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Context Food-induced anaphylaxis is potentially fatal but preventable by allergen avoidance and manageable through immediate treatment. Considerable effort has been invested in preventing fatalities from nut exposure among school-aged children, but few population-based studies exist to guide additional prevention efforts. Objectives To describe the epidemiology and trends of food-related anaphylaxis requiring emergency treatment during a 15-year span in New York City when public health initiatives to prevent deaths were implemented and to understand the situational circumstances of food-related deaths. Design/setting/participants Retrospective death record review and analysis of inpatient hospital discharges and emergency department (ED) visits in New York City residents, 2000-2014. Main outcome Vital statistics data, medical examiner reports, ED, and hospital discharge data were used to examine risk for death and incidence trends in medically attended food-related anaphylaxis. Potentially preventable deaths were those among persons with a known allergy to the implicated food or occurring in public settings. Results There were 24 deaths, (1.6 deaths/year; range: 0-5), 3049 hospitalizations, and 4014 ED visits, including 7 deaths from crustacean, 4 from peanut, and 2 each from tree nut or seeds and fish exposures. Risk for death among those hospitalized or treated in the ED was highest for persons older than 65 years and for those treated for crustacean reactions (relative risk 6.5 compared with those treated for peanuts, 95% confidence interval = 1.9-22.1). Eleven of 16 deaths with medical examiner data were potentially preventable. Hospitalizations (2000-2014) and ED visit rates (2005-2014) were highest for children and those with peanut exposure and increased across periods. Conclusions Deaths from food-related anaphylaxis were rare; however, rates of hospitalization and ED visits increased. Prevention efforts related to peanut allergies among children should continue, and additional attention is needed to prevent and treat anaphylaxis among adults, particularly those with known crustacean allergies where case fatality is highest.

Background In 2016, an influenza A(H7N2) virus outbreak occurred in cats in New York City's municipal animal shelters. One human infection was initially detected. Methods We conducted a serological survey using a novel approach to rule out cross-reactive antibodies to other seasonal influenza viruses to determine whether additional A(H7N2) human infections had occurred and to assess exposure risk. Results Of 121 shelter workers, one had serological evidence of A(H7N2) infection, corresponding to a seroprevalence of 0.8% (95% confidence interval, .02%-4.5%). Five persons exhibited low positive titers to A(H7N2) virus, indicating possible infection; however, we could not exclude cross-reactive antibody responses to seasonal influenza viruses. The remaining 115 persons were seronegative. The seropositive person reported multiple direct cat exposures without using personal protective equipment and mild illness with subjective fever, runny nose, and sore throat. Conclusions We identified a second case of A(H7N2) infection from this outbreak, providing further evidence of cat-to-human transmission of A(H7N2) virus.

Candida auris is an emerging yeast that causes healthcare-associated infections. It can be misidentified by laboratories and often is resistant to antifungal medications. We describe an outbreak of C. auris infections in healthcare facilities in New York City, New York, USA. The investigation included laboratory surveillance, record reviews, site visits, contact tracing with cultures, and environmental sampling. We identified 51 clinical case-patients and 61 screening case-patients. Epidemiologic links indicated a large, interconnected web of affected healthcare facilities throughout New York City. Of the 51 clinical case-patients, 23 (45%) died within 90 days and isolates were resistant to fluconazole for 50 (98%). Of screening cultures performed for 572 persons (1,136 total cultures), results were C. auris positive for 61 (11%) persons. Environmental cultures were positive for samples from 15 of 20 facilities. Colonization was frequently identified during contact investigations; environmental contamination was also common.

