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• • Genetic Differentiation of Glossina pallidipes Tsetse Flies in Southern Kenya

    Authors: Winnie A. Okeyo, Norah P. Saarman, Rosemary Bateta, Kirstin Dion, Michael Mengual, Paul O. Mireji, Collins Ouma, Sylvance Okoth, Grace Murilla, Serap Aksoy and Adalgisa Caccone

    Available online: 13 August 2018

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    The tsetse fly Glossina pallidipes, the major vector of the parasite that causes animal African trypanosomiasis in Kenya, has been subject to intense control measures with only limited success. The G. pallidipes population dynamics and dispersal patterns that underlie limited success in vector control campaigns remain unresolved, and knowledge on genetic connectivity can provide insights, and thereby improve control and monitoring efforts. We therefore investigated the population structure and estimated migration and demographic parameters in G. pallidipes using genotypic data from 11 microsatellite loci scored in 250 tsetse flies collected from eight localities in Kenya. Clustering analysis identified two genetically distinct eastern and western clusters (mean between-cluster F ST = 0.202) separated by the Great Rift Valley. We also found evidence of admixture and migration between the eastern and western clusters, isolation by distance, and a widespread signal of inbreeding. We detected differences in population dynamics and dispersal patterns between the western and eastern clusters. These included lower genetic diversity (allelic richness; 7.48 versus 10.99), higher relatedness (percent related individuals; 21.4% versus 9.1%), and greater genetic differentiation (mean within-cluster F ST; 0.183 versus 0.018) in the western than the eastern cluster. Findings are consistent with the presence of smaller, less well-connected populations in Western relative to eastern Kenya. These data suggest that recent anthropogenic influences such as land use changes and vector control programs have influenced population dynamics in G. pallidipes in Kenya, and that vector control efforts should include some region-specific strategies to effectively control this disease vector.

• • Effect of a School-Based Hygiene Behavior Change Campaign on Handwashing with Soap in Bihar, India: Cluster-Randomized Trial

    Authors: Henrietta E. Lewis, Katie Greenland, Val Curtis and Wolf-Peter Schmidt

    Available online: 13 August 2018

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    Changing hand hygiene behavior at scale in the community remains a challenge. The objective of this study was to estimate the effect of Unilever’s school-based “School of 5” handwashing campaign on handwashing with soap (HWWS) in schoolchildren and their mothers in the Indian state of Bihar. We conducted a cluster-randomized trial in two districts. We randomized a total of 32 villages with at least one eligible school to intervention and control groups (1:1) and recruited 338 households in each group for outcome measurement. We used structured observation in households to measure HWWS at target occasions (after defecation, soap use during bathing, and before each main meal) in schoolchildren and their mothers. Observers were blinded to intervention status. We observed 636 target occasions (297 in the intervention arm and 339 in the control arm) in mothers and school-going children. After the intervention, HWWS prevalence at target occasions was 22.4% in the control arm and 26.6% in the intervention arm (prevalence difference +4.4%, 95% confidence interval: −4.0, 12.8). The difference was similar in children and mothers. Observers appeared to be adequately blinded to intervention status, whereas observed households were successfully kept unaware of the purpose of observations. To conclude, we found no evidence for a health-relevant effect of the School of 5 intervention on HWWS in schoolchildren and their mothers. Qualitative research suggested that reasons for the low impact of the intervention included low campaign intensity, ineffective delivery, and a model possibly not well tailored to these challenging physical and social environments.

• • Recurrent Anthrax Outbreaks in Humans, Livestock, and Wildlife in the Same Locality, Kenya, 2014–2017

    Authors: Mathew Muturi, John Gachohi, Athman Mwatondo, Isaac Lekolool, Francis Gakuya, Alice Bett, Eric Osoro, Austine Bitek, S. Mwangi Thumbi, Peninah Munyua, Harry Oyas, Obadiah N. Njagi, Bernard Bett and M. Kariuki Njenga

    Available online: 13 August 2018

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    Epidemiologic data indicate a global distribution of anthrax outbreaks associated with certain ecosystems that promote survival and viability of Bacillus anthracis spores. Here, we characterized three anthrax outbreaks involving humans, livestock, and wildlife that occurred in the same locality in Kenya between 2014 and 2017. Clinical and epidemiologic data on the outbreaks were collected using active case finding and review of human, livestock, and wildlife health records. Information on temporal and spatial distribution of prior outbreaks in the area was collected using participatory epidemiology. The 2014–2017 outbreaks in Nakuru West subcounty affected 15 of 71 people who had contact with infected cattle (attack rate = 21.1%), including seven with gastrointestinal, six with cutaneous, and two with oropharyngeal forms of the disease. Two (13.3%) gastrointestinal human anthrax cases died. No human cases were associated with infected wildlife. Of the 54 cattle owned in 11 households affected, 20 died (attack rate = 37%). The 2015 outbreak resulted in death of 10.5% of the affected herbivorous wildlife at Lake Nakuru National Park, including 745 of 4,500 African buffaloes (species-specific mortality rate = 17%) and three of 18 endangered white rhinos (species-specific mortality rate = 16%). The species mortality rate ranged from 1% to 5% for the other affected wildlife species. Participatory epidemiology identified prior outbreaks between 1973 and 2011 in the same area. The frequency and severity of outbreaks in this area suggests that it is an anthrax hotspot ideal for investigating risk factors associated with long-term survival of anthrax spores and outbreak occurrence.

• • Molecular Detection of Residual Parasitemia after Pyronaridine–Artesunate or Artemether–Lumefantrine Treatment of Uncomplicated Plasmodium falciparum Malaria in Kenyan Children

    Authors: Johanna M. Roth, Patrick Sawa, George Omweri, Nicodemus Makio, Victor Osoti, Menno D. de Jong, Henk D. F. H. Schallig and Pètra F. Mens

    Available online: 13 August 2018

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    Artemisinin resistance is rapidly rising in Southeast Asia and may spread to African countries, where efficacy estimates are currently still excellent. Extensive monitoring of parasite clearance dynamics after treatment is needed to determine whether responsiveness to artemisinin-based combination therapies (ACT) is changing in Africa. In this study, Kenyan children with uncomplicated falciparum malaria were randomly assigned to pyronaridine–artesunate (PA) or artemether–lumefantrine (AL) treatment. Parasite clearance was evaluated over 7 days following the start of treatment by qPCR and direct-on-blood PCR nucleic acid lateral flow immunoassay (db-PCR-NALFIA), a simplified molecular malaria diagnostic. Residual parasitemia at day 7 was detected by qPCR in 37.1% (26/70) of AL-treated children and in 46.1% (35/76) of PA-treated participants (P = 0.275). Direct-on-blood PCR nucleic acid lateral flow immunoassay detected residual parasites at day 7 in 33.3% (23/69) and 30.3% (23/76) of AL and PA-treated participants, respectively (P = 0.692). qPCR-determined parasitemia at day 7 was associated with increased prevalence and density of gametocytes at baseline (P = 0.014 and P = 0.003, for prevalence and density, respectively) and during follow-up (P = 0.007 and P = 0.011, respectively, at day 7). A positive db-PCR-NALFIA outcome at day 7 was associated with treatment failure (odds ratio [OR]: 3.410, 95% confidence interval [CI]: 1.513–7.689, P = 0.003), but this association was not found for qPCR (OR: 0.701, 95% CI: 0.312–1.578, P = 0.391). Both qPCR and db-PCR-NALFIA detected substantial residual submicroscopic parasitemia after microscopically successful PA and AL treatment and can be useful tools to monitor parasite clearance. To predict treatment outcome, db-PCR-NALFIA may be more suitable than qPCR.

• • Chromobacterium violaceum in Northern Australia: A Sheep in Wolf’s Clothing?

    Authors: Alice Young, Simon Smith, Peter Horne, Bronwyn Thomsett and Josh Hanson

    Available online: 13 August 2018

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    In many parts of the world, the case-fatality rate of Chromobacterium violaceum infection approaches 60%. To evaluate the spectrum of disease associated with C. violaceum in Far North Queensland (FNQ), Australia, we reviewed all culture-confirmed isolates from 1997 to 2017. There were 28 isolates, 15 represented infection, 11 were contaminants, and two charts were destroyed preventing detailed evaluation of these cases. The most common sites of infection were the skin and soft tissue and the urinary tract; there were two cases of bacteremia without focus. There were no deaths attributable to C. violaceum during the study period and only two cases required intensive care unit support, although in both patients this was not for the C. violaceum infection, but for the management of other health issues. Globally, C. violaceum has a reputation as a deadly pathogen, but in FNQ, Australia, infections usually follow a relatively benign course.

• • Performance Evaluation of Gravity-Fed Water Treatment Systems in Rural Honduras: Verifying Robust Reduction of Turbidity and Escherichia coli during Wet and Dry Weather

    Authors: Yolanda M. Brooks, Erika A. Tenorio-Moncada, Nisarg Gohil, Yuqi Yu, Mynor R. Estrada-Mendez, Geovany Bardales and Ruth E. Richardson

    Available online: 06 August 2018

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    This is the first study to document the reduction of turbidity and Escherichia coli throughout the processes of full-scale gravity-fed drinking water plants (GFWTPs) and their downstream distribution systems in rural Honduras. The GFWTPs, which in these cases were designed by AguaClara, use standard treatment processes: coagulation, sedimentation, filtration, and chlorination. During the dry season, we measured E. coli, turbidity, and chlorine residual at five GFWTPs with < 1,000 connections and at three alternative piped-water systems in neighboring communities. Samples were evaluated from the raw water, settled water, filtered water, post-chlorination in the distribution tank, and at a distant-piped household connection. During the dry season, the treated water and household connections serviced by the GFWTPs met World Health Organization (WHO) recommendations for E. coli (< 1 most probable number [MPN]/100 mL). Alternative plants with the same water sources had comparable or higher E. coli and turbidity measurements posttreatment. We examined performance robustness of two GFWTPs during the transition into the rainy season. The turbidity of the filtered water met WHO recommendations (< 1 nephelometric turbidity units). Escherichia coli was not detected in treated water, indicating that the two GFWTPs can consistently remove particulates and E. coli from source waters containing varying levels of turbidity. During two sampling events during the rainy season, E. coli was detected at the household connection of a GFWTP system with intermittent service and a substandard chlorine residual (geometric mean = 1.0 MPN/100 mL). Strategies to avoid contamination or inactivate E. coli in the distribution system are needed to ensure safe drinking water at the points of delivery, especially for systems with intermittent service.

• • Bartonella rochalimae Detection by a Sensitive and Specific PCR Platform

    Authors: Dennis Chan, Joseph Andrew Geiger, Elton José Rosas Vasconcelos, Brian Oakley and Pedro Paulo Vissotto de Paiva Diniz

    Available online: 06 August 2018

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    Bartonella rochalimae is an emerging zoonotic pathogen present in the United States, South America, and Europe. The molecular detection of B. rochalimae frequently relies on PCR assays that target the genus Bartonella coupled with DNA sequencing for species determination. However, the presence of other Bartonella spp. in the sample being tested may result in false-negative results for B. rochalimae, especially when Sanger sequencing is used. We developed a sensitive and specific quantitative PCR platform for B. rochalimae by targeting the intergenic transcribed spacer, gltA, and rpoB genes, which are recommended for subtyping characterization. This PCR platform achieved the limit of detection between five and 10 genomic equivalents per reaction and did not amplify DNA from other Bartonella species or selected hosts. This PCR platform is a fast and cost-effective option to be used in epidemiological evaluations of reservoirs and vectors and in detecting and quantifying B. rochalimae infection in humans.

• • Water, Sanitation, and Hygiene Characteristics among HIV-Positive Households Participating in the Global Enterics Multicenter Study in Rural Western Kenya, 2008–2012

    Authors: K. A. Schilling, A. O. Awuor, A. Rajasingham, F. Moke, R. Omore, M. Amollo, T. H. Farag, D. Nasrin, J. P. Nataro, K. L. Kotloff, M. M. Levine, T. Ayers, K. Laserson, A. Blackstock, R. Rothenberg, C. E. Stauber, E. Mintz, R. F. Breiman and C. E. O’Reilly

    Available online: 06 August 2018

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    Diarrheal illness, a common occurrence among people living with HIV (PLHIV), is largely preventable through access to safe drinking water, sanitation, and hygiene (WASH) facilities. We examined WASH characteristics among households with and without HIV-positive residents enrolled in the Global Enteric Multicenter Study (GEMS) in rural Western Kenya. Using univariable logistic regression, we examined differences between HIV-positive and HIV-negative households in regard to WASH practices. Among HIV-positive households, we explored the relationship between the length of time knowing their HIV status and GEMS enrollment. No statistically significant differences were apparent in the WASH characteristics among HIV-positive and HIV-negative households. However, we found differences in the WASH characteristics among HIV-positive households who were aware of their HIV status ≥ 30 days before enrollment compared with HIV-positive households who found out their status < 30 days before enrollment or thereafter. Significantly more households aware of their HIV-positive status before enrollment reported treating their drinking water (odds ratio [OR] confidence interval [CI]: 2.34 [1.12, 4.86]) and using effective water treatment methods (OR [CI]: 9.6 [3.09, 29.86]), and had better drinking water storage practices. This suggests that within this region of Kenya, HIV programs are effective in promoting the importance of practicing positive WASH-related behaviors among PLHIV.

• • Antigen Detection in Urine for Noninvasive Diagnosis and Treatment Monitoring of Visceral Leishmaniasis in Human Immunodeficiency Virus Coinfected Patients: An Exploratory Analysis from Ethiopia

    Authors: Florian Vogt, Bewketu Mengesha, Helen Asmamaw, Tigist Mekonnen, Helina Fikre, Yegnasew Takele, Emebet Adem, Rezika Mohammed, Koert Ritmeijer, Wim Adriaensen, Yayehirad Melsew, Johan van Griensven and Ermias Diro

    Available online: 06 August 2018

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    Diagnosis of visceral leishmaniasis (VL) and assessment of treatment response in human immunodeficiency virus (HIV)–coinfected patients still relies on invasive tissue aspiration. This hampers scale-up and decentralization of care in resource-limited settings. Noninvasive diagnostics are urgently needed. KATEX is a frequently used latex agglutination test for Leishmania antigen in urine that has never been evaluated in HIV-coinfected individuals from Leishmania donovani–endemic areas. This was an exploratory sub-study embedded within the screening phase of a trial in highly endemic northwestern Ethiopia. All patients were HIV-positive and aspirate-confirmed VL cases. Accuracy of KATEX for VL diagnosis and as test of cure at treatment end was assessed against tissue aspirate parasite load (reference methods), and the evolution of weekly antigen levels during treatment was described. Most of the 87 included patients were male (84, 97%), young (median age 31 years), and had poor immune status (median cluster of differentiation type 4 count 56 cells/μL). KATEX had moderate sensitivity (84%) for VL diagnosis. KATEX had moderate sensitivity (82%) and a moderate negative predictive value (87%) but only low specificity (49%) and a low positive predictive value (40%) while assessing the treatment outcomes. Weekly antigen levels showed characteristic patterns during treatment of patients with different initial parasite loads and treatment outcomes. Antigen detection in urine using KATEX can contribute to improved VL diagnosis in HIV-coinfected patients but has limited use for monitoring of treatment response. Better noninvasive diagnostics are needed to reduce reliance on invasive methods and thus to expand and improve clinical care for VL in resource-limited settings.

