LEPTOSPIROSIS CASE by
MORBIDITY AND MORTALITY
CONFERENCE
June 14, 2007
Ledesma Hall
Gilbert Florentino M.D.
Medical Resident – year 1
General Data
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R.B.
44 years old
Male
Married
Filipino
Catholic
Dasmarinas, Cavite
Chief Complaint
Difficulty of breathing
History of present illness
6 days PTA
6 episodes LBM
(+)anorexia, (-)fever
4 days PTA
persistence of diarrhea
(+) Gen. body weakness
(+) Fever, undocumented
Tx: Paracetamol
History of present illness
3 days PTA
persistence of symptoms
(+) Gen. abdominal pain
consultation done
Dx: Infectious Diarrhea
Tx: Metronidazole
Loperamide
Hyoscine-N-butyl bromide
History of present illness
2 days PTA
1 day PTA
Few hrs PTA
Jaundice and icteric sclera
Dark colored urine
soft brown stool
(+)intermittent Fever
(+)Gen. muscle/joint pain
decreased urine output
Difficulty of breathing
Admission
Review of Systems
(-) weight loss
(-) pruritus
(-) visual dysfunction
(-) lacrimation
(-) tinnitus
(-) epistaxis
(-) bleeding gums
(-) sore throat
(-) neck vein distention
(-) cough and colds
(-) orthopnea
(-) PND
(-) syncope
(-) dysuria
(-) flank pain
(-) heat intolerance
(-) seizure
Past Medical History
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(-) Hypertension
(-) Diabetes Mellitus 2
(-) Bronchial asthma
No previous surgery
No previous hospitalization
No blood transfusion
No hx of vaccination
Family Medical History
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(-) Hypertension
(-) Diabetes Mellitus 2
(-) Bronchial asthma
(-) Malignancy
Personal and social History
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Camera man
20 pack years smoker
Occasional alcohol beverage drinker
No history of travel
No exposure to animal
Denies any substance abuse
Denies exposure to chemical and
radioactive materials
Physical examination
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Conscious, coherent, in respiratory distress
BP 80/60 HR 112 RR 35 Temp 37.1°C
Ht: 5’4’’(163cm) Wt 70 kg BMI 26 kg/m2 (obese 1)
Moist, Cold clammy skin, decrease capillary refill,
(+) Jaundice
Pale palpebral conjunctivae, (+) icteric sclera
No nasal discharge, no boggy turbinates, no mass
Moist buccal mucosa, non-hyperemic posterior
pharyngeal wall, tonsils not enlaged, no mass
Physical examination
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No palpable cervical lymph nodes, thyroid not
enlarged, no neck vein distention, JVP 3 cmH2O
Symmetrical chest expansion, (+) crackles BLF, (+)
supraclavicular and subcostal retractions
Adynamic precordium, AB 5th LICS MCL, S1>S2
apex, S2>S1 base, no murmurs
Flabby, Normoactive bowel sounds, soft, (+) RUQ
tenderness, no fluid wave, no organomegaly
Pulse weak and tready, no edema, no cyanosis
DTRs ++ all extremities
No sensory nor motor deficit
Salient features
44 male
Diarrhea
Anorexia
Fever
Abdominal pain
Jaundice
Oliguria
Dark colored urine
Myalgia
Dyspnea
Severe sepsis
Admitting Impression
Severe sepsis secondary to
cholangitis
versus
Fulminant hepatitis
Course in the ward
ER
CBC w/ plt
CXR
Na, K, Bun, Crea
U/A
CBG
SGPT/ SGOT/ ALKPhos
Hepatitis Profile
ABG
12 L ECG
Course in the ward
0000H
BP 80/50 HR 115 RR 30 T 37.1
cardiac monitor = sinus tachycardia
pulse oximeter = 88%
O2 support given
Fast drip 200cc PNSS
Course in the ward
0052H
pO2
68.9 80-100 pH
7.34
7.35-7.45
pCO2
30.7
pHCO3
16.5 22-26
93.2
80-100
BE
-7.7
O2sat
35-45
CXR showed Acute respiratory distress syndrome
SGOT
SGPT
Alk Phos
175
117
150
(15-37 umol/L)
(30-55 umol/L)
(50-136U/L)
Course in the ward
0107H
BP 80/60 HR 110 RR28 O2sat89%
MVM Fi02 50%
Dopamine 200mg in 100cc D5W
(5ug/kg) SBP > 90mmhg
Central line inserted, CVP 2-3cmH20
Course in the ward
0207H
BP 80/50 HR 120 RR32 O2sat88%
CVP 1-2cmH20
Na 127 (135-145)) BUN 77
K 2.9 (3.5-5.1
Creatinine 9.8
Foley catheter - no urine output
For STAT Dialysis
Course in the ward
0247H
CBC
Hgb 10.5
Hct 28.9
RBC 3.3
WBC 17,770
Seg
Lym
Mon
Plt
90
1.0
2.0
52000
Blood CS, Urine CS, Stool CS requested
Course in the ward
0257H
BP 80/60 HR124 RR36 O2sat 85%
Dopamine 200mg in 100cc D5W (3mcg/kg)
Dobutamine 250mg in 100cc D5W (3mcg/kg)
Furosemide 80mg/IV push
Furosemide 200mg in 200cc D5W (1mg/cc) 10cc
Pentoxyfylline 300mg in100ccD5W x 8°x 6doses
PNSS 1L x 80cc/hr
stilll no urine output
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On further investigation
He admitted that he fell in an open
canal more than a week ago which he
sustained an abrasion on his right leg.
