Leptospirosis

Introduction
Systemic infection due to bacteria
Leptospira spp
Worldwide most common re-
emerging zoonotic disease (BMC Infect Dis
2009;9:147)
First human case in Malaysia was
reported in 1925 endemic
Leptospirosis is a rising menace
gazetted as notifiable disease (2010)




Epidemiology
Disease burden in Malaysia (Health Facts 2012,
MOH Malaysia) :
- Incidence rate: 7.83 / 100,000 population
- Mortality rate: 0.19 / 100,000 population




2011 2012
Total Cases 2268 3665
Total Death 55 48
Cases of Leptospirosis in Malaysian Ministry of Health Hospitals
2004 to 2009 (Report of Morbidity and Mortality for Patients 2004 to 2009, MOH Malaysia)



State 2004 2009
Perak 29 (4) 280 (19)
Selangor 16 (5) 208 (7)
Pahang 29 (1) 184 (5)
Kelantan 15 (1) 138 (4)
Terengganu 7 (1) 126 (9)
Kedah 15 (1) 106 (9)
Negeri Sembilan 27 (1) 91
Sarawak 32 (2) 70 (4)
Johor 30 (1) 59 (3)
WP KL 31 54
Sabah 13 (1) 35 (1)
P Pinang 9 32
Melaka 7 (1) 20 (1)
Perlis 2 (1) 1
Highest
NB : ( ) Death
Epidemiology
El Jalii et al (2000) demonstrated in a
retrospective study of leptospirosis in
Malaysia 1983-1998 :
- Male to female ratio = 4:1
- Highest prevalence = age group 20-29 years
- Racial distribution of incidence:
Indians (16.7%)
Malays (11.5%)
Chinese (5.9%)
(Trop Biomed 2000;16:1-5)






Global Distribution of Leptospirosis Outbreaks
Atlas of Human Infectious Diseases, 2012
Case Cluster in Malaysia


Year Place Details
2000 Sabah
Eco-Challenge-Sabah international
multisport expedition race. US CDC
found 80 out of 189 (42%) had
illnesses that met case definition
while 29 were hospitalised
(Emerg Infect Dis 2003;9(6):702-7)
2010 Huran Lipur Lubuk Yu,
Maran
6 Deaths
(all among rescue team personnel
searching for drown victim)
2010 Kedah 4 cases with 1 death reported
(three recreational areas Puncak
Janing, Lata Bayu and Bukit Wang
were closed down)
Etiology
Zoonotic disease caused by bacteria
Leptospira spp (200 serovars , 25 serogroups)
Eight species are human pathogens (Atlas of
Human Infectious Diseases, 2012)
Leptospira interrogans the most
virulent strain
Natural reservoir renal tubules of rodents
and non-rodents (cats, dogs, rabbits,
cattles)





Rats Are Major Host
Electron micrograph of Leptospira
interrogans
(Source: Cecil Medicine 24
th
ed, 2012)
Motile spirochetes
Transmission
Mainly spread via urine of carrier animals
Port of entry: oral ingestion / skin break,
direct mucosa or conjunctival contact
No human to human transmission (rarely
transplacental, sexual and breastfeeding
transmission) BMC Infect Dis 2009;9:147






Transmission of Leptospirosis
BMC Infect Dis 2009;9:147
Risk Factors
Weather
- Humidity favors bacterial growth
- Incidence rate (Human leptospirosis: guidance for diagnosis, surveillance
and control, WHO 2003) :
temperate countries < 1/100,000 population /
year
tropical countries 10/100,000 population /
year
- Floods outbreaks with high incidence of
leptospirosis (Malaysian Journal of Community Health 2009;15S:5-23)




Risk Factors
Exposure risk
- Occupations farm or pet shop workers,
veterinarians, military personnels,
drainage cleaners etc
- Activities (camping, jungle trekking etc)
Host factors
- Nave immunity
- Chronic disease
- Open wound



Clinical Features
Incubation period average 10 days (range: 2
to 30 days) with broad spectrum of
presentation
Clinical course determinants:
- virulence and dose of infecting strain
- host susceptibility factors (Cecil Medicine 24
th
Ed, 2012)
Two major clinical subtypes:
- anicteric infection (90%)
- icteric infection (10%)
(Harrisons Principles of Internal Medicine 16
th
ed, 2005)




Anicteric Infection
Consists of two major phases :
- Acute Phase (Leptospiremia)
- Immune Phase (Leptospiruria)
Phases may not be distinguishable
Milder cases often are self-limiting and
do not include second phase illness
may recur in immune phase

