Perceptions of Seasonal Influenza Vaccine Among U.S. Army Civilians and Dependents in the Kaiserslautern Military Community: A Mixed-Methods Survey.

INTRODUCTION: Influenza is a globally occurring viral respiratory infection that can lead to hospitalizations and death. An influenza outbreak can interfere with combat readiness in a military setting, as the infection can incapacitate soldiers. Vaccination remains the most effective tool to prevent and mitigate seasonal influenza. Although influenza vaccinations for U.S. Army soldiers can be monitored through military health systems, those systems cannot capture DoD civilians and Army dependents who may not use military health services. This study aims to gauge flu vaccine uptake and perceptions in U.S. Army civilians and dependents. MATERIALS AND METHODS: An online survey was e-mailed to civilian and dependent enrollees of Landstuhl Regional Medical Center. The survey contained 24 questions pertaining to demographics, vaccine history, history of the flu, and beliefs toward vaccines. Chi-square tests, t-tests, and logistic regressions were performed to investigate the association between demographic, behavior, and belief factors with vaccine uptake. Free-text answers were coded and categorized by themes. RESULTS: Over 70% of respondents were vaccinated for the flu. There were differences between vaccinated and unvaccinated respondents regarding their perceptions of barriers to vaccination, benefits of the flu vaccine, severity of flu symptoms, and personal risk of getting ill with the flu. After controlling for confounders, flu vaccination in the previous season and healthcare worker status were associated with increased vaccine uptake, while perceived barriers to influenza vaccination were associated with decreased vaccine uptake. CONCLUSIONS: Flu vaccine uptake may be increased by increasing access to vaccination, promoting vaccination and addressing concerns at the provider level, and engaging positively framed public messaging. Increasing flu vaccine uptake is of particular importance as the flu season approaches during the COVID-19 (Coronavirus disease 2019) pandemic.

Outcomes From U.S. Military-Supported Overseas Training Rotations in Tropical Medicine and Global Health, 2006-2015.

BACKGROUND: Since 2006, the Division of Tropical Public Health at the Uniformed Services University (USU) has sponsored the Tropical Medicine Training Program (TMTP). Despite practice guidelines stating that global health education should include the collection and evaluation of data on the impact of the training experiences, no quantitative evaluation of program outcomes had previously occurred. The objective of this report was to evaluate TMTP outcomes to guide program improvement. METHODS: We developed an anonymous, web-based survey to assess program outcomes as part of routine program evaluation. The survey addressed four main areas of potential TMTP impact: (1) career engagement, (2) military service contributions, (3) scholarly activity, and (4) acquisition of knowledge and skills. In February 2016, we sent the survey electronically to 222 program participants between Fiscal Years 2006 and 2015 who had e-mails available in DoD administrative systems. FINDINGS: Ninety-eight (44%) of these responded to the survey. TMTP demonstrated impact in several areas. Increased knowledge and skills were reported by 81% of trainees, and 70% reported increased interest in serving at military overseas medical research laboratories. Subsequent career engagement by trainees included seven assignments to overseas research laboratories, 71 military deployments, and 193 short-term military missions. The ability to achieve many of the desired outcomes was associated with time elapsed since completion of formal medical education, including 24% who were still enrolled in graduate medical education. DISCUSSION/IMPACT/RECOMMENDATIONS: The TMTP has improved the U.S. military's ability to perform surveillance for emerging tropical and infectious diseases and has contributed to force health protection and readiness. Although many of the outcomes, such as service in the overseas research laboratories and military deployments, are dependent on military service requirements, these results remain perhaps the most relevant ways that the TMTP meets global health requirements of the US military and the nation. Additional outcomes from this training are expected to accrue as these participants complete their medical postgraduate training programs.

DoD-Supported Overseas Training Rotations in Tropical Medicine and Global Health, 2000-2015.

