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INTERNATIONAL REPORT

Leptospirosis: Prognostic Factors Associated with Mortality

Hervé Dupont, Déborah Dupont-Perdrizet, From the Medical, Surgical, and Burn Intensive Care Unit and the Emergency Section Unit, Pointe-à-Pı̂tre Hospital, Antilles-GuyaneJean Luc Perie, Sophie Zehner-Hansen, Bruno Jarrige,

University, French West Indiesand Jean Baptiste Daijardin

To determine the prognostic factors for leptospirosis, we conducted a retrospective study of data

collected in the emergency department of our hospital between 1989 and 1993. Sixty-eight patients,

for whom the diagnosis of leptospirosis was based on pertinent clinical and epidemiological data

and positive serology, were included in this study. Fifty-six patients (82%) were discharged from

the hospital, and 12 (18%) died. Multivariate logistic regression demonstrated that five factors were

independently associated with mortality: dyspnea (odds ratio [OR], 11.7; 95% confidence interval

[CI], 2.8–48.5; P õ .05), oliguria (OR, 9; CI, 2.1– 37.9; P õ .05); white blood cell count,

ú12,900/mm3 (OR, 2.5; CI, 1.8–3.5; P £ .01), repolarization abnormalities on electrocardiograms

(OR, 5.9; CI, 1.4– 24.8; P £ .01), and alveolar infiltrates on chest radiographs (OR, 7.3; CI, 1.7–

31.7; P £ .01). Identification of these factors on admission might provide useful selection criteria

for patients who need early transfer to the intensive care unit.

Leptospirosis, a zoonosis that occurs worldwide, is caused by This 1,000-bed hospital with a 20-bed intensive care unit (ICU)

is the only emergency facility for a population of 450,000 Leptospira interrogans. The incidence of the disease varies from

inhabitants, including those living on the small surroundingsporadic cases in temperate zones [1, 2] to endemicity in a few

islands.tropical countries, specifically those in the Caribbean [3].

All patients admitted over a period of 5 years (1989–1993)Leptospirosis is characterized by great clinical variability,

with suspected leptospirosis were retrospectively included inranging from a mild flu-like illness to an acute life-threatening

the study. Leptospirosis was defined in accordance with thecondition, but only patients with the symptomatic forms of the

World Health Organization criteria [5]. Briefly, six clinicaldisease are hospitalized. The criteria that identify the severecriteria (headache, fever, conjunctival suffusion, meningealforms of leptospirosis are not well defined at the early stagesigns, myalgia, and jaundice), two laboratory-determined crite-of the disease. In fact, rapid deterioration in clinical status canria (albuminuria or azotemia), and an epidemiological criterion be observed within a few hours of admission to the hospital(contact with rats or contaminated water) were scored. Lep-[4]. We believe that early evaluation of disease severity at thetospirosis was suspected when the score was §20, with a strongtime of admission might be useful in improving the care of presumption when the score was ú26. In every case, the diag- patients with leptospirosis, and we conducted this retrospectivenosis of leptospirosis was confirmed by positive serology and study to identify the prognostic factors associated with mortal-either a macroscopic slide agglutination test with use of Lepto-ity for a selected cohort of patients admitted for treatment of

spira biflexa antigen [6] or an IgM-specific ELISA [7]. Theleptospirosis.serum samples were then sent to Institut Pasteur (Paris), where

a microscopic agglutination test (MAT) [8] was performed toMethods identify the serotypes.

When the diagnosis had been confirmed, the patients’ records Patient population. This study was performed in thewere reviewed. The demographic data (age, gender, and occu-Teaching Hospital of Pointe-à-Pı̂tre in the French West Indies. pation) and epidemiological data (exposure and time between

the onset of clinical signs and hospitalization) were collected.

The severity of the disease at the time of admission to the

Received 30 October 1996; revised 28 February 1997. emergency department was assessed with use of the ApacheThis work was presented in part at the 36th Interscience Conference on II scoring system [9].