• • A Serological Survey of Human Onchocerciasis in Yemen

    Authors: Charles D. Mackenzie, Abdul-Samid Al-Kubati, Yasin Al-Qubati, Ashley Behan-Braman, Joseph Kubofcik, Adrian Hopkins and Thomas B. Nutman

    Available online: 06 August 2018

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    Yemen is a country that has been treating severe cases of oncho-dermatitis since 1992 and is now moving to a program aimed at the elimination of the transmission of Onchocerca volvulus. It is important to ensure that the currently acceptable tools used in epidemiological assessment of onchocerciasis in Africa and Latin America also apply to Yemen. Five hundred and ten blood samples from three known O. volvulus–endemic areas, locations that have never been under a mass treatment program, were tested for the presence of antibodies against a panel of O. volvulus–specific antigens using enzyme-linked immunosorbent assay (Ov16) and luciferase immunoprecipitation system (OvFAR-1 and Ov-MSA1) assays. Overall, 31.4% of the samples tested were positive, with positivity increasing with age. Positivity was seen in 76.5% of those presenting with clinical onchocerciasis but importantly also in more than 28.5% of those defined as free of oncho-dermatitis; these latter individuals are likely to be serving as a source for persistent reinfection. This study supports the use of the current O. volvulus–specific serologic methodology in Yemen.

• • Drinking Water Safety: Role of Hand Hygiene, Sanitation Facility, and Water System in Semi-Urban Areas of India

    Authors: Arti Kundu, Woutrina A. Smith, Danielle Harvey and Stefan Wuertz

    Available online: 30 July 2018

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    Poor drinking water quality is one of the main causes of acute diarrheal disease in developing countries. The study investigated the relationship between fecal contamination of hands, stored drinking water, and source waters in India. We further evaluated the environmental and behavioral factors associated with recontamination of water between collection and consumption. The bacterial contamination, that is, Escherichia coli (log10 most probable number per two hands), found on mothers’ hands (mean = 1.11, standard deviation [SD] = 1.2, N = 152) was substantially higher than that on their children younger than 5 years (mean = 0.64, SD = 1.0, and N = 152). We found a low level of E. coli (< 1 per 100 mL) in the source water samples; however, E. coli contamination in stored drinking water was above the recommended guidelines of the World Health Organization. The study also found that E. coli on hands was significantly associated with E. coli in the stored drinking water (P < 0.001). Moreover, E. coli was positively associated with gastrointestinal symptoms (odds ratio 1.42, P < 0.05). In the households with elevated levels (> 100 E. coli/100 mL) of fecal contamination, we found that 43.5% had unimproved sanitation facilities, poor water handling practices, and higher diarrheal incidences. The water quality deterioration from the source to the point of consumption is significant. This necessitates effective interventions in collection, transport, storage, and extraction practices when hand–water contact is likely to occur. These findings support the role of hands in the contamination of stored drinking water and suggest that clean source water does not guarantee safe water at the point of consumption.

• • Case Report: Imported Case of Lassa Fever—New Jersey, May 2015

    Authors: Prathit A. Kulkarni, Debra Chew, Manal Youssef-Bessler, Hanaa A. Hamdi, Lindsay A. Montoya, Kimberly B. Cervantes, Nicole L. Mazur, Diana Lucas, Julia W. Wells, David Cennimo, Anne Sutherland, Linda M. Di Domenico, Lincoln P. Miller, Frantz Pierre-Louis, Gregory Rokosz, Atif Nazir, Marie A. de Perio, Luis Lowe, Craig Manning, Kenneth R. Mead, Bryan E. Christensen, César G. Albariño, Ute Ströher, Maleeka Glover, Edward I. Lifshitz, Christina G. Tan, Pierre E. Rollin and Shereen Semple

    Available online: 30 July 2018

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    We report a fatal case of Lassa fever diagnosed in the United States in a Liberian traveler. We describe infection control protocols and public health response. One contact at high risk became symptomatic, but her samples tested negative for Lassa virus; no secondary cases occurred among health care, family, and community contacts.

• • Case Report: Typhoid Fever and Spotted Fever Group Rickettsiosis Presenting Concomitantly in an Indian Immigrant

    Authors: Regev Cohen, Frida Babushkin, Maurice Shapiro, Martina Uda, Yafit Atiya-Nasagi and Talya Finn

    Available online: 30 July 2018

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    We present a rare case of an Indian immigrant suffering from concomitant infection of Salmonella typhi and spotted fever group Rickettsia. We discuss the scarce reports of dual infections from the developing world and the related diagnostic challenges.

• • Social Influence on Handwashing with Soap: Results from a Cluster Randomized Controlled Trial in Bangladesh

    Authors: Elise Grover, Mohammed Kamal Hossain, Saker Uddin, Mohini Venkatesh, Pavani K. Ram and Robert Dreibelbis

    Available online: 30 July 2018

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    We analyzed data from a cluster-randomized controlled trial conducted among 20 schools in Rajshahi, Bangladesh, to explore the role of social influence on handwashing with soap (HWWS) in a primary school setting. Using data collected through covert video cameras outside of school latrines, we used robust Poisson regression analysis to assess the impact of social influence—defined as the presence of another person near the handwashing location—on HWWS after a toileting event. In adjusted analyses, we found a 30% increase in HWWS when someone was present, as compared with when a child was alone (Prevalence ratio 1.30 CI: 1.14–1.47, P < 0.001). The highest prevalence of HWWS was found when both child(ren) and adult(s) were present or when just children were present (64%). Our study supports the conclusion that the presence of another individual after a toileting event can positively impact HWWS in a primary school setting.

• • Outbreak of Hepatitis E Virus Infection in Displaced Persons Camps in Diffa Region, Niger, 2017

    Authors: Adamou Lagare, Alkasoum Ibrahim, Sani Ousmane, Bassira Issaka, Maman Zaneidou, Goumbi Kadadé and Jean Testa

    Available online: 30 July 2018

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    Hepatitis E virus (HEV) infection in developing countries is associated with poor hygiene, lack of clean drinking water, and inadequate sanitation. In this study, we report the first case investigation and describe the present situation of HEV outbreak within displaced persons camps in the Diffa region, Republic of the Niger. The investigation showed the outbreak to be closely linked to unclean water supply, low hygiene, and sanitation facility standards. Between January and September 2017, a total of 1,917 HEV suspect cases were recorded from which 736 (38.4%) have been confirmed positive for HEV by RT-PCR and ELISA. Overall, 38 (1.9%) deaths were recorded, including 17 (44.7%) pregnant women. The ongoing outbreak highlights poor drinking water quality and sanitation conditions in displaced persons camps in the Diffa region. Disease containment and patient care activities, particularly for pregnant women, may have resulted in decreased transmission of infection and deaths.

• • Impact of Ivermectin Mass Drug Administration for Lymphatic Filariasis on Scabies in Eight Villages in Kongwa District, Tanzania

    Authors: Diana Martin, Ryan Wiegand, Brook Goodhew, Patrick Lammie, Harran Mkocha and Mabula Kasubi

    Available online: 30 July 2018

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    Scabies was recently added to the World Health Organization list of neglected tropical diseases. The ability to treat scabies with oral ivermectin makes a mass drug administration (MDA) campaign a feasible option for scabies control. Ivermectin MDA in communities endemic for lymphatic filariasis (LF) or onchocerciasis may already be having an impact on scabies. We examined the effect of ivermectin MDA for LF on scabies prevalence over 4 years in eight Tanzanian villages. At baseline, 4.4% (95% confidence interval [CI]: 3.7–5.4) of individuals tested positive for scabies, decreasing to 0.84% (95% CI: 0.51–1.4) after one round of ivermectin MDA but increased in Year 3 (2.5% [95% CI: 1.9–3.3]) and Year 4 (2.9% [95% CI: 2.2–3.8]). Most scabies cases were seen in children younger than 15 years. The data suggest that single-dose ivermectin MDA may not be effective in attaining long-term decreases when scabies prevalence is less than 5%.

• • Platelet Transfusion Related Panophthalmitis and Endophthalmitis in Patients with Dengue Hemorrhagic Fever

    Authors: Karthikeya R, Dheepak Sundar M, Sohini Mandal, Raghav Ravani and Vinod Kumar

    Available online: 30 July 2018

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    Dengue is a vector-borne viral illness of major public health importance. It is endemic in many parts of India and also causes frequent epidemics. Platelet transfusions are given in severe cases of dengue fever to treat and prevent hemorrhagic complications. Here, we report three patients in North India with development of panophthalmitis and endophthalmitis shortly after receiving platelet transfusion.

• • Evaluation of an OV-16 IgG4 Enzyme-Linked Immunosorbent Assay in Humans and Its Application to Determine the Dynamics of Antibody Responses in a Non-Human Primate Model of Onchocerca volvulus Infection

    Authors: Vitaliano A. Cama, Circe McDonald, Alice Arcury-Quandt, Mark Eberhard, M. Harley Jenks, Jared Smith, Sindew M. Feleke, Francisca Abanyie, Lakwo Thomson, Ryan E. Wiegand and Paul T. Cantey

    Available online: 30 July 2018

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    Onchocerciasis is a neglected parasitic disease targeted for elimination. Current World Health Organization guidelines for elimination include monitoring antibody responses to the recombinant Onchocerca volvulus antigen OV-16 in children to demonstrate the absence of transmission. We report the performance characteristics of a modified OV-16 enzyme-linked immunosorbent assay (ELISA) and describe anti–OV-16 responses in serum samples from laboratory-inoculated nonhuman primates (NHPs) in relation to microfilariae (mf) in skin snip biopsies. This OV-16 IgG4 ELISA had sensitivity and specificity of 88.2% and 99.7%, respectively, as determined by receiver operator characteristic analysis using a serum panel of 110 positive and 287 negative samples from people infected with other filariae or other parasitic infections. Anti–OV-16 responses in inoculated NHP (N = 9) were evaluated at quarterly intervals for IgM and the four IgG subclasses. Enzyme-linked immunosorbent assay results showed a well-defined IgG4 reactivity pattern and moderate IgG1 antibody responses. Meanwhile, the reactivity by IgG2, IgG3, or IgM did not show a clear pattern. Temporal evolution of IgG4 reactivity was evaluated through monthly testing, showing that NHPs developed anti–OV-16 IgG4 on average at 15 months postinoculation (range: 10–18 months). The average time to detectable mf was also 15 months (range: 11–25). The OV-16 ELISA used in this study was robust and allowed the detection of IgG4 responses, which were observed only among animals with detectable mf (N = 5), four of which showed declines in antibody responses once mf cleared. These findings also confirmed that the most informative antibody subclass responses to OV-16 are IgG4.

• • Eating Centipedes Can Result in Angiostrongylus cantonensis Infection: Two Case Reports and Pathogen Investigation

    Authors: Huijie Wang, Lingli Lu, Dan She, Zhibo Wen, Zexun Mo, Jun Li and Hua Li

    Available online: 30 July 2018

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    Angiostrongyliasis is a food-borne parasitic disease caused by the nematode Angiostrongylus cantonensis that can lead to eosinophilic meningitis (EM) or meningoencephalitis in humans. Angiostrongylus cantonensis is prevalent in the Pacific Islands. In recent years, a large number of outbreaks and severe cases have occurred. Several species of mollusk, such as snails and slugs, act as intermediate and paratenic hosts of A. cantonensis. In this study, two cases of EM were found to have been caused by infection with A. cantonensis due to consumption of raw centipedes. To survey the A. cantonensis infections acquired through centipedes that the patients had bought at a vegetable market, we performed etiological examinations and polymerase chain reaction amplification of A. cantonensis genes. Third-instar larvae of A. cantonensis were detected in the centipedes, and specific genes from A. cantonensis were detected in all the specimens. This indicates that the centipede may act as a competent host for the transmission of A. cantonensis. To our knowledge, this is the first report of A. cantonensis infection through the consumption of centipedes.

• • Imported and Autochthonous Cases of Myiasis Caused by Dermatobia hominis: Taxonomic Identification Using the Internal Transcribed Spacer Region

    Authors: Sonia Toussaint Caire, Alejandro Woroszylski Yoselevitz, Maria Elisa Vega-Memije, Guiehdani Villalobos, Nancy Rivas, Ricardo Alejandre, Mirza Romero-Valdovinos, Pablo Maravilla and Fernando Martínez-Hernández

    Available online: 30 July 2018

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    Dermatobia hominis is a fly endemic to and widely distributed throughout the Americas; it is found from the southern regions of Mexico to Argentina. However, because of widespread travel, myiasis has become common in countries where neither the disease nor the species that cause this infection are endemic. Central Mexico, for instance, is not a region where myiasis is endemic. We, thus, describe three cases of D. hominis myiasis: two autochthonous cases from the southern part of Mexico and one imported from Costa Rica. In addition, morphological and genetic identification was performed on the maggots extracted from the patients.

• • Who Stays and Who Goes: Predictors of Admission among Patients Presenting with Febrile Illness and a Positive Malaria Rapid Diagnostic Test in a Rural Ugandan Health Center

    Authors: Jonathan L. Chang, Raquel Reyes, Michael Matte, Moses Ntaro, Edgar Mulogo, Matthew O. Wiens, Steven R. Meshnick, Mark J. Siedner and Ross Boyce

    Available online: 30 July 2018

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    Not much is known about clinical decision-making in rural, low-resource settings regarding fever, a common reason for presentation to care. In this prospective cohort study of patients presenting with febrile illness to a rural Ugandan health center, we examined demographic and clinical factors predictive of an initial disposition of inpatient admission after clinical evaluation, but before laboratory testing. We then assessed the association of laboratory results and system factors with a change between initial and final disposition plans. Four thousand nine hundred twenty-four patients with suspected febrile illness were included in the primary analysis. The strongest predictors for an initial disposition of admission after clinical examination were impaired consciousness (adjusted risk ratio [aRR], 3.21; 95% confidence interval [CI]: 2.44–4.21) and fever on examination (aRR, 2.27; 95% CI: 1.79–2.87). Providers initially planned to discharge patients with significant vital sign abnormalities, including tachypnea (3.6%) and hypotension (1.3%). Anemia strongly predicted a final disposition of admission after an initial disposition of discharge (aRR, 48.34; 95% CI: 24.22–96.49); other laboratory abnormalities, including hypoglycemia and acidosis, did not change disposition planning. In those with an initial disposition of admission, living farther than the two neighboring villages was associated with a final disposition of discharge (aRR, 2.12; 95% CI: 1.10–4.12). A concerning number of patients with abnormal vital signs and laboratory results were not admitted for inpatient care. Geographic factors may influence a patient’s final disposition contrary to a provider’s initial disposition plan. Future work should assess longer term outcomes after discharge and a broader study population.