In 1999, the Department of Defense developed a tropical medicine training program (TMTP) to train military physicians, medical students, and scientists in performing surveillance activities in an overseas environment. This review describes the competencies, educational approach, program participants, institutional collaborations, and process outcomes of the TMTP from 2000 to 2015. TMTP-sponsored rotations addressed a wide variety of interdisciplinary competencies, many of which have military-unique applications. Rotations consisted of both didactic and experiential (overseas) components. The program provided 282 rotations for 260 trainees between 2006 and 2015, the years for which data were available. The Department of Defense accrues benefits from this training program in three main ways: (1) building a cadre of health care professionals who will go on to work at the overseas research laboratories, (2) supporting force health protection and readiness through experiential tropical medicine training, and (3) engaging in global health collaborations and partnerships. The primary challenges include funding, health and security, trainee and site heterogeneity, supervision, trainee engagement, and burden on the host institution. The program will continue to focus on improvement in these areas, with special attention to trainee preparation, communication with both trainees and host sites, and increasing reciprocity with host sites and their faculty.

Detection of dengue virus serotypes 1, 2 and 3 in selected regions of Kenya: 2011-2014.

BACKGROUND: Dengue fever, a mosquito-borne disease, is associated with illness of varying severity in countries in the tropics and sub tropics. Dengue cases continue to be detected more frequently and its geographic range continues to expand. We report the largest documented laboratory confirmed circulation of dengue virus in parts of Kenya since 1982. METHODS: From September 2011 to December 2014, 868 samples from febrile patients were received from hospitals in Nairobi, northern and coastal Kenya. The immunoglobulin M enzyme linked immunosorbent assay (IgM ELISA) was used to test for the presence of IgM antibodies against dengue, yellow fever, West Nile and Zika. Reverse transcription polymerase chain reaction (RT-PCR) utilizing flavivirus family, yellow fever, West Nile, consensus and sero type dengue primers were used to detect acute arbovirus infections and determine the infecting serotypes. Representative samples of PCR positive samples for each of the three dengue serotypes detected were sequenced to confirm circulation of the various dengue serotypes. RESULTS: Forty percent (345/868) of the samples tested positive for dengue by either IgM ELISA (14.6 %) or by RT-PCR (25.1 %). Three dengue serotypes 1-3 (DENV1-3) were detected by serotype specific RT-PCR and sequencing with their numbers varying from year to year and by region. The overall predominant serotype detected from 2011-2014 was DENV1 accounting for 44 % (96/218) of all the serotypes detected, followed by DENV2 accounting for 38.5 % (84/218) and then DENV3 which accounted for 17.4 % (38/218). Yellow fever, West Nile and Zika was not detected in any of the samples tested. CONCLUSION: From 2011-2014 serotypes 1, 2 and 3 were detected in the Northern and Coastal parts of Kenya. This confirmed the occurrence of cases and active circulation of dengue in parts of Kenya. These results have documented three circulating serotypes and highlight the need for the establishment of active dengue surveillance to continuously detect cases, circulating serotypes, and determine dengue fever disease burden in the country and region.

Dengue Outbreak in Mombasa City, Kenya, 2013-2014: Entomologic Investigations.