Summary Adding low-dose primaquine to malaria treatment reduced gametocyte carriage by 73%. Patients who received primaquine had more frequent hemoglobinuria and there was a greater reduction in haemoglobin concentration in G6PD-deficient patients. One patient who received primaquine developed moderately severe anemia., Introduction More information is needed about the safety of low-dose primaquine in populations where G6PD deficiency is common. Methods Adults with Plasmodium falciparum malaria were randomized to receive 1 of 3 artemisinin combination therapies (ACTs) with or without primaquine (0.25 mg/kg). Glucose-6-phosphate dehydrogenase (G6PD) status was determined using a rapid test. Patients were followed for 28 days to record hemoglobin concentration, adverse events, and gametocyte carriage. The primary end point was the change in Hb at day 7. Results In sum, 274 patients were randomized, 139 received an ACT alone, and 135 received an ACT + primaquine. The mean reduction in Hb at day 7 was similar in each group, a difference in the ACT + PQ versus the ACT alone group of −0.04 g/dL (95% confidence interval [CI] −0.23, 0.31), but the effect of primaquine differed according to G6PD status. In G6PD-deficient patients the drop in Hb was 0.63 g/dL (95% CI 0.03, 1.24) greater in those who received primaquine than in those who received an ACT alone. In G6PD-normal patients, the reduction in Hb was 0.22 g/dL (95% CI −0.08, 0.52) less in those who received primaquine (interaction P = .01). One G6PD normal patient who received primaquine developed moderately severe anaemia (Hb < 8 g/dL). Dark urine was more frequent in patients who received primaquine. Primaquine was associated with a 73% (95% CI 24–90) reduction in gametocyte carriage (P = .013). Conclusion Primaquine substantially reduced gametocyte carriage. However, the fall in Hb concentration at day 7 was greater in G6PD-deficient patients who received primaquine than in those who did not and one patient who received primaquine developed moderately severe anemia. Clinical Trial registration PACTR201411000937373 (www.pactr.org)

Residential mobility is hypothesized to impact health through changes to the built environment and disruptions in social networks, and may vary by neighborhood deprivation exposure. However, there are few longitudinal investigations of residential mobility in relation to health outcomes. This study examined enrollees from the World Trade Center Health Registry, a longitudinal cohort of first responders and community members in lower Manhattan on September 11, 2001. Enrollees who completed ≥2 health surveys between 2004 and 2016 and did not have diabetes (N = 44,089) or hypertension (N = 35,065) at baseline (i.e., 2004) were included. Using geocoded annual home addresses, residential mobility was examined using two indicators: moving frequency and displacement. Moving frequency was defined as the number of times someone was recorded as living in a different neighborhood; displacement as any moving to a more disadvantaged neighborhood. We fit adjusted Cox proportional hazards models with time-dependent exposures (moving frequency and displacement) and covariates to evaluate associations with incident diabetes and hypertension. From 2004 to 2016, the majority of enrollees never moved (54.5%); 6.5% moved ≥3 times. Those who moved ≥3 times had a similar hazard of diabetes (hazard ratio (HR) = 0.78; 95% Confidence Interval (CI): 0.40, 1.53) and hypertension (HR = 0.99; 95% CI: 0.68, 1.43) compared with those who never moved. Similarly, displacement was not associated with diabetes or hypertension. Residential mobility was not associated with diabetes or hypertension among a cohort of primarily urban-dwelling adults.

Background The development of serologic assays that can rapidly assess human exposure to novel influenza viruses remains a public health need. Previously, we developed an 11‐plex magnetic fluorescence microsphere immunoassay (MAGPIX) by using globular head domain recombinant hemagglutinins (rHAs) with serum adsorption using two ectodomain rHAs. Methods We compared sera collected from two cohorts with novel influenza exposures: animal shelter staff during an A(H7N2) outbreak in New York City in 2016‐2017 (n = 119 single sera) and poultry workers from a live bird market in Bangladesh in 2012‐2014 (n = 29 pairs). Sera were analyzed by microneutralization (MN) assay and a 20‐plex MAGPIX assay with rHAs from 19 influenza strains (11 subtypes) combined with serum adsorption using 8 rHAs from A(H1N1) and A(H3N2) viruses. Antibody responses were analyzed to determine the novel influenza virus exposure. Results Among persons with novel influenza virus exposures, the median fluorescence intensity (MFI) against the novel rHA from exposed influenza virus had the highest correlation with MN titers to the same viruses and could be confirmed by removal of cross‐reactivity from seasonal H1/H3 rHAs following serum adsorption. Interestingly, in persons with exposures to novel influenza viruses, age and MFIs against exposed novel HA were negatively correlated, whereas in persons without exposure to novel influenza viruses, age and MFI against novel HAs were positively correlated. Conclusions This 20‐plex high‐throughput assay with serum adsorption will be a useful tool to detect novel influenza virus infections during influenza outbreak investigations and surveillance, especially when well‐paired serum samples are not available.

