and liver, any organ may be affected. In the kidney,
leptospires migrate to the interstitium, renal tubules, and tubular lumen, causing interstitial
nephritis and tubular necrosis. Hypovolemia due to dehydration or altered capillary permeability
may contribute to the development of renal failure. In the liver, centrilobular necrosis with
proliferation of Kupffer cells may be found. However, severe hepatocellular necrosis is not a
feature of leptospirosis. Pulmonary involvement is the result of hemorrhage and not of
inflammation. Invasion of skeletal muscle by leptospires results in swelling, vacuolation of the
myofibrils, and focal necrosis. In severe leptospirosis, vasculitis may ultimately impair the
microcirculation and increase capillary permeability, resulting in fluid leakage and hypovolemia.
When antibodies are formed, leptospires are eliminated from all sites in the host except the
eye, the proximal renal tubules, and perhaps the brain, where they may persist for weeks or
months. The persistence of leptospires in the aqueous humor occasionally causes chronic or
recurrent uveitis. The systemic immune response is effective in eliminating the organism but may
also produce symptomatic inflammatory reactions. A rise in antibody titer coincides with the
development of meningitis; this association suggests that an immunologic mechanism is
responsible.
After the start of antimicrobial treatment for leptospirosis, a Jarisch-Herxheimer reaction
similar to that seen in other spirochetal diseases may develop. Although frequently described in
older publications, this reaction seems to be a rare event in leptospirosis and is certainly less
frequent in this infection than in other spirochaetal diseases.

CLINICAL MANIFESTATIONS (Fig. 155-2)

It is important to try to obtain a history of exposure to contaminated materials. Serologic
evidence of past inapparent infection is found in 15 to 40% of persons who have been exposed but
have not become ill. In symptomatic cases of leptospirosis, clinical manifestations vary from mild
to serious or even fatal. More than 90% of symptomatic persons have the relatively mild and
usually anicteric form of leptospirosis, with or without meningitis. Severe leptospirosis with
profound jaundice (Weil’s syndrome) develops in 5 to 10% of infected individuals. The idea that
distinct clinical syndromes are associated with specific serogroups has been refuted.
The incubation period is usually 1 to 2 weeks but ranges from 2 to 20 days (Fig. 155-2).
Typically, an acute leptospiremic phase is followed by an immune leptospiruric phase. The
distinction between the first and second phases is not always clear, and milder cases do not
always include the second phase.
Anicteric Leptospirosis
Leptospirosis may present as an acute influenza-like illness, with fever, chills, severe
headache, nausea, vomiting, and myalgias. Muscle pain, which especially affects the calves, back,
and abdomen, is an important feature of leptospiral infection. Less common features include sore
throat and rash. The patient usually has an intense headache (frontal or retroorbital) and
sometimes develops photophobia. Mental confusion may be evident. Pulmonary involvement,
manifested in most cases by cough and chest pain and in a few cases by hemoptysis, is not
uncommon.
The most common finding on physical examination is fever with conjunctival suffusion. Less
common findings include muscle tenderness, lymphadenopathy, pharyngeal injection, rash,
hepatomegaly, and splenomegaly. The rash may be macular, maculopapular, erythematous,
urticarial, or hemorrhagic. Mild jaundice may be present.
Most patients become asymptomatic within 1 week. After an interval of 1 to 3 days, the illness
recurs in a number of cases. The start of this second (immune) phase coincides with the
development of antibodies. Symptoms are more variable than during the first (leptospiremic)
phase. Usually the symptoms last for only a few days, but occasionally they persist for weeks.
Often the fever is less pronounced and the myalgias are less severe than in the leptospiremic
phase. An important event during the immune phase is the development of aseptic meningitis.
Although no more than 15% of all patients have symptoms and signs of meningitis, many patients
have CSF pleocytosis.
Meningeal symptoms usually disappear within a few days but may persist for weeks. Similarly,
pleocytosis generally disappears within 2 weeks but occasionally persists for months. Aseptic
meningitis is more common among children than among adults. Iritis, iridocyclitis, and
chorioretinitis—late complications that may persist for years—can become apparent as early as the
third week but often present several months after the initial illness. One epidemic of uveitis among
patients with leptospirosis has been reported. Mortality in anicteric leptospirosis is almost nil,
although death as a result of pulmonary hemorrhage occurred in 2.4% of cases in a Chinese
outbreak.