Dengue outbreaks were first reported in East Africa in the late 1970s to early 1980s including the 1982 outbreak on the Kenyan coast. In 2011, dengue outbreaks occurred in Mandera in northern Kenya and subsequently in Mombasa city along the Kenyan coast in 2013-2014. Following laboratory confirmation of dengue fever cases, an entomologic investigation was conducted to establish the mosquito species, and densities, causing the outbreak. Affected parts of the city were identified with the help of public health officials. Adult Ae. aegypti mosquitoes were collected using various tools, processed and screened for dengue virus (DENV) by cell culture and RT-PCR. All containers in every accessible house and compound within affected suburbs were inspected for immatures. A total of 2,065 Ae. aegypti adults were collected and 192 houses and 1,676 containers inspected. An overall house index of 22%, container index, 31.0% (indoor = 19; outdoor = 43) and Breteau index, 270.1, were observed, suggesting that the risk of dengue transmission was high. Overall, jerry cans were the most productive containers (18%), followed by drums (17%), buckets (16%), tires (14%) and tanks (10%). However, each site had specific most-productive container-types such as tanks (17%) in Kizingo; Drums in Nyali (30%) and Changamwe (33%), plastic basins (35%) in Nyali-B and plastic buckets (81%) in Ganjoni. We recommend that for effective control of the dengue vector in Mombasa city, all container types would be targeted. Measures would include proper covering of water storage containers and eliminating discarded containers outdoors through a public participatory environmental clean-up exercise. Providing reliable piped water to all households would minimize the need for water storage and reduce aquatic habitats. Isolation of DENV from male Ae. aegypti mosquitoes is a first observation in Kenya and provides further evidence that transovarial transmission may have a role in DENV circulation and/or maintenance in the environment.

Epidemiology and Surveillance of Influenza Viruses in Uganda between 2008 and 2014.

INTRODUCTION: Influenza surveillance was conducted in Uganda from October 2008 to December 2014 to identify and understand the epidemiology of circulating influenza strains in out-patient clinic attendees with influenza-like illness and inform control strategies. METHODOLOGY: Surveillance was conducted at five hospital-based sentinel sites. Nasopharyngeal and/or oropharyngeal samples, epidemiological and clinical data were collected from enrolled patients. Real-time reverse transcription polymerase chain reaction (RT-PCR) was performed to identify and subtype influenza strains. Data were double-entered into an Epi Info 3.5.3 database and exported to STATA 13.0 software for analysis. RESULTS: Of the 6,628 patient samples tested, influenza virus infection was detected in 10.4% (n = 687/6,628) of the specimens. Several trends were observed: influenza circulates throughout the year with two peaks; the major one from September to November and a minor one from March to June. The predominant strains of influenza varied over the years: Seasonal Influenza A(H3) virus was predominant from 2008 to 2009 and from 2012 to 2014; Influenza A(H1N1)pdm01 was dominant in 2010; and Influenza B virus was dominant in 2011. The peaks generally coincided with times of higher humidity, lower temperature, and higher rainfall. CONCLUSION: Influenza circulated throughout the year in Uganda with two major peaks of outbreaks with similar strains circulating elsewhere in the region. Data on the circulating strains of influenza and its patterns of occurrence provided critical insights to informing the design and timing of influenza vaccines for influenza prevention in tropical regions of sub-Saharan Africa.

Whole-genome analysis of influenza A(H1N1)pdm09 viruses isolated in Uganda from 2009 to 2011.

We report a whole-genome analysis of 19 influenza A(H1N1)pdm09 isolates from four Ugandan hospitals between 2009 and 2011. The isolates differed from the vaccine strain A/California/07/2009 by three amino acid substitutions P100S, S220T, and I338V in the hemagglutinin and by two amino acid substitutions V106I and N248D in the neuraminidase proteins with consistent mutations in all gene segments distinguishing isolates from the 2009/2010 to 2010/2011 seasons. Phylogenetic analysis showed low genetic evolution, with genetic distances of 0%-1.3% and 0.1%-1.6% for HA and NA genes, respectively. The amino acid substitutions did not lead to antigenic differences from the reference strains.

Genotyping of enteroviruses isolated in Kenya from pediatric patients using partial VP1 region.