Background Birth defects surveillance in the United States is conducted principally by review of routine but lagged reporting to statewide congenital malformations registries of diagnoses by hospitals or other health care providers, a process that is not designed to rapidly detect changes in prevalence. Health information exchange (HIE) systems are well suited for rapid surveillance, but information is limited about their effectiveness at detecting birth defects. We evaluated HIE data to detect microcephaly diagnosed at birth during January 1, 2013–December 31, 2015 before known introduction of Zika virus in North America. Methods Data from an HIE system were queried for microcephaly diagnostic codes on day of birth or during the first two days after birth at three Bronx hospitals for births to New York City resident mothers. Suspected cases identified by HIE data were compared with microcephaly cases that had been identified through direct inquiry of hospital records and confirmed by chart abstraction in a previous study of the same cohort. Results Of 16,910 live births, 43 suspected microcephaly cases were identified through an HIE system compared to 67 confirmed cases that had been identified as part of the prior study. A total of 39 confirmed cases were found by both studies (sensitivity = 58.21%, 95% CI: 45.52–70.15%; positive predictive value = 90.70%, 95% CI: 77.86–97.41%; negative predictive value = 99.83%, 95% CI: 99.76–99.89% for HIE data). Conclusion Despite limitations, HIE systems could be used for rapid newborn microcephaly surveillance, especially in the many jurisdictions where more labor-intensive approaches are not feasible. Future work is needed to improve electronic medical record documentation quality to improve sensitivity and reduce misclassification.

Background Mass drug administration (MDA) has the potential to interrupt malaria transmission and has been suggested as a tool for malaria elimination in low-endemic settings. This study aimed to determine the effectiveness and safety of two rounds of MDA in Zanzibar, a pre-elimination setting. Methods A cluster randomised controlled trial was conducted in 16 areas considered as malaria hotspots, with an annual parasite index of > 0.8%. The areas were randomised to eight intervention and eight control clusters. The intervention included two rounds of MDA with dihydroartemisinin-piperaquine and single low-dose primaquine 4 weeks apart in May–June 2016. Primary and secondary outcomes were cumulative confirmed malaria case incidences 6 months post-MDA and parasite prevalences determined by PCR 3 months post-MDA. Additional outcomes included intervention coverage, treatment adherence, occurrence of adverse events, and cumulative incidences 3, 12, and 16 months post-MDA. Results Intervention coverage was 91.0% (9959/10944) and 87.7% (9355/10666) in the first and second rounds, respectively; self-reported adherence was 82.0% (881/1136) and 93.7% (985/1196). Adverse events were reported in 11.6% (147/1268) and 3.2% (37/1143) of post-MDA survey respondents after both rounds respectively. No serious adverse event was reported. No difference in cumulative malaria case incidence was observed between the control and intervention arms 6 months post-MDA (4.2 and 3.9 per 1000 population; p = 0.94). Neither was there a difference in PCR-determined parasite prevalences 3 months post-MDA (1.4% and 1.7%; OR = 1.0, p = 0.94), although having received at least the first MDA was associated with reduced odds of malaria infection (aOR = 0.35; p = 0.02). Among confirmed malaria cases at health facilities, 26.0% and 26.3% reported recent travel outside Zanzibar in the intervention and control shehias (aOR ≥ 85; p ≤ 0.001). Conclusions MDA was implemented with high coverage, adherence, and tolerability. Despite this, no significant impact on transmission was observed. The findings suggest that two rounds of MDA in a single year may not be sufficient for a sustained impact on transmission in a pre-elimination setting, especially when the MDA impact is restricted by imported malaria. Importantly, this study adds to the limited evidence for the use of MDA in low transmission settings in sub-Saharan Africa. Trial registration ClinicalTrials.gov, NCT02721186 (registration date: March 29, 2016) Electronic supplementary material The online version of this article (10.1186/s12916-018-1202-8) contains supplementary material, which is available to authorized users.

