LEPTOSPIROSIS

Dr. SARTONO Sp PD

Leptospirosis :
Emerging infectious disease global importance
Outbreaks in Asia , Central / South America & the USA
Caused by pathogenic leptospires
Characterized by broad spectrum of clinical manifestation , from
mild form ( influeza like illness , headache , myalgia ) to severe
leptospirosis ( jaundice , renal dysfunction & hemorrhagic
diathesis called Weils syndrome ).
Etiologic Agents :
Leptospires belonging to the order of SPIROCHAETALES and
family LEPTOSPIRACEAE
Current designation : L. interrogan sensu lato &
L. biflexa sensu lato

 Based on DNA : 17 genomospecies of pathogenic leptospires

The genome sequences of 2 strains have been published
Based on antigenic composition , pathogenic leptospires :
> 250 serovars ( 26 serogroups )

LEPTOSPIRES :
- coiled , thin , highly motile with hooked ends & two
periplasmic flagella ( permit burrowing into tissue )
- 6 20 m long & 0,1 m wide
- poorly stained , but can be seen by dark-field examination
and after silver impregnated staining
- Require special media/condition for growth ; takes weeks.

EPIDEMIOLOGY :
Leptospirosis important zoonosis , world wide distribution ,
affecting 160 mammalian species.
Reservoir :
- most important : rodents ( especially rats )
- other : wild mammals / domestic & farm animals
Establish a symbiotic relationship with host & can persist in
the renal tubules for years.
Some serovars associated with particular animals e.g.
- Icterohemorrhagiae & Copenhageni rats
- Grippotyphosa voles
- Hardjo cattle
- Canicola dogs
- Pomona pigs ; but may occur in other animals.

In most countries , leptospirosis is underestimated problem

Infection occurs in the tropics ( most common ) , due to :
- climate
- poor hygienic conditions favor the pathogens survivals
& distribution.
Most cases in men , peak incidence :
- during summer & fall in Western countries
- during rainy season in the tropics
Transmission of leptospires to humans follows :
- direct contact with urine , blood , tissue from infected animal
- exposure to a contaminated environment
Human to human transmission is rare
Leptospires , excreted in the urine & can survive in water for
many months important vehicle for transmission

Epidemics of leptospirosis may results from exposure to

flood waters contaminated by urine from infected animals
( in Nicaragua ).
INCIDENCE :
In 1999 , > 500,000 reported from China with case fatality
rate 0.9 7.9 %.
In Brazil , > 28,000 , reported in the same year
Among commonly infected humans , only a minority become
symptomatic or develop severe leptospirosis.
The incidence of severe leptospirosis in Brazil is 9.5 /100000
In USA , 40 120 cases reported annually to CDC.

HIGH RISK GROUPS

High risk occupational groups :
- Veterinarians
- Agricultural workers
- Sewage workers
- Slaughterhouse employees
- Workers in fishing industry
Recreational exposure & domestic-animal contact sources of
leptospirosis Recreational water activities :
canoeing, windsurfing, swimming, waterskiing.
Outbreak in 1998 among athletes after triathlon in Illinois
heavy rains , agricultural runoff increased contamination.
In 2000 , 80 participants contracted leptospirosis , during
multisport endurance race in Borneo, Malaysia.

Transmission via lab. accidents has been reported but rare.

Leptospirosis develops occasionally after unanticipated
immersion in contaminated water ( e.g. in an automobile
accident ) & rarely after an animal bite.

PATHOGENESIS :
incompletely undestood
leptospires enter the host via skin abrasions or via intact
mucous membrane ( conjunctiva & lining of oro &
nasopharynx )
drinking contaminated water may introduce leptospires
through the mouth , throat & esophagus leptospiremia
all organs.

Multiplication takes place in blood & tissues

Leptospires can be isolated from blood & CSF the 1st 10 -14
days.
CSF exam pleocytosis , but only a minority of Px develop
symptom & signs of meningitis.
All forms can damage the wall of small blood vessels
vasculitis with leakage & extravasation of cell, including
hemorrhage.
Pathogenic properties of leptospires :
- adhesion to cell surfaces
- cellular toxicity
Vasculitis responsible for the most important manifestations

Mainly infect the kidney & liver, any organ may be affected.
In the kidney , migrates to the interstitium , renal tubules , &
tubular lumen interstitial nephritis & tubular necrosis.
Hypovolemia ( due to dehydration ) or altered capillary
permeability contribution of renal failure.
In the liver : centrilobular necrosis + proliferation of Kupffer
cells , but severe hepatocellular necrosis is not a
feature of leptospirosis.
Pulmonary involvement : due to hemorrhage and not of
inflamation.
Skeletal muscles swelling , vacuolation of myofibrils & focal
necrosis.
Severe leptospirosis vasculitis impair microcirculation &
increase capillary permeability -> fluid leakage & hypovolemia