Enteroviruses (EV) are responsible for a wide range of clinical diseases in humans. Though studied broadly in several regions of the world, the genetic diversity of human enteroviruses (HEV) circulating in the sub-Saharan Africa remains under-documented. In the current study, we molecularly typed 61 HEV strains isolated in Kenya between 2008 and 2011 targeting the 3'-end of the VP1 gene. Viral RNA was extracted from the archived isolates and part of the VP1 gene amplified by RT-PCR, followed by sequence analysis. Twenty-two different EV types were detected. Majority (72.0 %) of these belonged to Enterovirus B species followed by Enterovirus D (21.3 %) and Enterovirus A (6.5 %). The most frequently detected types were Enterovirus-D68 (EV-D68), followed by Coxsackievirus B2 (CV-B2), CV-B1, CV-B4 and CV-B3. Phylogenetic analyses of these viruses revealed that Kenyan CV-B1 isolates were segregated among sequences of global CV-B1 strains. Conversely, the Kenyan CV-B2, CV-B3, CV-B4 and EV-D68 strains generally grouped together with those detected from other countries. Notably, the Kenyan EV-D68 strains largely clustered with sequences of global strains obtained between 2008 and 2010 than those circulating in recent years. Overall, our results indicate that HEV strains belonging to Enterovirus D and Enterovirus B species pre-dominantly circulated and played a significant role in pediatric respiratory infection in Kenya, during the study period. The Kenyan CV-B1 strains were genetically divergent from those circulating in other countries. Phylogenetic clustering of Kenyan EV-D68 strains with sequences of global strains circulating between 2008 and 2010 than those obtained in recent years suggests a high genomic variability associated with the surface protein encoding VP1 gene in these enteroviruses.

Molecular characterization of human coronaviruses and their circulation dynamics in Kenya, 2009-2012.

BACKGROUND: Human Coronaviruses (HCoV) are a common cause of respiratory illnesses and are responsible for considerable morbidity and hospitalization across all age groups especially in individuals with compromised immunity. There are six known species of HCoV: HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, MERS-CoV and SARS-HCoV. Although studies have shown evidence of global distribution of HCoVs, there is limited information on their presence and distribution in Kenya. METHODS: HCoV strains that circulated in Kenya were retrospectively diagnosed and molecularly characterized. A total of 417 nasopharyngeal specimens obtained between January 2009 and December 2012 from around Kenya were analyzed by a real time RT-PCR using HCoV-specific primers. HCoV-positive specimens were subsequently inoculated onto monolayers of LL-CMK2 cells. The isolated viruses were characterized by RT-PCR amplification and sequencing of the partial polymerase (pol) gene. RESULTS: The prevalence of HCoV infection was as follows: out of the 417 specimens, 35 (8.4 %) were positive for HCoV, comprising 10 (2.4 %) HCoV-NL63, 12 (2.9 %) HCoV-OC43, 9 (2.1 %) HCoV-HKU1, and 4 (1 %) HCoV-229E. The Kenyan HCoV strains displayed high sequence homology to the prototypes and contemporaneous strains. Evolution analysis showed that the Kenyan HCoV-OC43 and HCoV-NL63 isolates were under purifying selection. Phylogenetic evolutionary analyses confirmed the identities of three HCoV-HKU1, five HCoV-NL63, eight HCoV-OC43 and three HCoV-229E. CONCLUSIONS: There were yearly variations in the prevalence and circulation patterns of individual HCoVs in Kenya. This paper reports on the first molecular characterization of human Coronaviruses in Kenya, which play an important role in causing acute respiratory infections among children.

Serotype and genetic diversity of human rhinovirus strains that circulated in Kenya in 2008.

BACKGROUND: Human rhinoviruses (HRVs) are a well-established cause of the common cold and recent studies indicated that they may be associated with severe acute respiratory illnesses (SARIs) like pneumonia, asthma, and bronchiolitis. Despite global studies on the genetic diversity of the virus, the serotype diversity of these viruses across diverse geographic regions in Kenya has not been characterized. OBJECTIVES: This study sought to characterize the serotype diversity of HRV strains that circulated in Kenya in 2008. METHODS: A total of 517 archived nasopharyngeal samples collected in a previous respiratory virus surveillance program across Kenya in 2008 were selected. Participants enrolled were outpatients who presented with influenza-like (ILI) symptoms. Real-time RT-PCR was employed for preliminary HRV detection. HRV-positive samples were amplified using RT-PCR and thereafter the nucleotide sequences of the amplicons were determined followed by phylogenetic analysis. RESULTS: Twenty-five percent of the samples tested positive for HRV. Phylogenetic analysis revealed that the Kenyan HRVs clustered into three main species comprising HRV-A (54%), HRV-B (12%), and HRV-C (35%). Overall, 20 different serotypes were identified. Intrastrain sequence homology among the Kenyan strains ranged from 58% to 100% at the nucleotide level and 55% to 100% at the amino acid level. CONCLUSION: These results show that a wide range of HRV serotypes with different levels of nucleotide variation were present in Kenya. Furthermore, our data show that HRVs contributed substantially to influenza-like illness in Kenya in 2008.