The New York City (NYC) Department of Health and Mental Hygiene (DOHMH) used multiple methods to provide guidance to healthcare providers on the management and prevention of Zika virus disease during 2016. To better understand providers' use of information sources related to emerging disease threats, this article describes reported use of information sources by NYC providers to stay informed about Zika, and patterns observed by provider type and practice setting. We sent an electronic survey to all email addresses in the Provider Data Warehouse, a system used to maintain information from state and local health department sources on all prescribing healthcare providers in NYC. The survey asked providers about their use of information sources, including specific information products offered by the NYC DOHMH, to stay informed about Zika during 2016. Trends by provider type and practice setting were described using summary statistics. The survey was sent to 44,455 unique email addresses; nearly 20% (8,711) of the emails were undeliverable. Ultimately, 1,447 (5.8%) eligible providers completed the survey. Most respondents (79%) were physicians. Overall, the most frequently reported source of information from the NYC DOHMH was the NYC Health Alert Network (73%). Providers in private practice reported that they did not use any NYC DOHMH source of information about Zika more frequently than did those working in hospital settings (29% vs 23%); similarly, private practitioners reported that they did not use any other source of information about Zika more frequently than did those working in hospital settings (16% vs 8%). Maintaining timely and accurate databases of healthcare provider contact information is a challenge for local public health agencies. Effective strategies are needed to identify and engage independently practicing healthcare providers to improve communications with all healthcare providers during public health emergencies.

Mass drug administration (MDA) was a component of many malaria programs during the eradication era, but later was seldomly deployed due to concerns regarding efficacy and feasibility and fear of accelerating drug resistance. Recently, however, there has been renewed interest in the role of MDA as an elimination tool. Following a 2013 Cochrane Review that focused on the quantitative effects of malaria MDA, we have conducted a systematic, qualitative review of published, unpublished, and gray literature documenting past MDA experiences. We have also consulted with field experts, using their historical experience to provide an informed, contextual perspective on the role of MDA in malaria elimination. Substantial knowledge gaps remain and more research is necessary, particularly on optimal target population size, methods to improve coverage, and primaquine safety. Despite these gaps, MDA has been used successfully to control and eliminate Plasmodium falciparum and P. vivax malaria in the past, and should be considered as part of a comprehensive malaria elimination strategy in specific settings.

BACKGROUND:The Bangladeshi national treatment guidelines for uncomplicated malaria follow WHO recommendations but without G6PD testing prior to primaquine administration. A prospective observational study was conducted to assess the efficacy of the current antimalarial policy. METHODS:Patients with uncomplicated malaria, confirmed by microscopy, attending a health care facility in the Chittagong Hill Tracts, Bangladesh, were treated with artemether-lumefantrine (days 0-2) plus single dose primaquine (0.75mg/kg on day2) for P. falciparum infections, or with chloroquine (days 0-2) plus 14 days primaquine (3.5mg/kg total over 14 days) for P. vivax infections. Hb was measured on days 0, 2 and 9 in all patients and also on days 16 and 30 in patients with P. vivax infection. Participants were followed for 30 days. The study was registered with the clinical trials website (NCT02389374). RESULTS:Between September 2014 and February 2015 a total of 181 patients were enrolled (64% P. falciparum, 30% P. vivax and 6% mixed infections). Median parasite clearance times were 22.0 (Interquartile Range, IQR: 15.2-27.3) hours for P. falciparum, 20.0 (IQR: 9.5-22.7) hours for P. vivax and 16.6 (IQR: 10.0-46.0) hours for mixed infections. All participants were afebrile within 48 hours, two patients with P. falciparum infection remained parasitemic at 48 hours. No patient had recurrent parasitaemia within 30 days. Adjusted male median G6PD activity was 7.82U/gHb. One male participant (1/174) had severe G6PD deficiency (

