LEPTOSPIROSIS

DIAGNOSIS and MANAGEMENT

SUDIRMAN KATU
Division of Infectious and Tropical Medicine
Department of Internal Medicine, Faculty of Medicine
Hasanuddin University
Wahidin Sudirohusodo General Hospital
 Leptospirosis : zoonosis with global
distribution, caused by pathogenic
Leptospira (L. interrogans)
 Common cause of undifferentiated febrile
illness in developing countries
 Greatly underreported, particularly in tropical
regions
 Incidence in tropical regions :
> 10/ 100,000 per year (males > females);
peak incidence in the rainy season;
outbreaks may follow excess rainfall
 Leptospirosis : adalah penyakit zoonosis akut disebabkan oleh
bakteri Leptospira dengan spektrum penyakit yang luas dan
dapat menyebabkan kematian.
 Leptospira : adalah genus bakteri dari ordo spirochaeta, famili
Leptospiraceae, berbentuk ulir dan memiliki cambuk
erak/flagelum pada kedua ujungnya.
 Leptospiremia : adalah keberadaan kuman Leptospira dalam
darah.
 Serovar : adalah dasar klasifikasi kuman Leptospira berdasarkan
kesamaan dan perbedaan pada reaksi cross agglutination
absorption.
 Weill’s Disease = leptospirosis berat disebabkan oleh bakteri
Leptospira icterohemorrhagiae.
 Leptospirosis pada manusia beberapa nama Weill’s Disease,
Mud Fever, Canicola Fever, Hemorrhagic Jaundice, Trench
Fever, Swineherd’s Disease.
Leptospirosis in Indonesia
 400 – 600 cases reported every year
 Reported from at least 16 provinces

 Central Java (2011) : 184 reported cases,

33 deaths (CFR 17.93 %)
 Mortality : 2.5 – 16.4 %
 TRANSMISSION
direct or indirect contacts with urine
or tissue of infected animals (rodents, small
mammals)
PATHOGENESIS
 Leptospira enters the body through cuts, abrasions,
mucous membrane, conjunctivae, or aerosol
inhalation
 Widespread hematogenous dissemination,
penetration of tissue barriers, invasion of CNS,
aqueous humor of the eye
 Systemic vasculitis, endothelial damage, capillary
leakage, anterior iridocyclitis, chorioretinitis,
pulmonary hemorrhage, renal cortex ischemia,
necrosis of tubular epithelial cells, liver cell injury/
necrosis
 Severity of disease : hemolytic toxins (act as
sphingomyelinase, phospholipase, pore-forming
protein), immune responses
 pathogenesis
penetration

Localized in
fever
n g
lu
liver jaundic
kidney
br e
a in
Uterus in
pregnant animal

abortion
CLINICAL MANIFESTATIONS
 Self-limited systemic illness (90 %) to potentially
fatal illness(renal failure, liver failure, pneumonitis
with hemorrhagic diathesis)
 Incubation : 5 – 14 days
 Acute septicemic phase (5 – 7 days) and immune
phase (4 – 30 days)
 Weil’s disease : severe leptospirosis characterized
by impaired hepatic and renal function, hemorrhagic
diathesis (mortality 5 – 40 %)
 Rhabdomiolysis, myocarditis, pericarditis,
congestive heart failure, ARDS, necrotizing
pancreatitis also reported in severe cases
Clinical presentations

Clinical presentations vary, from

sub-clinical infection,
flu-like syndrome, acute undifferentiated fever
to potentially fatal illness

Risk factors for severity ?

 health status, nutrition or age of patient
 genotype or serovar of strains involved
 host genetic polymorphism, immunology etc
 early definitive and supportive treatment
Clinical presentations
2 clinical syndromes
 Mild, anicteric leptospirosis 85-90%
 Flu-like or acute undifferentiated fever
 Most cases are misdiagnosed as other febrile illness
 Patient may not seek medical attention
 Severe, icteric leptospirosis 10-15%
 Weil`s disease (Weil syndrome)
 High mortality rate 5 - 40%
Jaundice, bleeding tendency and renal failure
are major indicators for severity in leptospirosis
 Anicteric “mild” Leptospirosis
clinical diagnosis

