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LEPTOSPIROSIS

UPDATE
International Leptospirosis Society Meeting 2017
New Zealand, November 2017
INTRODUCTION
 Clinical manifestation of Leptospirosis range :

acute febrile illnes (fever myalgia)  serious systemic inflammation,

shock

jaundice

multiple organ hemorrhage&failure


 Presence of conjunctival
congestion along with jaundice in a
febrile patient is considered as
pathognomic of Leptospirosis (Van
Thiel PH)

Van Thiel PH (1948) The


Leptospirosis.University of Leiden,

The Netherlands
 Classic Weil Disease : kidney and liver

 Underreported : SPHSS (Severe Pulmonary Hemorrhagic


Syndrome) and Meningitis due to Leptospirosis.

 Varied syndromes  Clinical diagnosis : a challenge


TOOLS TO AID CLINICAL
D I AG N O S I S O F L E P T O S P I RO S I S

 Exposure history

 Clinical Presentation

 Laboratory test result


TOOLS TO A ID CLIN ICA L D IAG N OSIS OF
LEPTOSPIROSIS IN RESOURCE POOR AREAS

 Diagnostic model scoring system : WHO Faine Score 1982 


2004  2012
 Include  Epidemiological factors, Clinical Features, Lab
investigations – which can be done and very helpful in most of
peripheral centre and resource poor areas
L A B O R AT O RY M E T H O D S
O F D I AG N O S I S

• Serology : detect antibodies


– Screening test (Rapid detection test, ELISA)
– Microscopic agglutination test (MAT) : technically difficult to
perform, require maintenance of a panel of live strain

• Molecular test
– PCR

• Isolation
– Insensitive, slow growing ≠ early diagnosis
RAPID DETECTION TESTS
 Inexpensive

 Easy to use

 Require no additional equipment

 Useful in primary health care or


resource-poor areas

 Latex agglutination test, Lepto dipstick,


Lepto lateral flow / ICT, Lepto Dri Dot test
ELISA

 Detects IgM or IgG

 Simple

 High – throughout

 Considered a screening test


M I C RO S C O P I C
AG G LU T I N AT I O N T E S T ( M AT )
 Panel of live antigens (24 live
serogroup) is reacted against serial
dilutions of patient sera

 Agglutination read using darkfield


microscopy

 Complicated, cut-off titer


controversial

 Four-fold rise in titer is diagnostic


MOLECULAR DETECTION
• PCR assays : genes specific to leptospira ~
Incubation
Icterus
timing of specimen collection period
Renal Failure
Fever
Myalgia
• Detection of DNA is confirmatory Leptospiuria

• Specimen collection
Leptospiremia
– <7 days post onset : blood for PCR
Antibodies
– 7 days post onset : Serum (RDT, ELISA, MAT),
urine for PCR
– CSF for PCR : collect if symptomatic
– Due to transient nature of Leptospira in
Week 1 Week 2 Week 3 Week 4
bloodstream, window of optimal specimen
collection is very narrow for DNA detection
I N T E R P R E TAT I O N O F L A B T E S T

Serology
• Positive rapid test or screening test – presumptive,
needs confirmation
• MAT – 4x rise or seroconversion is confirmatory
no rise in titer or low titer in single specimen - inconclusive
PCR
• Positive – confirmatory
• Negative – will not rule out leptospirosis
• Some studies  reference standard test
Best practice – run multiple test on multiple specimens
LIMITATIONS
 Serological test cannot make an
early diagnosis as the antibody titers
rise in 2nd or 3rd week

 Facilities for culture, dark field


microscopy and PCR are not widely
available

 Communication with veterinary


community : critical  outbreak in
animals present increased risk to
human (L. Pomona, L. Hardjo)
Scientific Leptospirosis Researches
in ILS 2017
DIAGNOSIS OF LEPTOSPIROSIS UTILIZING
M O D I F I E D FA I N E ’ S C R I T E R I A ( 2 0 1 2 )
I N R U R A L H O S P I TA L O F I N D O N E S I A
Yosefin Ratnaningtyas1, Maela Rustiana Dewi1

 Background : Leptospirosis still being overlooked and underreported.