• • Quantitative Polymerase Chain Reaction for Diagnosis of Soil-Transmitted Helminth Infections: A Comparison with a Flotation-Based Technique and an Investigation of Variability in DNA Detection

    Authors: Naomi E. Clarke, Stacey Llewellyn, Rebecca J. Traub, James McCarthy, Alice Richardson and Susana V. Nery

    Available online: 30 July 2018

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    Appropriate diagnostic techniques are crucial to global soil-transmitted helminth (STH) control efforts. The recommended Kato–Katz method has low sensitivity in low-transmission settings. Quantitative polymerase chain reaction (qPCR) is a highly sensitive alternative diagnostic option. However, little is known about the variability in qPCR results, and there are few published comparisons between qPCR and other microscopy-based techniques such as sodium nitrate flotation (SNF). Using 865 stool samples collected from 571 individuals, we compared SNF and qPCR in terms of diagnostic sensitivity and infection intensity measurements. In addition, we conducted repeated examinations on a single Necator americanus–positive stool sample over a 6-month period. Results showed good diagnostic agreement between SNF and qPCR for Ascaris spp. (κ = 0.69, P < 0.001), and moderate agreement for hookworm (κ = 0.55, P < 0.001) and Trichuris spp. (κ = 0.50, P < 0.001). Quantitative polymerase chain reaction demonstrated higher sensitivity than SNF for Ascaris spp. (94.1% versus 68.1%) and hookworm (75.7% versus 66.9%) but not for Trichuris spp. (53.1% versus 81.3%), which had very low prevalence. Sodium nitrate flotation and qPCR infection intensity measurements were strongly correlated for Ascaris spp. (ρ = 0.82, P < 0.001) and moderately correlated for hookworm (ρ = 0.58, P < 0.001). Repeated examinations using qPCR showed that N. americanus cycle threshold values decreased significantly at 1 month and remained stable thereafter. Results confirm the high diagnostic sensitivity of qPCR for Ascaris spp. and hookworm, particularly for light-intensity infections, which is ideal for settings approaching transmission elimination. Results support the potential for qPCR to be used as a quantitative assay for STH. Further research is needed in settings where Trichuris trichiura is endemic.

• • Predicting Risk of Imported Disease with Demographics: Geospatial Analysis of Imported Malaria in Minnesota, 2010–2014

    Authors: Elizabeth H. Lee, Robin H. Miller, Penny Masuoka, Elizabeth Schiffman, Danushka Wanduragala, Robert DeFraites, Stephen Dunlop, William Stauffer and Patrick Hickey

    Available online: 30 July 2018

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    Although immigrants who visit friends and relatives (VFRs) account for most of the travel-acquired malaria cases in the United States, there is limited evidence on community-level risk factors and best practices for prevention appropriate for various VFR groups. Using 2010–2014 malaria case reports, sociodemographic census data, and health services data, we explored and mapped community-level characteristics to understand who is at risk and where imported malaria infections occur in Minnesota. We examined associations with malaria incidence using Poisson and negative binomial regression. Overall, mean incidence was 0.4 cases per 1,000 sub-Saharan African (SSA)–born in communities reporting malaria, with cases concentrated in two areas of Minneapolis–St. Paul. We found moderate and positive associations between imported malaria and counts of SSA- and Asian-born populations, respectively. Our findings may inform future studies to understand the knowledge, attitudes, and practices of VFR travelers and facilitate and focus intervention strategies to reduce imported malaria in the United States.

• • Introductory Article on Global Burden and Epidemiology of Typhoid Fever

    Authors: Amruta Radhakrishnan, Daina Als, Eric D. Mintz, John A. Crump, Jefferey Stanaway, Robert F. Breiman and Zulfiqar A. Bhutta

    Available online: 25 July 2018

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    This article is the introduction to a 12-paper supplement on global trends in typhoid fever. The Tackling Typhoid (T2) project was initiated in 2015 to synthesize the existing body of literature on typhoidal salmonellae and study national and regional typhoid fever trends. In addition to a global systematic review, eight case studies were undertaken to examine typhoid and paratyphoid fever trends in endemic countries alongside changes in relevant contextual factors. Incidence variations exist both within and between regions with large subnational differences as well, suggesting that public health changes impacting typhoid and paratyphoid fevers in one setting may not have similar impacts in another. This supplement also brings to light the lack of national typhoid fever surveillance systems, inconsistencies in diagnostics, and the lack of typhoid fever associated morbidity and mortality data in many countries, making it difficult to accurately quantify and track burden of disease. To better understand typhoid fever there is a need for more high-quality data from resource-poor settings. The implementation of typhoid surveillance systems alongside the transition to blood-culture confirmation of cases, where possible, would aid in the improvement of data quality in low-income settings. The following supplement includes the results of our global systematic review, eight-country case study articles, a qualitative article informed by semistructured interviews, and a conclusion article on potential ways forward for typhoid control.

• • Global Trends in Typhoidal Salmonellosis: A Systematic Review

    Authors: Daina Als, Amruta Radhakrishnan, Paul Arora, Michelle F. Gaffey, Susan Campisi, Russanthy Velummailum, Farhana Zareef and Zulfiqar A. Bhutta

    Available online: 25 July 2018

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    Typhoid and paratyphoid fever continue to significantly contribute to global morbidity and mortality. Disease burden is higher in low-and middle-income settings where surveillance programs are rare and little systematic information exists at population level. This review evaluates national, regional, and global trends in the incidence of typhoid fever and of related morbidity and mortality. A literature search in Medline, Embase, and Web of Science was conducted in June 2016, followed by screening and data extraction in duplicate. Studies reporting blood culture estimates of typhoid or paratyphoid morbidity and mortality were included in the analysis. Five thousand five hundred sixty-three unique records were identified, of which 1978 were assessed for relevance with 219 records meeting the eligibility criteria. Salmonella enterica serotype Typhi was the most commonly reported organism (91%), with the occurrence of typhoidal Salmonella (either incidence or prevalence) being the most commonly reported outcome (78%), followed by typhoid fever mortality, ileal perforation morbidity, and perforation mortality, respectively. Fewer than 50% of studies stratified outcomes by age or urban/rural locality. Surveillance data were available from 29 countries and patient-focused studies were available from 32 countries. Our review presents a mixed picture with declines reported in many regions and settings but with large gaps in surveillance and published data. Regional trends show generally high incidence rates in South Asia, sub-Saharan Africa, and East Asia and Pacific where the disease is endemic in many countries. Significant increases have been reported in certain countries but should be explored in the context of long-term trends and underlying at-risk populations.

• • The Control of Typhoid Fever in Vietnam

    Authors: Tran Vu Thieu Nga, Pham Thanh Duy, Nguyen Phu Huong Lan, Nguyen Van Vinh Chau and Stephen Baker

    Available online: 25 July 2018

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    Typhoid fever, caused by Salmonella enterica serovar Typhi (S. Typhi), is a diminishing public health problem in Vietnam, and this process may represent a prototype for typhoid elimination in Asia. Here, we review typhoid epidemiology in Vietnam over 20 years and assess the potential drivers associated with typhoid reduction. In the 1990s, multidrug resistant S. Typhi were highly prevalent in a sentinel hospital in southern Vietnam. A national typhoid incidence rate of 14.7/100,000 population per year was estimated around the new millennium. The Vietnamese government recognized the public health issue of typhoid in the 1990s and initiated vaccine campaigns to protect the most vulnerable members of the population. At their peak, these campaigns immunized approximately 1,200,000 children in 35 provinces. Concurrently, Vietnam experienced unprecedented economic development from 1998 to 2014, with the gross national income per capita increasing from $360 to $1,890 over this period. More recent typhoid incidence data are not available, but surveillance suggests that the current disease burden is negligible. This trajectory can be considered a major public health success. However, a paucity of systematic data makes it difficult to disaggregate the roles of immunization and water, sanitation, and hygiene (WASH) interventions in typhoid reduction in Vietnam. Given the limitations of typhoid vaccines, we surmise the practical elimination of typhoid was largely driven by economic development and improvement in general population living standards. Better designed WASH intervention studies with clinical endpoints and systematic incidence data are essential to glean a greater understanding of contextual factors that impact typhoid incidence reduction.

• • Typhoid Fever: Tracking the Trend in Nigeria

    Authors: Kabiru Olusegun Akinyemi, Akeeb Oriowo Bola Oyefolu, Wasiu Bamidele Mutiu, Bamidele Abiodun Iwalokun, Edward Sunday Ayeni, Samuel Oluwasegun Ajose and Stephen K. Obaro

    Available online: 25 July 2018

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    Typhoid fever continues to pose a serious health challenge in developing countries. A reliable database on blood-positive cultures is essential for prompt interventions. To generate reliable data on Salmonella enterica serovar Typhi (S. Typhi)–positive blood culture trends in typhoidal Salmonella in Nigeria alongside changing contextual factors and antimicrobial resistance patterns, a retrospective cohort study was conducted in two hospitals in Lagos between 1993 and 2015. Medical records of typhoid patients were reviewed for positive culture and antibiogram, using standard procedures and analyzed. Additional data were retrieved from a previous study in seven facilities in Abuja and three hospitals in Kano from 2008 to 2017 and 2013 to 2017, respectively. A declining trend in percent positivity of S. Typhi was observed in Abuja with more erratic trends in Lagos and Kano. In Lagos, more than 80% of the isolates from the entire study period exhibited multiple drug resistance with a generally increasing trend. Of the chosen contextual factors, improvements were recorded in female literacy, access to improved water supply, diarrheal mortality in children younger than 5 years, gross domestic product, and poverty while access to improved sanitation facilities decreased over time nationally. Typhoid fever still poses a serious health challenge in Nigeria and in antibiotic resistance, and is a major health security issue. A combined approach that includes the use of typhoid vaccines, improvements in sanitation, and safe water supply is essential.

• • Typhoidal Salmonella Trends in Thailand

    Authors: Chonnamet Techasaensiri, Amruta Radhakrishnan, Daina Als and Usa Thisyakorn

    Available online: 25 July 2018

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    Typhoid and paratyphoid fever remain endemic diseases in Thailand with wide variation in subnational incidence trends. We examined these trends alongside contextual factors to study potential interactions and guide control strategies for this disease. Culture-confirmed typhoid and paratyphoid fever data from 2003 to 2014 were collected from the Ministry of Public Health website. Contextual factor data were collected from various sources including World Health Organization/United Nations Children’s Fund Joint Monitoring Program, United Education Statistical World Bank database, World Bank, Development Research group, and global child mortality estimates published in the Lancet. Typhoid fever exhibited a declining trend with peak incidence reported in 2003 at 8.6 cases per 100,000 persons per year. Incidence dropped to three cases per 100,000 persons in 2014. The trend in paratyphoid fever remained stable with the peak incidence of 0.77 cases per 100,000 persons observed in 2009. Subnational variations of typhoid were seen throughout the study period with the highest incidence observed in the northwestern region of Thailand. Increases in female literacy, and access to improved water and sanitation were observed with decreases in poverty head count ratio and diarrheal mortality rate per 1,000 live births. Case fatality remained consistently low at 0.4% or less in all years with reported deaths. At the national level, typhoid fever incidence has shown a notable decline; however, incidence appears to have plateaued since 2007 with access to improved water supply and sanitation above 80%. Eliminating this disease will require strong disease prevention measures in conjunction with effective treatment interventions.

• • Enteric Fever and Related Contextual Factors in Bangladesh

    Authors: Shampa Saha, Senjuti Saha, Rajib Chandra Das, A. S. G. Faruque, M. Abdus Salam, Maksuda Islam and Samir K. Saha

    Available online: 25 July 2018

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    Enteric fever remains a major public health problem in the developing world. With the emergence of antimicrobial resistance, disease prevention is becoming essential. There is evidence that improvement of contextual factors, such as socioeconomic development and water supply and sanitation, reduce the burden of this disease. However, such positive results are not universal. This study describes enteric fever trends in Bangladesh along with these factors’ progress between 1990 and 2014. Retrospective enteric fever data were collected from Dhaka Shishu (children) Hospital (DSH), Shishu Shasthya Foundation Hospital (SSFH), International Center for Diarrheal Disease Research, Bangladesh, and Popular Diagnostic Center (PDC). Contextual factors data were gathered from relevant organizations and their websites and plotted against time to see trends. During 2001–2014, data for a total of 131,449 blood cultures were available at DSH, SSFH, and PDC. Of those, 7,100 (isolation rate 5.4%) yielded either Salmonella enterica serovar Typhi or Salmonella enterica serovar Paratyphi growth without visible change in isolation rate trends. Contextual factors data were reported from 1990 to 2014. There were significant developments for sanitation facilities, drinking water supply, female literacy, and reduction in poverty head count ratio. During this time period, population density also increased significantly. Despite improvements in these contextual factors in Bangladesh, the enteric fever trend seems steady, possibly because of high population density and unplanned development of water supply and sewerage system. Although proper development of these two factors is important, immunization with an effective vaccine is instrumental to prevent this disease immediately in endemic countries such as Bangladesh, specifically to overcome the challenge of emerging resistance to available antibiotics.

• • Implementation of Interventions for the Control of Typhoid Fever in Low- and Middle-Income Countries

    Authors: Raluca Barac, Daina Als, Amruta Radhakrishnan, Michelle F. Gaffey, Zulfiqar A. Bhutta and Melanie Barwick

    Available online: 25 July 2018

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    Past research has focused on typhoid fever surveillance with little attention to implementation methods or effectiveness of control interventions. This study purposefully sampled key informants working in public health in Chile, India, Pakistan, Bangladesh, Thailand, Vietnam, South Africa, and Nigeria to 1) scope typhoid-relevant interventions implemented between 1990 and 2015 and 2) explore contextual factors perceived to be associated with their implementation, based on the Consolidated Framework for Implementation Research (CFIR). We used a mixed methods design and collected quantitative data (CFIR questionnaire) and qualitative data (interviews with 34 public health experts). Interview data were analyzed using a deductive qualitative content analysis and summary descriptive statistics are provided for the CFIR data. Despite relatively few typhoid-specific interventions reportedly implemented in these countries, interventions for diarrheal disease control and regulations for food safety and food handlers were common. Most countries implemented agricultural and sewage treatment practices, yet few addressed the control of antibiotic medication. Several contextual factors were perceived to have influenced the implementation of typhoid interventions, either as enablers (e.g., economic development) or barriers (e.g., limited resources and habitual behaviors). Consolidated Framework for Implementation Research factors rated as important in the implementation of typhoid interventions were remarkably consistent across countries. The findings provide a snapshot of typhoid-relevant interventions implemented over 25 years and highlight factors associated with implementation success from the perspective of a sample of key informants. These findings can inform systematic investigations of the implementation of typhoid control interventions and contribute to a better understanding of the direct effects of implementation efforts.

