Leptospirosis causes significant morbidity and mortality worldwide; however, the role of the host immune response in disease progression and high case fatality (>10–50%) is poorly understood. We conducted a multi-parameter investigation of patients with acute leptospirosis to identify mechanisms associated with case fatality. Whole blood transcriptional profiling of 16 hospitalized Brazilian patients with acute leptospirosis (13 survivors, 3 deceased) revealed fatal cases had lower expression of the antimicrobial peptide, cathelicidin, and chemokines, but more abundant pro-inflammatory cytokine receptors. In contrast, survivors generated strong adaptive immune signatures, including transcripts relevant to antigen presentation and immunoglobulin production. In an independent cohort (23 survivors, 22 deceased), fatal cases had higher bacterial loads (P = 0.0004) and lower anti-Leptospira antibody titers (P = 0.02) at the time of hospitalization, independent of the duration of illness. Low serum cathelicidin and RANTES levels during acute illness were independent risk factors for higher bacterial loads (P = 0.005) and death (P = 0.04), respectively. To investigate the mechanism of cathelicidin in patients surviving acute disease, we administered LL-37, the active peptide of cathelicidin, in a hamster model of lethal leptospirosis and found it significantly decreased bacterial loads and increased survival. Our findings indicate that the host immune response plays a central role in severe leptospirosis disease progression. While drawn from a limited study size, significant conclusions include that poor clinical outcomes are associated with high systemic bacterial loads, and a decreased antibody response. Furthermore, our data identified a key role for the antimicrobial peptide, cathelicidin, in mounting an effective bactericidal response against the pathogen, which represents a valuable new therapeutic approach for leptospirosis.

Abstract. Leptospirosis is a zoonotic disease that causes severe manifestations such as Weil's disease and pulmonary hemorrhage syndrome. The aim of this study was to evaluate whether reactive oxygen species (ROS) production and antioxidant reduced glutathione (GSH) levels are related to complications in patients hospitalized with leptospirosis. The ROS production and GSH levels were measured in blood samples of 12 patients and nine healthy controls using chemiluminescence and absorbance assays. We found that ROS production was higher and GSH levels were lower in leptospirosis patients compared with healthy individuals. Among patients, GSH depletion was correlated with thrombocytopenia and elevated serum creatinine, whereas a strong positive correlation was observed between ROS production and elevated serum potassium. Additional investigation of the biological significance of ROS production and GSH levels is warranted as they may guide the development of novel adjuvant therapies for leptospirosis targeting oxidative stress.

Objective: To characterize the epidemiological profile of the hospitalized population in the ICU of Hospital das Clínicas de Marília (Famema). Method: A retrospective, descriptive and quantitative study. Data regarding patients admitted to the ICU Famema was obtained from the Technical Information Center (Núcleo Técnico de Informações, NTI, Famema). For data analysis, we used the distribution of absolute and relative frequencies with simple statistical treatment. Results: 2,022 ICU admissions were recorded from June 2010 to July 2012 with 1,936 being coded according to the ICD-10. The epidemiological profile comprised mostly males (57.91%), predominantly seniors ≥ 60 years (48.89%), at an average age of 56.64 years (±19.18), with limited formal education (63.3% complete primary school), mostly white (77.10%), Catholic (75.12%), from the city of Marília, state of São Paulo, Brazil (53.81%). The average occupancy rate was 94.42%. The predominant cause of morbidity was diseases of the circulatory system with 494 admissions (25.5%), followed by traumas and external causes with 446 admissions (23.03%) and neoplasms with 213 admissions (11.00%). The average stay was 8.09 days (±10.73). The longest average stay was due to skin and subcutaneous tissue diseases, with average stay of 12.77 days (±17.07). There were 471 deaths (24.32%), mainly caused by diseases of the circulatory system (30.99%). The age group with the highest mortality was the range from 70 to 79 years with 102 deaths (21.65%). Conclusion:The ICU Famema presents an epidemiological profile similar to other intensive care units in Brazil and worldwide, despite the few studies available in the literature. Thus, we feel in tune with the treatment of critical care patients.

