Browsing by Author "Kevin C. Kain"
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Publication Metadata only A common TLR1 polymorphism is associated with higher parasitaemia in a Southeast Asian population with Plasmodium falciparum malaria(2016-01-06) William O. Hahn; Susanna Harju-Baker; Laura K. Erdman; Srivicha Krudsood; Kevin C. Kain; Mark M. Wurfel; Wayne C. Liles; Harborview Medical Center; Toronto General Hospital; University of Toronto; Mahidol University© 2016 Hahn et al. Background: The factors leading to poor outcomes in malaria infection are incompletely understood. Common genetic variation exists in the human genes for Toll like receptors (TLRs) that alter host responses to pathogen-associated molecular patterns. Genetic variation in TLR1 and TLR6 could alter the risk of development of complicated malaria and ability of the host to control the parasite burden during acute Plasmodium falciparum infection. Methods: Five single nucleotide polymorphisms in TLR1 and TLR6 in 432 patients with clinical P. falciparum monoinfection acquired on the Thai-Myanmar border were genotyped. Using logistic regression, associations with the development of complicated malaria and the percentage of infected erythrocytes (parasitaemia) on the day of presentation to clinical care (day zero) were tested. Results: Genotypes carrying the T (major) allele of TLR1 rs5743551 - an allele associated with improved outcomes in sepsis - were associated with higher parasitaemia measured on day zero (p = 0.03). Discussion: Since malaria exerts strong genetic pressure on the human genome, protection from parasitaemia associated with TLR1 rs5743551 may account for the maintenance of an allele associated with poor outcomes in Caucasians with sepsis. Conclusion: These data suggest that genetic variation in TLR1 has effects on the host response to Plasmodium falciparum malaria in Asian populations. Genotypes from TLR6 showed no evidence of association with either complicated malaria or parasite burden.Publication Metadata only Detection of plasmodium falciparum by polymerase chain reaction in a field study(1992-01-01) Orntipa Sethabutr; Arthur E. Brown; Sakol Panyim; Kevin C. Kain; H. Kyle Webster; Peter Echeverria; Mahidol University; Walter Reed Army Institute of Research; Armed Forces Research Institute of Medical SciencesDetection of Plasmodium falciparum by polymerase chain reaction (PCR) was evaluated in 33 P. falciparum-infected patients with two different amplification systems over 5-7 days of curative treatment. In the Kl-14 system, a P. falciparum DNA fragment of 206 bp was detected, and in the circumsporozoite (CS) system, a fragment of 800 bp was detected. The Kl-14 and CS systems identified 95% and 93%, respectively, of 103 microscopically identified specimens; both systems detected as few as 11 parasites/*d among these specimens. Specimens from 20 smear- and history-negative controls were all negative by both PCR systems. The Kl-14 and CS systems detected P. falciparum DNA in 53% and 20%, respectively, of blood films collected on the first day and 3% and 0 of the blood films collected on the fourth day after reversion to microscopic negative. The simultaneous use of two independent PCR systems to monitor patients during curative treatment of P. falciparum infections convincingly demonstrated that P. falciparum DNA was present transiently in the blood of infected patients at a time when the parasite could no longer be detected microscopically. © 1992 by the University of Chicago.Publication Metadata only Efficacy of atovaquone-proguanil for treatment of acute multidrug-resistant Plasmodium falciparum malaria in Thailand(2007-04-01) Srivicha Krudsood; Samir N. Patel; Nopaddon Tangpukdee; Wipa Thanachartwet; Wattana Leowattana; Karnchana Pornpininworakij; Andrea K. Boggild; Sornchai Looareesuwan; Kevin C. Kain; Toronto General Hospital; Mahidol UniversityA combination of atovaquone-proguanil (Malarone®; GlaxoSmithKline, Research Triangle Park, NC) was previously shown to be highly effective in the treatment of uncomplicated Plasmodium falciparum malaria. However, there are only limited recent efficacy data, particularly from regions of multidrug resistance. In this study, we examined the efficacy of atovaquone-proguanil for the treatment of uncomplicated P. falciparum malaria on the Thailand-Myanmar border. Patients