• • Typhoid Fever: Way Forward

    Authors: Zulfiqar A. Bhutta, Michelle Gaffey, John A. Crump, Duncan Steele, Robert F. Breiman, Eric D. Mintz, Robert E. Black, Stephen P. Luby and Myron M. Levine

    Available online: 25 July 2018

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    The Tackling Typhoid supplement shows that typhoid fever continues to be a problem globally despite socioeconomic gains in certain settings. Morbidity remains high in many endemic countries, notably in sub-Saharan Africa and South Asia. In addition, antimicrobial resistance is a growing issue that poses a challenge for clinical management. The findings from this supplement revealed that outside of high-income countries, there were few reliable population-based estimates of typhoid and paratyphoid fever derived from surveillance systems. This indicates the need for monitoring systems that can also characterize the effectiveness of interventions, particularly in low- and middle-income settings. The country case studies indicated that gains in economic conditions, education, and environmental health may be associated with reductions in typhoid fever burden. Over the study period, the effect is mainly notable in countries with higher baseline levels of economic development, female literacy, and investments in public sanitation. High burden countries must continue to invest in strategies at the local level to address environmental factors such as access to safe drinking water and improved public sanitation that are known to interrupt transmission or diminish the risk of acquiring typhoid. Developing more effective vaccines and incorporating appropriate immunization strategies that target populations with the greatest risk could potentially alleviate disease burden.

• • Typhoid Fever in Chile 1969–2012: Analysis of an Epidemic and Its Control

    Authors: Claudia Marco, Iris Delgado, Claudio Vargas, Ximena Muñoz, Zulfiqar A. Bhutta and Catterina Ferreccio

    Available online: 25 July 2018

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    From 1975 to 1983, a large epidemic of typhoid fever (TF) affected the metropolitan region (MR) of Chile (incidence rate [IR] of 219.6 per 105 in 1983). In 1983–1984, interventions were implemented focusing on person-to-person transmission (vaccination, food handlers’ control, and mass communication) and regulations to control irrigation waters containing fecal contaminates. In 1991, a second intervention was quickly implemented to avoid the cholera epidemic–affecting neighboring countries (total prohibition of growing or selling crops in the MR). We explored the potential impact of these interventions on the epidemic. We created a yearly database of the MR TF cases, population, and contextual factors of TF from 1969 to 2012. We first analyzed the epidemic (Joinpoint regression), identified predictors of TF (Poisson multiple regression), and then analyzed the effect of the interventions (interrupted time series model). The main predictor of the TF epidemic was the rate of unemployment. In relation to the 1983–1984 person-to-person interventions, TF came down by 51% (95% confidence interval [CI]: 30.2–65.0%) and continued to decrease at a rate of 10.4% (95% CI: 5.8–15.6%) per year until 1991. In 1991, with the strong environmental control of the sewage-irrigated crops, TF further decreased by 77% (95% CI: 69.0–83.1%) and continued decreasing thereafter at 13% (95% CI: 11.3–15.6%) per year until the end of the study period. Today, 40 years after the epidemic, TF is a rare disease in the MR of Chile.

• • Longitudinal Typhoid Fever Trends in India from 2000 to 2015

    Authors: Veeraraghavan Balaji, Arti Kapil, Jayanthi Shastri, Agila Kumari Pragasam, Geeta Gole, Sirshendu Choudhari, Gagandeep Kang and Jacob John

    Available online: 25 July 2018

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    A very high incidence of typhoid was described in studies conducted in urban locations on the Indian subcontinent at the end of the twentieth century. Despite their availability, licensed immunogenic conjugate typhoid vaccines have not been introduced in the national immunization program, in part, because of a lack of understanding of where and for whom prevention is most necessary. Uncertainty regarding the burden of disease is based on the lack of reliable, recent estimates of culture-confirmed typhoid and an observed trend of low isolations of Salmonella Typhi and fewer complications at large referral hospitals in India. In this article, we examine the trends of S. Typhi isolation at three large tertiary care centers across India over 15 years and describe trends of recognized risk factors for typhoid from published literature. There appears to be a decline in the isolation of S. Typhi in blood culture, which is more apparent in the past 5 years. These trends are temporally related to economic improvement, female literacy, and the use of antibiotics such as cephalosporins and azithromycin. The analysis of trends of culture-confirmed typhoid may not accurately capture the trends of incidence of typhoid if antibiotic use confounds the burden of disease presenting to larger facilities. Emerging antimicrobial resistance may result in a resurgence of disease if the underlying incidence and transmission of typhoid are not adequately addressed through public health approaches.

• • Trends, Associations, and Antimicrobial Resistance of Salmonella Typhi and Paratyphi in Pakistan

    Authors: Jai K. Das, Rumina Hasan, Afia Zafar, Imran Ahmed, Aamer Ikram, Summiya Nizamuddin, Saleel Fatima, Nauman Akbar, Faisal Sultan and Zulfiqar A. Bhutta

    Available online: 25 July 2018

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    Typhoid remains a major cause of morbidity and mortality in endemic countries. This review analyzed typhoid burden changes in Pakistan and its association with contextual factors. A retrospective cohort study on blood culture–positive typhoid and antibiotic resistance was conducted from three tertiary hospitals and contextual factor data obtained from primary household surveys. Salmonella Typhi/Paratyphi positivity rate was estimated and trend analysis was carried out using positive cases out of total number of blood cultures performed. Contextual factors’ associations were determined through bivariate correlation analysis, using STATA (SataCorp, College Station, TX). We report a total of 17,387 S. Typhi–positive and 8,286 S. Paratyphi A and B–positive specimens from 798,137 blood cultures performed. The results suggest an overall decline in typhoid incidence as S. Typhi positivity rates declined from 6.42% in 1992 to 1.32% in 2015 and S. Paratyphi (A and B) from 1.29% to 0.39%. Subgroup analysis suggests higher S. Typhi prevalence in adults older than 18 years, whereas S. Paratyphi is greater in aged children 5–18 years. The relative contribution of S. Paratyphi to overall confirmed cases increased from 16.8% in 1992 to 23% in 2015. The analysis suggests high burden of fluoroquinolone resistance and multidrug-resistant S. Typhi strains. Statistically significant associations of water, sanitation indicators, and literacy rates were observed with typhoid positivity. Despite some progress, typhoid remains endemic and a strong political will is required for targeted typhoid control strategies. A multipronged approach of improving water, sanitation and hygiene in combination with large-scale immunization in endemic settings of Pakistan could help reduce burden and prevent epidemics.

• • The Burden of Typhoid Fever in South Africa: The Potential Impact of Selected Interventions

    Authors: Karen H. Keddy, Anthony M. Smith, Arvinda Sooka, Nomsa P. Tau, Hlengiwe M. P. Ngomane, Amruta Radhakrishnan, Daina Als and Frew G. Benson

    Available online: 25 July 2018

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    Typhoid fever is notifiable in South Africa but clinical notification is notoriously poor. South Africa has an estimated annual incidence rate of 0.1 cases per 100,000 population of culture-confirmed typhoid fever, decreased from 17 cases per 100,000 population in the 1980s. This work was undertaken to identify the reasons for this decrease and identify potential weaknesses that may result in an increase of observed cases. Culture-confirmed cases, with additional demographic and clinical data have been collected from selected sentinel sites since 2003. Data on contextual factors (gross domestic product [GDP], sanitation, female education, and childhood diarrhea mortality) were collected. National incidence rates of culture-confirmed typhoid fever have remained constant for the past 13 years, with the exception of an outbreak in 2005: incidence was 0.4 per 100,000 population. Paratyphoid fever remains a rare disease. Antimicrobial susceptibility data suggest resistance to ciprofloxacin and azithromycin is emerging. The South African population increased from 27.5 million in 1980 to 55.0 million in 2015: urbanization increased from 50% to 65%, GDP increased from United States Dollar (USD) $2,910 to USD $6,167, access to sanitation improved from 64.4% to 70.0% in the urban population and 26.4% to 60.5% in rural areas. Female literacy levels improved from 74.8% to 92.6% over the period. Improved socioeconomic circumstances in South Africa have been temporally associated with decreasing incidence rates of typhoid fever over a 35-year period. Ongoing challenges remain including potential for large outbreaks, a large immigrant population, and emerging antimicrobial resistance. Continued active surveillance is mandatory.

• • Reducing Typhoid Burden within a Generation

    Authors: Zulfiqar A. Bhutta, Anita K. M. Zaidi and Tikki Pangestu

    Available online: 25 July 2018

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• • Epidemiology of Human Leptospirosis in French Guiana (2007–2014): A Retrospective Study

    Authors: Paul Le Turnier, Emilie Mosnier, Roxane Schaub, Pascale Bourhy, Anne Jolivet, Claire Cropet, Nicolas Villemant, Sabine Trombert-Paolantoni, Alain Berlioz-Arthaud, Mathieu Nacher, Magalie Demar, Mathieu Picardeau, Félix Djossou and Loïc Epelboin

    Available online: 23 July 2018

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    Leptospirosis is a worldwide zoonotic bacterial infection with a rising incidence. French Guiana is mostly covered by Amazonian rain forest. Despite a potentially favorable environment, leptospirosis has been barely studied in French Guiana. The objective of this study was to describe the current trends of leptospirosis epidemiology in French Guiana. A cross-sectional study was performed in the two main hospitals of French Guiana. Cases of leptospirosis from 2007 to 2014 were retrospectively identified with a systematic screening of serological and polymerase chain reaction results to classify them as confirmed, probable, or excluded cases. Medical files were reviewed to collect epidemiological data. Among the 72 included patients, 55 (76.4%) cases were confirmed and 17 (23.6%) were probable. The median age was 39 years (range: 16–82 years) and the M/F sex ratio 6.2. Sixty-two (86.1%) patients required hospitalization, including 12 (16.7%) in the intensive care unit. Three (4.2%) patients died. The monthly distribution of cases was correlated with rainfall (P = 0.004) and moisture (P = 0.038). Professional exposure was frequently identified (especially gold mining and construction). Among 16 different serogroups identified by microagglutination test, Icterohaemorrhagiae was the most frequent (38.0%). This study revealed an epidemiology close to that observed in Brazilian regions, and professional and climatic risk factors. The high diversity of serogroups may reveal a complex environmental reservoir requiring further investigations. Only 20% of leptospirosis patients were suspected as such on hospital admission, thus emphasizing the need to inform local physicians.

• • Epidemiology of Severe Acute Respiratory Illness and Risk Factors for Influenza Infection and Clinical Severity among Adults in Malawi, 2011–2013

    Authors: Antonia Ho, Jane Mallewa, Ingrid Peterson, Miguel SanJoaquin, Shikha Garg, Naor Bar-Zeev, Mavis Menyere, Maaike Alaerts, Gugulethu Mapurisa, Moses Chilombe, Mulinda Nyirenda, David G. Lalloo, Camilla Rothe, Marc-Alain Widdowson, Meredith McMorrow, Neil French, Dean Everett and Robert S. Heyderman

    Available online: 23 July 2018

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    Data on the epidemiology of severe acute respiratory illness (SARI) in adults from low-income, high human immunodeficiency virus (HIV) prevalence African settings are scarce. We conducted adult SARI surveillance in Blantyre, Malawi. From January 2011 to December 2013, individuals aged ≥ 15 years with SARI (both inpatients and outpatients) were enrolled at a large teaching hospital in Blantyre, Malawi. Nasopharyngeal aspirates were tested for influenza and other respiratory viruses by polymerase chain reaction. We estimated hospital-attended influenza-positive SARI incidence rates and assessed factors associated with influenza positivity and clinical severity (Modified Early Warning Score > 4). We enrolled 1,126 SARI cases; 163 (14.5%) were positive for influenza. Human immunodeficiency virus prevalence was 50.3%. Annual incidence of hospital-attended influenza-associated SARI was 9.7–16.8 cases per 100,000 population. Human immunodeficiency virus was associated with a 5-fold greater incidence (incidence rate ratio 4.91, 95% confidence interval [CI]: 3.83–6.32). On multivariable analysis, female gender, as well as recruitment in hot, rainy season (December to March; adjusted odds ratios (aOR): 2.82, 95% CI: 1.57–5.06) and cool, dry season (April to August; aOR: 2.47, 95% CI: 1.35–4.15), was associated with influenza positivity, whereas influenza-positive patients were less likely to be HIV-infected (aOR: 0.59, 95% CI: 0.43–0.80) or have viral coinfection (aOR: 0.51, 95% CI: 0.36–0.73). Human immunodeficiency virus infection (aOR: 1.86; 95% CI: 1.35–2.56) and recruitment in hot, rainy season (aOR: 4.98, 95% CI: 3.17–7.81) were independently associated with clinical severity. In this high HIV prevalence population, influenza was associated with nearly 15% of hospital-attended SARI. Human immunodeficiency virus infection is an important risk factor for clinical severity in all-cause and influenza-associated SARI. Expanded access to HIV testing and antiretroviral treatment, as well as targeted influenza vaccination, may reduce the burden of SARI in Malawi and other high HIV prevalence settings.

• • Waterborne Infections in Reunion Island, 2010–2017

    Authors: Nicolas Allou, Aurélien Soubeyrand, Nicolas Traversier, Romain Persichini, Caroline Brulliard, Dorothée Valance, Olivier Martinet, Sandrine Picot, Olivier Belmonte and Jérôme Allyn

    Available online: 23 July 2018

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    Gram-negative bacilli Vibrio spp., Aeromonas spp., and Shewanella spp. are a major cause of severe waterborne infection. The aim of this study was to assess the clinical and microbiological characteristics and prognosis of patients hospitalized in Reunion Island for a waterborne infection. This retrospective study was conducted in the two university hospitals of Reunion Island between January 2010 and March 2017. Patients diagnosed with a Vibrio, Aeromonas, or Shewanella infection were evaluated. Over the study period, 112 aquatic strains were isolated at Reunion Island: Aeromonas spp. were found in 91 patients (81.3%), Shewanella spp. in 13 patients (11.6%), and Vibrio spp. in eight patients (7.2%). The in-hospital mortality rate was 11.6%. The main sites of infection were skin and soft tissue (44.6%) and the abdomen (19.6%). Infections were polymicrobial in 70 cases (62.5%). The most commonly prescribed empiric antibiotic regimen was amoxicillin–clavulanate (34.8%). Eighty-four percent of the aquatic strains were resistant to amoxicillin–clavulanate and more than > 95% were susceptible to third or fourth generation cephalosporins and fluoroquinolones. After multivariate analysis, the only independent risk factor of in-hospital mortality was the presence of sepsis (P < 0.0001). In Reunion Island, the most commonly isolated aquatic microorganisms were Aeromonas spp. Sepsis caused by aquatic microorganisms was frequent (> 50%) and associated with higher in-hospital mortality. This study suggests that empiric antibiotic regimens in patients with sepsis or septic shock caused by suspected aquatic microorganisms (tropical climate, skin lesion exposed to seawater…) should include broad-spectrum antibiotics (third or fourth generation cephalosporins).