Diagnostic test  expensive, limited availability, esp. in rural areas

 Aims: To evaluate the use of the Modified Faine’s Criteria (2012)


for leptospirosis patients in a rural hospital of Indonesia
METHODS
 All patients with Acute Undifferentiated Fever were screened (August 2016
to July 2017).

 Inclusion criteria: All cases presenting with symptoms of part A of the


WHO Modified Faine's Criteria.

 Leptospirosis diagnosis established after laboratory tests using lateral flow


assay (Uji Leptospira IgM, Indonesia). Results were analyzed according to
Modified Faine’s Criteria (2012).

 Seropositive results + score of 26 or more when using Part A or Part A+B


of Modified Faine's Criteria were considered true positive infections.
RESULTS

 38 cases (25.85%) of 147 AUF patients Leptospirosis

 Male-to-female ratio of 1.7:1, mean age 52 ± 15.2 years.

 22 cases (57,89 %) were designated as severe leptospirosis.

 7 cases = score ≥ 26 (Part A+B) Modified Faine’s Criteria (2012)


Table 3. Clinical Features
Signs & Symptoms n = 38 (%)
Fever / High Grade Fever > 390C 100 % / 26,31%

Headache 84,21 %
Myalgia 97,37 %
Conjunctival suffusion 76,32 %
Meningism 21,05 %
Renal Dysfunction 63,12 %
Icteric Presentation 57,89 %
Abdominal pain 47,37 %
Rash 10,52 %
Hypotension 5,26 %
Table 4. Characteristic Performance of
Modified Faine’s (2012) Criteria
Characteristic Performance A + B only
Sensitivity (%) 18,42
Specificity (%) 94,50
(+) Likelihood Ratio 3,35
(-) Likelihood Ratio 0,86
PPV (%) 53,85
NPV (%) 76,87
CONCLUSION
 Modified Faine Criteria (2012) : useful and simple guideline esp in
poor resources area, featuring : clinical features, exppsure history,
lab outcomes

 It may help clinicians in rural areas to increase awareness of


leptospirosis and give early continuing care and management for
patients

 Rapid diagnostic test have been included ~ more likely to be


provided in rural areas
LABORATORY FINDINGS AND SEVERITY OF
LEPTOSPIROSIS: A CROSS -SECTIONAL STUDY
I N R U R A L H O S P I TA L I N I N D O N E S I A

Maela Rustiana Dewi1, Yosefin Ratnaningtyas1

 Background : Clinical presentation is unspecific  may mimic other


acute febrile ilnesses  challenging clinicians to differentiate case
 The patterns of simple laboratory findings  potential to clinicians in
differentiating disease, especially in rural hospital where laboratory
confirmation is not available.
 Aims: To determine patterns of laboratory findings of leptospirosis
and their relationship to disease severity.
METHODS