were given directly observed atovaquone-proguanil (1,000 mg/400 mg) once a day for three days and followed-up for four weeks in a non-transmission area. Of 140 eligible patients enrolled in this open-label study, 97.8% (95% confidence interval = 95.4-100%) responded to therapy and remained clear of parasitemia at follow-up. Mean parasite clearance time was 41.9 hours and mean fever clearance time was 37.1 hours. On the basis of genotyping, three cases of treatment failure were identified (1 RIII and 2 RI). These data indicate that atovaquone-proguanil remains highly efficacious for the treatment of multidrug-resistant P. falciparum malaria in Thailand. Copyright © 2007 by The American Society of Tropical Medicine and Hygiene.Publication Metadata only Qualitative and semiquantitative polymerase chain reaction to predict plasmodium falciparum treatment failure(1994-01-01) Kevin C. Kain; Dennis E. Kyle; Chansuda Wongsrichanalai; Arthur E. Brown; H. Kyle Webster; S. Vanijanonta; Sornchai Looareesuwan; University of Toronto; Mahidol UniversityMultidrug-resistant falciparum malaria is increasing in most malaria-endemic areas. Rapid methods for predicting treatment failure would aid management and control of drug-resistant infections. In this study, Plasmodium falciparum DNA clearance was examined by qualitative and semiquantitative polymerase chain reaction (PCR). Thai patients with acute falciparum malaria were prospectively followed by light microscopy and by PCR of P. falciparum DNA eluted from filter paper blood samples. A 206-bp P. falciparum sequence was amplified and detected radiometrically and by high-performance liquid chromatography. Clearance of P.falciparum DNA was significantly delayed in treatment failures compared with that in successfully treated patients (P =.02). Semiquantitative PCR levels did not drop to < 50% of pretreatment levels until day 3 or later in treatment failures compared with day 1 or earlier for successfully treated parasitemia-matched controls (P =.005). These results suggest that qualitative and semiquantitative PCR may be useful as a method for monitoring response to therapy. © 1994 by The University of Chicago.Publication Metadata only Rabies post-exposure prophylaxis started during or after travel: A GeoSentinel analysis(2018-11-01) Philippe Gautret; Kristina M. Angelo; Hilmir Asgeirsson; David G. Lalloo; Marc Shaw; Eli Schwartz; Michael Libman; Kevin C. Kain; Watcharapong Piyaphanee; Holly Murphy; Karin Leder; Jean Vincelette; Mogens Jensenius; Jesse Waggoner; Daniel Leung; Sarah Borwein; Lucille Blumberg; Patricia Schlagenhauf; Elizabeth D. Barnett; Davidson H. Hamer; Oslo University Hospital; Aix Marseille Université; National Institute for Communicable Diseases; University of Utah, School of Medicine; Centers for Disease Control and Prevention; Liverpool School of Tropical Medicine; James Cook University, Australia; Monash University; Karolinska University Hospital; Boston University School of Public Health; University of Toronto; Mahidol University; University of Zurich; Centre Hospitalier de L'Universite de Montreal; Boston University School of Medicine; Tel Aviv University, Sackler Faculty of Medicine; McGill University; Emory University School of Medicine; CIWEC Travel Medicine Centre; Central Health Medical Practice; Worldwise Travellers Health Centres of New Zealand© 2018, Public Library of Science. All rights reserved. https://creativecommons.org/publicdomain/zero/1.0/. Background: Recent studies demonstrate that rabies post-exposure prophylaxis (RPEP) in international travelers is suboptimal, with only 5–20% of travelers receiving rabies immune globulin (RIG) in the country of exposure when indicated. We hypothesized that travelers may not be receiving RIG appropriately, and practices may vary between countries. We aim to describe the characteristics of travelers who received RIG and/or RPEP during travel. Methodology/Principal findings: We conducted a multi-center review of international travelers exposed to potentially rabid animals, collecting information on RPEP administration. Travelers who started RPEP before (Group A) and at (Group B) presentation to a GeoSentinel clinic during September 2014–July 2017 were included. We included 920 travelers who started RPEP. About two-thirds of Group A travelers with an indication for rabies immunoglobulin (RIG) did not