Severe Leptospirosis (Weil’s Syndrome)

Weil’s syndrome, the most severe form of leptospirosis, is characterized by jaundice, renal
dysfunction, hemorrhagic diathesis, and a mortality rate ranging from 5 to 15%. In Europe,
this syndrome is frequently but not exclusively associated with infection due to serovar
icterohaemorrhagiae/copenhageni. The onset of illness is no different from that of less severe
leptospirosis; however, after 4 to 9 days, jaundice as well as renal and vascular dysfunction
generally develop. Although some degree of defervescence may be noted after the first week of
illness, a biphasic disease pattern like that seen in anicteric leptospirosis is lacking. The jaundice of
Weil’s syndrome, which can be profound and give an orange cast to the skin, is usually not
associated with severe hepatic necrosis. Death is rarely due to liver failure. Hepatomegaly and
tenderness in the right upper quadrant are usually detected. Splenomegaly is found in 20% of
cases.
Renal failure may develop, often during the second week of illness. Hypovolemia and
decreased renal perfusion contribute to the development of acute tubular necrosis with
oliguria or anuria. Dialysis is sometimes required, although a fair number of cases can be
managed without dialysis. Renal function may be completely regained.
Pulmonary involvement occurs frequently; in some clusters of cases, it is a major
manifestation, resulting in cough, dyspnea, chest pain, and blood-stained sputum and sometimes
in hemoptysis or even respiratory failure. Hemorrhagic manifestations are seen in Weil’s
syndrome: epistaxis, petechiae, purpura, and ecchymoses are found commonly, while severe
gastrointestinal bleeding and adrenal or subarachnoid hemorrhage are detected rarely.
Rhabdomyolysis, hemolysis, myocarditis, pericarditis, congestive heart failure, cardiogenic
shock, adult respiratory distress syndrome, necrotizing pancreatitis, and multiorgan failure have
all been described during severe leptospirosis.

LABORATORY AND RADIOLOGIC FINDINGS

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
anicteric leptospirosis to renal failure and azotemia in severe disease.
The erythrocyte sedimentation rate is usually elevated. In anicteric leptospirosis, peripheral
leukocyte counts range from 3000 to 26,000/µL, with a left shift; in Weil’s syndrome,
leukocytosis is often marked. Mild thrombocytopenia occurs in up to 50% of patients and is
associated with renal failure.
 In contrast to patients with acute viral hepatitis, those with leptospirosis typically have
elevated serum bilirubin and alkaline phosphatase as well as mild increases (up to 200 U/L)
in serum levels of aminotransferases. In Weil’s syndrome, the prothrombin time may be
prolonged but can be corrected with vitamin K. Levels of creatine phosphokinase, which are
elevated in up to 50% of patients with leptospirosis during the first week of illness, may help to
differentiate this infection from viral hepatitis.
When a meningeal reaction develops, polymorphonuclear leukocytes predominate initially
and the number of mononuclear cells increases later. The protein concentration in the CSF
may be elevated; CSF glucose levels are normal.
In severe leptospirosis, pulmonary radiographic abnormalities are more common than would be
expected on the basis of physical examination. These abnormalities most frequently develop 3 to 9
days after the onset of illness. The most common radiographic finding is a patchy alveolar pattern
that corresponds to scattered alveolar hemorrhage. Radiographic abnormalities most often affect
the lower lobes in the periphery of the lung fields.