Anicteric Infection
Acute / Leptospiremic Phase
- Flu-like symptoms
sudden fever of 39C with chills and rigors
headache
pulmonary symptoms (cough, dysnea, chest pain)
~ 20-70% cases (Lancet Infect Dis 2003;3:75771)
conjunctival suffusion (30%)
myalgia (esp calves and lumbar area)
diarrhea, nausea and vomiting
maculopapular rashes (10-20%)
hepatosplenomegaly and lymphadenopathy are
less common (< 20%)

Conjunctival Suffusion in Leptospiremia
Source: Cecil Medicine 24
th
ed, 2012
Hyperemia of conjunctival
vessels with chemosis
Anicteric Infection
Immune / Leptospiruric Phase
- Self-limiting illness may recur lasting up to
30 days or more
- Coincides with antibody production
- Similar but more severe manifestations
- Rarely fatal mortality is almost nil
despite risk of lung haemorrhage
- Often associated with aseptic meningitis
Icteric Infection
Jaundice develops by week 3 of infection
More severe symptomatology
No discernible biphasic illness
Hemorrhagic manifestations are common
(epistaxis, petechiae, purpura etc)
Multiorgan damage occurs within 10 days
Jaundice + renal dysfunction and bleeding
Weils syndrome ~5-10% of cases (Acta Trop 2008;108:15)
Higher fatality (BMC Infect Dis 2009;9:147)


Laboratory Features
Renal dysfunction with abnormal urinary
sediment / proteinuria
ESR with leukocytosis / thrombocytopenia
Elevated bilirubin, alkaline phosphatase and
mild aminotransferases (< 400 U/L)
Prolonged prothrombin time
creatine phosphokinase (up o 50% cases)
CXR patchy alveolar pattern (hemorrhage)
CSF exam pleocytosis, protein and
normal glucose
Diagnosis
Diagnosing leptospirosis is a great challenge
due to varied presentations The Great
Mimicker
Retrospective study of 353 confirmed cases in
Hawaii (1974-1998) non-specific symptoms
are the commonest presentation (Am J Trop Med Hyg
2002;66(1):61-70)
History of possible exposure is critical to aid
diagnosis (CPG Management of Leptospirosis, MOH Malaysia 2011)
Definite diagnosis is via laboratory isolation of
leptospires or serology test


Diagnosis
Three major case definitions may be
used in establishing diagnosis :
- Clinical Case
- Probable Case
- Confirmed Case
(CPG Management of Leptospirosis, MOH Malaysia 2011)

Clinical Case
Acute febrile illness with history of exposure
to water and/or environment possibly
contaminated with infected animal urine with
ANY of the following symptoms:


1. Headache
2. Myalgia (calf muscles and
lumbar region)
3. Arthralgia
4. Conjunctival suffusion
5. Meningeal irritation
6. Anuria or oliguria and/or
proteinuria



7. Jaundice
8. Hemorrhages (from the
intestines and lungs)
9. Cardiac arrhythmia or
failure
10. Skin rash
11. Gastrointestinal symptoms
(nausea, vomiting etc)


Probable Case
A clinical case AND positive ELISA/other
rapid tests
Confirmed Case
A confirmed case of leptospirosis is a
clinical OR probable case with ANY one of
the following laboratory tests:
Microscopic Agglutination Test (MAT)
- For single serum specimen titre 1:400
- For paired sera - four fold or greater rise in titre
Positive culture for pathogenic leptospires
- blood sampling within 7 days of onset
- urine sampling after the 10th day of onset
Leptospires die quickly in urine sample must
be cultured within 2 hours
Confirmed Case
Positive PCR (sampling within 10 days of
disease onset)
Demonstration of leptospires in tissues
using immunohistochemical staining (e.g. in
post mortem cases)
In limited laboratory facility setting, case may be
confirmed if TWO different rapid diagnostic tests
are positive
Confirmation is required in hospitalised
patients and ALL suspected mortality cases
Immunohistochemistry showing leptospires
(stained brown) in liver
Lancet Infect Dis 2003;3:75771
Biphasic nature vs Lab Test
1 & 2: Acute phase samples ; 3: Convalescent phase sample ; 4 & 5: Follow-up samples
(Source: Harrisons Principles of Internal Medicine 16
th
ed, 2005)
Clinical Pearls On Lab Test
MAT is gold standard highly specific
(requires paired sampling)
Rapid test kit for leptospira simple
screening aid
Elisa detects IgM antibodies (positive
after 5-10 days of onset and persist for
several years)
Early antibiotics use may delay
antibody response
Case Notification
All probable and confirmed cases
must be notified within 1 week of the
date of diagnosis
Notification is done using Rev/ 2010
form
Notification Form
Outbreak
Outbreak is defined as more than one
probable or confirmed cases of
leptospirosis with an epidemiological
link within one incubation period