Course in the ward
Impression:
 Septic Shock prob 2° to leptospirosis
 ARF 2° to septic shock versus
prob 2° to tubulo-interstitial disease 2° to
leptospirosis
 ARDS prob 2° to leptospirosis
Leptospirosis and Malarial smear antibody test
was requested
Course in the ward
0307H
BP 80/60 HR118 RR30 O2sat 85%
Started Piperacillin-Tazobactam
2.25mg/IV q8hrs
still no urine output
STAT Dialysis
0652H
pO2
60
80-100 pH
pHCO3
19.5 22-26
7.38
O2sat 85
7.35-7.45
pCO2
33.6
80-100
BE
-4.7
35-45
Course in the ward
0717H
BP 100/40 HR 80 RR28 O2sat 88%
dialysis was completed
0914H
pO2
65
80-100 pH
pHCO3
18.8 22-26
O2sat
7.33
7.35-7.45
pCO2
36.5
92.6
80-100
BE
-6.3
35-45
Course in the ward
1000H
Intubated
AC mode Fi02 100% VT 420
RR 24 PEEP 15
Obtunded, and no spontaneous movement
1300H
NaHCO3 50meq push
HaHCO3 100meq in 100cc D5W x 24hrs
hyrdation and pressors was continued
Course in the ward
1309H
BP 90/60 HR 130 RR24 O2sat 70%
pO2
52.6
80-100
pH
7.06
7.35-7.45
pCO2
53
pHCO3
14.9
22-26
O2sat
72.5
80-100
BE
-15.4
35-45
1825H
BP 80/40 HR 118 RR24 O2sat 63
DNR signed
2233H
Patient expired
Course in the ward
Leptospira IgM Antibody test: positive
Rapid malarial antibody test: negative
Malarial smear: negative
Course in the ward
Final Diagnosis
Weil’s syndrome
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Septic shock 2° leptospirosis
Acute renal Failure 2° tubulo-interstitial
disease 2° leptospirosis
Adult respiratory distress sydrome 2 °
leptospirosis
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Introduction
Microbiology
Pathogenesis
Clinical manifestations
Complications
Lab findings
Diagnosis
Treatment
LEPTOSPIROSIS
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Claimed to be the most widespread zoonosis in the
world
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Exact local / global incidence unknown; it’s likely
that many mild cases were left undiagnosed
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Reliable incidence data are not available because
of non-specific nature of illness & diagnostic
capabilities are limited in countries with highest
burden of diseases
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More common in warm-climate places & developing
countries
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In 90% of cases, it manifests as an
acute febrile illness (anicteric phase)
with a biphasic course and an
excellent prognosis.