• • Quality Assurance and Quality Control in the Global Trachoma Mapping Project

    Authors: Anthony W. Solomon, Rebecca Willis, Alexandre L. Pavluck, Wondu Alemayehu, Ana Bakhtiari, Sarah Bovill, Brian K. Chu, Paul Courtright, Michael Dejene, Philip Downs, Rebecca M. Flueckiger, Danny Haddad, P. J. Hooper, Khumbo Kalua, Biruck Kebede, Amir Bedri Kello, Colin K. Macleod, Siobhain McCullagh, Tom Millar, Caleb Mpyet, Jeremiah Ngondi, Benjamin Nwobi, Nicholas Olobio, Uwazoeke Onyebuchi, Lisa A. Rotondo, Boubacar Sarr, Oumer Shafi, Oliver Sokana, Sheila K. West, Allen Foster and for the Global Trachoma Mapping Project

    Available online: 23 July 2018

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    In collaboration with the health ministries that we serve and other partners, we set out to complete the multiple-country Global Trachoma Mapping Project. To maximize the accuracy and reliability of its outputs, we needed in-built, practical mechanisms for quality assurance and quality control. This article describes how those mechanisms were created and deployed. Using expert opinion, computer simulation, working groups, field trials, progressively accumulated in-project experience, and external evaluations, we developed 1) criteria for where and where not to undertake population-based prevalence surveys for trachoma; 2) three iterations of a standardized training and certification system for field teams; 3) a customized Android phone–based data collection app; 4) comprehensive support systems; and 5) a secure end-to-end pipeline for data upload, storage, cleaning by objective data managers, analysis, health ministry review and approval, and online display. We are now supporting peer-reviewed publication. Our experience shows that it is possible to quality control and quality assure prevalence surveys in such a way as to maximize comparability of prevalence estimates between countries and permit high-speed, high-fidelity data processing and storage, while protecting the interests of health ministries.

• • Shortage of Albendazole and Its Consequences for Patients with Cystic Echinococcosis Treated at a Referral Center in Italy

    Authors: Tommaso Manciulli, Ambra Vola, Mara Mariconti, Raffaella Lissandrin, Marcello Maestri, Christine M. Budke, Francesca Tamarozzi and Enrico Brunetti

    Available online: 23 July 2018

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    Albendazole (ABZ) is the best drug available to treat cystic echinococcosis (CE), a neglected tropical disease. Cystic echinococcosis patients often receive a continuous course of the drug for 6–12 months. In Italy, ABZ shortages occur almost on a yearly basis. We searched clinical records at the World Health Organization Collaborating Center for the Clinical Management of CE in Pavia, Italy, to estimate the amount of ABZ prescribed to patients between January 2012 and February 2017. The cost of ABZ was estimated at €2.25 per tablet based on the current market price in Italy. Patients to whom ABZ had been prescribed were contacted to determine if they had experienced difficulties in purchasing the drug and to assess how such problems affected their treatment. Of 348 identified CE patients, 127 (36.5%) were treated with ABZ for a total of 20,576 days. This led to an estimated cost of €92,592. Seventy-five patients were available for follow-up, 42 (56%) reported difficulties in obtaining ABZ. Of these patients, four (9.5%) had to search out of their region and 10 (23.8%) had to go out of the country. A total of 27 patients (64%) had to visit more than five pharmacies to locate the drug and 10 patients (23.8%) interrupted treatment because of ABZ nonavailability. Shortages in ABZ distribution can disrupt CE treatment schedules and jeopardize patient health.

• • Cost-Effectiveness of Indoor Residual Spraying of Households with Insecticide for Malaria Prevention and Control in Tanzania

    Authors: Rachel Stelmach, Rajeev Colaço, Shabbir Llaji, Deborah McFarland and Richard Reithinger

    Available online: 16 July 2018

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    Using a decision-tree approach, we examined the cost-effectiveness of indoor residual spraying of households with insecticide (IRS) combined with insecticide-treated bed net (ITN) distribution (IRS + ITN), compared with ITN distribution alone in the programmatic context of mainland Tanzania. The primary outcome of our model was the expected economic cost to society per case of malaria averted in children ≤ 5 years of age. Indoor residual spraying of households with insecticide data came from a program implemented in northwest Tanzania from 2008 to 2012; all other data originated from the published literature. Through sensitivity and scenario analyses, the model also examined the effects of variations in insecticide resistance, malaria prevalence, and different IRS modalities. In the base case, IRS + ITN is expected to be more expensive and more effective than the ITN-only intervention (incremental cost per case averted [ICER]: $152.36). The number of IRS rounds, IRS insecticide costs, ITN use, malaria prevalence, and the probability that a child develops symptoms following infection drove the interventions’ cost-effectiveness. Compared with universal spraying, targeted spraying is expected to lead to a higher number of malaria cases per person targeted (0.211–0.256 versus 0.050–0.076), but the incremental cost per case of malaria averted is expected to be lower (ICER: $41.70). In a scenario of increasing pyrethroid resistance, the incremental expected cost per case of malaria averted is expected to increase compared with the base case (ICER: $192.12). Tanzania should pursue universal IRS only in those regions that report high malaria prevalence. If the cost per case of malaria averted of universal IRS exceeds the willingness to pay, targeted spraying could provide an alternative, but may result in higher malaria prevalence.

• • Accuracy, Ease of Use, Safety, and Acceptability of a 23-μL Conical Cup Blood Transfer Device for Use with Rapid Diagnostic Tests

    Authors: Sandra Incardona, Daniel J. Kyabayinze, David Bell, Bbale Ndawula, Marvis C. Kanyago, Magoma C. Mwancha-Kwasa and Iveth J. González

    Available online: 16 July 2018

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    Devices to safely transfer fixed amounts of finger prick blood to rapid diagnostic tests (RDTs) pose a significant challenge, especially in non-laboratory settings. Following the success of an “inverted cup device” for transfer of 5 μL blood, a prototype with a conical cup shape was developed for transfer of 20 μL blood, the amount needed for human immunodeficiency virus or human African trypanosomiasis (HAT) RDTs. This study determined the volume of blood transferred by this new blood transfer device (BTD) and compared its ease of use, safety, and acceptability with that of a plastic pipette when used by health workers (HWs) for HAT RDTs in northwestern Uganda. After a half-day training, 48 HWs had used the two BTDs with at least 10 patients. The conical cup BTD effectively transferred a mean of 22.76 μL of blood (standard deviation 3.31 μL). A significantly higher proportion of HWs were able to collect the full amount of blood using the conical cup BTD, as compared with the pipette (92.4% versus 74.2%, P < 0.001). In HW questionnaires, the conical cup BTD scored higher than the pipette in various aspects of ease of use and safety. In addition, HWs preferred the conical cup BTD (79%), indicating that it was easy to handle, made work faster, and increased their confidence in front of the patient. These findings suggest that the design of the conical cup BTD may be adapted for RDTs requiring 20 μL of blood to facilitate safe and accurate blood transfer.

• • Hepatitis B Surface Antigen Seroprevalence among Prevaccine and Vaccine Era Children in Bangladesh

    Authors: Repon C. Paul, Mahmudur Rahman, Eric Wiesen, Minal Patel, Kajal C. Banik, Ahmed R. Sharif, Sharmin Sultana, Mizanur Rahman, Jayantha Liyanage, Nihal Abeysinghe, Saleem Kamili, Trudy Murphy, Stephen P. Luby and Eric E. Mast

    Available online: 16 July 2018

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    Bangladesh introduced hepatitis B vaccine in a phased manner during 2003–2005 into the routine childhood vaccination schedule. This study was designed to evaluate the impact of the introduction of hepatitis B vaccine in Bangladesh by comparing hepatitis B surface antigen (HBsAg) prevalence among children born before and after vaccine introduction and to estimate the risk of vertical transmission of chronic hepatitis B virus (HBV) infection from mother to infant. We also evaluated the field sensitivity and specificity of an HBsAg point-of-care test strip. We selected a nationally representative sample of 2,100 prevaccine era and 2,100 vaccine era children. We collected a 5-mL blood sample from each child. One drop of blood was used to perform rapid HBsAg testing. If a child had a positive HBsAg test result with the rapid test, a blood sample was collected from the mother of the HBsAg-positive child and from the mothers of two subsequently enrolled HBsAg-negative children. All samples were tested for serologic markers of HBV infection using standard enzyme-linked immunosorbent assay. One (0.05%) child in the vaccine era group and 27 (1.2%; 95% confidence interval [CI]: 0.8–1.7%) children in the prevaccine era group were HBsAg positive. Mothers of HBsAg-positive children were more likely to be HBsAg positive than mothers of HBsAg-negative children (odds ratios = 4.7; 95% CI: 1.0–21.7%). Sensitivity of the HBsAg rapid test was 91.2% (95% CI: 76.6–98.1%) and specificity was 100% (95% CI: 99.9–100%). The study results suggest that even without a birth dose, the hepatitis B vaccine program in Bangladesh was highly effective in preventing chronic HBV infection among children.

• • Mentoring in Global Health: Formative Evaluation of Tuberculosis Research Training Programs in Ethiopia and Georgia

    Authors: Dawn L. Comeau, Kathryn Mishkin, Nestani Tukvadze, Zaza Avaliani, Russell R. Kempker, Lisa Sthreshley, Matthew J. Magee, Hannah Eisen, Damen Haile Mariam, Abraham Aseffa and Henry M. Blumberg

    Available online: 16 July 2018

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    Mentoring is a critical component of career development for research scientists and is related to mentee success both in terms of career selection and advancement. However, there are limited data on the role of mentoring in low- and middle-income countries (LMICs). Cross-cultural mentorship programs have the potential to foster the transfer of knowledge and the development of capacity to resource-poor settings. This formative evaluation explores the cultural context of mentoring in the countries of Georgia and Ethiopia. Results were used to build culturally relevant mentor training programs for the National Institutes of Health Fogarty International Center funded Global Infectious Diseases grants focused on tuberculosis (TB) research and research training. Four focus group discussions were conducted with research trainees and mentors to explore the perceptions of mentorship, identify obstacles for successful mentoring, and generate recommendations to strengthen mentoring in each program situated in a LMIC. Data revealed the barriers to mentoring in Ethiopia and Georgia included gaps in knowledge about mentoring roles and responsibilities, lack of knowledge about the responsibilities of the trainee in a mentoring relationship, and the need to set clear expectations between mentors and trainees. All of the focus group participants desired formal mentor training. These data informed six key components of the development and implementation of the mentor training programs in both countries. The topics included the following: a foundation in mentoring, establishing expectations between mentees and mentors, increasing interactions between mentees and mentors, additional mentor training, a case study curriculum, and methods of evaluating mentoring relationships.

• • First Report of Trypanosoma cruzi Infection in Salivary Gland of Bats from the Peruvian Amazon

    Authors: Fredy E. Villena, Luis A. Gomez-Puerta, Erik J. Jhonston, O. Melisa Del Alcazar, Jorge L. Maguiña, Christian Albujar, V. Alberto Laguna-Torres, Sergio E. Recuenco, Sarah-Blythe Ballard and Julia S. Ampuero

    Available online: 16 July 2018

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    In the Americas, 8 million people are infected with Chagas disease, and an additional 90 million people are at risk for infection. Little is known about the role bats play in the sylvatic transmission cycle of Trypanosoma cruzi, the parasite causing Chagas disease. Here, we captured bats in the villages of Palmiche, Pachacutec, Nuevo San Martin, and Mayuriaga located in the Datem del Marañon Province in Loreto, Peru. Venous blood samples were collected by cardiac puncture or from the upper extremities, and trypanosomatids were identified by microscopy and molecularly. We collected blood samples from 121 bats on filter paper for molecular studies and 111 slides for microscopic examination of thin and thick blood smears from 16 different bat species. The prevalence of trypanosomatids in all bats species was 34.7% (42/121) and the prevalence of T. cruzi was 4.1% (5/121). In hematophagous bat species, the prevalence of trypanosomatids and T. cruzi was 36.9% (27/73) and 2.7% (2/73), respectively. In non-hematophagous bats, the prevalences of trypanosomatids and T. cruzi were 31.2% (15/48) and 6.2% (3/48), respectively. Also, we confirm the presence of T. cruzi in salivary glands of hematophagous bats Diaemus youngi. These results suggest a sylvatic cycle of trypanosomatid transmission in which bats may harbor infectious T. cruzi parasites that could be transmitted to humans via hematophagous bat bites or salivary contamination by non-hematophagous bats of vegetables consumed by humans.

• • Characterizing Pediatric Tuberculosis with and without Human Immunodeficiency Virus Coinfection in Harare, Zimbabwe

    Authors: Michelle Earley, Joconiah Chirenda, Alexandra Highet, Hilda A. Mujuru and Zhenhua Yang

    Available online: 16 July 2018

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    Pediatric tuberculosis (TB) represents a major barrier to reducing global TB mortality, especially in countries confronting dual TB and human immunodeficiency virus (HIV) epidemics. Our study aimed to characterize pediatric TB epidemiology in the high-burden setting of Harare, Zimbabwe, both to fill the current knowledge gap around the epidemiology of pediatric TB and to indicate areas for future research and interventions. We analyzed de-identified data of 1,051 pediatric TB cases (0–14 years) found among a total of 11,607 TB cases reported in Harare, Zimbabwe, during 2011–2012. We performed Pearson’s χ2 test and multivariate logistic regression analysis to characterize pediatric TB and to assess predictors of HIV coinfection. Pediatric TB cases accounted for 9.1% of all TB cases reported during 2011–2012. Approximately 50% of pediatric TB cases were children younger than 5 years. Almost 60% of the under-5 age group were male, whereas almost 60% of the 10–14 age group were female. The overall HIV coinfection rate was 58.3%. Odds for HIV coinfection was higher for the 5–9 age group (adjusted odds ratio [AOR]: 2.77, 95% confidence interval [CI]: 1.97–3.94), the 10–14 group (AOR: 3.57, 95% CI: 2.52–5.11), retreatment cases (AOR: 6.17, 95% CI: 2.13, 26.16), and pulmonary TB cases (AOR: 2.39, 95% CI: 1.52, 3.75). In conclusion, our study generated evidence that pediatric TB, compounded by HIV coinfection, significantly impacts children in high-burden settings. The findings of our study indicate a critical need for targeted interventions.

