Anne Spichler

Leptospirosis-associated disturbances of blood vessels, lungs and hemostasis

The frequency of massive pulmonary hemorrhages seems to be increasing in different geographic areas; however, there is no clear explanation for this trend. Although data on the pathogenesis of such complications are scarce, recent research indicates a potential role of autoimmunity and/or multifactorial mechanisms. However, much information is already available on the disturbance of hemostasis and blood vessels in leptospirosis-related literature, even if some contradictory concepts coexist. The purpose of this review is to integrate both new and classical information from human and animal studies on severe pulmonary forms of leptospirosis and disorders of hemostasis and blood vessels. We propose that the involvement of blood vessels in leptospirosis must be understood as a sepsis-like, diffuse process of endothelial activation/damage rather than as a classical systemic vasculitis. Pulmonary hemorrhages are most likely multifactorial and there has recently been evidence against the role of autoimmunity; however, further investigation of strain variations, exposure to hydrocarbons and association with renal dysfunction is required. Thrombocytopenia is a consistent feature of leptospirosis but it is not clear whether it is attributable to sepsis-related mechanisms. In addition, further investigation is required to define whether platelet function is activated or inhibited during severe leptospirosis.

Renal involvement in leptospirosis: new insights into pathophysiology and treatment

Acute renal failure (ARF) is one of the most common complications of leptospirosis although the causal mechanisms are still unclear. Diverse mechanisms are implicated in leptospiral nephropathy and new data supports the role of peculiar ion transport defects. Besides antibiotic therapy, ARF management in leptospirosis requires dialytic therapy which is most efficient when started early. Dialysis is the standard supportive therapy even though recent evidence suggests clinical benefit from alternative treatments such as plasmapheresis and hemofiltration. Renal recovery is achieved soon after clinical improvement. The comprehension of the primary mechanisms of renal dysfunction will be helpful in the development of additional therapeutic tools for improving supportive therapy for leptospiral nephropathy. This review discusses new insights into mechanisms implicated in leptospiral ARF and recent advances in treatment.

The Contribution of Bats to Leptospirosis Transmission in São Paulo City, Brazil

The biodiversity of potential leptospiral reservoir hosts is lower in urban than in rural environments. Previous data indicate the potential for bats to act as carriers of Leptospira in regions such as the Amazon of South America and in Australia. Yet, little is known about the contribution of bats to leptospirosis in urban environments in South America. This study aimed to test the hypothesis that bats infected with Leptospira are sources of leptospirosis transmission to humans in São Paulo City, Brazil. Six of 343 bats caught in different districts within the city of Sao Paulo (182 insectivorous, 161 frugivorous or nectarivorous) were polymerase chain reaction (PCR) positive for pathogenic Leptospira; no seropositive bats were found. That few renal carriers of Leptospira were found in the city of Sao Paulo suggests that bats are not important in the transmission of leptospirosis to humans in this, and possibly other urban settings.

Acute kidney injury in human leptospirosis: an immunohistochemical study with pathophysiological correlation

Tubulointerstitial nephritis is a common clinicopathological finding in leptospirosis. Clinically, nonoliguric acute kidney injury (AKI), hypokalemia, sodium, and magnesium wasting frequently occur in leptospirosis. The exact mechanisms of renal involvement remain largely unclear. Immunohistochemistry to detect expression of the endogenous sodium/hydrogen exchanger isoform 3 (NHE 3), aquaporin 1 and 2, α-Na+K+ATPase, and sodium–potassium–chloride cotransporter in its NKCC2 isoform was performed on kidneys removed during autopsy of human leptospirosis cases and kidneys removed during autopsy of human non-leptospirosis cases with and without evidence of acute tubular necrosis (ATN). A decrease in NHE 3, aquaporin 1, and α-Na+K+ATPase expression occurred in proximal convoluted tubule cells. Expression of aquaporin 1 was preserved along the descending thin limb of the loop of Henle in the outer medulla. α-Na+K+ATpase expression was essentially preserved in the distal tubules, i.e., the thick ascending limb of the loop of Henle, macula densa, and distal convoluted tubule. Aquaporin 2 expression in the collecting tubules was enhanced compared to those of non-leptospirotic kidneys. NKCC2 cotransport isoform was expressed in the thick ascending limb of the loop of Henle and was essentially preserved in leptospirotic kidneys. Primary injury of the proximal convoluted tubules is regarded as the hallmark of the kidney in leptospirosis. Sodium and water transport are particularly affected with increased distal potassium excretion, hypokalemia, and polyuria. Enhanced expression of aquaporin 2 in medullary collecting tubules is probably an attempt to retain water during the nonoliguric phase of renal failure.

Using Death Certificate Reports to Find Severe Leptospirosis Cases, Brazil

Severe leptospirosis with pulmonary hemorrhage is emerging globally. Measures to control leptospirosis through sanitation depend on accurate case finding and reporting. Rapid death certificate reporting, plus necropsy of persons who died of leptospirosis, facilitates public health intervention and could provide an important tool in assessing the global burden of leptospirosis.