 Clinical diagnosis is difficult

 Mild, atypical, anicteric leptospirosis cases are often

confused with other febrile illnesses  misdiagnosis

 Anicteric leptospirosis should be included in the

differential diagnosis of every patient with acute fever

 Risk factors associated with leptospirosis should be

identified  as high index of suspicion for diagnosis
 Severe Leptospirosis
clinical diagnosis
 Diagnosis of severe leptospirosis is easy to
be recognized especially in endemic areas

 Most hospitalized patients with leptospirosis

in the tropics are severe icteric leptospirosis

 A fatal leptospirosis mortality rates: 5–40%

despite in-hospital treatment

 Should be included in the DD of other potentially fatal

infectious diseases like severe falciparum malaria etc.
Biphasic Nature of Leptospirosis

Levett PN. Clin Microbiol Rev 2001;14: 296-326

CLINICAL MANIFESTATIONS
• Acute septicemic phase : high remittent fever,
headache, chills, rigors, muscle tenderness (in the
calf, most characteristic), conjunctival suffusion (most
characteristic), abdominal pain, nausea, vomiting,
diarrhea, cough, pharyngitis, lymphadenopathy,
hepatomegaly, splenomegaly

• Immune phase : jaundice, renal failure, arrhythmia,

hemorrhagic pneumonitis, aseptic meningitis ( 80 % ),
conjunctival suffusion with or without hemorrhage,
muscle tenderness, adenopathy, hepatosplenomegaly,
abdominal pain (may be an indication of pancreatitis)
Differential Diagnosis
 Viral hepatitis
 Severe malaria
 Hemolytic-uremic syndrome
 Meningococcal disease
 Yellow fever
 Hantavirus infection
 Rickettsial diseases
Anicteric “mild” leptospirosis
differential diagnosis