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10% mortality rates. Known as Weil
disease or icteric leptospirosis
LEPTOSPIROSIS
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Icteric leptospirosis with renal failure
1st reported by Adolf Weil 100 years
ago
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Etiology of leptospirosis was 1st
described in 1915 independently in
Japan & Germany
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Gram negative spirochaetes
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helical amplitude of 0.1to 0.15 μm and
wavelength of 0.5 μm
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• 0.1μm x 6 – 20 μm
• Right handed helix with
• Pointed ends bent into
distinct hooks
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• Two axial flagella with polar insertions
All leptospires are morphologically
indistinguishable
• Typical double membrane structure
• LPS similar to G -ve bacteria but less
endotoxic
LEPTOSPIROSIS
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Obligate aerobes
• Optimal growth temp: 28 – 30oC
• Use long-chain fatty acids as sole
carbon source for metabolism
• Grow in media enriched with vitamins,
growth factors and ammonium salts
• Produce catalase & oxidase
LEPTOSPIROSIS
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Serologic:
– Phenotypic
– L interrogans (pathogenic) v.s. L biflexa
(saprophytic)
– Both were subdivided into different
serovars; >200 for L interrogans & >60 for
L biflexa
– Serovars that are antigenically related →
serogroups
LEPTOSPIROSIS
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Genotypic:
– By means of DNA hybridization
studies
– In theory, considered to be the
correct method of classification
taxonomically
Pathogenesis
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Toxin production:
– LPS: endotoxic but potency is low
– Haemolysin: sphingomyelinase,
phospholipase C, pore forming protein
– Cytotoxin
• Outer envelope: antiphagocytic component
• Outer membrane proteins: role in
interstitial nephritis
Pathogenesis
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Immune mechanisms:
– Immune complex mediated inflammation:
• deposition of immune complexes in kidney
interstitium, wall of small blood vessels
• Circulating immune complex level fall
concurrently with clinical improvement
– Cross reaction of anti-leptospiral antibodies to
body tissue → uveitis
– Autoantibodies: anti-platelet, anticardiolipin, ANCA
– Apoptosis: stimulated by LPS via induction of TNF-α
Wide spectrum of presentations
– Mild or subclinical infection, especially those who
have frequent exposure
– Self-limiting systemic illness for 90% of patients
who had initial exposure
– Severe, potentially fatal illness illness
accompanied by any combination of liver failure,
renal failure & pneumonitis with bleeding diathesis
Severe disease in human frequently due to
seovar icterohaemorrhagiae
The specific serovars involved depend largely on
geographic location & ecology of maintenance
hosts,
• Biphasic clinical presentation
• Incubation period: 5 – 14 days
• Septicaemic phase lasted about 1 week
• Immune phase: characterized by antibody
production & excretion of leptospires in urine
• Complications usually develop during the 2nd
week, associated with localization of leptospires
within tissue
Anicteric Leptospirosis
Febrile illness of sudden onset
• Chills, headache, myalgia, abdominal pain,
conjunctival suffusion, rash
• Lasting about 1 week
• Fever may recur after a remission of 3 – 4 days
• Aseptic meningitis may occur
• Mortality is almost nil
Icteric Leptospirosis
• 5 – 10 % of cases
• Mortality: 5 – 50 %
• Acute phase illness preceded by few days’ of
improvement, with high fever and rapid
progression to liver failure, renal failure,
pneumonitis, cardiac arrhythmia or circulatory
collapse
Liver damage
– Resulted from injury of liver capillaries in
the absence of frank hepatocellular necrosis
– Hepato +/- splenomegaly ≥ 25 %
– Bilirubin may be grossly elevated
– moderate rise of transaminase & mildly
elevated ALP
– hypoprothrombinaemia was uncommon
– CPK (MM fraction) may be grossly
elevated
Renal damage
– Mainly due to interstitial nephritis
– Abrupt onset of renal impairment with
progression to oliguria during 2nd week of
illness
– Frequently associated with jaundice
– Accompanied by thrombocytopenia without
evidence of DIC
Pulmonary damage
– May occur in the absence of renal or liver
failure
– Pulmonary haemorrhage
– Cough, dyspnea, haemoptysis, ARDS
– Radiograhic changes include diffuse small
opacities which may coalesce, pleural
effusion
Cardiac damage
– Myocarditis, coronary arteritis and