 Cross-sectional study : all patients diagnosed with leptospirosis


from August 2016 to July 2017

 Diagnosis was based on clinical manifestation, physical exam, and


laboratory using IgM Leptospira : Mild and Severe

 Analyzed in SPSS 16.0 using two sampe t-test or Mann-Whitney’s


test
Results
• Table 1. Distributions of Socio-demographic (N=38)
Social Demographics n (%)/ mean (min-
max)
Age 52 (25 - 77)
Sex
Male 24 (63.2%)
Female 14 (36.8%)
Occupation
Farmers 19 (50%)
Laborers 7 (18.4%)
Housewives 3 (7.9%)
Others 9 (23.7%)
Table 2. Laboratory findings in patients with leptospirosis in
Ajibarang Hospital
Laboratory findings Patients with Mean ± SD Range
data
Haemoglobin (g/dL) 38 12.4 ± 1.8 7.2 to 16.9
White blood count (/mm3) 38 14,540 ± 8,410 5,250 to 50,710
Neutrophil count (/mm3) 38 12,010 ± 5,520 4,690 to 35,450
Lymphocyte count (/mm3) 38 980 ± 120 150 to 7,840
Platelet count (/mm3) 38 69,600 ± 42,430 14,000 to 175,000
Serum urea (mg/dL) 38 135.4 ± 92.4 18 to 354
Serum creatinine (mg/dL) 38 4.0 ± 3.4 0.82 to 14.2
AST (IU/L) 38 67.6 ± 76.3 6 to 428
ALT (IU/L) 38 50.3 ± 35.4 3 to 177
Serum sodium (mmol/L) 14 129.9 ± 4.6 118 to 134
Serum potassium (mmol/L) 14 3.9 ± 1.0 2.9 to 7
Serum chloride (mmol/L) 14 93.9 ± 3.9 88 to 101
Figure 1. Laboratory abnormalities
Haemoglobin < 12 g/dL 10
White blood count > 11,000/mm3 26
Neutrophil count > 8,000/mm3 29
Lymphocyte count < 1,200/mm3 31
Platelets < 150,000/mm3 37
Urea > 70 mg/dL (25 mmol/L) 23
Creatinine >1.50 mg/dL (133 μmol/L) 25
AST > 40 IU/L 16
ALT > 40 IU/L 12
K < 3.5 mmol/L 5
K > 5.1 mmol/L 1
Table 3. Comparison of mild and severe
diseases
Laboratory findings Mean ± SD
White blood count Mild 11350 ± 4,330 p=0.045*
Severe 16,860 ± 9,980
Platelets Mild 70,938 ± 3,300 p=0.867*
Severe 68,630 ± 4,680
Serum urea Mild 54.9 ± 32.6 p < 0.001**
Severe 185.9 ± 86.1
Serum creatinine Mild 1.4 ± 0.5 p < 0.001*
Severe 5.6 ± 3.5
AST Mild 58.4 ± 3.6 p=0.666*
Severe 69.4 ± 9.6
ALT Mild 50.2 ±3.2 p=0.894**
Severe 50.4 ± 3.8
CONCLUSIONS

 Leukocytosis, neutrophilia, lymphopenia, thrombocytopenia,


elevated serum urea and creatinine are seen in the majority of
leptospirosis.
• Leukocytosis, neutrophilia, lymphopenia  potential use to
differentiate leptospirosis over dengue

 High level of leukocyte counts, serum urea and serum creatinine


levels appears to predict the severity of the disease.
S T U DY O F D I AG N O S T I C AC C U R AC Y
C O M PA R I S O N O F 3 D I A G N O S T I C T E S T F O R
EA RLY D IAG N OSIS HUMA N LEPTOSPIROSIS

Prospective cohort study December 2015-July 2017


conducted in 15 hospital in Thailand
Compare between : Culture, MAT, & RDT
265 suspicious leptospirosis, 71,7 % positive.
PCR as standard test
RDT showed highest sensitivity followed by
MAT and Culture
(Tachaboon et al. 2017. Study of Diagnostic Accuracy Comparison of 3
Diagnostic test for early Diagnosis Human Leptospirosis, Thailand. ILS 2017)
CHALLENGES OF DIAGNOSING LEPTOSPIROSIS
IN INDONESIA : ATYPICAL MANIFESTATIONS
AND LACK OF DIAGNOSTIC METHODS

 Acute fever study conducted in 2013-2016 in 7 major cities


(Semarang, Jakarta, Bandung, Yogyakarta, Surabaya, Denpasar,
Makassar)
 43 Case were confirmed by PCR and ELISA ranging from 2,1
% in Jakarta and 5,5% in Semarang. No case was found in
Denpasar.
 19 case  leptospirosis,
24 case other infectious disease
 Leptospira serovar Hardjo
 20 patients did not show jaundice nor acute kidney injury
(Muh. Hussein Gasem et al. 2017. Challenges of Diagnosing Leptospirosis in
Indonesia : Atypical Manifestations and Lack of Diagnostic Methods)
C Y T O K I N E R E S P O N S E A M O N G PA T I E N T S
WITH COMPLICATED LEPTOSPIROSIS : A
SYSTEMATIC REVIEW