Background Countries remain reluctant to adopt the 2012 World Health Organization recommendation for single low-dose (0.25 mg/kg) primaquine (SLD PQ) for Plasmodium falciparum transmission-blocking due to concerns over drug-related haemolysis risk, especially among glucose-6-phosphate dehydrogenase-deficient (G6PDd) people, without evidence demonstrating that it can be safely deployed in their settings. Pharmacovigilance methods provide a systematic way of collecting safety data and supporting the rollout of SLD PQ. Methods The Primaquine Roll Out Monitoring Pharmacovigilance Tool (PROMPT), comprising: (1) a standardized form to support the surveillance of possible adverse events following SLD PQ treatment; (2) a patient information card to enhance awareness of known adverse drug reactions of SLD PQ use; and (3) a database compiling recorded information, was developed and piloted. Data on patient characteristics, malaria diagnosis and treatment are collected. Blood samples are taken to measure haemoglobin (Hb) and test for G6PD deficiency. Active follow-up includes a repeat Hb measurement and adverse event monitoring on or near day 7. A 13-month prospective pilot study in two hospital facilities in Swaziland alongside the introduction of SLD PQ generated preliminary evidence on the feasibility and acceptability of PROMPT. Results PROMPT was well received by nurses as a simple, pragmatic approach to active surveillance of SLD PQ safety data. Of the 102 patients enrolled and administered SLD PQ, none were G6PDd. 93 (91.2 %) returned on or near day 7 for follow-up. Four (4.6 %) patients had falls in Hb ≥25 % from baseline, none of whom presented with signs or symptoms of anaemia. No patient’s Hb fell below 7 g/dL and none required a blood transfusion. Of the 11 (11 %) patients who reported an adverse event over the study period, three were considered serious and included two deaths and one hospitalization; none were causally related to SLD PQ. Four non-serious adverse events were considered definitely, probably, or possibly related to SLD PQ. Conclusion Improved pharmacovigilance to monitor and promote the safety of the WHO recommendation is needed. The successful application of PROMPT demonstrates its potential as an important tool to rapidly generate locally acquired safety data and support pharmacovigilance in resource-limited settings. Electronic supplementary material The online version of this article (doi:10.1186/s12936-016-1410-7) contains supplementary material, which is available to authorized users.

Background Single low doses of primaquine, when added to artemisinin-based combination therapy, might prevent transmission of Plasmodium falciparum malaria to mosquitoes. We aimed to establish the activity and safety of four low doses of primaquine combined with dihydroartemisinin–piperaquine in male patients in Mali. Methods In this phase 2, single-blind, dose-ranging, adaptive randomised trial, we enrolled boys and men with uncomplicated P falciparum malaria at the Malaria Research and Training Centre (MRTC) field site in Ouelessebougou, Mali. All participants were confirmed positive carriers of gametocytes through microscopy and had normal function of glucose-6-phosphate dehydrogenase (G6PD) on colorimetric quantification. In the first phase, participants were randomly assigned (1:1:1) to one of three primaquine doses: 0 mg/kg (control), 0·125 mg/kg, and 0·5 mg/kg. Randomisation was done with a computer-generated randomisation list (in block sizes of six) and concealed with sealed, opaque envelopes. In the second phase, different participants were sequentially assigned (1:1) to 0·25 mg/kg primaquine or 0·0625 mg/kg primaquine. Primaquine tablets were dissolved into a solution and administered orally in a single dose. Participants were also given a 3 day course of dihydroartemisinin–piperaquine, administered by weight (320 mg dihydroartemisinin and 40 mg piperaquine per tablet). Outcome assessors were masked to treatment allocation, but participants were permitted to find out group assignment. Infectivity was assessed through membrane-feeding assays, which were optimised through the beginning part of phase one. The primary efficacy endpoint was the mean within-person percentage change in mosquito infectivity 2 days after primaquine treatment in participants who completed the study after optimisation of the infectivity assay, had both a pre-treatment infectivity measurement and at least one follow-up infectivity measurement, and who were given the correct primaquine dose. The safety endpoint was the mean within-person change in haemoglobin concentration during 28 days of study follow-up in participants with at least one follow-up visit. This study is registered with ClinicalTrials.gov, number NCT01743820. Findings Between Jan 2, 2013, and Nov 27, 2014, we enrolled 81 participants. In the primary analysis sample (n=71), participants in the 0·25 mg/kg primaquine dose group (n=15) and 0·5 mg/kg primaquine dose group (n=14) had significantly lower mean within-person reductions in infectivity at day 2—92·6% (95% CI 78·3–100; p=0·0014) for the 0·25 mg/kg group; and 75·0% (45·7–100; p=0·014) for the 0·5 mg/kg primaquine group—compared with those in the control group (n=14; 11·3% [–27·4 to 50·0]). Reductions were not significantly different from control for participants assigned to the 0·0625 mg/kg dose group (n=16; 41·9% [1·4–82·5]; p=0·16) and the 0·125 mg/kg dose group (n=12; 54·9% [13·4–96·3]; p=0·096). No clinically meaningful or statistically significant drops in haemoglobin were recorded in any individual in the haemoglobin analysis (n=70) during follow-up. No serious adverse events were reported and adverse events did not differ between treatment groups. Interpretation A single dose of 0·25 mg/kg primaquine, given alongside dihydroartemisinin–piperaquine, was safe and efficacious for the prevention of P falciparum malaria transmission in boys and men who are not deficient in G6PD. Future studies should assess the safety of single-dose primaquine in G6PD-deficient individuals to define the therapeutic range of primaquine to enable the safe roll-out of community interventions with primaquine. Funding Bill & Melinda Gates Foundation.