When antibodies are formed leptospires are eliminated

from all sites , except eye , prox. renal tubules & perhaps the
brain persist for weeks or months.
Systemic immune response is effective in eliminating
organism but may produce symptomatic inflamatory
reactions.
A rise in antibody titer coincides with development of
meningitis.
After the start of antimicrobial treatment , a JarischHerxheimer reaction similar to that in other spirochetal
diseases may develop.

CLINICAL MANIFESTATION

Many Px remain asymptomatic

Serologic evidence of past inapparent infection is frequently

found in persons who have been exposed but have not

become ill.
Symptomatic cases vary from mild to serious even fatal.
> 90 % symptomatic Px have relatively mild & unicteric form
of leptospirosis with or without meningitis.
Severe leptospirosis with profound jaundice ( Weils
syndrome ) , develop in 5 10 % of infected individuals.
Incubation Period : 1-2 weeks , ranges from 2 20 days.
Typically , acute leptospiremic phase is followed by an immune
leptospiruric phase.
The distinction between the 1st & 2nd phase is not always clear;
Milder cases do not always include the 2nd phase.

ANICTERIC LEPTOSPIROSIS

Leptospirosis may present as an acute influenza-like illness,

with fever, chills, severe headache , nausea , vomiting &

myalgia.
Important features : muscle pain , especially affects the calves
, back & abdomen.
Less common features : sore throat and rash.
Px usually has an intense headache ( frontal or retroorbital );
sometimes develops photophobia.
Mental confusion may be evident.
Pulmonary involvement , manifested by cough , chest pain or
hemoptysis.
The most common finding on PE : fever & conjunctival
suffusion.

Less common findings : muscle tenderness, lympadenopathy,

pharyngeal injection, rash, hepatomegaly & splenomegaly.
Rash : macular, maculopapular, erythemateous, urticarial,
hemorrhagic.
Px -> asymptomatic within 1 week ;
After interval of 1-3 days the illness recur
The start of this 2nd (immune) phase coincides with the
development of antibodies ; symptoms , more variable than
the 1st ( leptospiremic ) phase ; Usually last for a few days ,
but occasionally persist for weeks. Fever are less pronounced
& myalgia less severe than in the leptospiremic phase.
Important event during the immune phase : development of
aseptic meningitis.

Although no more than 15% of all Px have symptoms & signs

of meningitis, many Px CSF pleocytosis.
Meningeal symptoms usually disappear within a few days but
may persist for weeks ; pleocytosis disappear within 2 weeks
but occasionally persists for months.
Aseptic meningitis is more common in children.
Iritis, iridocyclitis & chorioretinitis late complications , may
persistfor years.
Mortality rates in anicteric leptospirosis are low although
death ( due to pulmonary hemorrhage ) occured in 2.4 %of
cases in a Chinese outbreak.

SEVERE LEPTOSPIROSIS ( WEILS SYNDROME )

The most severe form ; characterized by :

- jaundice
- renal dysfunction
- hemorrhagic diathesis
- pulmonary involvement
Mortality rate : 5 15 %
In Europe its frequently associated with serovar Ictero hemorrhagiae & Copenhageni.
The onset is about the same with less severe leptospirosis ;
after 4-9 days , jaundice/renal/vascular dysfunction develop.
Defervescence may be noted after the 1st week of illness , but
biphasic disease pattern (like in anicteric leptosp.), is lacking.
The jaundice is usually not associated with severe hepatic
necrosis.

 Death is rarely due to liver failure.

Hepatomegaly & tenderness (+) ; slenomegaly : 20% of cs.

Renal failure (+) in the 2nd week of illness.
Hypovolemia & decreased renal perfusion ATN with oliguria
or anuria. Dialysis , is sometimes required.
Pulmonary involvement occurs frequently cough, chest pain,
blood stained sputum & hemoptysis or respiratory failure.
Hemorrhagic manifestations are seen in Weils syndrome :
epistaxis, petechiae, purpura & ecchymoses found commonly ;
while severe GI bleeding & adrenal/subarachnoid hemorrhage
detected rarely.
Severe leptospirosis may present with rhabdomyolysis,
hemolysis, myocarditis, pericarditis, CHF, cardiogenic shock,
ARDS, necrotizing pancreatitis, multiorgan failure.