Influenza uncomplicated malaria

dengue infection HIV seroconversion illness

hantavirus infection ricketsiosis / murine typhus

typhoid fever infectious mononucleosis

meningitis other viral / bacterial infections

Icteric Leptospirosis
differential diagnosis

 Severe falciparum malaria

 Severe complicated typhoid fever

 Haemorrhagic fevers with renal failure

(HFRF) hantavirus type Dobrava

 Other severe viral haemorrhagic fevers

DIAGNOSIS
 History of exposure (accidental, occupational,
traveling, recreational) to dirty water, damp soil
(flooding after heavy rain, milking sheds on dairy
farm, fish farming, sewage and canal works,
abbattoir works, butchers, hunters, animals
handlers, jungle training, white-water rafting )
 Clinical signs and symptoms
 Laboratory examination
Evaluation of microscopic agglutination test as a diagnostic tool during acute
stage of leptospirosis in high & low endemic areas.
Vijayachari P, Sugunan AP, Sehgal SC.
Source
National Leptospirosis Reference Centre, Regional Medical Research Centre, (ICMR), Port Blair, India.
Abstract
BACKGROUND & OBJECTIVES:
Making a diagnosis on the results of a single microscopic agglutination test (MAT) is difficult because of the
uncertainties about the cut-off titre. The present study was conducted to determine the significant titre
for a single MAT in areas of high and low endemicity for leptospirosis.
METHODS:
A total of 1944 serum samples were collected from healthy individuals and confirmed patients residing in
areas of high and low endemicity. All the sera were screened by MAT using 10 live leptospiral strains
as antigens. From the distribution of titres among healthy individuals and in patients, the sensitivity and
specificity at different cut-off titres were calculated. Likelihood ratio positive (LR+), likelihood ratio
negative (LR-), and LR+/LR- were calculated. Receiver operating characteristics (ROC) curves were
plotted for the early and late stages of the disease in both the areas.
RESULTS:
The ROC plot was totally below the no benefit line during the first week of illness in high endemic area.
During the second to fourth weeks it showed better characteristics and the best cut-off titre was 1:200,
where the sensitivity was 93.4 per cent and specificity 74.7 per cent LR+ LR- ratio was 41.82 indicating
reasonable separation between the positive and negative test results. In the other states the ROC plot
was above the no benefit line even during the first week, the best cut-off being 1:50 where the
sensitivity was 56.7 per cent and specificity was 90.6 per cent. During the second to fourth weeks the
test showed the best characteristics in the low endemicity regions with an ROC curve having the ideal
shape. Best cut-off was at 1:100 where the sensitivity was 96.6 per cent and specificity 94.8 per cent
LR+ LR- ratio was 523.25 indicating a wide separation between the positive and negative test results.
INTERPRETATION & CONCLUSION:
MAT does not have any diagnostic value during the first week, particularly in high
endemic areas. The best cut-off to be used will be 1:50 in low endemicity areas
during the first week, 1:100 during the second to fourth week and 1:200 in high
endemicity regions during the second to fourth weeks.
Indian J Med Res 2011;114:99-106
A sensitive and specific IgM-ELISA for the serological diagnosis of
human leptospirosis using a rLipL32/1-LipL21-OmpL1/2 fusion
protein.
Sun A, Wang Y, DU P, Wu S, Yan J.
 Source :Zhejiang Medical College, Hangzhou, China
Abstract
OBJECTIVE:
 To construct a lipL32/1-lipL21-OmpL1/2 fusion gene and its prokaryotic expression system,
and to establish an enzyme-linked immunosorbent assay (ELISA) using the rLipL32/1-
LipL21-OmpL1/2 fusion antigen of Leptospira interrogans for sensitive and specific
detection of IgM in the serum of patients with leptospirosis.
METHODS:
 lipL32/1-lipL21-OmpL1/2 fusion genes were constructed using a primer-linking PCR. The
target recombinant protein antigens, rLipL32/1, rLipL21, rOmpL1/2 and rLipL32/1-LipL21-
OmpL1/2, were expressed and the purified antigens were then immobilized to the surface
of microplate wells for ELISA-based detection of IgM in the sera of leptospirosis patients.
RESULTS:
 Of 493 acute leptospirosis patients, 95.7% and 97.8% were positive by
rLipL32/1-LipL21- OmpL1/2-IgM-ELISA using different serum dilutions, which
was higher than the rLipL32/1-IgM-ELISA (93.1% and 90.3%), rLipL21-IgM-
ELISA (90.3% and 87.0%), and rOmpL1-IgM-ELISA (85.6% and 81.1%)
(P<0.01). All IgM-ELISAs tested negative against 56 non-leptospirosis patients
with typhoid fever, hemorrhagic fever or dengue fever.
CONCLUSION:
 Trigeminal fusion antigen increases ELISA sensitivity and the rLipL32/1-LipL21-OmpL1/2-
IgM-ELISA is a sensitive and specific serological diagnostic method for clinical
leptospirosis.
Biomed Environ Sci 2011;24(31):291-9
 Clinical features suggestive of current Leptospirosis

Leptospiremic phase < 7days Immune phase ≥ 7 days

Blood culture PCR ELISA /MSAT

Confirm
(if available)
Negative Positive MAT

Repeat
(> 3 days) Positive Negative

Repeat (if low titer) Repeat

High titer Rising titer Seroconversion

 MAT and ELISA

ELISA / SAT MAT Interpretation

+ Single high titer Current infection
+ - Current infection
- Single high titer Past infection
± Seroconversion / Current infection
4 fold rise in titer
TREATMENT
 Antibiotic : early administration in suspected
cases
 Symptomatic and supportive therapy
 Treatment of complications (hemodialysis,
intubation and mechanical ventilation)
Treatment
PREVENTION
 Avoidance of high risk exposure
 Adoption of protective measures
 Immunization (animals and humans)
 Chemoprophylaxis
SUMMARY
 Leptospirosis is a preventable zoonosis disease
 Wide range of clinical manifestations : mild
illness to potentially fatal (5 – 10 % of cases with
mortality 5 – 40 %)
 Diagnosis is based on history of exposure to
urine or tissue of infected animals, clinical signs
and symptoms (most characteristic : conjunctival
suffusion, calf muscle tenderness, aseptic
meningitis), serologic tests (MAT, IgM-ELISA)
 Treatment : early antibiotics administration,
symptomatic and supportive treatments,
treatments of complications
THANK YOU