• • Case Report: Delayed Diagnosis of Congenital Malaria by Plasmodium vivax in a Newborn of an Eritrean Woman with Varicella Infection

    Authors: Saba Gebremeskel Tekle, Angela Corpolongo, Alessandra D’Abramo, Maria Letizia Giancola, Marco Iannetta, Laura Scorzolini, Paola Marcozzi, Elsa Buffone, Giuseppina Liuzzi and Emanuele Nicastri

    Available online: 16 July 2018

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    Congenital malaria (CM) is uncommon in both malaria-endemic and non-endemic countries. It may be caused by any Plasmodium spp., although Plasmodium falciparum and Plasmodium vivax are the more frequent etiologic agents. We report a case of delayed diagnosis of CM by P. vivax in a newborn of an Eritrean primigravida. The mother developed pregnancy-related immunodepression and varicella-zoster viral infection 9 days before natural delivery; therefore, the child was admitted in the neonatal intensive care unit (NICU) to administer specific varicella-zoster immunoglobulin prophylaxis and for clinical monitoring. During the NICU stay, the newborn presented a febrile syndrome with vomiting, anemia, and thrombocytopenia. A P. vivax severe malaria diagnosis was made by detecting trophozoites in the thick and thin blood smears. The infant was successfully treated with intravenous artesunate and clindamycin. Our experience suggests that malaria diagnostic tests need to be included in routine blood analyses in newborns with febrile syndrome from mothers with an epidemiologic link to malaria-endemic areas.

• • Case Report: First Report of Autochthonous Human Cutaneous Myiasis Caused by Hypoderma lineatum in Europe

    Authors: Paola Rappelli, Antonio Varcasia, Arnoldo Vargiu and Antonio Scala

    Available online: 16 July 2018

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    We report a case of human cutaneous myiasis by Hypoderma lineatum, contracted by a farmer who never traveled outside Italy. Identification at species level has been performed by both morphological examination and sequencing of cytochrome c oxidase subunit I gene. This is the first description of human hypodermosis by H. lineatum contracted in Europe.

• • Case Report: Corneal Coinfection with Fungus and Amoeba: Report of Two Patients and Literature Review

    Authors: Joveeta Joseph, Sunita Chaurasia and Savitri Sharma

    Available online: 16 July 2018

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    We report two cases of corneal coinfection with Acanthamoeba and Fusarium sp. along with the review of published literature. A 35-year-old woman and 65-year-old man presented to the institute with corneal ulcer refractory for treatment with topical antibiotics. Microbiological examination revealed the presence of Acanthamoeba cysts along with septate, hyaline fungal filaments. After emergency therapeutic penetrating keratoplasty (TPK) in both, the corneal tissue was sent for histopathologic examination, which confirmed the presence of Acanthamoeba and fungal coinfection. One patient had a recurrence of fungal infection after TPK. In subjects with a rapid progression of mycotic ulcer, coinfection with other microorganisms including Acanthamoeba should be suspected. The two cases presented here emphasize the importance of microbiology in making prompt diagnosis and appropriate management of these cases at an early stage.

• • Comprehensive Assessment of a Hotspot with Persistent Bancroftian Filariasis in Coastal Sri Lanka

    Authors: Ramakrishna U. Rao, Sandhya D. Samarasekera, Kumara C. Nagodavithana, Charles W. Goss, Manjula W. Punchihewa, Tharanga D. M. Dassanayaka, Udaya S. B. Ranasinghe, Devika Mendis and Gary J. Weil

    Available online: 16 July 2018

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    The Sri Lankan Anti-Filariasis campaign distributed five rounds of mass drug administration (MDA with diethylcarbamazine plus albendazole) to some 10 million people in eight districts between 2002 and 2006. Sri Lanka was recognized by the WHO for having eliminated lymphatic filariasis (LF) as a public health problem in 2016. However, recent studies by our group documented pockets with persistent LF in coastal Sri Lanka, especially in Galle district. The present study was performed to reexamine an area previously identified as a potential hotspot for persistent LF (Balapitiya Public Health Inspector, population 17,500). A community survey documented high rates for circulating filarial antigenemia (3%, confidence interval [CI]: 1.8–4.9) and microfilaremia (1%, CI: 0.5–2.5%). Circulating filarial antigenemia rates were 2.8-fold higher in males than females. High prevalence was also observed for anti-filarial antibodies in young children (5.7%, CI: 3.7–8.4%) and for filarial DNA in vector mosquitoes (5.2%, CI: 4.2–6.3%). Spatial data showed that persistent LF was dispersed across the entire study area. Other studies showed that persistent LF was not limited to Balapitiya and not solved by additional rounds of MDA. Molecular xenomonitoring studies conducted in 2016 in 22 of 168 Public Health Midwife areas in the coastal Galle evaluation unit (approximate population 600,000) found that 179 of 660 (27%) pools of Culex collected from all areas were positive for Wuchereria bancrofti DNA by qPCR; the estimated infection rate in mosquitoes was 1.26%, CI: 1.0–1.5%. Interventions other than routine MDA will be required to remove LF hotspots in Balapitiya and in other areas in coastal Sri Lanka.

• • Salmonella enterica serovars Panama and Arechavaleta, Risk Factors for Invasive Non-Typhoidal Salmonella Disease in Guadeloupe, French West Indies

    Authors: Stephanie Guyomard-Rabenirina, Blandine Muanza, Sylvaine Bastian, Edith Malpote, Pauline Jestin, Meggie Guerrin, Antoine Talarmin, François-Xavier Weill, Arnaud Legrand and Sebastien Breurec

    Available online: 16 July 2018

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    A retrospective study was conducted to identify the risk factors associated with Salmonella enterica bacteremia in infants and children in Guadeloupe, French West Indies. The 171 patients with S. enterica infection seen between 2010 and 2014 included 155 (90.6%) with acute gastroenteritis, of whom 42 (27.1%) had concomitant bacteremia and 16 (9.4%) with primary bacteremia. Most cases (97.7%) were in infants and children with no underlying health condition. Two subspecies were recovered: enterica (N = 161, 94.2%) and houtenae (N = 10, 5.8%). All but one (serovar Typhi) were non-typhoidal Salmonella. The most common serovars were Panama (N = 57, 33.3% of isolates) and Arechavaleta (N = 28, 16.4%). Univariate analysis showed a strong association only between age > 6 months and infection with the Panama or Arechavaleta serovar (P = 0.002). The rate of resistance to all classes of antibiotics during the study period was low (< 15%); however, the detection of one extended-spectrum beta-lactamase–producing S. enterica strain highlights the need for continued monitoring of antimicrobial drug susceptibility. Infection with Panama (P < 0.001) or Arechavaleta (P < 0.001) serovar was significantly associated with bacteremia in a multivariate analysis. These serovars are probably poorly adapted to humans or are more virulent. A delay between onset of symptoms and hospital admission > 5 days (P = 0.01), vomiting (P = 0.001), and increased respiratory rate (P = 0.001) contributed independently to bacteremia in the multivariate analysis. Thus, if non-typhoidal infection is suspected, blood should be cultured and antibiotic treatment initiated in all patients who meet these criteria.

• • Controlled Human Malaria Infection with Graded Numbers of Plasmodium falciparum NF135.C10- or NF166.C8-Infected Mosquitoes

    Authors: Marijke C. C. Langenberg, Linda J. Wammes, Matthew B. B. McCall, Else M. Bijker, GeertJan van Gemert, Wouter Graumans, Marga van de Vegte, Karina Teelen, Cornelis C. Hermsen, Rob Koelewijn, Jaap J. van Hellemond, Perry J. J. van Genderen and Robert W. Sauerwein

    Available online: 16 July 2018

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    Controlled human malaria infections (CHMIs) with Plasmodium falciparum (Pf) parasites are well established. Exposure to five Pf (NF54)-infected Anopheles mosquitoes results in 100% infection rates in malaria-naïve volunteers. Recently Pf clones NF135.C10 and NF166.C8 were generated for application in CHMIs. Here, we tested the clinical infection rates of these clones, using graded numbers of Pf-infected mosquitoes. In a double-blind randomized trial, we exposed 24 malaria-naïve volunteers to bites from one, two, or five mosquitoes infected with NF135.C10 or NF166.C8. The primary endpoint was parasitemia by qPCR. For both strains, bites by five infected mosquitoes resulted in parasitemia in 4/4 volunteers; 3/4 volunteers developed parasitemia after exposure to one or two infected mosquitoes infected with either clone. The prepatent period was 7.25 ± 4.0 days (median ± range). There were no serious adverse events and comparable clinical symptoms between all groups. These data confirm the eligibility of NF135.C10 and NF166.C8 for use in CHMI studies.

• • Anthropometry and Malaria among Children in Niger: A Cross-Sectional Study

    Authors: Kieran S. O’Brien, Abdou Amza, Boubacar Kadri, Beido Nassirou, Sun Y. Cotter, Nicole E. Stoller, Sheila K. West, Robin L. Bailey, Travis C. Porco, Bruce D. Gaynor, Thomas M. Lietman and Catherine E. Oldenburg

    Available online: 16 July 2018

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    The complex relationship between malnutrition and malaria affects morbidity and mortality in children younger than 5 years, particularly in parts of sub-Saharan Africa where these conditions occur together seasonally. Previous research on this relationship has been inconclusive. Here, we examine the association between anthropometric indicators and malaria infection in a population-based sample of children younger than 5 years in Niger. This cross-sectional study is a secondary analysis of a cluster-randomized trial comparing treatment strategies for trachoma in Niger. We included children aged 6–60 months residing in the 48 communities enrolled in the trial who completed anthropometric and malaria infection assessments at the final study visit. We evaluated the association between anthropometric indicators, including height-for-age z-score (HAZ) and weight-for-age z-score (WAZ) and indicators of malaria infection, including malaria parasitemia and clinical malaria. In May 2013, we collected data from 1,649 children. Of these, 780 (47.3%) were positive for malaria parasitemia and 401 (24.3%) had clinical malaria. In models of malaria parasitemia, the adjusted odds ratio (aOR) was 1.05 (95% confidence interval [CI]: 1.00–1.10) for HAZ and 1.07 (95% CI: 0.99, 1.15) for WAZ. In models of clinical malaria, the aOR was 1.07 (95% CI: 1.02–1.11) for HAZ and 1.09 (95% CI: 1.01–1.19) for WAZ. Overall, we did not find evidence of an association between most anthropometric indicators and malaria infection. Greater height may be associated with an increased risk of clinical malaria.

• • Operational Performance of the Onchocerca volvulus “OEPA” Ov16 ELISA Serological Assay in Mapping, Stop Mass Drug Administration, and Posttreatment Surveillance Surveys

    Authors: Frank O. Richards Jr.,, Moses Katabarwa, Firdaweke Bekele, Zerihun Tadesse, Aderajew Mohammed, Mauricio Sauerbrey, Alfredo Dominguez-Vazquez, Mario A. Rodriguez-Perez, Nadia A. Fernández-Santos, Nidia Rizzo, Harland R. Schuler Martínez, Raquel Lovato Silva, Zoraida Morales Monroy, Peace Habomugisha, David W. Oguttu, Issam M. A. Zarroug, Nabil A. Aziz and Thomas R. Unnasch

    Available online: 16 July 2018

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    Onchocerciasis is a neglected tropical disease targeted for elimination. The World Health Organization (WHO) has developed guidelines for the verification of onchocerciasis elimination that include entomological and epidemiological criteria. The latter require demonstrating with statistical confidence that the infection prevalence in children is less than 0.1%, necessitating an assay with a high degree of specificity. We present an analysis of the performance of the Onchocerciasis Elimination Program for the Americas (OEPA) version of the Ov16 ELISA when used under operational conditions. In Africa and Latin America, the assay demonstrated 99.98% specificity in 69,888 children in 20 foci where transmission was believed to be interrupted. The assay produced a prevalence estimate equal to that of skin snip microscopy when applied in putatively hypo-endemic zones of Ethiopia. The OEPA Ov16 ELISA demonstrated the specificity required to be effectively deployed to verify transmission elimination under the WHO guidelines, while exhibiting a sensitivity equivalent to skin snip microscopy to identify hypo-endemic areas.

• • Effect of Antibiotics on Short-Term Growth among Children in Burkina Faso: A Randomized Trial

    Authors: Ali Sié, Clarisse Dah, Lucienne Ouermi, Charlemagne Tapsoba, Pascal Zabre, Till Bärnighausen, Elodie Lebas, Ahmed M. Arzika, Blake M. Snyder, Travis C. Porco, Thomas M. Lietman, Jeremy D. Keenan and Catherine E. Oldenburg

    Available online: 16 July 2018

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    Antibiotics improve both weight and height gain in randomized trials of preschool children with preexisting morbidity. Here, we assess the effect of a short course of three different antibiotics (amoxicillin, azithromycin, and cotrimoxazole) on short-term linear and ponderal growth in a population-based sample of preschool children in rural Burkina Faso. We randomized households with at least two children in the Nouna district, Burkina Faso, to a 5-day course of amoxicillin, azithromycin, cotrimoxazole, or placebo. Within each antibiotic-randomized household, one child was randomly assigned to receive the antibiotic and the other to receive the placebo. Weight and height measurements were taken at baseline and 30 days following the last study medication dose. Weight-for-height Z (WHZ), height-for-age Z (HAZ), and weight-for-age Z (WAZ) scoreswere calculated based on the 2006 World Health Organization standards. Of the 124 households and 248 children enrolled, 229 had anthropometry measurements at 1 month and were analyzed. Children randomized to amoxicillin gained significantly more weight compared with both the placebo household (mean difference 317 g, 95% CI: 115–519 g) and placebo sibling (mean difference 315 g, 95% CI: 147–482 g) controls. Growth velocity in g/kg/day, and WHZ and WAZ scores were higher in amoxicillin-treated children compared with placebo households and siblings. There were no differences in weight gain in children randomized to azithromycin or cotrimoxazole compared with placebo households or placebo siblings. There were no differences in height gain or HAZ across any of the study arms. Amoxicillin may have short-term growth-promoting effects in healthy children.

