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

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Presentation on theme: "LEPTOSPIROSIS CASE by MORBIDITY AND MORTALITY CONFERENCE June 14, 2007 Ledesma Hall Gilbert Florentino M.D. Medical Resident – year 1."— Presentation transcript:

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 Chief Complaint Difficulty of breathing

4 History of present illness 6 days PTA6 episodes LBM (+)anorexia, (-)fever 4 days PTApersistence of diarrhea (+) Gen. body weakness (+) Fever, undocumented Tx: Paracetamol

5 History of present illness 3 days PTApersistence of symptoms (+) Gen. abdominal pain consultation done Dx: Infectious Diarrhea Tx: Metronidazole Loperamide Hyoscine-N-butyl bromide

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

7 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

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 112 RR 35 Temp 37.1°C Ht: 54(163cm) Wt 70 kg BMI 26 kg/m 2 (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 5 th 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 Admitting Impression Severe sepsis secondary to cholangitis versus Fulminant hepatitis

15 Course in the ward ER CBC w/ pltCXR Na, K, Bun, CreaABG U/A12 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 175 (15-37 umol/L) SGPT 117 (30-55 umol/L) Alk Phos150 (50-136U/L) pO pH pCO pHCO O2sat 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 127 ( )) BUN 77 K 2.9 ( 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 3.3 Mon 2.0 WBC 17,770Plt 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 2.25mg/IV q8hrs still no urine output STAT Dialysis 0652H pO pH pCO pHCO O2sat BE-4.7

26 Course in the ward 0717H BP 100/40 HR 80 RR28 O2sat 88% dialysis was completed 0914H pO pH pCO pHCO O2sat 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% pO pH pCO pHCO O2sat 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 Weils 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; its 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 1 st reported by Adolf Weil 100 years ago Etiology of leptospirosis was 1st described in 1915 independently inin 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 taxonomicallythe

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-αTNF-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 collapseof

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 thethe 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 CPKCPK

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 basedbased 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 Dupont H et al. CID 1997 Sep; 25: Retrospective study in an emergency department between 1989 and 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)

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

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

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

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

69 Immunization Limited success so far Needs to give vaccine containing serovars representative to those present in the population to bebe 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


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 Optimal treatment of leptospirosis: queries and projections Georgios Pappasa,, and Antonio Casciob International Journal of Antimicrobial Agents Volume 28, Issue 6, December 2006, Pages a b International Journal of Antimicrobial Agents Volume 28, Issue 6 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.

74 Human leptospirosis: management and prognosis. Kobayashi Y. PMID: [PubMed - indexed for MEDLINE] Kobayashi Y 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.



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