The only currently available drug that effectively removes malaria hypnozoites from the human host is primaquine. The use of 8-aminoquinolines is hampered by haemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. Recently a number of qualitative and a quantitative rapid diagnostic test (RDT) format have been developed that provide an alternative to the current standard G6PD activity assays. The WHO has recently recommended routine testing of G6PD status prior to primaquine radical cure whenever possible. A workshop was held in the Philippines in early 2015 to discuss key challenges and knowledge gaps that hinder the introduction of routine G6PD testing. Two point-of-care (PoC) test formats for the measurement of G6PD activity are currently available: qualitative tests comparable to malaria RDT as well as biosensors that provide a quantitative reading. Qualitative G6PD PoC tests provide a binomial test result, are easy to use and some products are comparable in price to the widely used fluorescent spot test. Qualitative test results can accurately classify hemizygous males, heterozygous females, but may misclassify females with intermediate G6PD activity. Biosensors provide a more complex quantitative readout and are better suited to identify heterozygous females. While associated with higher costs per sample tested biosensors have the potential for broader use in other scenarios where knowledge of G6PD activity is relevant as well. The introduction of routine G6PD testing is associated with additional costs on top of routine treatment that will vary by setting and will need to be assessed prior to test introduction. Reliable G6PD PoC tests have the potential to play an essential role in future malaria elimination programmes, however require an improved understanding on how to best integrate routine G6PD testing into different health settings. Electronic supplementary material The online version of this article (doi:10.1186/s12936-015-0896-8) contains supplementary material, which is available to authorized users.

Objective Intravaginal practices—including behaviors such as intravaginal cleansing and insertion of products—have been linked to a number of adverse reproductive health outcomes, including increased risk for bacterial vaginosis, sexually transmitted infections, and HIV. Currently, little is known about the motivations for intravaginal practices among women in the United States. The objective of this study was to identify and describe motivations for intravaginal washing and intravaginal insertion of products among women of differing ages and racial/ethnic groups. Methods Between 2008 and 2010, we enrolled a convenience sample of sexually active women aged 18–65 years living in Los Angeles recruited through community education and outreach activities in HIV/AIDS service organizations, women’s health clinics, community-based organizations, and HIV testing sites. At the enrollment visit, women completed a self-administered, computer-assisted questionnaire covering demographics, sexual behaviors, intravaginal practices, and motivations for intravaginal practices over the past month and past year. Results We enrolled 141 women; 34% of participants were Caucasian, 40% African American, and 26% Latina. Peri-sexual intravaginal washing was common in all groups, whether to clean up after sex (70%) or to prepare for sex (54%). African American women were more likely to report learning to wash intravaginally from their mothers compared to Latina or Caucasian women (70% vs. 49%, P = 0.04). Sixty-one percent of African American women reported using a douching device over the past year compared to 41% of Latina and 40% of Caucasian women (p = 0.02). Younger women were more likely to report that their male partners wanted them to wash intravaginally than older women (77% vs. 24%, P