Antimicrobial Agents and Chemotherapy held in New Orleans, on 15-18 Sep-Clinical definitions. The clinical data collected included tember 1996.

the presence of jaundice, fever (temperature, §38.5C), oligu-Reprints or correspondence: Dr. Hervé Dupont, Service de RéanimationPolyvalente, Centre Hospitalier Universitaire, BP465 Pointe-à-Pı̂tre Cedex, ria (urine output, £0.5 L/24 h), cardiovascular collapse (sys-France.

tolic arterial pressure, õ80 mm Hg), and dyspnea (respiratoryClinical Infectious Diseases 1997;25:720– 4 rate, ú20). We recorded the presence of abdominal pain, nau- 1997 by The University of Chicago. All rights reserved.1058–4838/97/2503–0025$03.00 sea, vomiting, and diarrhea. Neurological signs were defined

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721CID 1997; 25 (September) Prognostic Factors for Leptospirosis

by at least one of the following: alteration of consciousness nonsurvivors all died in the ICU, but only 3 (25%) were directly

admitted to the ICU. The mean delay { SD between admission(Glasgow Coma Score, õ13), meningeal signs, motor or sen-

sory defect, convulsions, or dizziness. We recorded the follow- and death was 8 days{ 7 days. Death was attributed to myocar-

ditis (4 patients), irreversible septic shock (2), acute respiratorying hemorrhagic signs: epistaxis, conjunctival bleeding, hema-

turia, hematoma, and gastrointestinal hemorrhage. failure (2), massive organ failure (2), and multiple organ failure

(2). The mean hospital stay { SD for the survivors was 11 Laboratory tests. At the time of admission to the hospital,

the following laboratory values were determined: levels of alka- days{

7 days.line phosphatase, g-glutamyl transferase, aspartate aminotrans- Demographic data are presented in table 1. Pertinent epide-

ferase, alanine aminotransferase, total bilirubin, creatine phos- miological contexts were found for 41 patients, including occu-

phokinase, lactate dehydrogenase, and amylase; WBC and RBC pational exposure (56% of patients), cattle breeding (20%),

counts; coagulation parameters (prothrombin time, partial poor sanitary conditions (no running water in the home) (7%),

thromboplastin time, and fibrinogen); and blood gas levels. swimming in a river (10%), and rat bites (7%). The mean

Electrocardiography. The following abnormalities on elec- delay { SD between onset of the first symptoms and hospital

trocardiograms (EKG) were recorded: rhythm abnormalities admission was 5 days { 3 days. Nonsurvivors were signifi-

(sinus tachycardia [ú120 bpm]; bradycardia [õ50 bpm]; atrial cantly older than survivors ( P õ .01).

or ventricular extra-systoles; and atrial fibrillation), repolariza- The serological diagnosis was made with the results of the

tion abnormalities (T wave inversion, abnormal positive T macroscopic agglutination test for 38 patients and the IgM-

wave, and depression of the ST segment), or conduction abnor- specific ELISA for 17 patients (mean titer, 1:3,200). The diag-

malities (right or left bundle branch block, left anterior hemi- nosis was made with the MAT for 13 patients (mean titer,

block, and atrioventricular block). 1/4,200). Serotypes were assayed for the 68 patients, but in 50%Chest radiography. The following abnormalities on chest of the cases, the serotypes could not be determined because of

radiographs were recorded: diffuse or localized alveolar infil- the presence of numerous coagglutinins. The most common

trates, an interstitial pattern, lobar pneumonia, and pleural effu- serotypes were L. icterohaemorrhagiae, observed in 23 patients

sions. A radiological score derived from the method of Wein- (68%); L. ballum, observed in 4 patients (12%); L. canicola,

berg et al. [10] was used. Briefly, anterior-posterior chest observed in 3 patients (9%); L. australis, observed in 2 patients

radiographs were divided into four zones with use of a hori- (6%); and L. sejroe, observed in 2 patients (6%).

zontal line originating from the hilus. Each zone was then Clinical signs and symptoms observed at the time of admis-

graded as follows: grade 0, normal; grade 1, interstitial pulmo- sion are presented in table 2. Chest radiographic findings are

nary infiltrates; grade 2, fluffy alveolar infiltrates; and grade 3, presented in table 3. The increased frequency of alveolar infil-

dense alveolar infiltrates. trates and the increased severity of the radiological score wereOutcome. The patients were observed until they com- the only differences observed between nonsurvivors and survi-

pletely recovered and were discharged from the hospital or vors ( P £ .0001 and P õ .05, respectively). It should be noted

until they died. The cause of death was recorded in every case, but no postmortem examinations were performed.