aortitis
– Strong association with pulmonary
involvement in several case series
– Presented with features of CHF,
arrhythmia & sudden circulatory
collapse
Ocular Involvement
• Conjunctival suffusion
• Uveitis which may persists for long time
• Immune phenomenon
Other Complications
• Infection in pregnancy associated with abortion and
fetal death
• Other reported complications: CVA,rhabdomyolysis,
TTP, acalculous cholecystitis, erythema nodosum,
epididymitis, nerve palsy, GBS, reactive arthritis
Chronic or Latent Infection
Immunity
• Largely humoral
• Immunity is strongly restricted to the
homologous serovar or closely
related serovars
General Lab Findings
Anicteric phase:
– Elevated ESR
– WCC from below normal to moderately elevated
– Slight elevation of transaminase,
ALP and bilirubin
– Proteinuria, sterile pyruria +/- microscopic
haematuria, hyaline & granular casts
– Normal to slightly elevated pressure, normal
glucose, normal or slightly elevated protein,
elevated WCC with lymphocyte predominance
General Lab Findings
Icteric phase:
Elevated WCC with left shift,
thrombocytopenia,
Renal impairment, deranged liver
function with
Disproportional rise of bilirubin, grossly
elevated CPK
Microscopic Demonstration
Dark field microscopy /
immunofluorescence /
appropriate staining
• Specimen:
body fluid e.g. blood, urine, CSF
• Insensitive and non-specific
Isolation of Leptospires
• 1st week: blood, CSF, dialysate
• Urine: beginning of 2nd week. Duration of
excretion varies
• Special semi-solid medium containing
5-fluorouracil
• Slow growing, examined weekly with dark
field microscopy for 13 weeks before being
discarded
• Identification by serological or molecular
techniques. Limited number of labs
which can perform the identification
Serological Diagnosis
Antibodies start to appear in blood about 5 – 7
days after onset of illness
• Gold standard:
microscopic agglutination test (MAT)
• CDC case definition: a titre of ≥ 200 with
clinically compatible illness
• Cut-off value depends on
seroprevalence
Serological Diagnosis
• Titres following acute infection may be
extremely high (≥25600) and take months or
even years to fall to low level
• Rarely, seroconversion may be delayed for
many weeks after recovery
• “paradoxical response” vs. “anamnestic
response
Serological Diagnosis
• Other serologic methods: RIA / ELISA
• More sensitive and comparable
specificity to MAT
• Commercial dipstick test methods
available for rapid diagnosis
Molecular Diagnosis
• PCR based methods for diagnosis
• Restriction endonuclease (REA),
restriction fragment length
polymorphism (RFLP), PCR based
methods and PFGE for identification
Treatment
Drugs of choice:
– Severe disease:
• Penicillin 1.5MU q6h iv
• Ampicilin 0.5 - 1 gm q6h iv
– Mild disease:
• Doxycycline 100mg BD po
• Ampicillin 500 – 750mg q6h po
• Amoxycillin 500mg q8h po
• Doxycycline 200mg once weekly for
prophylaxis
N.B. Watch out for Jarisch-Herxheimer rxn
•
68 patients, 56 (82%) were discharged from the
hospital, and 12 (18%) died
• Independent predictors of mortality:
– dyspnea (OR, 11.7; 95% CI, 2.8–48.5; P < 0.05)
– oliguria (OR, 9; CI, 2.1–37.9; P < 0.05)
– WCC > 12,900/mm3 (OR, 2.5; CI, 1.8–3.5; P < 0.01)
– repolarization abnormalities on electrocardiograms
(OR, 5.9; CI, 1.4–24.8; P < 0.01)
– alveolar infiltrates on chest radiographs
(OR, 7.3; CI, 1.7– 31.7; P < 0.01)
Dupont H et al. CID 1997 Sep; 25: 720-4
• Retrospective study in an emergency department
between 1989 and 1993
29 patients
– randomised, double-blinded trial with doxycycline
100 mg orally twice a day or placebo for 7 days;
followed for 3/52
– Duration of illness before therapy and severity of
illness were the same in both groups
– Doxycycline reduced the duration of illness by 2
days and favorably affected fever, malaise,
headache, and myalgias. Treatment prevented
leptospiruria
McClain JB et al. Ann Intern Med 1984 May;
100(5): 696-8
42 patients
– 7-day course of i.v. penicillin (6 MU/day) on
severe, advanced leptospirosis in a randomised,
placebo-controlled, double-blind fashion
– Fever >2x as long in the placebo group (11.6 [SD
8.34] days vs. 4.7 [4.19] days, p < 0.005)
– Creatinine rise persisted >3x as long in the
placebo group
(8.3 [8.46] days vs. 2.7 [1.90] days;p < 0.01)
– Penicillin also shortened the hospital stay and
prevented leptospiruria
Watt G et al. Lancet 1988 Feb 27; 1(8583):
433-5
Randomized, double-blind, placebo-controlled field trial
– Doxycycline (200 mg) or placebo on a weekly
basis and at the completion of training to 940
volunteers from two U.S. Army units deployed in
Panama for approximately three weeks of jungle
training.
