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(J Formos Med Assoc2002;101:514–8)

Key words:leptospirosisWeil’s syndromeTaiwan

Department of Emergency Medicine, Divisions of 1Infectious Diseases and 2Nephrology, Department of Internal Medicine,Chang Gung Memorial Hospital-Kaohsiung, Kaohsiung.Received: 21 December 2001. Revised: 18 February 2002. Accepted: 2 April 2002.Reprint requests and correspondence to: Dr. Jien-Wei Liu, Division of Infectious Diseases, Department of Internal Medicine,Chang Gung Memorial Hospital-Kaohsiung, 123 Ta Pei Road, Niao Sung Hsiang, Kaohsiung Hsien, Taiwan.

CASE REPORTS OF LEPTOSPIROSIS

IN SOUTHERN TAIWAN

Kun-Jung Chung, Cheng-Ting Hsiao, Jien-Wei Liu,1 and Chih-Hsiung Lee2

Leptospirosis is a zoonotic disease with worldwidedistribution. Animals excrete urine-borne Leptospiraspp. into soil or water, which may cause human infec-tion through skin abrasions, mucous membranecontact, conjunctiva exposure, or by swallowing con-taminated water. Leptospirosis has protean clinicalmanifestations ranging from a flu-like illness to a severeor fatal Weil’s syndrome characterized by fever,hemorrhage, jaundice, and acute renal failure. Cur-rent diagnostic methodologies for leptospirosis in-clude microscopic agglutination test (MAT),polymerase chain reaction (PCR), and microorganismculture [1]. Because the clinical manifestations ofsevere leptospirosis often overlap with sepsis of otheretiologies, and the serologic diagnostic tools are notalways readily available at most hospitals, leptospirosisis probably unrecognized or underdiagnosed by clini-cians in most countries. Clinicians at Chang GungMemorial Hospital-Kaohsiung became alert to the po-tential for leptospirosis after it was diagnosed in apatient with a full-blown clinical picture of Weil’s syn-drome at the hospital’s emergency department in earlySeptember 2000. The diagnosis was subsequently con-firmed by the growth of Leptospira inadai from urineculture. Four additional cases (two definitive, one

Abstract: Leptospirosis, a zoonotic disease with worldwide distribution, is oftenoverlooked in Taiwan. Clinicians at our medical center in southern Taiwan becamealert to the potential for leptospirosis after the first documented case of severeleptospirosis— Weil’s syndrome was diagnosed at our emergency department in earlySeptember 2000. Four additional cases of leptospirosis were subsequently diagnosedwithin a 2-month period. All of the patients were hospitalized, and presented withhigh fever, severe myalgia, jaundice, and acute renal failure. Two of these patientswho rapidly received doxycycline therapy survived, while the remaining three patientswho received delayed penicillin therapy died. These cases suggest that the incidenceof leptospirosis may have been underestimated in Taiwan, and underscore the urgentneed for increased clinician awareness of this infectious disease.

probable, one seropositive) of leptospirosis diagnosedby MAT were found within short intervals betweenSeptember 2000 and November 2000 at our hospital.All MATs were performed by the staff of the Depart-ment of Veterinary Medicine of National TaiwanUniversity. Here we report on this cluster of leptospiro-sis cases, in which all patients were admitted via ouremergency department. This cluster of cases (Table)suggests that the incidence of leptospirosis may longhave been underestimated in Taiwan.

Case Reports

Case 1A previously healthy 27-year-old woman who had sufferedfrom sore throat, headache, conjunctival suffusion, nausea,vomiting, and low abdominal pain for 10 days visited a localclinic where common cold was diagnosed and she wastreated accordingly. The patient had a history of raising petdogs. Her symptoms were temporarily relieved at that time.However, fever and subsequent severe myalgia over limbs,yellowish skin discoloration, and oliguria developed. Shewas admitted to a local hospital where she was found to have

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hepatic and renal failure. She was transferred to our emer-gency department on September 10, 2000. On arrival, shewas acutely ill but conscious, and had high fever, tachycardiaand tachypnea, and lowered blood pressure. Physical exami-nation revealed pale conjunctiva with suffusion, icteric sclera,supple neck, tenderness over the abdomen and lowerextremities, bilateral leg edema, and petechiae over both thewrists. Hemogram showed a peripheral white cell count of17,400/mL with 96.8% polymorphonuclear cells, hemoglo-bin 11.1 g/dL, and a platelet count of 24,000/mL (normal,150,000–450,000). Coagulation studies showed a prolongedprothrombin time (PT) of 24.6 seconds (control, 11.5 sec) andactivated partial thromboplastin time (APTT) of 62.3 seconds(control, 28.4 sec). Blood chemistry showed elevated bloodurea nitrogen (BUN) of 72 mg/dL (normal, 6.0–21.0 mg/dL),creatinine (Cr) of 6.8 mg/dL (normal, 0.4–1.4 mg/dL),aspartate aminotransferase (AST) of 1,172 IU/L (normal,< 37.0 IU/L), alanine aminotransferase (ALT) of 80 IU/L(normal, < 40.0 IU/L), total bilirubin of 7.60 mg/dL (normal,< 1.4 mg/dL) with a direct bilirubin component of 6.93 mg/dL,myoglobin of 408 mg/dL (normal, < 90 mg/dL), and alkalinephosphatase within normal limits. Urinalysis showedproteinuria and microscopic hematuria. Disseminatedintravascular coagulation (DIC) profile showed a prolongedthrombin time (TT) of 50 seconds (control, 18.4 seconds),decreased fibrinogen concentration of 48.6 mg/dL (normal,200–400 mg/dL), and elevated fibrin degradationproduct (FDP) concentration of more than 100 mg/mL (normal,< 10 mg/mL).