Statistical methods. Results are expressed as means { SDTable 1. Demographic characteristics of survivors and nonsurvivorsor as percentages. Clinical and laboratory data were statisticallyamong patients with leptospirosis.

analyzed with use of the x2 test or Fisher’s exact test for the

comparison of proportions and analysis of variance for the Survivors Nonsurvivorscomparison of intergroup difference. Variable (n Å 56) (n Å 12) P value

Risk factors for death were identified with use of the x2

Age (y) { SD 42 { 16.1 57 { 18 .003statistic for differences in the distribution of categorical vari-Gender (M/F) 48/8 12/0 NS

ables between nonsurvivors and survivors. Variables found toDelay between first 5 { 3 5 { 4 NS

be relevant and associated with death ( P õ .05) were entered symptoms and in a multiple stepwise logistic regression model (SPSS software admission (d)

{ SDfor Macintosh; SPSS, Chicago). Adjusted odds ratios and 95%Medical historyconfidence intervals were calculated. A value of P õ .05 was

No. (%) with 5 (9) 1 (8) NSconsidered significant.

diabetes

mellitus

No. (%) with 7 (12) 2 (16) NSResults

hypertension

No. (%) with 1 (2) 0 NSSixty-eight patients met the inclusion criteria, including 56other cause of

survivors (82%) and 12 nonsurvivors (18%). Of these 68 pa-renal disease

tients, 48 patients (71%) were initially admitted to the medical

NOTE. NS Å nonsignificant.ward and 20 patients (29%) were admitted to the ICU. The 12

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722 Dupont et al. CID 1997; 25 (September)

Table 2. Clinical signs and symptoms in survivors and nonsurvivors Table 4. Results of univariate analysis of laboratory values betweensurvivors and nonsurvivors among patients with leptospirosis.among patients with leptospirosis.

Survivors Nonsurvivors Survivors Nonsurvivors

Value (n Å 56) (n Å 12) P valueSign or symptom (n Å 56) (n Å 12) P value

Jaundice 46 (82) 12 (100) NS Potassium (mmol/L) 3.8 { 0.8 4.5 { 1.1 .01

Glucose (mmol/L) 8.1 { 4.1 9.5 { 5.8 NSCardiovascular collapse 8 (14) 4 (33) NS

Oliguria 14 (25) 9 (75) .003 Total protein (g/L) 66 { 9 59.6 { 11.4 .04

Urea nitrogen (mmol/L) 16.5 { 13.2 37.7 { 14.3 .0001Fever 28 (50) 5 (42) NS

Dyspnea 6 (11) 7 (58) .0007 Creatinine (mmol/L) 270 { 250 550 { 180 .0005

Total bilirubin (mmol/L) 230 { 190 430 { 240 .002Abdominal symptoms 44 (76) 9 (75) NS

Neurological symptoms 31 (55) 10 (83) NS Aspartate aminotransferase (IU/L) 110{ 110 230 { 320 .02

Creatinine kinase (IU/L) 1020 { 1720 3160{ 4300 .01Respiratory symptoms 17 (30) 8 (67) NS

Hemorrhagic symptoms 10 (18) 2 (17) NS Lactate dehydrogenase (IU/L) 470 { 265 930 { 450 .0001

PaO2 (kPa) 10.8 { 2.6 10.1 { 3.1 NS NOTE. Data are number (%). NS Å nonsignificant. Prothrombin time (%) 89 { 16 69 { 18 .0005

WBC count (109/L) 12.4 { 6 23.7 { 10.3 .0001

Platelet count (109/L) 123.3 { 106.8 71 { 56.7 NSthat the radiographs for only 52% of the patients did not show Hemoglobin (g/L) 12.3 { 2.2 11.1 { 2.4 NS

Hematocrit (%) 36 { 8 34 { 6 NSany abnormalities.

The presence of repolarization abnormalities was the only NOTE. Values are means { SD. NS Å not significant.

electrocardiographic difference observed between nonsurvivorsand survivors (42% vs. 9%, respectively; P õ .05), despite the

fact that none of these patients had a history of coronary disease Barbados [12], and the United States [1, 13, 14]; in one Frenchor had received any cardiac medication. There was no statisti- study, the mortality rate was £50% [15]. Such a discrepancycally significant difference in the incidence of arrhythmia or in mortality is attributed to different criteria selected for patientconduction abnormalities between nonsurvivors and survivors inclusion and to the severity of leptospirosis.(36% vs. 23% and 36% vs. 12%, respectively). Although the severity scores commonly used in the ICU