Differential Diagnosis
Dengue fever
Malaria
Typhoid
Melioidosis
Hantavirus infection
Viral Hepatitis



Clinical Pearls On Diagnosis
Conjunctival suffusion is highly specific but not
sensitive (Cecil Medicine 24
th
Ed, 2012)
Kidneys are invariably involved range from
urinary sediment changes (leukocytes,
erythrocytes and hyaline or granular casts) with
mild proteinuria to renal failure and azotemia in
severe disease (Harrisons Principles of Internal Medicine 16
th
ed, 2005)
Flu-like illness with disproportionately severe
myalgia / aseptic meningitis consider
leptospirosis (Harrisons Principles of Internal Medicine 16
th
ed, 2005)
Complications
Multiple organ failures shock
Acute renal failure ~16-40% of cases (BMC Infect
Dis 2009;9:147)
Hemorrhage
- massive spontaneous gastrointestinal
bleeding and pulmonary hemorrhage are
major causes of death (Cecil Medicine 24
th
ed, 2012)
Myocarditis
- autopsy study of 44 patients 93%
myocarditis (J Infect 2008;56:197-203)

Complications
Uveitis late complications that may persists
for years (Harrisons Principles of Internal Medicine 16
th
ed, 2005)
Aseptic meningitis commonest neurologic
manifestation (Cecil Medicine 24
th
ed, 2012)
Leptospirosis during pregnancy high fetal
mortality (Harrisons Principles of Internal Medicine 16
th
ed, 2005)

Hemorrhagic voluminous lungs covering the heart almost
completely, a common and classic finding in leptospirosis.
J Infect 2008;56:197-203
Management
Definitive
- Eradication of leptospires

Supportive
- Symptomatic treatment
- Preventing and managing complications
Definitive Management
Antimicrobial is definitive treatment
In adults, choice depends on severity:
- Mild to moderate :
oral antibiotics doxycycline (2 mg/kg up to 100
mg BD for 5-7 days), tetracycline, ampicillin or
amoxicillin
- Severe case :
High dose IV C-Penicillin (2 MU QID for 5-7 days)

.
Third generation cephalosporins and quinolone
antibiotics may also be effective
In children, recommended choice as follows:
(CPG Management of Leptospirosis, MOH Malaysia 2011)
Supportive Management

.
Dialysis (kidney failure)
Ventilation (respiratory failure)
Transfusion (massive bleeding, DIC)


Clinical Pearls In Management
Institute antibiotics early in suspected cases
diagnostic test is time-consuming and
patient may deteriorate fast (BMC Infect Dis 2009;9:147)
Jaundice indicates poorer prognosis higher
risk for complications (Cecil Medicine 24
th
Ed, 2012)
Despite profound jaundice, death is rarely due
to liver cause (Harrisons Principles of Internal Medicine 16
th
ed, 2005)
Jarisch-Herxheimer reaction may occur during
early phase of antibiotic treatment
Prognosis
Majority are self-limiting, becoming asymptomatic
within a week (Harrisons Principles of Internal Medicine 16
th
ed, 2005)
High mortality in severe illness (Weils disease 5-
40% while pulmonary hemorrhage syndrome > 50%)
Prognostic predictors for death are:
- older age (>40 years)
- oliguria and respiratory insufficiency
- jaundice
- pulmonary hemorrhage
- cardiac arrhythmias
- altered mental status (Cecil Medicine 24
th
Ed, 2012)
Prognosis
Follow-up studies :
- hepatic function normalizes within 1
month
- renal function normalizes within 6
months
- unilateral / bilateral uveitis may last up
to 18 months and persist for years
(Cecil Medicine 24
th
Ed, 2012)
Prevention
Core strategies:
- Controlling animal reservoir
- Transmission disruption
- Preventing human diseases


Effective Health Education and Promotion =
Mainstay of Prevention


National campaign launched on 24
th
Aug 2013
against rat menace to fight leptospirosis


Source: http://www.thestar.com.my/News/Nation/2013/08/12/Drive-to-wipe-out-rat-
menace-Ministry-to-launch-nationwide-campaign-to-keep-rodent-problem-in-check.aspx/
Archive: 12/08/2013
Prevention
Controlling animal reservoir
- Vaccination of domestic animals
serological study of domestic animals in
West Malaysia (1987) found that 25.5 % of
the animals examined were carriers (Epidemiol
Infect 1987;99(2):379-92)
- Cleanliness and rodent control in private
premises and public places (restaurants,
recreational parks etc)






Penyerahan perangkap tikus kepada seorang tuai rumah
panjang sempena Kempen Kawalan Penyakit Leptospirosis
Peringkat Bahagian Kapit di Kapit, Sarawak