No Significant Acute and Subacute Differences between Blast and Blunt Concussions across Multiple Neurocognitive Measures and Symptoms in Deployed Soldiers.

Seventy-one deployed U.S. Army soldiers who presented for concussion care due to either blast or blunt mechanisms within 72 h of injury were assessed using the Military Acute Concussion Evaluation, the Automated Neuropsychological Assessment Metrics (ANAM), traditional neuropsychological tests, and health status questionnaires. Follow-up ANAM testing was performed 10 d after initial testing (±5 d). Twenty-one soldiers were excluded: two for poor effort and 19 who had combined blast/blunt injuries. Of the remaining 50 male participants, 34 had blast injuries and 16 had blunt injuries. There were no statistically significant differences between blast injury and blunt injury participants in demographic, physical, or psychological health factors, concussive symptoms, or automated and traditional neurocognitive testing scores within 72 h post-injury. In addition, follow-up ANAM scores up to 15 d post-injury were not significantly different (available on 21 blast-injured and 13 blunt-injured subjects). Pre-injury baseline ANAM scores were compared where available, and revealed no statistically significant differences between 22 blast injury and eight blunt injury participants. These findings suggest there are no significant differences between mechanisms of injury during both the acute and subacute periods in neurobehavioral concussion sequelae while deployed in a combat environment. The current study supports the use of sports/mechanical concussion models for early concussion management in the deployed setting and exploration of variability in potential long-term outcomes.

Eight-Day Temporal Stability of the Automated Neuropsychological Assessment Metric (ANAM) in a Deployment Environment.

Automated neurocognitive tests are commonly used by military providers for making clinical decisions about the recovery of postconcussive cognitive sequelae. This practice often utilizes baseline assessments that precede the concussive injury. As such, investigating and establishing the psychometrics of an instrument is necessary to minimize confounds for interpreting assessment scores. Test-retest reliability (TRR) values for an 8.3 ± 2-day retest window for the Automated Neuropsychological Assessment Metrics-Version 4 (ANAM) were calculated in 86 healthy U.S. Army soldiers deployed to Iraq. After removal of outliers, all but 1 subtest, Simple Reaction Time, had adequate or greater TRR values (intraclass correlation coefficient = 0.72-0.86). The findings suggest that overall, the ANAM has good temporal stability when the retesting intertrial interval is less than 11 days while in a deployed environment.

Genetic diversity of human enterovirus 68 strains isolated in Kenya using the hypervariable 3'-end of VP1 gene.

Reports of increasing worldwide circulation of human enterovirus-68 (EV68) are well documented. Despite health concerns posed by resurgence of these viruses, little is known about EV68 strains circulating in Kenya. In this study, we characterized 13 EV68 strains isolated in Kenya between 2008 and 2011 based on the Hypervariable 3'-end of the VP1 gene. Viral RNA was extracted from the isolates and partial VP1 gene amplified by RT-PCR, followed by nucleotide sequencing. Alignment of deduced amino acid sequences revealed substitutions in Kenyan EV68 isolates absent in the prototype reference strain (Fermon). The majority of these changes were present in the BC and DE-loop regions, which are associated with viral antigenicity and virulence. The Kenyan strains exhibited high sequence homology with respect to those from other countries. Natural selection analysis based on the VP1 region showed that the Kenyan EV68 isolates were under purifying selection. Phylogenetic analysis revealed that majority (84.6%) of the Kenyan strains belonged to clade A, while a minority belonged to clades B and C. Overall, our results illustrate that although EV68 strains isolated in Kenya were genetically and antigenically divergent from the prototype strain (Fermon), they were closely related to those circulating in other countries, suggesting worldwide transmissibility. Further, the presence of shared mutations by Kenyan EV68 strains and those isolated in other countries, indicates evolution in the VP1 region may be contributing to increased worldwide detection of the viruses. This is the first study to document circulation of EV68 in Kenya.