Laboratory results are displayed in table 4. In the nonsurvi- (Apache II, organ system failure) have never been validated vor group, the severity of the disease at the time of admission for emergency practice, these values give some interestingwas reflected by a high mean Apache II severity score ({SD) points for comparing patients admitted to the ICU. The criteria(30 { 11 for nonsurvivors vs. 11 { 8 for survivors; P £ .001). reported in our study might help medical staff decide whether

Univariate analysis revealed that 17 risk factors were sig- to admit patients to the ICU or to a ward.nificantly associated with death. Seven of these factors were The reasons for the differences in the severity of leptospirosis

directly related to the clinical presentation of the disease, and remain obscure. No relationship has been established betweenthe remaining 10 factors were laboratory values. Five indepen- the severity of the disease and the serotype of the pathogendent variables were found to be significantly associated with [12, 16, 17]. The serotype icterohaemorrhagiae has been ob-mortality after stepwise logistic regression analysis (table 5). served in most of the sickest patients [3], who had renal or

liver failure [13, 14, 18], while meningeal forms of the diseaseDiscussion seem to be more frequently associated with the serotype grippo-

typhosa [18] or canicola [13, 14, 18].The mortality rates reported for cases of leptospirosis varyThe severity of the disease at the time of admission mightlargely between 4% and 10% in studies from France [11],

be related to a delay in hospitalization after the onset of the

Table 3. Chest radiographic findings in survivors and nonsurvivors

among patients with leptospirosis. Table 5. Results of multivariate stepwise logistic regression analy-

sis of risk factors for patients with leptospirosis.Survivors Nonsurvivors

Variable (n Å 56) (n Å 12) P value Risk factor OR 95% CI P value

Alveolar infiltrates 5 (9) 5 (42) .02 Dyspnea 11.7 2.8 – 48.5 .04Interstitial pattern 20 (38) 8 (67) NS Oliguria 9 2.1 – 37.9 .03Lobar pneumonia 2 (4) 1 (8) NS Alveolar infiltrates 7.3 1.7 – 31.7 .04Diffuse pneumonia 11 (12) 3 (25) NS R epolarization abnormalities 5.95 1.4 – 24.8 .0001Pleural effusion 6 (11) 4 (33) NS WBC count of ú12,900/mm3 2.54 1.8 – 3.5 .005Mean radiological score 0.9 { 1.4 3 { 2.1 .0001

NOTE. Fraction of concordant pairs of predicted probabilities and re-sponses Å .92; rank correlation between predicted probability and response Å NOTE. Data are frequency of signs (%) or means{ SD. NS Å nonsignifi-

cant. .69.

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723CID 1997; 25 (September) Prognostic Factors for Leptospirosis

first symptoms. Our data do not confirm this assumption. Con- to 100% of cases [39]. In our study, 25% of deaths were directly

attributable to myocarditis, but this figure might be a consider-versely, the delay between the first symptoms and admission

might be a reflection of rapidly evolving disease, suggesting a able underestimate since we did not perform any postmortem

examinations.higher pathogenicity for the shorter delays, a hypothesis not

confirmed in our study. As previously reported by Pertuiset et al. [32], leukocytosis

was more common in nonsurvivors than in survivors. The roleAlthough early antibiotic therapy shortens the duration of

fever, renal failure, and hospital stay [19, 20], no decrease in of a larger bacterial inoculum or of a more pronounced in-flammatory or immunological reaction in these severe casesthe mortality rate has been demonstrated. This point suggests

the potential role of underlying disease in the outcomes for the has been suggested [29] but remains to be confirmed.

In summary, the mortality of leptospirosis remains high de- patients.

Pulmonary manifestations are frequently observed in patients spite improvements in patient care. In order to improve the

early treatment of high-risk patients, five clinical and laboratorywith leptospirosis; these manifestations are evident in 20%–

70% of the patients, depending on the studies [21]. Clinical criteria, independently associated with mortality, could be used

at the time of admission. These reproducible and easy to deter-symptoms are infrequent, ranging from mild-to-moderate forms

represented by dyspnea, nonproductive cough [4], or moderate mine criteria could help physicians to decide on early admission

of patients to the ICU. The effects of intensive monitoringhemoptysis [22] to severe forms with acute respiratory distress

syndrome [23– 25] or massive pulmonary hemorrhage [26]. and early symptomatic treatment on the prognosis of high-risk

patients remain to be evaluated in prospective studies.Chest radiographic abnormalities are frequently observed in

patients with leptospirosis (11% [21] to 60% [27]), most often

as an interstitial pattern. Alveolar infiltrates are unusual and are observed in 6%–10% of cases [21]. In our study, chest Acknowledgementsradiographic abnormalities were reported for 49% of our pa-

The authors thank Philippe Montravers, MD, for his criticaltients, but the presence of alveolar infiltrates appeared to bereading of the manuscript.the most sensitive radiological finding with respect to the sever-

ity of lung injury.