DIAGNOSIS
A definite diagnosis of leptospirosis is based either on isolation of the organism from the
patient or on seroconversion or a rise in antibody titer in the microscopic agglutination test (MAT).
In the United States, the MAT is performed only at the CDC. In cases with strong clinical evidence
of infection, a single antibody titer of 1:400 to 1:800 (depending on whether the case occurs in a
lowor high-endemic area) in the 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.
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. These tests usually are available only in specialized laboratories and are used for
determination of the antibody titer and for tentative identification of the serogroup—and in some
cases the serovar—involved (thus the importance of using antigens representative of the serovars
prevalent in the particular geographic area). Since cross-reactions occur frequently, however, it is
often impossible to identify the infecting serogroup or serovar. Serologic testing cannot be used as
the basis for a decision about whether to start treatment.
In addition to the MAT and the ELISA, various other tests with diagnostic value have been
developed. Some tests, such as an indirect hemagglutination test and a microcapsule
agglutination test, are commercially available. A recent advance is the development of rapid
serologic assays that apply lateral flow, latex agglutination, or ELISA methodology with reasonable
sensitivity and specificity. These methods do not require culture or MAT facilities. However, in
endemic areas, pooled serum samples from the local population are required as positive and
negative controls. Polymerase chain reaction (PCR) techniques have been developed but so far
have not found widespread use outside research and reference laboratories.
Leptospires can be isolated from blood and/or CSF during the first 10 days of illness and from
urine for several weeks beginning at around 1 week. Cultures most often become positive after 2
to 4 weeks, with a range of 1 week to 4 months. Sometimes urine cultures remain positive for
months or years after the start of illness. For isolation of leptospires from body fluids or tissues,
Ellinghausen-McCullough-Johnson-Harris (EMJH) medium is useful; other possibilities are Fletcher
medium and Korthof medium. Specimens can be mailed to a reference laboratory for culture, since
leptospires remain viable in anticoagulated blood (heparin, EDTA, or citrate) for up to 11 days.
Isolation of leptospires is important since it is the only way the infecting serovar can be correctly
identified. Dark-field examination of blood or urine frequently results in misdiagnosis and should
not be used.

DIFFERENTIAL DIAGNOSIS
Leptospirosis should be differentiated from other febrile illnesses associated with headache and
muscle pain, such as dengue, malaria, enteric fever, viral hepatitis, Hantavirus infections, and
rickettsial diseases. In light of the strong similarity in epidemiology and clinical presentation
between leptospirosis and Hantavirus infections and given the reported occurrence of dual
infections, it is advisable to conduct serologic testing for Hantavirus in cases of suspected
leptospirosis. When patients have a flulike disease with disproportionately severe myalgia or
aseptic meningitis, a diagnosis of leptospirosis should be considered.

TREATMENT
The effectiveness of antimicrobial therapy for the mild febrile form of leptospirosis is
controversial, but such treatment is indicated for more severe forms. Treatment should be
initiated as early as possible; nevertheless, contrary to previous reports, treatment started after
the first 4 days of illness is effective. For severe cases of leptospirosis, intravenous administration
of penicillin G, amoxicillin, ampicillin, or erythromycin is recommended (Table 155-1). In milder
cases, oral treatment with tetracycline, doxycycline, ampicillin, or amoxicillin should be
considered. Although several other antibiotics, including newer cephalosporins, are highly active
against leptospires in vitro, no clinical experience has yet been gained with these drugs.
In rare cases, a Jarisch-Herxheimer reaction develops within hours after the start of
antimicrobial therapy. Although so far the only effective mode of management is supportive, the
role of antibodies to tumor necrosis factor in the treatment of this reaction deserves further study.
A beneficial effect of the use of such antibodies for the modulation of the reaction has been
demonstrated in patients with louse-borne relapsing fever. Patients with severe leptospirosis and
renal failure may require dialysis. Those with Weil’s syndrome may need transfusions of whole
blood and/or platelets. Intensive care may be necessary.

PROGNOSIS
Most patients with leptospirosis recover. Mortality is highest among patients who are elderly
and those who have Weil’s syndrome. Leptospirosis during pregnancy is associated with high fetal
mortality. 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 leptospires through their occupations or their involvement
in recreational water activities should be informed about the risks. Measures for controlling
leptospirosis include avoidance of exposure to urine and tissues from infected animals, vaccination
of animals, and rodent control. The animal 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.
Chemoprophylaxis with doxycycline (200 mg once a week) has appeared to be efficacious to some
extent but is indicated only in rare instances of sustained shortterm exposure.