Respiratory failure developed later on the same day. Shewas intubated for mechanical ventilatory support and admit-ted to the intensive care unit (ICU). Under the impression ofsepsis with multiorgan failure, ceftriaxone and inotropicagents were used initially. Sonogram showed bilateral pleuraleffusion and slight splenomegaly. Doxycycline was addedshortly after sonographic study due to suspicion of leptospiro-sis with Weil’s disease. Improvement in the patient’s condi-tion became apparent 3 days later. Urine and blood serologicand molecular biologic studies were negative for hantavirusinfection, dengue fever, Rickettsia tsutsugamushi, and

leptospirosis. However, urine culture grew spirochetes, whichwere subsequently identified as L. inadai on PCR. Intravenousinjection of penicillin 3.0 million units per 6 hours wasadditionally prescribed. Histopathology of a kidney biopsyperformed on hospitalization Day 30 and again on hospital-ization Day 61 both showed necrosis of glomerular tufts withfragmented red blood cells (RBC) in capillary lumens, somenecrotic renal tubules stuffed with RBC casts, and scatteredinterstitial lymphatic infiltration, which was compatible withthrombotic microangiopathy (Figs. 1, 2). After a total of 67days of treatment, the patient was discharged with partialrecovery of renal function.

Case 2A 66-year-old diabetic man suffered from abrupt fever,headache, myalgia, nausea, and abdominal pain1 week after hiking in the mountains. He was initially treatedfor suspected common cold at a local clinic. However, feverpersisted, jaundice and respiratory distress developed 3 dayslater, and he was transferred to our emergency department onNovember 11, 2000. Peripheral white cell count was 10,600/mL with 70.0% polymorphonuclear cells, and platelet countwas 100,000/mL. Blood chemistry showed AST concentra-tion of 157 IU/L, ALT of 57 IU/L, bilirubin of 4.0 mg/dL, BUNof 47 mg/dL, and Cr of 5.7 mg/dL, and elevated creatinephosphokinase (CPK) at 1,019 mg/dL (normal, 8.0–114 mg/dL). Under suspicion of possible Legionnaire’s disease orleptospirosis, antibiotics, including ciprofloxacin,clarithromycin, and doxycycline, were prescribed for sepsis.The patient’s clinical condition and renal function hadimproved markedly 1 week later. Subsequent serology studyrevealed a four-fold increase in titer with paired-sera againstleptospiral serogroup Shermani. The patient was discharged2 weeks after hospitalization.

Case 3A 79-year-old woman with chief complaints of fever, cough,and shortness of breath for 4 days was admitted to our

Table. Summary of the clinical characteristics of five patients with leptospirosis

Case Age (yr)/ Risk factor Laboratory Antimicrobial Creatinine AST Bilirubin Outcomeno. Sex for exposure diagnosis treatment* (mg/dL) (IU/L) (mg/dL)

1 27/F Pet dogs Leptospira inadai isolated from Doxycycline 6.8 1172 7.6 Survived urine

2 66/M Mountain 4-fold increase in paired sera Doxycycline 5.7 157 4.0 Survivedhiking (serogroup Shermani)

3 79/F None 1:100 dilution in single serum Penicillin G 3.6 241 3.6 Diedidentified (serogroup Icterohaemorrhagiae)

4 43/M Farmer 1:200 dilution in single serum Penicillin G 2.1 97 15.8 Died(serogroup Shermani)

5 60/M Farmer 16-fold increase in paired sera Penicillin G 7.5 4814 8.2 Died(serogroup Shermani)

*Doxycycline was started early in Cases 1 and 2, while Penicillin G was started late in the remaining cases. AST = aspartate aminotransferase;F = female; M = male.