Background Global ambitions to eliminate malaria are intensifying, underscoring a critical need for transmission blocking tools. In 2012, the WHO recommended the use of 0.25 mg/kg of single low-dose (SLD) primaquine to stop Plasmodium falciparum transmission. To ensure the availability of SLD primaquine to countries in need of this tool, more information on the supply, programmatic, and regulatory barriers to the rollout of SLD primaquine is required. Methods Challenges to the rollout of SLD primaquine in sub-Saharan Africa were established through semi-structured qualitative interviews with three primaquine manufacturers, 43 key informants from Ethiopia, Senegal, Swaziland, Zambia, and Tanzania, and 16 malaria research experts. Results Sanofi and Remedica are the only two sources of SRA-approved primaquine suitable for procurement by international donors. Neither manufacturer produces primaquine tablet strengths suitable for the transmission blocking indication. In-country key informants revealed that the WHO weight-based recommendation to use SLD primaquine is challenging to implement in actual field settings. Malaria programmes expressed safety concerns of SLD primaquine use in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, as well as potential interactions between primaquine and co-morbidities, and drug-drug interactions with HIV and/or tuberculosis treatments. Regulatory processes are a major barrier to the rollout of SLD primaquine, requiring multiple steps at both the country and global level. Despite these barriers, demand for SLD primaquine is growing, and malaria researchers are interested in primaquine deployment through mass screen and treat and/or mass drug administration campaigns. Conclusion Demand for primaquine as a transmission blocking agent is growing rapidly yet multiple barriers to SLD primaquine use exist. Research is needed to define the therapeutic dose range, which will guide dosing regimens in the field, inform the development of new, lower strength primaquine tablets and/or formulation(s), and allay programmatic safety concerns in individuals with G6PD deficiency. Potential interactions between primaquine and co-morbidities and treatments should be explored. To minimize regulatory delays, countries need to prepare for product registration at an early stage, WHO prequalification for suitable primaquine tablet strengths and/or new formulations should be sought, and in the meanwhile only Stringent Regulatory Authority (SRA)-approved primaquine should be used. Electronic supplementary material The online version of this article (doi:10.1186/s12936-015-0714-3) contains supplementary material, which is available to authorized users.

Establishing and strengthening pharmacovigilance in resource-limited settings provides a valuable opportunity to identify, quantify and address pertinent safety concerns regarding the use of single low-dose (SLD) primaquine. While it is understood that primaquine causes dose-dependent hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals with P. falciparum and P. vivax malaria, the extent of this risk when using low doses of primaquine remains to be defined. Prospective pharmacovigilance methods are needed to confirm or refute these safety concerns that have likely hindered the uptake of the new WHO policy for SLD primaquine. Pharmacovigilance in resource-limited settings is challenging, especially when attempting to identify unknown or poorly understood adverse drug reactions over weeks of follow-up. In contrast, the objectives of a pharmacovigilance program for SLD primaquine are specific, measurable, and attainable within a short time frame. The nadir of primaquine-induced hemolytic anemia, measurable by hemoglobin concentrations, has been shown to occur on or near day 7. Thus, it is expected that adverse drug reactions related to primaquine can be captured within a week of drug administration by active surveillance methods involving patient follow-up. Furthermore, dark urine is a characteristic sign of acute hemolytic anemia, an easily identifiable and documentable symptom of hemolysis. Numerous pharmacovigilance efforts are ongoing, supporting individual countries in the collection of standardized SLD primaquine safety data. These efforts seek to establish the expected fall in hemoglobin from baseline levels before treatment to levels seven days post-treatment and include G6PD testing and recording of adverse events using standard data collection instruments. Each participating in-country program or study site aims to collect data on 100-400 subjects depending on malaria endemicity and expected G6PD prevalence. We plan to collate data across these countries in a global database of individual patient data, contributing to the evidence-base for benefit-risk assessments of SLD primaquine. As other 8-aminoquinoline drugs such as tafenoquine come to market, we will be faced with related safety concerns of dose-dependent hemolysis in G6PD-deficient individuals. Active pharmacovigilance and the establishment of a standardized database for SLD primaquine not only provide opportunities to harmonize efforts, address unanswered questions regarding the safe use of SLD primaquine, and assist programs planning widespread roll-out of SLD primaquine in routine malaria case management they can also serve as a common platform for other current and future pharmacovigilance needs. The methods used in these efforts and the composition of this database will be described.

As the only marketed drug that is capable of clearing mature P. falciparum gametocytes, primaquine offers a unique ability to stop malaria transmission from humans to mosquitoes. Despite its potential role in malaria control and elimination, the widespread adoption of primaquine has been slow due to its ability to induce hemolysis in G6PD-deficient individuals. While hemolysis is understood to be dose dependent, there are limited data to support the safety and efficacy of current WHO recommendation to give, in conjunction with an artemisinin-based combination therapy, single low-dose primaquine (0.25 mg/kg) to all parasitologically-confirmed P. falciparum cases in areas threatened by artemisinin resistance or in settings approaching elimination. In March 2012, a group of experts from academia, industry, non-governmental organizations, malaria programs, and funders convened to discuss existing data on the use of primaquine as a malaria transmission blocker. The meeting served to identify roadblocks and to propose a roadmap to establish whether low-dose primaquine can be safely and effectively deployed to block P. falciparum malaria transmission in sub-Saharan Africa [1]. Since then, much knowledge has been gained on the pharmacokinetics, safety and efficacy of low-dose primaquine. Regulatory barriers to the supply and manufacture of low-dose primaquine in Africa have also been investigated. In March 2014, the group of experts reconvened to discuss roadmap progress and update potential knowledge gaps that need to be addressed in order to determine if and how low-dose primaquine can be implemented as a malaria transmission blocker. We will provide roadmap updates based on the latest meeting and will highlight gaps to welcome discussion and advice from the malaria research community.