receive it. Travelers exposed in Indonesia were less likely to receive RIG in the country of exposure (relative risk: 0.30; 95% confidence interval: 0.12–0.73; P = 0.01). Travelers exposed in Thailand [Relative risk (RR) 1.38, 95% Confidence Interval (95% CI): 1.0–1.8; P = 0.02], Sri Lanka (RR 3.99, 95% CI: 3.99–11.9; P = 0.013), and the Philippines (RR 19.95, 95% CI: 2.5–157.2; P = 0.01), were more likely to receive RIG in the country of exposure. Conclusions/Significance: This analysis highlights gaps in early delivery of RIG to travelers and identifies specific countries where travelers may be more or less likely to receive RIG. More detailed country-level information helps inform risk education of international travelers regarding appropriate rabies prevention.Publication Metadata only Regional variation in travel-related illness acquired in Africa, March 1997-May 2011(2014-01-01) Marc Mendelson; Pauline V. Han; Peter Vincent; Frank von Sonnenburg; Jakob P. Cramer; Louis Loutan; Kevin C. Kain; Philippe Parola; Stefan Hagmann; Effrossyni Gkrania-Klotsas; Mark Sotir; Patricia Schlagenhauf; Rahul Anand; Hilmir Ásgeirsson; Elizabeth D. Barnett; Sarah Borwein; Gerd Dieter Burchard; John D. Cahill; Daniel Campion; Francesco Castelli; Eric Caumes; Lin H. Chen; Bradley A. Connor; Christina M. Coyle; Jakob Cramer; Jane Eason; Cécile Ficko; Vanessa Field; David O. Freedman; Abram Goorhuis; Martin P. Grobusch; Alejandra Gurtman; Devon C. Hale; Annemarie Hern; Noreen Hynes; Mogens Jensenius; Robert Kass; Amy D. Klion; Phyllis E. Kozarsky; Karin Leder; Carmelo Licitra; Rogelio López-Vélez; Michael W. Lynch; Alberto Matteelli; Anne McCarthy; George MckInley; Susan McLellan; José Antonio Pérez Molina; Robert Muller; Thomas B. Nutman; Alice Pérignon; Phi Truong Hoang Phu; Watcharapong Piyaphanee; Christophe Rapp; David Roesel; Eli Schwartz; Marc Shaw; Udomsak Silachamroon; William Stauffer; Natsuo Tachikawa; Joseph Torresi; Johan Ursing; Jean Vincelette; Patricia Walker; Andy Wang; Mary E. Wilson; Henry Wu; Yukihiro Yoshimura; University of Cape Town; Centers for Disease Control and Prevention; Tokai Medicross Travel Clinic; Ludwig-Maximilians-Universitat Munchen; Universitatsklinikum Hamburg-Eppendorf und Medizinische Fakultat; Universite de Geneve; University of Toronto; North University Hospital; Bronx-Lebanon Hospital Center; Cambridge University Hospitals NHS Foundation Trust; University of Zurich; University of Utah; Karolinska University Hospital; Boston University; Travel-Safe Medical Centre; Bernhard Nocht Institut fur Tropenmedizin Hamburg; St. Luke's-Roosevelt Hospital Center; InterHealth; Università degli Studi di Brescia; Hopital Universitaire Pitie Salpetriere; Harvard University; Cornell University; Albert Einstein College of Medicine of Yeshiva University; Beijing United Family Hospital and Clinics; Hopital d'Instruction des Armees Begin; University of Alabama at Birmingham; University of Amsterdam; The Mount Sinai Medical Center; Worldwise Travellers Health and Vaccination Centre; Johns Hopkins University; Oslo University Hospital; Travellers Medical and Vaccination Centre; National Institutes of Health, Bethesda; Emory University; Royal Melbourne Hospital; Orlando Regional Health Center; Hospital Ramon y Cajal; Fresno International Travel Medical Center; University of Ottawa, Canada; Tulane University; Travel Clinic Services; Hôpital Pitié-Salpêtrière; International SOS Vietnam; Mahidol University; University of Washington, Seattle; Chaim Sheba Medical Center Israel; Regions Hospital; Yokohama Municipal Citizen's Hospital; Centre Hospitalier de L'Universite de Montreal; HealthPartnersTo understand geographic variation in travel-related illness acquired in distinct African regions, we used the GeoSentinel Surveillance Network database to analyze records for 16,893 ill travelers returning from Africa over a 14-year period. Travelers to northern Africa most commonly reported gastrointestinal illnesses and dog bites. Febrile illnesses were more common in travelers returning from sub-Saharan countries. Eleven travelers died, 9 of malaria; these deaths occurred mainly among male business travelers to sub-Saharan Africa. The profile of illness varied substantially by region: malaria predominated in travelers returning from Central and Western Africa; schistosomiasis, strongyloidiasis, and dengue from Eastern and