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emergency department on September 23, 2000. Laboratorytests were normal except for thrombocytopenia with a plate-let count of 75,000/mL and AST of 241 IU/L. Three days later,she developed hemoptysis, jaundice, oliguria, and bilateralcalf tenderness. Repeated laboratory data showed acutehepatic and renal failure. Leptospirosis was suspected andpenicillin was administered on Day 7 of hospitalization. Thepatient’s clinical condition deteriorated despite the intensive

treatment and she died on Day 11 of hospitalization. Serologystudy subsequently disclosed leptospiral serogroupIcterohaemorrhagiae in a single serum specimen with 1:100dilution, indicating seropositivity for leptospirosis [1].

Case 4A 43-year-old farmer was admitted to our ICU via the emer-gency department on December 4, 2000, with the chiefcomplaints of fever, bilateral calf pain, headache, and ab-dominal pain for 4 days and subsequent progressive jaundiceand respiratory distress. Hemogram showed a peripheralwhite cell count of 20,560/mL with 10% band formgranulocytes, and a platelet count of 34,000/mL. Bloodchemistry showed potassium at 2.1 meq/L (normal, 3.5–4.5meq/L), and AST concentration of 97 IU/L, ALT of 30 IU/L, Crof 2.1 mg/dL, bilirubin (direct/total) of 7.0/15.8 mg/dL, andCPK of 471 mg/dL. Coagulation studies showed DIC-likecoagulopathy with prolonged APTT, PT, TT, and elevatedFDP. He was treated for bacterial sepsis with multiorganfailure. Hemoptysis, subconjunctival hemorrhage, petechiaeover the lower limbs, and shock developed abruptly on Day4 of hospitalization. Penicillin was added on Day 6 ofhospitalization because of suspected leptospirosis. The pa-tient died of overwhelming sepsis on Day 15 of hospitalization.Serology study subsequently disclosed leptospiral serogroupShermani in a single serum specimen with 1:200 dilution,indicating probable leptospirosis [1].

Case 5A previously healthy 60-year-old farmer, suffering from diar-rhea and vomiting for 3 days, accompanied by abdominalpain, fever and chills, jaundice, and decreased urine output,visited our emergency department on December 26, 2000.Hemogram revealed a normal peripheral white cell count of6,600/mL and decreased platelet count of 14,000/mL. Bloodchemistry showed elevated AST at 4,814 IU/L, ALT of 1,526IU/L, bilirubin of 8.2 mg/dL, and Cr of 7.5 mg/dL. Severe calfmyalgia and shortness of breath developed 2 days later andpenicillin was administered under the impression ofleptospirosis. The patient died on Day 6 of hospitalizationdue to progressive multiorgan failure. Subsequent serologystudy revealed a 16-fold increase in titer with paired seraagainst leptospiral serogroup Shermani.

Discussion

While leptospirosis has a worldwide distribution, it is alsounderdiagnosed globally [2–4]. There are several pos-sible causes of underdiagnosis: most cases of leptospirosisare subclinical, or they have mild clinical manifestationsand are self-limited; lack of clinician awareness of lep-tospirosis renders the disease unrecognizable; and ad-equate diagnostic tools are not always readily available atmost hospitals, making confirmation of clinical suspiciondifficult, if not impossible. A previous report from the

Fig 2. Biopsied kidney from Case 1 shows necrotic tubules with scatteredinterstitial lymphatic infiltration. (Hematoxylin and eosin x 100)

Fig 1. Biopsied kidney from Case 1 shows necrosis of glomerular tuftswith red blood cell casts in renal tubules. (Hematoxylin and eosin x 100).

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USA found that active, as opposed to passive, surveillancefor leptospirosis disclosed a five-fold increase in its actualincidence [2]. As a result, the need for a high index ofsuspicion and awareness of the clinical manifestations ofleptospirosis cannot be overemphasized.

Risk factors for exposure to leptospirae include occu-pational exposure (farmers and ranchers, abattoir workers,trappers, veterinarians, loggers, sewer workers, rice-fieldworkers, and military personnel), recreational activities(freshwater swimming, canoeing and kayaking, trail biking,and hunting), and household environmental factors(domestic dogs and livestock, rainwater catchment systems,and rodent infestation) [5]. All of the cases in this reportexcept for Case 3 had distinct histories of either animal orenvironmental exposure risk factors for contractingleptospirosis. The diagnosis of leptospirosis is indicatedby at least a four-fold increase in paired sera againstleptospiral antigens. The rapid fatality resulting fromoverwhelming sepsis in Cases 3 and 4 made comparisonof the serum titers at convalescence and septic phasesimpossible.