• • Case Report: A Cluster of Plasmodium falciparum Malaria Cases among Thai Workers in Gembu, Nigeria

    Authors: Wasin Matsee, Lapakorn Chatapat, Kesinee Chotivanich and Watcharapong Piyaphanee

    Available online: 16 July 2018

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    Although falciparum malaria is an important risk among travelers to sub-Saharan Africa, many travelers remain unaware of this risk. In October 2015, we found a cluster of imported Plasmodium falciparum malaria cases among Thai gem mine workers in Nigeria; none had received malaria chemoprophylaxis or information regarding malaria risk. The index case developed fever and visited our hospital on arrival day in Thailand after his 3-week stay in Nigeria. Plasmodium falciparum was found in his blood. He recovered completely 3 days post-admission. After we requested he contact his colleagues in Nigeria regarding malaria risk, we found that three of his five colleagues currently had fever, were diagnosed with malaria, and were being treated in a local hospital. Two were successfully treated in Nigeria. Although their blood films were negative for malaria, we could confirm that they recently had malaria because the polymerase chain reaction (PCR) was still positive for P. falciparum. Tragically, the last febrile case died in Nigeria 6 days post-admission, after developing jaundice and alteration of consciousness. The two colleagues without fever symptoms were also tested by PCR, which was negative for malaria. In conclusion, we found that four of six workers had malaria in this cluster, which was equal to 66.7% attack rate. There is an urgent need to raise awareness of malaria among workers in highly endemic areas. Clinical practice for travelers who are ill on their return should not only focus on individual cases but also consider potential disease clusters.

• • Epidemiology of Plasmodium vivax Malaria Infection in Nepal

    Authors: Komal Raj Rijal, Bipin Adhikari, Prakash Ghimire, Megha Raj Banjara, Borimas Hanboonkunupakarn, Mallika Imwong, Kesinee Chotivanich, Kedar Prasad Ceintury, Bibek Kumar Lal, Garib Das Thakur, Nicholas P. J. Day, Nicholas J. White and Sasithon Pukrittayakamee

    Available online: 16 July 2018

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    Malaria is endemic in the southern plain of Nepal which shares a porous border with India. More than 80% cases of malaria in Nepal are caused by Plasmodium vivax. The main objective of this study was to review the epidemiology of P. vivax malaria infections as recorded by the national malaria control program of Nepal between 1963 and 2016. National malaria data were retrieved from the National Malaria program in the Ministry of Health, Government of Nepal. The epidemiological trends and malariometric indicators were analyzed. Vivax malaria has predominated over falciparum malaria in the past 53 years, with P. vivax malaria comprising 70–95% of the annual malaria infections. In 1985, a malaria epidemic occurred with 42,321 cases (82% P. vivax and 17% Plasmodium falciparum). Nepal had experienced further outbreaks of malaria in 1991 and 2002. Plasmodium falciparum cases increased from 2005 to 2010 but since then declined. Analyzing the overall trend between 2002 (12,786 cases) until 2016 (1,009 cases) shows a case reduction by 92%. The proportion of imported malaria cases has increased from 18% of cases in 2001 to 50% in 2016. The current trends of malariometric indices indicate that Nepal is making a significant progress toward achieving the goal of malaria elimination by 2025. Most of the cases are caused by P. vivax with imported malaria comprising an increasing proportion of cases. The malaria control program in Nepal needs to counter importation of malaria at high risk areas with collaborative cross border malaria control activities.

• • Antibiotic Therapy in Adults with Malaria: High Rate of Clinically Significant Bacteremia in Hospitalized Adults Diagnosed with Falciparum Malaria

    Authors: Ne Myo Aung, Phyo Pyae Nyein, Thu Ya Htut, Zaw Win Htet, Tint Tint Kyi, Nicholas M. Anstey, Mar Mar Kyi and Josh Hanson

    Available online: 16 July 2018

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    It has been believed that concomitant bacteremia is uncommon in adults hospitalized with falciparum malaria. Accordingly, the World Health Organization treatment guidelines presently only recommended additional antibacterial therapy in these patients if they have a clinical syndrome compatible with serious bacterial infection. Admission blood cultures were collected from 20 consecutive adults in Myanmar, hospitalized with a positive immunochromatographic test and blood film, suggesting a diagnosis of falciparum malaria; four (20%) had bacteremia with a clinically significant pathogen. These case series’ data were pooled with a previously published multicenter study from Myanmar which had also collected blood cultures in adults hospitalized with a diagnosis of falciparum malaria. Among 87 patients in the two studies, 13 (15%) had clinically significant bacteremia on admission, with Gram-negative organisms in 10 (77%) and Staphylococcus aureus in the remaining three (23%). Bacteremic patients had more severe disease than non-bacteremic patients (median [interquartile range] RCAM score 2 [1–4] versus 1 [1–2], P = 0.02) and were more likely to die (2/13 [15%] versus 1/74 [1%], P = 0.02). However, bacterial coinfection was suspected clinically in a minority of bacteremic patients (5/13 [38%] compared with 13/70 [19%] of non-bacteremic patients, P = 0.11). Concomitant bacteremia in adults diagnosed with falciparum malaria may be more common than previously believed and is difficult to identify clinically in resource-poor settings. Death is more common in these patients, suggesting that clinicians should have a lower threshold for commencing empirical antibacterial therapy in adults diagnosed with falciparum malaria in these locations than is recommended presently.

• • Melioidosis is in the Americas: A Call to Action for Diagnosing and Treating the Disease

    Authors: Alfredo G. Torres, Franco E. Montufar, Jay E. Gee, Alex R. Hoffmaster, Mindy G. Elrod, Carolina Duarte-Valderrama, Monica G. Huertas and David E. Blaney

    Available online: 16 July 2018

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    Melioidosis, a disease caused by the pathogen Burkholderia pseudomallei, is a significant underreported endemic disease found in tropical countries worldwide. Recent studies have demonstrated that human melioidosis cases have been increasingly recognized in the Americas. Therefore, the first Scientific Reunion of Melioidosis in the Americas was organized in Colombia, with the participation of health authorities of 11 Latin American countries and the United States. This report summarizes the topics reviewed during the meeting, including how to identify human infections and properly diagnose them, with the goal of increasing recognition of the disease in the Americas.

• • Antibiotic Prophylaxis for Melioidosis in Patients Receiving Hemodialysis in the Tropics? One Size Does Not Fit All

    Authors: Ken W. T. Chau, Simon Smith, Katherine Kang, Shyam Dheda and Josh Hanson

    Available online: 16 July 2018

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    Melioidosis has a high case fatality rate and is more common in patients with chronic kidney disease. Some authors recommended trimethoprim/sulfamethoxazole (TMP/SMX) prophylaxis for all hemodialysis (HD) patients during the wet season in melioidosis-endemic regions. Historical data were reviewed to determine if TMP/SMX prophylaxis was warranted in the HD population of Far North Queensland, Australia. Between 1997 and 2017, there were 242 culture-confirmed cases of melioidosis in the region, three (1.2%) occurred in HD patients; all survived without intensive care support. During the study period, there were 843 HD patients in the region with 3,024 cumulative patient years of risk. Even assuming 100% efficacy, it would have been necessary to prescribe TMP/SMX for 1,008 patient years to prevent one case of melioidosis. Given the significant additional cost and potentially life-threatening side effects of TMP/SMX therapy, clinicians should review the local epidemiology of melioidosis before the implementation of universal TMP/SMX prophylaxis in their HD population.

• • Genomic Investigation of a Mycobacterium tuberculosis Outbreak Involving Prison and Community Cases in Florida, United States

    Authors: Marie Nancy Séraphin, Xavier Didelot, David J. Nolan, Justin R. May, Md. Siddiqur Rahman Khan, Ellen R. Murray, Marco Salemi, J. Glenn Morris Jr. and Michael Lauzardo

    Available online: 09 July 2018

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    We used whole-genome sequencing to investigate a tuberculosis outbreak involving U.S.-born persons in the prison system and both U.S.- and foreign-born persons in the community in Florida over a 7-year period (2009–2015). Genotyping by spacer oligonucleotide typing and 24-locus mycobacterial interspersed repetitive unit-variable number tandem repeat suggested that the outbreak might be clonal in origin. However, contact tracing could not link the two populations. Through a multidisciplinary approach, we showed that the cluster involved distinct bacterial transmission networks segregated by country of birth. The source strain is of foreign origin and circulated in the local Florida community for more than 20 years before introduction into the prison system. We also identified novel transmission links involving foreign and U.S.-born cases not discovered during contact investigation. Our data highlight the potential for spread of strains originating from outside the United States into U.S. “high-risk” populations (such as prisoners), with subsequent movement back to the general community.

• • Non-Respiratory and Non-Diarrheal Causes of Acute Febrile Illnesses in Children Requiring Hospitalization in a Tertiary Care Hospital in North India: A Prospective Study

    Authors: Abdul Rauf, Sunit Singhi, Karthi Nallasamy, Mandeep Walia and Pallab Ray

    Available online: 09 July 2018

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    Acute febrile illnesses (AFIs) in children from the developing world can have varying etiologies. Awareness of local epidemiology helps in prioritizing investigations and empiric treatment. This prospective study was carried out in a tertiary care center in North India, aiming to determine the burden, etiology, and outcome of AFI other than pneumonia and diarrhea in hospitalized children. A total of 613 consecutive children aged 3 months to 12 years with febrile illness of < 7 days during four selected months of 2014 representing different seasons were screened for eligibility. Those with acute respiratory diseases (N = 175, 28.5%) and diarrheal illness (N = 46, 7.5%) were excluded and 217 children were enrolled. Mean (standard deviation) age was 4.8 (3.4) years. Nearly half (N = 91, 41.9%) presented in post-monsoon season. Diagnosis could be established in 187 (86.2%) children. Acute CNS infections were the most common (N = 54, 24.8%). Among specific infections, scrub typhus was the most frequent (N = 23, 10.5%) followed by malaria (N = 14, 6.4%), typhoid (N = 14, 6.5%), and viral hepatitis (N = 13, 6.0%). Blood culture had a low (6.5%) yield; Salmonella typhi (N = 6) and Staphylococcus aureus (N = 5) were the common isolates. Serological tests were helpful in 50 (23%) cases. In multivariate analysis, hepatomegaly and/or splenomegaly independently predicted scrub typhus. Mortality rate was 10.1%. We conclude that AFI other than pneumonia and diarrhea are a significant burden and follow a seasonal trend. Scrub typhus has emerged as an important etiology of childhood AFIs in northern India. Periodic review of regional epidemiology will help in understanding the changing pattern of infectious diseases.

• • Accuracy of a Rapid Diagnostic Test Based on Antigen Detection for the Diagnosis of Cutaneous Leishmaniasis in Patients with Suggestive Skin Lesions in Morocco

    Authors: Issam Bennis, Kristien Verdonck, Nora el Khalfaoui, Myriam Riyad, Hajiba Fellah, Jean-Claude Dujardin, Hamid Sahibi, Souad Bouhout, Gert Van der Auwera and Marleen Boelaert

    Available online: 09 July 2018

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    In rural areas in Morocco, diagnosing cutaneous leishmaniasis (CL) can be challenging. We evaluated the accuracy of a rapid diagnostic test (RDT) based on antigen detection, CL Detect Rapid Test™ (Inbios International Inc., Seattle, WA), in this setting. We consecutively recruited patients with new skin ulcers in nine primary health centers. We took a dental broach sample for the RDT and two other tissue samples by scraping the border and center of the lesion with a scalpel and smearing it on a slide. We duplicated each smear by pressing a clean slide against it and processed the slides by using microscopy, polymerase chain reaction (PCR) internal transcribed spacer 1, and kDNA minicircle PCR. In a subgroup with positive PCR, the Leishmania species was identified using PCR-restriction fragment length polymorphism and PCR-sequencing of hsp70 genes. A participant with positive microscopy and/or PCR was considered a confirmed CL case. We computed sensitivity (Se) and specificity (Sp) of the RDT compared with this reference standard (ClinicalTrials.gov registration: NCT02979002). Between December 2016 and July 2017, we included 219 patients, 50% of them were under 18 years old. Rapid diagnostic test Se was 68% [95% confidence interval (CI): 61–74], Sp 94% [95% CI: 91–97], positive predictive value 95% [95% CI: 92–98], and negative predictive value 64% [95% CI: 58–70]. Despite its low Se, this novel RDT is a useful addition to clinical management of CL in Morocco, especially in isolated localities. Rapid diagnostic test–positive lesions can be treated as CL; but when RDT negative, microscopy should be performed as a second step. The Se of the RDT can probably be optimized by improving the sampling procedure.

• • Relative Contribution of Schistosomiasis and Malaria to Anemia in Western Kenya

    Authors: Emily M. Valice, Ryan E. Wiegand, Pauline N. M. Mwinzi, Diana M. S. Karanja, John M. Williamson, Elizabeth Ochola, Aaron Samuels, Jennifer R. Verani, Juan S. Leon, W. Evan Secor and Susan P. Montgomery

    Available online: 09 July 2018

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    Because anemia is one of the markers of morbidity associated with schistosomiasis, it has been proposed as a potential measure to evaluate the impact of control programs. However, anemia is also a common consequence of malaria, and schistosomiasis and malaria are often co-endemic. To estimate the attributable fraction of anemia due to Schistosoma mansoni and Plasmodium falciparum infections, we applied a log-binomial model to four studies measuring these parameters of a combined 5,849 children in western Kenya. In our studies, malaria contributed 23.3%, schistosomiasis contributed 6.6%, and co-infection contributed 27.6% of the anemia. We conclude that in areas where S. mansoni and P. falciparum are co-endemic, the contribution of schistosomiasis to anemia is masked by anemia resulting from malaria, thus limiting anemia as a useful measure for schistosomiasis control programs in these settings.

• • Seroepidemiology of Dengue, Zika, and Yellow Fever Viruses among Children in the Democratic Republic of the Congo

    Authors: Alexandra C. Willcox, Matthew H. Collins, Ramesh Jadi, Corinna Keeler, Jonathan B. Parr, Dieudonné Mumba, Melchior Kashamuka, Antoinette Tshefu, Aravinda M. de Silva and Steven R. Meshnick

    Available online: 09 July 2018

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    Flaviviruses such as Zika, dengue, and yellow fever cause epidemics throughout the tropics and account for substantial global morbidity and mortality. Although malaria and other vector-borne diseases have long been appreciated in Africa, flavivirus epidemiology is incompletely understood. Despite the existence of an effective vaccine, yellow fever continues to cause outbreaks and deaths, including at least 42 fatalities in the Democratic Republic of the Congo (DRC) in 2016. Here, we leveraged biospecimens collected as part of the nationally representative 2013–2014 Demographic and Health Survey in the DRC to examine serological evidence of flavivirus infection or vaccination in children aged 6 months to 5 years. Even in this young stratum of the Congolese population, we find evidence of infection by dengue and Zika viruses based on results from enzyme-linked immunosorbent assay and neutralization assay. Surprisingly, there was remarkable discordance between reported yellow fever vaccination status and results of serological assays. The estimated seroprevalences of neutralizing antibodies against each virus are yellow fever, 6.0% (95% confidence interval [CI] = 4.6–7.5%); dengue, 0.4% (0.1–0.9%); and Zika, 0.1% (0.0–0.5%). These results merit targeted, prospective studies to assess effectiveness of yellow fever vaccination programs, determine flavivirus seroprevalence across a broader age range, and investigate how these emerging diseases contribute to the burden of acute febrile illness in the DRC.