Renal failure is frequently reported in patients with lep-Referencestospirosis (50%–80% of cases) [13, 28–30]. However, in nu-

merous studies, the definition of renal failure was based on 1. Sasaki DM, Pang L, Minette HP, et al. Active surveillance and risk factorsfor leptospirosis in Hawai. Am J Trop Med Hyg 1993;48:35–43.laboratory data alone; clinical parameters, such as urine output,

2. Baranton G, Postic D. La leptospirose humaine en France de 1986 à 1992.were not taken into account [4, 31]. In contrast, Pertuiset et al.Méd Mal Infect 1993;23S:499–503.[32] reported that when clinical and laboratory data were used

3. Strobel M, De-La Vareille B, Chevallier J, et al. La leptospirose en Guade-to define renal failure, the latter was associated with mortality

loupe: aspects cliniques, biologiques et é pidémiologiques. Méd Mal

in 21% of the cases. In our study, oliguria was a very sensitive Infect 1992;22:648–51.4. Duval G, Guerot E, Guiserix J, et al. Leptospiroses ictéro-hémorragiquescriterion of the severity of the disease. Similarly, Seguro et al.

graves. Réan Soins Intens Méd Urg 1990;6:473–9.[33] noted that the mortality rate for oliguric patients with acute5. Faine S. Guidelines for the control of leptospirosis. Geneva: World Healthrenal failure appeared to be higher than that for patients with

Organization, 1982;67:1–171. persistent diuresis.

6. Sulzer CR, Jones WL. Evaluation of a hemagglutination test for humanThe role of rhabdomyolysis in the pathophysiology of renal leptospirosis. Appl Microbiol 1973;26:655–7.

7. Pappas MG, Ballou WP, Gray MR, Takafuji ET, Miller RN, Hockemeyer failure is often underestimated. Several authors [34, 35] re-WT. Rapid serodiagnosis of leptospirosis using the IGM-specific Dot- ported severe rhabdomyolysis and suggested that this complica-ELISA: comparison with the microscopic agglutination test. Am J Troption might increase the severity of renal failure [34]. On theMed Hyg 1985;34:346–54.

other hand, rhabdomyolysis might reflect the severity of the8. Galton MM, Sulzer CR, Santa-Rosa CA, Fields MJ. Application of a

disease. Solbrig et al. [36] reported that in severe forms of microtechnique to the agglutination test for leptospiral antibodies. ApplMicrobiol 1965;13:81–5.leptospirosis with high mortality rates (50%), signs of rhabdo-

9. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. Apache II: a severitymyolysis were observed in £48% of the cases.of disease classification system. Crit Care Med 1985;13:818–29.EKG abnormalities are frequently reported in the course of

10. Fagon JY, Chastre J, Domart Y, et al. Nosocomial pneumonia in patientsleptospirosis [30]. Dussarat et al. [37] noted that P-R interval

receiving continuous mechanical ventilation: prospective analysis of 52lengthening, repolarization abnormalities, and atrial fibrillation episodes with use of a specimen brush and quantitative culture tech-

niques. Am Rev Respir Dis 1989;139:877–84.were criteria indicating a poor prognosis. In contrast to the11. Bourrier P, Chennebault JM, Achard J, et al. Leptospiroses: analyse rétro-EKG abnormalities that are frequently reported, clinical signs

spective de 99 cas observés en 10 ans dans le Centre-Ouest de la France.of cardiac failure in leptospirosis are rarely seen [37], althoughMéd Mal Infect 1988;1:4–8.

the latter might be responsible for much of the mortality. In12. Edwards CN, Nicholson GD, Hassell TA, Everard COR, Callender J.

fact, postmortem examination of patients who died of acute Leptospirosis in Barbados: a clinical study. West Indian Med J 1990;39:27–34.leptospirosis has revealed interstitial myocarditis in 50% [38]

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