Western Africa; and loaisis from Central Africa. There were few reports of vaccine-preventable infections, HIV infection, and tuberculosis. Geographic profiling of illness acquired during travel to Africa guides targeted pretravel advice, expedites diagnosis in ill returning travelers, and may influence destination choices in tourism.Publication Metadata only Serum angiopoietin-1 and -2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children(2009-03-20) Fiona E. Lovegrove; Noppadon Tangpukdee; Robert O. Opoka; Erin I. Lafferty; Nimerta Rajwans; Michael Hawkes; Srivicha Krudsood; Sornchai Looareesuwan; Chandy C. John; W. Conrad Liles; Kevin C. Kain; University Health Network University of Toronto; Mahidol University; Makerere University; University of Minnesota Medical School; University of TorontoBackground: Limited tools exist to identify which individuals infected with Plasmodium falciparum are at risk of developing serious complications such as cerebral malaria (CM). The objective of this study was to assess serum biomarkers that differentiate between CM and non-CM, with the long-term goal of developing a clinically informative prognostic test for severe malaria. Methodology/Principal Findings: Based on the hypothesis that endothelial activation and blood-brain-barrier dysfunction contribute to CM pathogenesis, we examined the endothelial regulators, angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), in serum samples from P. falciparum-infected patients with uncomplicated malaria (UM) or CM, from two diverse populations - Thai adults and Ugandan children. Angiopoietin levels were compared to tumour necrosis factor (TNF). In both populations, ANG-1 levels were significantly decreased and ANG-2 levels were significantly increased in CM versus UM and healthy controls (p,0.001). TNF was significantly elevated in CM in the Thai adult population (p,0.001), but did not discriminate well between CM and UM in African children. Receiver operating characteristic curve analysis showed that ANG-1 and the ratio of ANG-2:ANG-1 accurately discriminated CM patients from UM in both populations. Applied as a diagnostic test, ANG-1 had a sensitivity and specificity of 100% for distinguishing CM from UM in Thai adults and 70% and 75%, respectively, for Ugandan children. Across both populations the likelihood ratio of CM given a positive test (ANG-1,15 ng/mL) was 4.1 (2.7-6.5) and the likelihood ratio of CM given a negative test was 0.29 (0.20-0.42). Moreover, low ANG-1 levels at presentation predicted subsequent mortality in children with CM (p = 0.027). Conclusions/Significance: ANG-1 and the ANG-2/1 ratio are promising clinically informative biomarkers for CM. Additional studies should address their utility as prognostic biomarkers and potential therapeutic targets in severe malaria. © 2009 Lovegrove et al.Publication Metadata only Use of peroxisome proliferator-activated receptor γ agonists as adjunctive treatment for Plasmodium falciparum malaria: A randomized, double-blind, placebo-controlled trial(2009-09-15) Andrea K. Boggild; Srivicha Krudsood; Samir N. Patel; Lena Serghides; Noppadon Taagpukdee; Kevin Katz; Polrat Wilairatana; W. Conrad Liles; Sornchai Looareesuwan; Kevin C. Kain; Toronto General Hospital; Department of Laboratory Medicine and Pathobiology; University of Toronto; North York General Hospital; Mahidol UniversityBackground. Despite the use of potent antimalarial drugs, the fatality rate associated with severe malaria remains high. Adjunctive therapies that target the immunopathological responses to infection may decrease mortality associated with severe malaria. We hypothesized that peroxisome proliferator-activated receptor γ agonists (eg, rosiglitazone) would modulate the host's innate immune response to malaria and improve outcome. Methods. In a randomized, double-blind, placebo-controlled, phase I/II trial of treatment for malaria acquired in Thailand, we investigated the safety, tolerability, and efficacy of rosiglitazone use for parasite clearance and for reducing malaria-induced inflammation. Sequential patients with uncomplicated Plasmodium falciparum malaria were randomly assigned to 1 of 2 groups: 70 patients received rosiglitazone 4 mg twice daily for 4 days, and 70 patients received a placebo twice daily for 4 days. Both groups also received standard antimalarial therapy (ie, a