Sumber:http://www.utusan.com.my/utusan/Sabah_&_Sarawak/20130827/wb_04/Masy
arakat-perlu-cegah-penyakit-kencing-tikus#ixzz2ptpfBT2b

Arkib: 27/08/2013


Health Department officials using ultraviolet light to look
for traces of rat urine at a food outlet



Source: http://www.nst.com.my/nation/general/2-775-leptospirosis-cases-
23-deaths-this-year-1.340149
Archive: 19/08/2013
Prevention
Transmission disruption
- Good personal hygiene and sanitation
- Adequate protection for high risk exposure
wear waterproof protective clothing such as
rubber boots and gloves
cover skin lesions with waterproof dressings
wash with clean water immediately after
exposure
- Contamination risk assessment of water
source (CPG Management of Leptospirosis, MOH Malaysia 2011)











Prevention
Preventing human disease
- Chemoprophylaxis
pre-exposure
post-exposure





The role of prophylaxis in children
has not been adequately studied

Pre-Exposure Prophylaxis

May be used for people at sustained high
risk exposure eg military personnel in
jungle op or people in risky outdoor sports
Dosing :
- Oral doxycycline 200mg stat dose then
weekly throughout the stay OR
- Oral azithromycin 500mg stat dose then
weekly throughout the stay (if pregnant or
allergic to doxycycline)
Controversial Use : Assess Risk-Benefit Ratio

Post-Exposure Prophylaxis

May be used during outbreak situation
Dosing :
- Oral Doxycycline 200mg stat dose then
followed by 100mg BD for 5 7 days for
those symptomatic with the first onset of
fever OR
- Oral azithromycin 1gm Day 1, then 500mg
daily for 2 days
Azithromycin is better tolerated but more
expensive
CONCLUSION
Early treatment prevents
complications
Prompt triage of high risk patients
and aggressive supportive care
reduces mortality
Prevention is better than cure

References
1. Goldman L, Ausiello D, eds. Cecil Medicine. 24
th
ed. Philadelphia:
Saunders Elsevier; 2012.
2. Kasper DL, Braunwald E, Fauci AS, et al, eds. Harrisons Principles of
Internal Medicine. 16
th
ed. New York: McGraw-Hill Companies Inc;
2005.
3. Clinical Practice Guidelines for the Diagnosis, Management, Prevention
and Control of Leptospirosis in Malaysia 2011, MOH Malaysia.
4. Health Facts 2012, MOH Malaysia.
5. Ann Florence BV, Lee DS, Nina Gloriani B, Lolita LC,Takeshi K,
Khanchit L, et al. Leptospirosis in the Asia Pacific region. BMC Infect
Dis 2009;9:147
6. Badrul Hisham AS, Nor Azian Shaharom CMD,Marzukhi MI, Norli R,
Fatimah O, et al. Spectrum of flood-related diseases encountered
during flood disaster in Johore, Malaysia. Malaysian J ournal of
Community Health 2009;15S:5-23
7. Human leptospirosis: guidance for diagnosis, surveillance and control.
WHO 2003.



References
8. El Jalii IM, Bahaman AR, Mohd Azmi ML, Mutalib AR. Occurrence of human
Leptospirosis in Malaysia: A retrospective study. Trop Biomed 2000;16:1-5
9. Bahaman AR, Ibrahim AL, Adam H. Serological prevalence of leptospiral
infection in domestic animals in West Malaysia. Epidemiol Infect
1987;99(2):379-92
10. Katz AR, Ansdell VE, Effler PV, Middleton CR, Sasaki DM. Leptospirosis in
Hawaii, 1974-1998: epidemiologic analysis of 353 laboratory-confirmed cases.
Am J Trop Med Hyg 2002;66(1):61-70
11. Wertheim HFL, Horby P, Woodall JP, eds. Atlas of Human Infectious Diseases.
West Sussex: Blackwell Publishing; 2012.
12. Sejvar J, Bancroft E, Winthrop K, et al. Leptospirosis in Eco-Challenge Athletes,
Malaysian Borneo, 2000. Emerg Infect Dis 2003;9(6):702-7
13. Chakurkar G, Vaideeswar P, Pandit SP, Divate SA. Cardiovascular lesions in
leptospirosis: an autopsy study. J Infect 2008;56:197-203
14. de Faria MT, Calderwood MS, Athanazio DA, et al.Carriage of Leptospira
interrogans among domestic rats from an urban setting highly endemic for
leptospirosis in Brazil. Acta Trop 2008;108:15
15. Bharti AR, Nally JE, Ricaldi JN, et al. Leptospirosis: a zoonotic disease of global
importance Lancet Infect Dis 2003;3:75771






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