The malaria burden in the Greater Mekong Subregion has been dramatically reduced over the last 20 years but the disease remains an important public health issue in all six countries. This chapter introduces the standard tools for malaria control (long lasting insecticidal nets; indoor residual spraying; early diagnosis and appropriate treatment; epidemic surveillance and response; and, communication) and presents the evidence base supporting the use of each of these tools in the Subregion. Targeting approaches and delivery mechanisms for these tools are presented and discussed country by country. The technical limitations of these standard tools and delivery mechanisms are then discussed in the context of local variations in the epidemiology of the disease. The challenges presented by the feeding and resting habits of local vectors, by the characteristics and behavior of different human population groups, and by particular species and drug resistant strains of malaria parasites are considered. A range of innovative tools and delivery mechanism that have been developed to address these problems are presented and moves to bring these various innovations together to provide a comprehensive package of malaria control services for each risk group are discussed. Implementation arrangements are introduced and an overview of the stakeholder landscape at regional and country level is provided. Finally, remaining programmatic gaps (which include limited coverage, declining funds, drug resistance, weak surveillance and weak health systems) are highlighted and areas in need of further action (including the need for continued innovation) are discussed.

Background This study assessed the safety of the new World Health Organization (WHO) recommendation of adding a single low-dose of primaquine (PQ) to standard artemisinin-based combination therapy (ACT), regardless of individual glucose-6-phosphate dehydrogenase (G6PD) status, for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania. Methods Men and non-pregnant, non-lactating women aged ≥1 year with uncomplicated P. falciparum malaria were enrolled and randomized to either standard artemether-lumefantrine (AL) regimen alone or with a 0.25 mg/kg single-dose of PQ. PQ was administered concomitantly with the first AL dose. All drug doses were supervised. Safety was evaluated between days 0 and 28. G6PD status was assessed using rapid test (CareStart™) and molecular genotyping. The primary endpoint was mean percentage relative reduction in haemoglobin (Hb) concentration (g/dL) between days 0 and 7 by genotypic G6PD status and treatment arm. Results Overall, 220 patients, 110 per treatment arm, were enrolled, of whom 33/217 (15.2 %) were phenotypically G6PD deficient, whereas 15/110 (13.6 %) were genotypically hemizygous males, 5/110 (4.5 %) homozygous females and 22/110 (20 %) heterozygous females. Compared to genotypically G6PD wild-type/normal [6.8, 95 % confidence interval (CI) 4.67–8.96], only heterozygous patients in AL arm had significant reduction in day-7 mean relative Hb concentration (14.3, 95 % CI 7.02-21.55, p=0.045), however, none fulfilled the pre-defined haemolytic threshold value of ≥25 % Hb reduction. After adjustment for baseline parasitaemia, Hb, age and sex the mean relative Hb reduction was not statistically significant in both heterozygous and hemizygous/homozygous patients in both arms. A majority of the adverse events (AEs) were mild and unrelated to the study drugs. However, six (4.4 %) episodes, three per treatment arm, of acute haemolytic anaemia occurred between days 0 and 7. Three occurred in phenotypically G6PD deficient patients, two in AL and one in AL + PQ arm, but none in genotypically hemizygous/homozygous patients. All patients with acute haemolytic anaemia recovered without medical intervention. Conclusion The findings support that the WHO recommendation of adding a single low-dose of PQ to standard AL regimen is safe for the treatment of acute uncomplicated P. falciparum malaria regardless of G6PD status in Tanzania. Trial registration number NCT02090036 Electronic supplementary material The online version of this article (doi:10.1186/s12936-016-1341-3) contains supplementary material, which is available to authorized users.