• • Plasmodium falciparum Histidine-Rich Protein 2 Gene Variation in a Malaria-Endemic Area of Papua New Guinea

    Authors: Nigani Willie, Peter A. Zimmerman and Rajeev K. Mehlotra

    Available online: 02 July 2018

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    Histidine-rich protein 2 of Plasmodium falciparum (PfHRP2) forms the basis of many current malaria rapid diagnostic tests (RDTs). It is concerning that there are parasites that lack part or all of the pfhrp2 gene, and thus do not express the PfHRP2 protein; such parasites are not identifiable by PfHRP2-detecting RDTs. Very limited information is available regarding pfhrp2 genetic variation in Papua New Guinea (PNG). In the present study, this gene variation was evaluated using 169 samples previously collected from the Wosera area in East Sepik Province of PNG. Molecular diagnosis of these samples showed that 81% were infected, and P. falciparum was present in 91% of those infected samples. One hundred and twenty samples were amplified for pfhrp2 exon-2, from which 12 randomly selected amplicons were sequenced, yielding 18 sequences, all of which were unique. Baker repeat type 2 × type 7 numbers ranged from 0 to 108. Epitope mapping analysis revealed that three major epitopes, DAHHAHHA, AHHAADAHHA, and AHHAADAHH, were present in high prevalence and frequencies. These major epitopes have been shown to be recognized by the monoclonal antibodies 3A4 and PTL-3 (DAHHAHHA), C1-13 (AHHAADAHHA), and S2-5 and C2-3 (AHHAADAHH). This study provides further information on the high genetic variation of pfhrp2 and its unclear relationship with prediction of RDT detection sensitivity, and identifies major epitopes in this gene from PNG. These results could be relevant and useful to understand the genetic diversity of this gene and the performance of current and future RDTs in this malarious region of the world.

• • The Effect of Nonrandom Mating on Wolbachia Dynamics: Implications for Population Replacement and Sterile Releases in Aedes Mosquitoes

    Authors: Heng Lin Yeap, Nancy Margaret Endersby-Harshman and Ary Anthony Hoffmann

    Available online: 02 July 2018

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    Wolbachia bacteria are known to cause deviations from random mating and affect sperm competition (SC) in some of their arthropod hosts. Because these effects could influence the effectiveness of Wolbachia in mosquito population replacement and suppression programs, we developed a theoretical framework to investigate them and we collected relevant data for the wMel infection in Aedes aegypti. Using incompatibility patterns as a measure of mating success of infected versus uninfected mosquitoes, we found some evidence that uninfected males sire more offspring than infected males. However, our theoretical framework suggests that this effect is unlikely to hamper Wolbachia invasion and has only minor effects on population suppression programs. Nevertheless, we suggest that mating effects and SC need to be monitored in an ongoing manner in release programs, given the possibility of ongoing selection for altered mating patterns.

• • Associations between Use of Antimalarial Medications and Health among U.S. Veterans of the Wars in Iraq and Afghanistan

    Authors: Aaron I. Schneiderman, Yasmin S. Cypel, Erin K. Dursa and Robert Bossarte

    Available online: 25 June 2018

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    Mefloquine (Lariam®) has been linked to acute neuropsychiatric side effects. This is a concern for U.S. veterans who may have used mefloquine during recent Southwest Asia deployments. Using data from the National Health Study for a New Generation of U.S. Veterans, a population-based study of U.S. veterans who served between 2001 and 2008, we investigated associations between self-reported use of antimalarial medications and overall physical and mental health (MH) using the twelve-item short form, and with other MH outcomes using the post-traumatic stress disorder Checklist-17 and the Patient Health Questionnaire (anxiety, major depression, and self-harm). Multivariable logistic regression was performed to examine associations between health measures and seven antimalarial drug categories: any antimalarial, mefloquine, chloroquine, doxycycline, primaquine, mefloquine plus any other antimalarial, and any other antimalarial or antimalarial combination while adjusting for the effects of deployment and combat exposure. Data from 19,487 veterans showed that although antimalarial use was generally associated with higher odds of negative health outcomes, once deployment and combat exposure were added to the multivariable models, the associations with each of the MH outcomes became attenuated. A positive trend was observed between combat exposure intensity and prevalence of the five MH outcomes. No significant associations were found between mefloquine and MH measures. These data suggest that the poor physical and MH outcomes reported in this study population are largely because of combat deployment exposure.

• • Efficacy of Artemisinin-Based Combination Treatments of Uncomplicated Falciparum Malaria in Under-Five-Year-Old Nigerian Children Ten Years Following Adoption as First-Line Antimalarials

    Authors: Joy C. Ebenebe, Godwin Ntadom, Jose Ambe, Robinson Wammanda, Nma Jiya, Finomo Finomo, George Emechebe, Olugbenga Mokuolu, Kazeem Akano, Chimere Agomo, Onikepe A. Folarin, Stephen Oguche, Francis Useh, Wellington Oyibo, Temitope Aderoyeje, Mohammed Abdulkadir, Nnenna M. Ezeigwe, Christian Happi, Akintunde Sowunmi and for the Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria

    Available online: 25 June 2018

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    The efficacies of 3-day regimens of artemether–lumefantrine (AL), artesunate–amodiaquine (AA), and dihydroartemisinin–piperaquine (DHP) were evaluated in 910 children < 5 years old with uncomplicated malaria from six geographical areas of Nigeria. Parasite positivity 1 day and Kaplan–Meier estimated risk of persistent parasitemia 3 days after therapy initiation were both significantly higher, and geometric mean parasite reduction ratio 1 day after treatment initiation (PRRD1) was significantly lower in AL-treated children than in AA- and DHP-treated children. No history of fever, temperature > 38°C, enrollment parasitemia > 75,000 μL−1, and PRRD1 < 5,000 independently predicted persistent parasitemia 1 day after treatment initiation. Parasite clearance was significantly faster and risk of reappearance of asexual parasitemia after initial clearance was significantly lower in DHP-treated children. Overall, day 42 polymerase chain reaction–corrected efficacy was 98.3% (95% confidence interval [CI]: 96.1–100) and was similar for all treatments. In a non-compartment model, declines of parasitemias were monoexponential with mean terminal elimination half-life of 1.3 hours and unimodal frequency distribution of half-lives. All treatments were well tolerated. In summary, all three treatments evaluated remain efficacious treatments of uncomplicated malaria in young Nigerian children, but DHP appears more efficacious than AL or AA.

• • Development of Loop-Mediated Isothermal Amplification–Based Lateral Flow Device Method for the Detection of Malaria

    Authors: Prudhvi Chand Mallepaddi, Meng-Yee Lai, Sudhakar Podha, Choo-Huck Ooi, Jonathan Wee-Kent Liew, Rathnagiri Polavarapu and Yee-Ling Lau

    Available online: 25 June 2018

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    The present study aims to develop a method for rapid diagnosis of malaria using loop-mediated isothermal amplification (LAMP) combined with a lateral flow device (LFD). By adding the biotin-labeled and FAM-labeled loop primers to the LAMP reaction solution, the end product can be visualized on a lateral flow dipstick. The entire procedure takes approximately 42 minutes to complete, LAMP assay exhibited high sensitivity, as the detection limit was 0.01 pg/μL for all five Plasmodium species. It was demonstrated that all Plasmodium knowlesi (N = 90) and Plasmodium vivax (N = 56) were positively amplified by LAMP-LFD assay, whereas healthy donor samples (N = 8) were negative. However, not all mixed infections were positive, and other infected nonmalaria samples were negative. Loop-mediated isothermal amplification-LFD represents a robust approach with potential suitability for use in resource-constrained laboratories. We believe that LAMP-LFD has a potential to be developed as point-of-care diagnostic tool in future.

• • Protobothrops mucrosquamatus Bites to the Head: Clinical Spectrum from Case Series

    Authors: Ying-Tse Yeh, Min-Hui Chen, Julia Chia-Yu Chang, Ju-Sing Fan, David Hung-Tsang Yen and Yen-Chia Chen

    Available online: 25 June 2018

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    Protobothrops mucrosquamatus (Trimeresurus mucrosquamatus) is a medically important species of pit viper with a wide geographic distribution in Southeast Asia. Bites by P. mucrosquamatus mostly involve the extremities. Little is known about the toxic effects of P. mucrosquamatus envenoming to the head because of the infrequency of such occurrence. To better delineate the clinical manifestations of envenoming to the head, we report three patients who suffered from P. mucrosquamatus bites to the head and were treated successfully. All three patients developed progressive soft tissue swelling extending from head to neck, with two patients expanding further onto the anterior chest wall. Mild thrombocytopenia was noted in two patients. One patient had transient acute renal impairment and airway obstruction, necessitating emergent intubation. All three patients received high doses of species-specific antivenom with recovery within 1 week. No adverse reactions to antivenom were observed.

• • Zika Virus and the World Health Organization Criteria for Determining Recent Infection Using Plaque Reduction Neutralization Testing

    Authors: Matthew J. Ward, Jackeline Alger, Mabel Berrueta, Harry Bock, Pierre Buekens, Maria Luisa Cafferata, Alvaro Ciganda, Jorge García, Kimberly García, Ivette Lorenzana, Wendy Lopez, Leda Parham and Dawn M. Wesson

    Available online: 25 June 2018

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    The recent Zika virus (ZIKV) epidemic swept across Latin America and the Caribbean, where dengue virus (DENV) is endemic. The antigenic similarities of these closely related flaviviruses left researchers and clinicians with challenges to interpret serological tests. Thirty-six women attending a prenatal clinic in Honduras and with positive DENV IgM enzyme-linked immunoabsorbent assays (ELISAs) were screened with a ZIKV IgM ELISA, RT-PCR for ZIKV and DENV 1–4, and plaque reduction neutralization tests (PRNTs) for ZIKV and DENV-2. Plaque reduction neutralization test results were interpreted using the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) criteria. Using the WHO criteria of a PRNT90 titer ≥ 20 and a 4-fold difference between ZIKV and DENV titers, we determined that 69.4% of samples had a recent ZIKV infection, compared with 5.6% using CDC criteria. The interpretation of ZIKV PRNTs in a DENV-endemic region is highly dependent on the choice of interpretation criteria.

• • Calcified Neurocysticercosis and Headache in an Endemic Village: A Case–Control Study Nested to a Population-Based Cohort

    Authors: Oscar H. Del Brutto, Ana M. Robles, Robertino M. Mera, Aldo F. Costa, Elizabeth Darsan, Lucía Milla, Jessica Montes, Julio Lama, Victor J. Del Brutto, Mauricio Zambrano and Mark J. Sedler

    Available online: 25 June 2018

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    Headache in patients with calcified neurocysticercosis (NCC) is probably common but has been largely overlooked. We aimed to assess the presence, characteristics, and diagnosis of headache across patients with calcified NCC and their matched controls. In this case–control study nested to a population-based cohort, Atahualpa residents aged ≥ 20 years with calcified NCC were identified as case patients and paired 1:1 to age- and gender-matched randomly selected controls. A culturally adapted questionnaire was derived from the EUROLIGHT. Headache diagnosis was established according to the International Classification of Headache Disorders, 3rd edition. Conditional logistic regression models for matched paired data were fitted to assess the independent association between calcified NCC (as the exposure) and headache variables, after adjusting for education, alcohol intake, depression, and epilepsy. The selection process generated 106 case patients and their matched controls. Lifetime headache prevalence (OR: 4.18; 95% Confidence Interval [CI]: 1.79–9.75; P = 0.001), current headaches (OR: 4.19; 95% CI: 1.92–9.16; P < 0.001), and intense headaches (OR: 9.47; 95% CI: 2.88–31.19; P < 0.001) were more frequent among cases than in controls. In addition, migraine (but not other forms of headache) was more frequent among subjects with calcified NCC (OR: 4.89; 95% CI: 2.36–11.39; P < 0.001). This study shows a robust epidemiological association between headache—particularly migraine—and calcified NCC.

• • How Far Are We from Reaching Universal Malaria Testing of All Fever Cases?

    Authors: Mateusz M. Plucinski, Timothée Guilavogui, Alioune Camara, Médoune Ndiop, Moustapha Cisse, John Painter and Julie Thwing

    Available online: 25 June 2018

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    Universal malaria diagnostic testing of all fever cases is the first step in correct malaria case management. However, monitoring adherence to universal testing is complicated by unreliable recording and reporting of the true number of fever cases. We searched the literature to obtain gold-standard estimates for the proportion of patients attending outpatient clinics in sub-Saharan Africa with malarial and non-malarial febrile illness. To correct for differences in malaria transmission, we calculated the proportion of patients with fever after excluding confirmed malaria cases. Next, we analyzed routine data from Guinea and Senegal to calculate the proportion of outpatients tested after exclusion of confirmed malaria cases from the numerator and denominator. From 12 health facility surveys in sub-Saharan Africa with gold-standard fever screening, the median proportion of febrile illness among outpatients after exclusion of confirmed malaria fevers was 57% (range: 46–80%). Analysis of routine data after exclusion of confirmed malaria cases demonstrated much lower testing proportions of 23% (Guinea) and 13% (Senegal). There was substantial spatial and temporal heterogeneity in this testing proportion, and testing in Senegal was correlated with malaria season. Given the evidence from gold-standard surveys that at least 50% of non-malaria consultations in sub-Saharan Africa are for febrile illness, it appears that a substantial proportion of patients with fever are not tested for malaria in health facilities when considering routine data. Tracking the proportion of patients tested for malaria after exclusion of the confirmed malaria cases could allow programs to make inferences about malaria testing practices using routine data.

• • Molecular Identification of Onchocerca spp. Larvae in Simulium damnosum sensu lato Collected in Northern Uganda

    Authors: Guilherme G. Verocai, Hassan K. Hassan, Thomson Lakwo, Peace Habomugisha, Moses N. Katabarwa, Stephen Begumisa, Philbert Clouds, James Katamanywa, Christine Nahabwe and Thomas R. Unnasch

    Available online: 02 October 2017

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    Previous studies have demonstrated that the presence of larvae of other filarial species in Simulium damnosum sensu lato can distort estimates of transmission potential for Onchocerca volvulus in West Africa. However, studies conducted in foci of onchocerciasis in West Central Uganda indicated that larvae other than O. volvulus were not common in vectors collected there. Recent data collected in Northern Uganda revealed a striking discordance between estimates of the prevalence of flies carrying O. volvulus infective larvae obtained from molecular pool screening and dissection methods. To resolve this discrepancy, sequences from three mitochondrially encoded genes were analyzed from the larvae collected by dissection. All larvae analyzed were Onchocerca ochengi v. Siisa, a parasite of cattle, or Onchocerca ramachandrini, a parasite of warthogs. These results suggest that nonhuman parasite larvae are common in vectors in Northern Uganda, underscoring the necessity for molecular identification methods to accurately estimate O. volvulus transmission.