Weil's Disease: An Unusually Fulminant Presentation Characterized by Pulmonary Hemorrhage and Shock

A case of fulminant leptospirosis is presented, manifesting as rapid progression from acute undifferentiated febrile illness to refractory shock, jaundice, renal failure and massive pulmonary hemorrhage. The patient received aggressive intensive care unit support including prolonged intubation and ventilation. This case emphasizes that acute leptospirosis may well not be characterized by the classic scenario of a biphasic illness, but rather by a fulminant, monophasic illness.

Comparative Analysis of Severe Pediatric and Adult Leptospirosis in São Paulo, Brazil

Although leptospirosis may be fatal in childhood, the experience of many clinicians working in disease-endemic areas is that classic Weils disease and death are less common among pediatric patients. The aim of the study was to ascertain disease spectrum and outcome differences in severe pediatric and adult leptospirosis in a large at-risk population. Epidemiologic, clinical, and laboratory data were obtained on hospitalized cases from São Paulo during 2004-2006. A total of 42 case-patients < 18 years of age and 328 case-patients ≥ 18 years of age were tested during the study. Compared with children, adults had higher rates of jaundice (P = 0.01), elevated serum bilirubin levels (P < 0.01), oliguria (P = 0.02), and elevated creatinine levels (P = 0.01) but not for thrombocytopenia or pulmonary involvement. The overall case-fatality rate was 27% (adult) versus 5% (pediatric) (P < 0.01). Severe pediatric leptospirosis may be less likely to show all classic features of Weils disease and may be less fatal than in adults.

Outpatient follow-up of patients hospitalized for acute leptospirosis

OBJECTIVE The outcome of leptospirosis after the resolution of acute disease, either spontaneously or after treatment, is not well described. The aim of this study was to assess the possible sequelae of acute leptospirosis after hospital discharge. METHODS We report here a prospective study carried out in São Paulo, Brazil in which patients hospitalized for leptospirosis were followed in the outpatient setting. RESULTS Forty-seven patients were serially assessed: 32 severe and 15 mild cases. Early and late complications were not common in either group, but subjective complaints were common in the first few weeks after hospital discharge (53% of severe cases, 40% of mild cases). Two patients had continuing complaints: one had profound general malaise and the other developed new onset panic disorder. The sample analyzed represented 26% of the patients hospitalized with leptospirosis in the city of São Paulo during the study period. The duration of follow-up was an average of approximately 20 days at the first visit, and approximately 40 days at the second visit. Forty-seven patients came for one follow-up visit and 22 of the same patients had two follow-up visits. CONCLUSIONS While two of 47 patients reported continuing symptoms after hospitalization for acute leptospirosis, no definitive, objective evidence of chronic sequelae due to this infection was proven. While preliminary, these observations point to the need for a prospective, rigorous and systematic study to definitively determine and characterize late complications and chronic disease after acute leptospirosis.

Reversal of renal tubule transporter down-regulation during severe leptospirosis with antimicrobial therapy

Tubular dysfunction is a hallmark of severe leptospirosis. Antimicrobial therapy is thought to interfere on renal involvement. We evaluated the expression of a proximal tubule type-3 Na+/H+ exchanger (NHE3) and a thick ascending limb Na+-K+-2Cl(-) cotransporter (NKCC2) in controls and treated hamsters. Animals infected by a serovar Copenhageni isolate, were treated or not with ampicillin (AMP) and/or N-acetylcysteine (NAC). Leptospiral antigen(s) and expression of renal transporters were evaluated by immunohistochemistry, and serum thiobarbituric acid (TBARS) was quantified. Infected hamsters had high amounts of detectable leptospiral antigen(s) in target tissues while renal expression of NHE3 and NKCC2 decreased. Ampicillin treatment was associated with minimal or no detection of leptospiral antigens, normal expression of NHE3 and NKCC2 transporters, and reduced levels of TBARS. NAC effect was restricted to lowering TBARS. Early and late AMP treatment rescued tubular defects in severe leptospirosis disease, and there was no evidence of benefit from antioxidant therapy.

Hemoptysis associated with leptospirosis acquired in Hawaii, USA.