No Effect of Deployment Environment in Establishing Baseline Neurocognitive Scores in U.S. Army Soldiers.

With heavy reliance on neurocognitive testing for concussion status assessments in the U.S. warfighter, there is a need to investigate the impact of testing environment on neurocognitive functioning. The current study compared scores on computerized neurocognitive tests of 166 soldiers who were deployed to Iraq. Predeployment baseline scores (n = 53) were compared to baseline scores collected while deployed (n = 113) on the battery of tests. There was no significant difference between baseline scores acquired from the predeployment group versus the deployed group. Furthermore, only one subtest revealed a significant difference in change scores from the follow-up test session when comparing the location of initial baseline testing. The results suggest that testing environment does not significantly influence baseline neurocognitive testing. The findings also provide support for the use of neurocognitive testing in a deployment environment.

No effect of mild nonconcussive injury on neurocognitive functioning in U.S. Army soldiers deployed to Iraq.

UNLABELLED: With neurocognitive testing being heavily relied on for concussion assessments in the U.S. Warfighter, there is a need to investigate the impact of nonconcussive injury on neurocognitive functioning. OBJECTIVES: To determine if a nonconcussive injury may have a negative effect on neurocognitive functioning in a deployment setting. METHODS: The current study compared scores on computerized and traditional neurocognitive tests of 166 Soldiers deployed to Iraq. Performance on a battery of tests was compared between a group of healthy deployed Soldiers (n = 102) versus a group of deployed Soldiers seeking outpatient care for mild injuries not involving the head or blast exposure (n = 62). RESULTS: The injured group's performance was not significantly lower on any of the measures administered compared to healthy Soldiers. CONCLUSIONS: The results suggest that there was no significant effect of nonconcussive injury on neurocognitive functioning. Findings lend support to feasibility of using neurocognitive tests to evaluate the effects of concussion in theater.

Assessment of acute concussion in the combat environment.

Despite the prevalence of concussion in soldiers deployed to Iraq and Afghanistan, neuropsychological tests used to assist in concussion management have not been validated on the battlefield. This study evaluated the validity of the Automated Neuropsychological Assessment Metrics (ANAM) in the combat environment. Cases meeting criteria for concussion, healthy controls, and injured controls were assessed. Soldiers were administered the ANAM, traditional neuropsychological tests, and a background questionnaire. Cases were enrolled within 72 h of concussion. Cases exhibited poorer performance than controls on all ANAM subtests, with significant differences on simple reaction time (SRT), procedural reaction time (PRT), code substitution, and matching to sample (p<.001). Discriminant ability of scores on SRT and PRT subtests was 71%, which improved to 76% when pre-deployment baseline scores were available. An exploratory clinical decision tool incorporating ANAM scores and symptoms improved discriminant ability to 81%. Results provide initial validation of the ANAM for detecting acute effects of battlefield concussion.

Antibiotics for leptospirosis.