– 20 cases of leptospirosis occurred in the placebo
group (an attack rate of 4.2 per cent), as
compared with only one case in the doxycycline
group (attack rate, 0.2 per cent, P less than 0.001),
yielding an efficacy of 95.0 per cent
Takafuji ET et al. NEJM 1984 Feb 23; 310(8):
497-500
A prospective, open-label, randomized trial in
Northen Thailand
– 173 patients with severe leptospirosis were randomly
assigned to be treated with either intravenous
ceftriaxone (1 g daily for 7 days) or intravenous
penicillin G (1.5 million U every 6 h for7 days)
– Primary outcome: time to fever resolution
– Median duration of fever was 3 days for both groups.
– Ten patients (5 in each group) died of leptospirosis
infection
– No statistically significant differences in the duration of
organ dysfunction
Panaphut et al. CID 2003 Jun 15; 36: 150713
Immunization
• Limited success so far
• Needs to give vaccine containing
serovars representative to those
present in the population to be
immunized
Summary
• A ubiquitous pathogen with protean
manifestations
• High index of suspicion: fever +
constellations of C/F (esp. conjunctivital
suffusion) + appropriate hx of exposure
• Serology for Dx
• Supportive care + antimicrobial therapy;
watch out for complications
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Induction of the antiviral cytokine interferon α/β (IFN-α/β) is common in many viral
infections. In human disease, bacterial superinfection complicating a viral infection can
result in significant morbidity and mortality. We injected mice with polyinosinicpolycytidylic (PIC) acid, a TLR3 ligand and known IFN-α/β inducer as well as nuclear
factor κB (NF-κB) activator to simulate very early antiviral pathways. We then challenged
mice with an in vivo septic shock model characterized by slowly evolving bacterial
infection to simulate bacterial superinfection early during a viral infection. Our data
demonstrated robust induction of IFN-α in serum within 24 h of PIC injection with IFNα/β–dependent major histocompatibility antigen class II up-regulation on peritoneal
macrophages. PIC pretreatment before septic shock resulted in augmented tumor
necrosis factor alpha and interleukins 6 and 10 and heightened lethality compared with
septic shock alone. Intact IFN-α/β signaling was necessary for augmentation of the
inflammatory response to in vivo septic shock and to both TLR2 and TLR4 agonists in
vitro. To assess the NF-κB contribution to PIC-modulated inflammatory responses to
septic shock, we treated with parthenolide an NF-κB inhibitor before PIC and septic
shock. Parthenolide did not inhibit IFN-α induction by PIC. Inhibition of NF-κB by
parthenolide did reduce IFN-α–mediated potentiation of the cytokine response and
lethality from septic shock. Our data demonstrate that pathways activated early during
many viral infections can have a detrimental impact on the outcome of subsequent
bacterial infection. These pathways may be critical to understanding the heightened
morbidity and mortality from bacterial superinfection after viral infection in human
disease.
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New options, such as ceftriaxone, have a
superior safety profile to penicillin.
In vitro studies have outlined potential
antimicrobial candidates such as macrolides
and ketolides.
Development of a globally accepted subunit
vaccine for humans is warranted but is not
expected in the near future.
Optimal treatment of leptospirosis: queries and projections
Georgios Pappasa, , and Antonio Casciob
International Journal of Antimicrobial Agents
Volume 28, Issue 6, December 2006, Pages 491-496
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Leptospires are sensitive to a variety of antimicrobial agents,
including penicillin, cephems, aminoglycosides, tetracyclines
and macrolides.
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Of these antimicrobial agents, short-term treatment with
streptomycin exterminates, leptospires.
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When penicillin, cephems, tetracylines and macrolides are
used, long-term therapy with large doses may be required
from the early stage of the disease until the appearance of
antibodies.
Human leptospirosis: management and prognosis.
Kobayashi Y.
PMID: 16333193 [PubMed - indexed for MEDLINE]