The incubation period of leptospirosis ranges be-tween 7 and 14 days. A clinically milder form of thisdisease can be found in approximately 90% of infections.The acute septicemic phase begins abruptly with highfever and headache (> 95%); chills, rigors, and myalgia(> 80%); conjunctival suffusion (30%–40%); abdominalpain (30%); anorexia, nausea, and vomiting (30%–60%);and a pretibial maculopapular cutaneous eruption(< 10%) lasting from 3 to 7 days [6]. During this period oftime, spirochetes may be recovered from blood or cere-brospinal fluid culture. Conjunctival suffusion and muscletenderness, most notable in the calf and lumbar area, arethe most distinguishing physical findings. Two of the fivepatients in this report presented with conjunctivalsuffusion. All of the patients showed clinical and labora-tory evidence of myositis, and they all complained ofmyalgia and abdominal pain and had higher serumconcentrations of AST than ALT. A large portion of theirAST was presumably from a muscular source instead ofthe liver. In addition, Case 1 had elevated serum myoglobin,and both Cases 2 and 3 had elevated serum CPK.

In more severe forms of leptospirosis, the course ofthe illness may be biphasic. In the subsequent immunephase (4 to 30 d), spirochetes are no longer found inthe blood but may be excreted in the urine. Theseparation between these two phases is often unclear.In the most severe icteric form of leptospirosis — Weil’ssyndrome, the aforementioned symptoms and signsfor anicteric patients are more severe and prolonged,and profound jaundice rapidly develops about 3 to 7days after the beginning of illness. The mortality ratevaries from 5% to 40% [7].

Hemorrhagic complications are common in severeleptospirosis. Thrombocytopenia, commonly seen in

leptospirosis, was found in all our patients and was in therange of 14,000 to 100,000/µL. Coagulation studies wereperformed in three patients, and disclosed prolonged PT,APTT, and TT and increased FDP, suggestive of DIC.

Pulmonary involvement occurs in 20% to 70% ofpatients with leptospirosis, and is presumably due tovascular injury [8]. Cough and hemoptysis are the mostprominent signs reflective of pulmonary damage. Se-vere respiratory distress and pulmonary hemorrhageare not characteristics of leptospirosis in the westernhemisphere, but in Oriental populations a compara-tively higher frequency of these characteristics andmore severe clinical conditions have been found [9].

Renal impairment is frequently seen, and ismore severe in Weil’s syndrome than in anictericleptospirosis. Azotemia, oliguria, and anuria commonlyoccur during the second week of the illness but mayappear as early as 3 to 4 days after the onset [4, 5].Remarkably, renal histopathology for Case 1 showedthrombotic microangiopathy which was compatiblewith thrombotic thrombocytopenic purpura (TTP). Itseems likely that TTP is a complication of leptospirosis.Leptospirosis-associated TTP is rarely seen [10], and itsmechanism and clinical implications deserve furtherstudy.

It is well known that penicillin is the drug of choicefor acute and severe leptospirosis. Doxycycline isreserved for prophylaxis and mild infection. Double-blind and placebo-controlled studies have demon-strated that oral doxycycline 100 mg twice daily for1 week is beneficial in shortening the course of earlyleptospirosis [11], and that intravenous penicillin1.5 million units four times daily for 7 days decreasesthe duration of fever and renal impairment in severe,late illness [12]. Penicillin should be given evenif the diagnosis is ascertained late in the course ofdisease. In our patients, doxycycline was prescribedearly in both Cases 1 and 2, and both patients survived.The remaining patients who received delayed therapywith penicillin died. Further study is required to deter-mine whether or not a timely and effective antimicro-bial therapy is an independent prognostic factor forsurvival.

Leptospirosis was first reported in Taiwan in 1976[13]. Twenty years elapsed until further cases of lep-tospirosis were reported in Taiwan in 1996 [14]. Prob-ably as a result of greater clinician alertness, leptospirosishas been sporadically reported in Taiwan thereafter.This sporadic reporting suggests that leptospirosis inTaiwan is more likely to be an ignored infectiousdisease rather than a newly emerging one. Leptospiraeare found worldwide, and are particularly distributedin tropical and subtropical areas [15]. Taiwan geo-graphically lies in a subtropical area where leptospiraeprevail. The large agricultural population in southern

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Taiwan and the increasing island-wide number of ur-ban residents raising pets may contribute to the highincidence of leptospirosis on this island [16].Additionally, in Taiwan, there have been an increasingnumber of foreign laborers from South-East Asiancountries, and an increasing number of brides fromeither these tropical countries or from the southernprovinces of China, where leptospirae prevail. Thesepeople may suffer from incubation-stage leptospirosisat the time of their arrival. The septic and immunephases of leptospirosis might subsequently develop[17]. Awareness of the clinical manifestations of lep-tospirosis and its inclusion in the list of differentialdiagnosis is of particular importance in Taiwan.

References

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15. Tappero JW, Ashford DA, Perkins BA: Leptospira species(leptospirosis). In: Mandell GL, Bennett JE, Dolin R, eds.Mandell, Douglas, and Bennett’s Principles and Practice ofInfectious Diseases. 5th ed. Philadelphia: ChurchillLivingstone, 2000:2495–501.

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