fixed combination of 1000 mg of atovaquone per day for 3 days and 400 mg of proguanil per day for 3 days). Primary efficacy outcomes were 50% and 90% parasite clearance times (PCTs). Secondary outcomes were fever clearance time, levels of inflammatory mediators, blood glucose measurements, aminotransferase levels, admission to intensive care, and subjective tolerability of study drug. Results. For the 70 patients who received rosiglitazone, parasite clearance from peripheral blood was significantly enhanced, compared with the 70 patients who received a placebo (mean 50% PCT, 19.0 h vs. 24.6 h [P = .029]; mean 90% PCT, 30.9 h vs. 40.4 h [P = .004]). Also, the patients who received rosiglitazone had reduced inflammatory responses to infection, compared with the patients who received a placebo (ie, interleukin6 levels at 24 h [P <.005] and at 48 h [P = .013] and monocyte chemoattractant protein-1 level at 48 h [P = .05]). There were no significant differences between the 2 groups with regard to safety and tolerability of treatment, and there were no admissions the intensive care unit or deaths. Conclusions. The use of rosiglitazone is a well-tolerated adjunct to standard therapy for nonsevere P. falciparum malaria. Treatment with rosiglitazone increased parasite clearance and decreased inflammatory biomarkers associated with adverse malaria outcomes. Trial registration. ClinicalTrials.gov identifier NCT00149383. © 2009 by the Infectious Diseases Society of America. All rights reserved.Publication Metadata only Whole blood angiopoietin-1 and-2 levels discriminate cerebral and severe (non-cerebral) malaria from uncomplicated malaria(2009-12-01) Andrea L. Conroy; Erin I. Lafferty; Fiona E. Lovegrove; Srivicha Krudsood; Noppadon Tangpukdee; W. Conrad Liles; Kevin C. Kain; Toronto General Hospital; Mahidol University; University of TorontoBackground. Severe and cerebral malaria are associated with endothelial activation. Angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2) are major regulators of endothelial activation and integrity. The aim of this study was to investigate the clinical utility of whole blood angiopoietin (ANG) levels as biomarkers of disease severity in Plasmodium falciparum malaria. Methods. The utility of whole blood ANG levels was examined in Thai patients to distinguish cerebral (CM; n = 87) and severe (non-cerebral) malaria (SM; n = 36) from uncomplicated malaria (UM; n = 70). Comparative statistics are reported using a non-parametric univariate analysis (Kruskal-Wallis test or Chi-squared test, as appropriate). Multivariate binary logistic regression was used to examine differences in whole blood protein levels between groups (UM, SM, CM), adjusting for differences due to ethnicity, age, parasitaemia and sex. Receiver operating characteristic curve analysis was used to assess the diagnostic accuracy of the ANGs in their ability to distinguish between UM, SM and CM. Cumulative organ injury scores were obtained for patients with severe disease based on the presence of acute renal failure, jaundice, severe anaemia, circulatory collapse or coma. Results. ANG-1 and ANG-2 were readily detectable in whole blood. Compared to UM there were significant decreases in ANG-1 (p < 0.001) and significant increases in ANG-2 (p < 0.001) levels and the ratio of ANG-2: ANG-1 (p < 0.001) observed in patients with SM and CM. This effect was independent of covariates (ethnicity, age, parasitaemia, sex). Further, there was a significant decrease in ANG-1 levels in patients with SM (non-cerebral) versus CM (p < 0.001). In participants with severe disease, ANG-2, but not ANG-1, levels correlated with cumulative organ injury scores; however, ANG-1 correlated with the presence of renal dysfunction and coma. Receiver operating characteristic curve analysis demonstrated that the level of ANG-1, the level of ANG-2 or the ratio of ANG-2: ANG-1 discriminated between individuals with UM and SM (area under the curve, p-value: ANG-2, 0.763, p < 0.001; ANG-1, 0.884, p < 0.001; Ratio, 0.857, p < 0.001) or UM and CM (area under the curve, p-value: ANG-2, 0.772, p < 0.001; ANG-1, 0.778, p < 0.001; Ratio, 0.820, p < 0.001). Conclusions. These results suggest that whole blood ANG-1/2 levels are promising clinically informative biomarkers of disease severity in malarial syndromes. © 2009 Conroy et al; licensee BioMed Central Ltd.