Early detection of leptospirosis with field-ready diagnostics may improve clinical management and mitigate outbreaks. We previously validated the point-of-care Dual Path Platform (DPP) for leptospirosis with sera in the laboratory. This prospective study compares the diagnostic accuracy and clinical utility of the DPP using finger stick blood (FSB) against the serum DPP, venous whole blood (VWB) DPP, IgM-ELISA, and clinical impression. We sequentially enrolled 98 patients hospitalized for acute febrile illnesses, of which we confirmed 32 by leptospirosis reference tests. Among syndromes consistent with classic leptospirosis, the FSB DPP showed similar sensitivity and specificity (Se 93% and Sp 80%), and positive and negative predictive values (PPV 74% and NPV 95%), to VWB DPP (Se 96%, Sp 75%, PPV 68%, and NPV 97%), serum DPP (Se 85%, Sp 87%, PPV 79%, and NPV 91%) and IgM-ELISA (Se 81%, Sp 100%, PPV 100%, and NPV 90%). The FSB DPP provided a favorable likelihood ratio profile (positive LR 4.73, negative LR 0.09) in comparison to other assays and clinical impression alone. Additionally, we identified four of five leptospirosis-associated meningitis patients by whole blood DPP, none of which clinicians suspected. This demonstrates potential for the DPP in routine detection of this less common syndrome. The FSB DPP demonstrated similar discrimination for severe human leptospirosis compared with serum assays, and it is a simpler option for diagnosing leptospirosis. Its performance in other epidemiological settings and geographic regions, and for detecting atypical presentations, demands further evaluation.

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T he clinical signs of leptospirosis can vary widely, which complicates timely diagnosis and targeted therapy. Aseptic meningitis associated with Leptospira infection, hereafter termed leptospirosis-associated meningitis (LAM), has been well described (1-3). However, clinicians diagnose atypical forms of leptospirosis less frequently, particularly in the absence of classic signs (i.e., renal insufficiency or hepatitis). Detection requires a high level of clinical suspicion, and even then imperfect diagnostics for leptospirosis limit timely confirmation. Leptospirosis causes ≈1 million illnesses annually; this figure does not include LAM (4). Despite the high global burden of leptospirosis and early knowledge that anicteric LAM is underappreciated (1), few existing studies delineate the proportion of aseptic meningitis caused by Leptospira sp. infection in settings in which it is endemic. We performed surveillance for aseptic meningitis in an area of high transmission of urban leptospirosis. Hospital Couto Maia, the Oswaldo Cruz Foundation, and Yale University provided ethics approval for this study. The Study We conducted the study at a public referral hospital for infectious diseases in Salvador, Brazil, April 18-October 18, 2012, during a period of seasonal increased risk for severe leptospirosis such as Weil's disease (5) and severe pulmonary hemorrhagic syndrome (6). We enrolled consecutive patients >5 years of age who had a diagnosis of aseptic meningitis, defined by clinical meningitis (fever with severe headache or meningismus); nonturbid, nonpurulent cerebrospinal fluid (CSF) containing 10-2,000 cells/m 3 , protein <150 mg/dL, glucose >40 mg/dL; and negative results for bacterial meningitis on Gram stain, culture isolation, and latex agglutination tests. From the patients with aseptic meningitis, we aimed to select those most likely to elicit clinical suspicion for leptospirosis; a selection requirement was >1 epidemiologic risk factor for classic leptospirosis in the 30 days before symptom onset for leptospirosis testing. Risk factors were contact with floodwater, sewer water, or mud; rats at home or work; and residence or employment in a high-risk environment (i.e., slum community or animal farm) (7). We confirmed LAM by either Leptospira blood culture on EMJH media using 150 µL inoculum, or by reactive microagglutination test (MAT) by >1 of the following criteria: >4-fold acute-convalescent titer rise; seroconversion (undetectable acute-phase titer and convalescent-phase titer >1:200); or sample titer >1:800. The public hospital received regional referrals for lumbar puncture and CSF analysis for suspected meningitis as standard practice; CSF showing >10 cells/ mm 3 required inpatient observation. At enrollment, we obtained demographic, epidemiologic, and clinical data from patients. We followed the patients during hospitalization to ascertain outcomes. We compared clinical characteristics between leptospirosis-confirmed and unconfirmed patients >15 years of age to avoid age confounding. Comparisons we...

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