BACKGROUND: Leptospirosis has a wide-ranging clinical and public health impact. Leptospira are globally distributed. Case attack rates are as high as 1:4 to 2:5 persons in exposed populations. In some settings mortality has exceeded 10% of infected people. The benefit of antibiotic therapy in the disease has been unclear. OBJECTIVES: We sought to characterise the risks and benefits associated with use of antibiotic therapy in the management of leptospirosis. SEARCH METHODS: We searched the The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded regardless of study language. This was augmented by a manual search. The last date of search was November, 2011. SELECTION CRITERIA: To be included in assessment of benefits, trials had to specifically assess the use of antibiotics in a randomised clinical trial. A broad range of study types were incorporated to seek potential harms. DATA COLLECTION AND ANALYSIS: Included trials were systematically abstracted, as were excluded studies for the purposes of assessing harms. Analyses were conducted in accordance with The Cochrane Handbook and practices of The Cochrane Hepato-Biliary Group. MAIN RESULTS: Seven randomised trials were included.  Four trials with 403 patients compared an antibiotic with placebo or no intervention. Three trials compared at least one antibiotic regimen with another antibiotic regimen. The trials all had high risk of bias. The trials varied in the severity of leptospirosis among trial patients. The ability to group data for meta-analysis was limited. While all four trials that compared antibiotics with placebo reported mortality and used parenteral penicillin, there were no deaths in two of them. Since odds ratio calculations cannot employ zero-event trials, only two trials contributed to this estimate. The number of deaths were 16/200 (8.0%) in the antibiotic arm versus 11/203 (5.4%) in the placebo arm giving a fixed-effect OR 1.56 (95% CI 0.70 to 3.46). The random-effects OR is 1.16 (95% CI 0.23 to 5.95). The heterogeneity among these four trials for the mortality outcome was moderate (I(2)= 50%). Only one trial (253 patients) reported days of hospitalisation. It compared parenteral penicillin to placebo without significant effect of therapy (8.9 versus 8.8 days; mean difference (MD) 0.10 days, 95% CI -0.83 to 1.03). The difference in days of clinical illness was reported in two of these trials (71 patients). While parenteral penicillin therapy conferred 4.7 to 5.6 days of clinical illness in contrast to 7.7 to 11.6 days in the placebo arm, the size of the estimate of effect increased but statistical significance was lost under the random-effect model (fixed-effect: MD -2.13 days, 95% CI -2.46 to -1.80; random-effects: MD -4.04, 95% CI -8.66 to 0.58). I(2) for this outcome was high (81%). When duration of fever alone was assessed between antibiotics and placebo in a single trial (79 patients), no significant difference existed (6.9 versus 6.6 days; MD 0.30, 95% CI -1.26 to 1.86). Two trials with 332 patients in relatively severe and possibly late leptospirosis, resulted in trends towards increased dialysis when penicillin was used rather than placebo, but the estimate of effect was small and did not reach statistical significance (42/163 (25.8%) versus 31/169 (18.4%); OR 1.54, 95% CI 0.91 to 2.60). When one antibiotic was assessed against another antibiotic, there were no statistically significant results. For mortality in particular, these comparisons included cephalosporin versus penicillin (2 trials, 6/176 (3.4%) versus 9/175 (5.2%); fixed-effect: OR 0.65, 95% CI 0.23 to 1.87, I(2)= 16%), doxycycline versus penicillin (1 trial, 2/81 (2.5%) versus 4/89 (4.5); OR 0.54, 95% CI 0.10 to 3.02), cephalosporin versus doxycycline (1 trial, 1/88 (1.1%) versus 2/81 (2.5%); OR 0.45, 95% CI 0.04 to 5.10). There were no adverse events of therapy which reached statistical significance. AUTHORS' CONCLUSIONS: Insufficient evidence is available to advocate for or against the use of antibiotics in the therapy for leptospirosis. Among survivors who were hospitalised for leptospirosis, use of antibiotics for leptospirosis may have decreased the duration of clinical illness by two to four days, though this result was not statistically significant. When electing to treat with an antibiotic, selection of penicillin, doxycycline, or cephalosporin does not seem to impact mortality nor duration of fever. The benefit of antibiotic therapy in the treatment of leptospirosis remains unclear, particularly for severe disease. Further clinical research is needed to include broader panels of therapy tested against placebo.