• According to literature, serious systemic inflammation occurs due to


 “cytokine storm”
• Systematic review of studies (2000-2016) :
• serum cytokine levels were significantly elevated, severe
leptospirosis induces a “cytokine storm” by over production
of IL-6 and IL-10 during the first few days
• high IL-10/TNF-α ratio was found to be a good prognosis
indicator in weil syndrome
• Sustained dialysis via Haemodialysis and haemodiafiltration
had equal efficiency in lowering cytokine levels of patients
with AKI and ARDS
• The door-to-dialysis time was more important in lowering
inflammatory mediators than the mode of dialysis

(Senavirathna et al. 2017. Cytokine Response among Patients with


Complicated Leptospirosis : a Systematic Review. ILS 2017)
A S T U DY O N T H E C L I N I C A L A N D
L A B O R AT O RY P RO F I L E O F L E P T O S P I RO S I S
IN INDIA

 Cohort study : patients admitted with febrile illness, headache and myalgia.
History, clinical examination, lab investigations, and IgM Leptospira antibody
test by ELISA were collected.
 110 (28,3 %) from 389 AUF were Leptospirosis vs other fevers (dengue
fever, viral hepatitis, Acute diarrheal disease, enteric fever, UTI, cellulitis)
 Symptoms include : Joint pain, Catarrhal symptoms, Cough, Hemoptysis,
Abdominal pain, Diarrhea, Oliguria
 Physical signs : Jaundice, conj. Suffusion, skin rashes, muscle
tenderness, hepatomegaly, tachypnea, skin ulcers
 Lab investigation : anemia, leukositosis, thrombocytopenia,
neutophilia, elevated urea, elevated creatinine, elevated bilirubine,
elevated SGOT, elevated SGPT, elevated Alk. Phospatase,
Hypoalbuminemia

(Padma Kumar. 2017. A Study on the Clinical and Laboratory profile of Leptospirosis with a view to
develop a Prediction Model in India. ILS 2017)
D I S T R I B U T I O N O F L E P T O S P I R A S E R O VA R S
A M O N G R AT S A S T H E P O T E N T I A L R E S E RVO I R
OF LEPTOSPIROSIS IN INDONESIA

 A cross sectional study in 3 districts of each 15 provinces


collected rats using live traps, blood sera and kidneys were
collected. Leptospira serovar was identified by MAT and
PCR of kidney tissue
 Results : 1259 rats collected from 15 provinces. 15 % rats
contained 14 serovars in each province. Serovar canicola,
Djasiman, and Icterohaemorraghiae were commonly found.
 Conclusion : Rats are a potential reservoir for human
leptospirosis
(Farida et al. 2017. Distribution of Leptospira serovars among rats as the
potential reservoir of Leptospirosis in Indonesia. ILS 2017).
E VA L UA T I O N O F A L E P T O S P I R A L E N Z Y M E
FOR D IAG N OSIS OF ACUTE LEPTOSPIROSIS

 52 kDa Leptospiral enzyme : 3-hydroxyacyl-CoA (3-HADH) is


released in urine of infected hamsters
 32 urine samples from confirmed case patients (culture/MAT) : 53 %
detected 52 kDa protein
 Need more investigations

(Claudia Toma et al. 2017. Evaluation of a Leptospiral Enzyme for Diagnosis of Acute
Leptospirosis in Japan. ILS 2017)
SUMMARY

 Leptospirosis has varied clinical presentations


• Physician awareness

 Testing is imperfect
• Awareness
• Interpret using multiple sources (clinical presentation, lab values,
exposure history)
Thank
You