To the Editor: Severe pulmonary hemorrhagic syndrome (SPHS) is a serious complication of Leptospira infection, a globally widespread bacterial zoonosis that is increasing in incidence in tropical and subtropical regions. Despite decreasing endemicity of leptospirosis in industrialized regions, the disease is reemerging in travelers and recreationalists. Leptospirosis is an appreciable attributable cause of travel-related infections (typically associated with waterborne activities), and the incidence of travel-related leptospirosis is proportionally higher than that for endemic leptospirosis. Disease risk epidemiology has shifted concomitantly from occupational to recreational in industrialized countries (1–3). Risk factors include urbanization, climatic changes, and agricultural practices (1–3). Clinical features of leptospirosis range from asymptomatic infections and undifferentiated febrile syndromes to multiorgan dysfunction and death. Weil syndrome (i.e., severe leptospirosis) is characterized by renal and hepatic dysfunction, hyperbilirubinemia (disproportionate to transaminase elevation), and hemorrhage (pulmonary, gastrointestinal, or intracranial). Pulmonary involvement predicts poor clinical outcome: the case-fatality rate for persons with SPHS is >50% (4–6). Most US leptospirosis cases are reported from Hawaii, where the annual incidence is 1.63 cases/100,000 person-years (1). Leptospirosis is endemic to Hawaii; however, SPHS is uncommonly reported (7). We treated a 21-year-old active-duty Navy sailor for SPHS after he had a 5-day port visit in Hawaii, during which he went cliff-diving in Maunawili Falls. Afterwards, he returned to California and 2 days later sought medical attention in an outpatient clinic. Pharyngitis was diagnosed and azithromycin prescribed. Two days later, he was hospitalized with fever, chills, pharyngitis, dyspnea, nonproductive cough, headache, myalgias, hemoptysis, epistaxis, diarrhea, nausea, emesis, meningismus, and a lower-extremity rash. Vital signs included temperature 38.3°C, pulse 132 beats/min, blood pressure 128/72 mm Hg, and oxygen saturation 98% on room air. Physical examination noted conjunctival suffusion, epistaxis, posterior cervical and inguinal lymphadenopathy, bilaterally diminished breath sounds, rhonchi and crackles, bloody cough, tachycardia, hepatosplenomegaly, and a macular rash over the lower extremities. Laboratory studies were noteworthy for reference range leukocyte count, hemoglobin (11.8 g/dL), platelets (102 × 103/mm3), creatine phosphokinase (1,719 IU/L), sodium (128 mmol/L), bicarbonate (23 mmol/L), blood urea nitrogen (29 mg/dL), creatinine (2.2 mg/dL), aspartate aminotransferase (171 U/L), alanine aminotransferase (147 U/L), bilirubin (1.9 mg/dL), and urinalysis (7 erythrocytes and 9 leukocytes/high-power field). Chest radiography showed multilobar bilateral opacities, and cerebrospinal fluid (CSF) showed mild pleocytosis. The patient received intravenous acyclovir, ceftriaxone, and vancomycin and continued azithromycin. At hospital admission, the patient experienced respiratory decompensation requiring endotracheal intubation and mechanical ventilation. Results of blood, urine, and CSF cultures and CFS PCR (herpes simplex virus and enterovirus) remained negative at 48 hours, prompting discontinuation of vancomycin and acyclovir. Serologic test results for HIV, dengue fever virus, mycoplasma, and Chlamydophila and Rickettsia species were negative. Nasopharyngeal influenza PCR, Streptococcus pneumoniae and Legionella spp. urinary antigen test results and hepatitis panel results were negative. Leptospira spp. test results by culture, PCR, and serologic testing (ELISA and microscopic agglutination testing) were negative. Given an elevated suspicion for leptospirosis, ceftriaxone and azithromycin were continued through hospital day 7. The patient rapidly improved, was extubated after 48 hours, and was discharged on hospital day 7 with a 7-day course of oral doxycycline. A convalescent-phase serum sample had a titer of 1,600 against L. interrogans serovar Copenhageni, as determined by microscopic agglutination testing. SPHS is associated with infection with L. interrogans serovars Copenhageni and Icterohaemorrhagiae (8), and the syndrome has been identified in diverse settings, including the Andaman Islands. Recent outbreaks have occurred in Nicaragua and Brazil (4,5). SPHS pathogenesis remains poorly understood. In animal models and human autopsy studies, immunoglobulin and complement are deposited along alveolar septa without a clear cause-and-effect relationship (9). Bacterial virulence factors are postulated but unproven. Leptospires induce endothelial activation and pulmonary endothelial and epithelial injury (possibly by immune-complex deposition and/or autoimmune mechanisms) (9). Pulmonary histopathology demonstrates a paucity of leptospires, and antigen levels do not correlate with injury severity (9). Steroids, intravenous immunoglobulin, and plasma exchange are of unproven benefit but have been reported to be useful (9). Genetically determined responses include associations with human leukocyte antigen–DQ6 and hyperactive Toll-like receptor 4–dependent immunity. Diagnosis of leptospirosis may have been delayed for this patient because of early empiric azithromycin administration. Azithromycin is increasingly recognized as a potentially effective treatment that is comparable or superior to doxycycline (10) and thus warrants testing in human trials. Given the paucity of SPHS in leptospirosis case reports from Hawaii, potential sentinel cases may be harbingers of more virulent disease expression. A potential parallel is the emergence of SPHS in Salvador, Brazil, in 2003. No cases were identified before 2003, but 47 cases and a 75% case-fatality rate were identified during 2003–2005 (4,5). The entrenched active surveillance and physician awareness of SPHS in neighboring Brazilian cities suggests it is unlikely that this observation stemmed from prior underrecognition of disease; instead, it suggests de novo emergence. Clinicians should consider leptospirosis (SPHS) in patients with acute fever accompanied by hemoptysis after travel to Hawaii, and leptospirosis should be suspected in any traveler with undifferentiated febrile illness, especially those reporting water exposures (2). Vigilant national surveillance is needed to determine further emergence of SPHS in Hawaii.