1. LEPTOSPIROSIS CASE by MORBIDITY AND MORTALITY CONFERENCE
June 14, 2007
Ledesma Hall
Gilbert Florentino M.D.
Medical Resident – year 1

2. General Data R.B. 44 years old Male Married Filipino Catholic
Dasmarinas, Cavite

3. Difficulty of breathing
Chief Complaint
Difficulty of breathing

4. 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

5. 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

6. History of present illness
2 days PTA Jaundice and icteric sclera
Dark colored urine
soft brown stool
1 day PTA (+)intermittent Fever
(+)Gen. muscle/joint pain
decreased urine output
Few hrs PTA Difficulty of breathing
Admission

7. Review of Systems (-) cough and colds (-) orthopnea (-) PND
(-) 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

8. Past Medical History (-) Hypertension (-) Diabetes Mellitus 2
(-) Bronchial asthma
No previous surgery
No previous hospitalization
No blood transfusion
No hx of vaccination

9. Family Medical History
(-) Hypertension
(-) Diabetes Mellitus 2
(-) Bronchial asthma
(-) Malignancy

10. Personal and social History
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

11. Physical examination Conscious, coherent, in respiratory distress
BP 80/60 HR 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

12. Physical examination
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

13. Salient features 44 male Diarrhea Anorexia Fever Abdominal pain
Jaundice
Oliguria
Dark colored urine
Myalgia
Dyspnea
Severe sepsis

14. Severe sepsis secondary to
Admitting Impression
Severe sepsis secondary to
cholangitis
versus
Fulminant hepatitis

15. Course in the ward ER CBC w/ plt CXR Na, K, Bun, Crea ABG U/A 12 L ECG
CBG
SGPT/ SGOT/ ALKPhos
Hepatitis Profile

16. 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

17. Course in the ward
0052H
CXR showed Acute respiratory distress syndrome
SGOT (15-37 umol/L)
SGPT (30-55 umol/L)
Alk Phos 150 (50-136U/L)
pO2
68.9
80-100 pH
7.34
pCO2
30.7
35-45
pHCO3
16.5
22-26
O2sat
93.2 BE
-7.7

19. 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

20. Course in the ward 0207H BP 80/50 HR 120 RR32 O2sat88% CVP 1-2cmH20
Na ( )) BUN 77
K ( Creatinine 9.8
Foley catheter - no urine output
For STAT Dialysis

21. Course in the ward 0247H CBC Hgb 10.5 Seg 90 Hct 28.9 Lym 1.0
RBC Mon 2.0
WBC 17,770 Plt
Blood CS, Urine CS, Stool CS requested

22. 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

23. 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.

24. 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

25. Course in the ward 0307H BP 80/60 HR118 RR30 O2sat 85%
Started Piperacillin-Tazobactam mg/IV q8hrs
still no urine output
STAT Dialysis
0652H
pO2 60
80-100 pH
7.38
pCO2
33.6
35-45
pHCO3
19.5
22-26
O2sat 85 BE
-4.7

26. Course in the ward 0717H BP 100/40 HR 80 RR28 O2sat 88% 0914H
dialysis was completed
0914H
pO2 65
80-100 pH
7.33
pCO2
36.5
35-45
pHCO3
18.8
22-26
O2sat
92.6 BE
-6.3

27. 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

28. Course in the ward 1309H BP 90/60 HR 130 RR24 O2sat 70% pO2 52.6
80-100 pH
7.06
pCO2 53
35-45
pHCO3
14.9
22-26
O2sat
72.5 BE
-15.4

29. 1825H
BP 80/40 HR 118 RR24 O2sat 63
DNR signed
2233H
Patient expired

30. Course in the ward Leptospira IgM Antibody test: positive
Rapid malarial antibody test: negative
Malarial smear: negative

31. Course in the ward Final Diagnosis Weil’s syndrome
Septic shock 2° leptospirosis
Acute renal Failure 2° tubulo-interstitial disease 2° leptospirosis
Adult respiratory distress sydrome 2 ° leptospirosis

32. Introduction
Microbiology
Pathogenesis
Clinical manifestations
Complications
Lab findings
Diagnosis
Treatment

33. LEPTOSPIROSIS Claimed to be the most widespread zoonosis in the world
Exact local / global incidence unknown; it’s likely that many mild cases were left undiagnosed
Reliable incidence data are not available because of non-specific nature of illness & diagnostic capabilities are limited in countries with highest burden of diseases
More common in warm-climate places & developing countries

34. In 90% of cases, it manifests as an acute febrile illness (anicteric phase) with a biphasic course and an excellent prognosis.
10% mortality rates. Known as Weil disease or icteric leptospirosis

35. LEPTOSPIROSIS
Icteric leptospirosis with renal failure 1st reported by Adolf Weil 100 years ago
Etiology of leptospirosis was 1st
described in 1915 independently in
Japan & Germany

36. Gram negative spirochaetes
• 0.1μm x 6 – 20 μm
• Right handed helix with
helical amplitude of 0.1to 0.15 μm and
wavelength of 0.5 μm
• Pointed ends bent into
distinct hooks
• Two axial flagella with polar insertions

37. All leptospires are morphologically indistinguishable
• Typical double membrane structure
• LPS similar to G -ve bacteria but less
endotoxic

38. LEPTOSPIROSIS 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

39. LEPTOSPIROSIS 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

40. LEPTOSPIROSIS Genotypic: – By means of DNA hybridization studies
– In theory, considered to be the correct method of classification taxonomically

41. Pathogenesis 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

42. Pathogenesis 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

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

49. 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

51. 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

52. 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

53. Chronic or Latent Infection
Immunity
• Largely humoral
• Immunity is strongly restricted to the
homologous serovar or closely related serovars

54. 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

55. General Lab Findings Icteric phase:
Elevated WCC with left shift, thrombocytopenia,
Renal impairment, deranged liver function with
Disproportional rise of bilirubin, grossly elevated CPK

56. Microscopic Demonstration
Dark field microscopy /
immunofluorescence /
appropriate staining
• Specimen:
body fluid e.g. blood, urine, CSF
• Insensitive and non-specific

57. 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

58. 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

59. 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

60. Serological Diagnosis
• Other serologic methods: RIA / ELISA
• More sensitive and comparable
specificity to MAT
• Commercial dipstick test methods
available for rapid diagnosis

61. Molecular Diagnosis • PCR based methods for diagnosis
• Restriction endonuclease (REA),
restriction fragment length
polymorphism (RFLP), PCR based
methods and PFGE for identification

63. Treatment Drugs of choice: – Severe disease: • Penicillin 1.5MU q6h iv
• Ampicilin 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

64. • Independent predictors of mortality:
• 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: • Retrospective study in an emergency department between 1989 and 1993

65. McClain JB et al. Ann Intern Med 1984 May; 100(5): 696-8
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

66. Watt G et al. Lancet 1988 Feb 27; 1(8583): 433-5
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

67. Takafuji ET et al. NEJM 1984 Feb 23; 310(8): 497-500
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):

68. Panaphut et al. CID 2003 Jun 15; 36: 1507- 13
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:

69. Immunization • Limited success so far
• Needs to give vaccine containing
serovars representative to those
present in the population to be
immunized

70. 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

71. Thank you

72. 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 polyinosinic-polycytidylic (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 IFN-α/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.

73. 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

74. Leptospires are sensitive to a variety of antimicrobial agents, including penicillin, cephems, aminoglycosides, tetracyclines and macrolides.
Of these antimicrobial agents, short-term treatment with streptomycin exterminates, leptospires.
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: [PubMed - indexed for MEDLINE]