LABORATORY & RADIOLOGIC FINDINGS

The kidney invariably involved in leptospirosis

urinary sediment changes ( leucocytes, erythrocytes & hyaline

or granular casts ) & mild proteinuria in anicteric leptospirosis
renal failure / azotemia in severe disease.
ESR , usually elevated
In anicteric leptospirosis, peripheral leucocyte counts rise (
3000 26000 / L with a left shift ; in Weils syndrome ,
leucocytosis is often marked.
Mild thrombocytopenia occurs in 50% px & assoc. w. RF
In contrast to acute viral hepatitis , leptospirosis have elevated
bilirubin, alkali phosphatase & mild increase ( 200 U/L ) of
aminotransferases.
In Weils syndrome, prothrombine time may be prolonged ( can
be corrected w. Vit. K )
Creatin phosphokinase , elevated in 50% px ( DD w. Hepatitis)

 When meningeal reaction develops , pmn leucocytes

predominate initially, mononuclear cells increase later.

CSF protein elevated , but CSF glucose level , normal.
In severe leptospirosis , pulmunory radiographic abnormalities,
are more common than would be expected on PE freq.ly
develop 3 9 days after the onset.
Radiographic finding : patchy alveolar pattern ( most com
mon ) , corresponds to scattered alveolar hemorrhage ;
Most often, affect the lower lobes in the periphery of the lung
fields.

DIAGNOSIS

Definite Dx of Leptospirosis , based on :

* isolation of organism from the px. or

* seroconversion or
* a rise in antibody titer in the microscopic agglutination test
( MAT ) ; in USA , MAT performed at CDC.
In strong evident of leptospirosis infection , a single antibody
titer of 1 : 200 - 1 : 800 in the MAT is required.
A four fold or greater rise in titer is detected between acute &
convalescent-phase serum specimens.
Antibodies generally do not reach detectable levels until the
2nd week of illness ; AB response can be affected by early Tx

 Leptospires can be isolated from blod and / or CSF during the

1st 10 days and from urine for several weeks beginning at first
week .
Cultures often become positive after 2-4 weeks, with a range
of 1 week to 6 months.
Urine cultures remains pos. for months or years.
For isolation of leptospires from body fluids or tissues , EMJH
(Ellinghausen-Mc Cullough-Johson-Harris) medium is useful;
Other medium are Fletcher or Korthof medium.
Specimens can be mailed to a reference lab. for culture
remain viable in anticoagulated blood (heparin,EDTA,citrate) ,
up to 11 days.
Isolation of leptospires is important , since dark-field exam.
results in misdiagnosis.

DIFFERENTIAL DIAGNOSIS :
Leptospirosis should be differentiated from other febrile
illnesses ( associated with headache & muscle pain ) :
- Dengue
- Viral Hepatitis
- Malaria
- Hantavirus infection
- Enteric Fever
- Rickettsial Disease

Therapy

- Based on randomised clinical trials penicillin &

doxycycline, the most commonly used antibioyics.
- Tx should be initiated as soon as possible ;
Tx after the first 4 days is still effective.
In milder cases, Tx with tetracyclin, doxycyclin, apicillin, or
amoxicillin should be considered.

 For severe cases of leptospirosis, IV administration of

penicillin G, ampicillin, amoxicillin or erythromycinis
recommended.

No significant differences between antibiotics with regard to:

- mortality
- defervescent
- time to resolution of abnormal lab.findings

Thus doxycyclin, cefotaxime, or ceftriazon is a satisfactory

alternative to penicillin G

Purpose of drug
Administration
Treatment
Mild leptospirosis

Moderate/severe
leptospirosis

Chemoprophylaxis

Regimen
Doxicyclin 100mg orally, bid or
Ampicillin, 500-750mg orally qid
or
Amoxicillin, 500mg orally qid
Penicillin G, 1.5 million U IV qid
or
Ampicillin, 1 g IV qid or
Amoxicillin , 1g IV qid or
Ceftriazon, 1 g IV once daily or
Cefotaxime, 1g qid or
Erythromycin, 500 mg IV qid
Doxycyclin, 200 mg orally/week

PROGNOSIS
- Most Px recover
- Mortality rates, highest in elderly & Weils syndrome ; also
in those with pregnancy

PREVENTION
- Those who may be exposed (through occupation or
recreational water activities ) should be informed about the
risk.
- Avoidance of exposure to urine & tissues from infected
animals.
- Vaccination of animals and
- Rodent control