Correction: Comparison of artemether-lumefantrine and chloroquine with and without primaquine for the treatment of Plasmodium vivax infection in Ethiopia: A randomized controlled trial.

[This corrects the article DOI: 10.1371/journal.pmed.1002299.].

Comparison of artemether-lumefantrine and chloroquine with and without primaquine for the treatment of Plasmodium vivax infection in Ethiopia: A randomized controlled trial.

BACKGROUND: Recent efforts in malaria control have resulted in great gains in reducing the burden of Plasmodium falciparum, but P. vivax has been more refractory. Its ability to form dormant liver stages confounds control and elimination efforts. To compare the efficacy and safety of primaquine regimens for radical cure, we undertook a randomized controlled trial in Ethiopia. METHODS AND FINDINGS: Patients with normal glucose-6-phosphate dehydrogenase status with symptomatic P. vivax mono-infection were enrolled and randomly assigned to receive either chloroquine (CQ) or artemether-lumefantrine (AL), alone or in combination with 14 d of semi-supervised primaquine (PQ) (3.5 mg/kg total). A total of 398 patients (n = 104 in the CQ arm, n = 100 in the AL arm, n = 102 in the CQ+PQ arm, and n = 92 in the AL+PQ arm) were followed for 1 y, and recurrent episodes were treated with the same treatment allocated at enrolment. The primary endpoints were the risk of P. vivax recurrence at day 28 and at day 42. The risk of recurrent P. vivax infection at day 28 was 4.0% (95% CI 1.5%-10.4%) after CQ treatment and 0% (95% CI 0%-4.0%) after CQ+PQ. The corresponding risks were 12.0% (95% CI 6.8%-20.6%) following AL alone and 2.3% (95% CI 0.6%-9.0%) following AL+PQ. On day 42, the risk was 18.7% (95% CI 12.2%-28.0%) after CQ, 1.2% (95% CI 0.2%-8.0%) after CQ+PQ, 29.9% (95% CI 21.6%-40.5%) after AL, and 5.9% (95% CI 2.4%-13.5%) after AL+PQ (overall p < 0.001). In those not prescribed PQ, the risk of recurrence by day 42 appeared greater following AL treatment than CQ treatment (HR = 1.8 [95% CI 1.0-3.2]; p = 0.059). At the end of follow-up, the incidence rate of P. vivax was 2.2 episodes/person-year for patients treated with CQ compared to 0.4 for patients treated with CQ+PQ (rate ratio: 5.1 [95% CI 2.9-9.1]; p < 0.001) and 2.3 episodes/person-year for AL compared to 0.5 for AL+PQ (rate ratio: 6.4 [95% CI 3.6-11.3]; p < 0.001). There was no difference in the occurrence of adverse events between treatment arms. The main limitations of the study were the early termination of the trial and the omission of haemoglobin measurement after day 42, resulting in an inability to estimate the cumulative risk of anaemia. CONCLUSIONS: Despite evidence of CQ-resistant P. vivax, the risk of recurrence in this study was greater following treatment with AL unless it was combined with a supervised course of PQ. PQ combined with either CQ or AL was well tolerated and reduced recurrence of vivax malaria by 5-fold at 1 y. TRIAL REGISTRATION: ClinicalTrials.gov NCT01680406.

Field assessment of dried Plasmodium falciparum samples for malaria rapid diagnostic test quality control and proficiency testing in Ethiopia.

BACKGROUND: Rapid diagnostic tests (RDTs) are now widely used for laboratory confirmation of suspected malaria cases to comply with the World Health Organization recommendation for universal testing before treatment. However, many malaria programmes lack quality control (QC) processes to assess RDT use under field conditions. Prior research showed the feasibility of using the dried tube specimen (DTS) method for preserving Plasmodium falciparum parasites for use as QC samples for RDTs. This study focused on the use of DTS for RDT QC and proficiency testing under field conditions. METHODS: DTS were prepared using cultured P. falciparum at densities of 500 and 1,000 parasites/µL; 50 µL aliquots of these along with parasite negative human blood controls (0 parasites/µL) were air-dried in specimen tubes and reactivity verified after rehydration. The DTS were used in a field study in the Oromia Region of Ethiopia. Replicate DTS samples containing 0, 500 and 1,000 parasites/µL were stored at 4°C at a reference laboratory and at ambient temperatures at two nearby health facilities. At weeks 0, 4, 8, 12, 16, 20, and 24, the DTS were rehydrated and tested on RDTs stored under manufacturer-recommended temperatures at the RL and on RDTs stored under site-specific conditions at the two health facilities. Reactivity of DTS stored at 4°C at the reference laboratory on RDTs stored at the reference laboratory was considered the gold standard for assessing DTS stability. A proficiency-testing panel consisting of one negative and three positive samples, monitored with a checklist was administered at weeks 12 and 24. RESULTS: At all the seven time points, DTS stored at both the reference laboratory and health facility were reactive on RDTs stored under the recommended temperature and under field conditions, and the DTS without malaria parasites were negative. At the reference laboratory and one health facility, a 500 parasites/µL DTS from the proficiency panel was falsely reported as negative at week 24 due to errors in interpreting faint test lines. CONCLUSIONS: The DTS method can be used under field conditions to supplement other RDT QC methods and health worker proficiency in Ethiopia and possibly other malaria-endemic countries.

A description of malaria sentinel surveillance: a case study in Oromia Regional State, Ethiopia.

BACKGROUND: In the context of the massive scale up of malaria interventions, there is increasing recognition that the current capacity of routine malaria surveillance conducted in most African countries through integrated health management information systems is inadequate. The timeliness of reporting to higher levels of the health system through health management information systems is often too slow for rapid action on focal infectious diseases such as malaria. The purpose of this paper is to: 1) describe the implementation of a malaria sentinel surveillance system in Ethiopia to help fill this gap; 2) describe data use for epidemic detection and response as well as programmatic decision making; and 3) discuss lessons learned in the context of creating and running this system. CASE DESCRIPTION: As part of a comprehensive strategy to monitor malaria trends in Oromia Regional State, Ethiopia, a system of ten malaria sentinel sites was established to collect data on key malaria morbidity and mortality indicators. To ensure the sentinel surveillance system provides timely, actionable data, the sentinel facilities send aggregate data weekly through short message service (SMS) to a central database server. Bland-Altman plots and Poisson regression models were used to investigate concordance of malaria indicator reports and malaria trends over time, respectively. DISCUSSION: This paper describes three implementation challenges that impacted system performance in terms of: 1) ensuring a timely and accurate data reporting process; 2) capturing complete and accurate patient-level data; and 3) expanding the usefulness and generalizability of the system's data to monitor progress towards the national malaria control goals of reducing malaria deaths and eventual elimination of transmission. CONCLUSIONS: The use of SMS for reporting surveillance data was identified as a promising practice for accurately tracking malaria trends in Oromia. The rapid spread of this technology across Africa offers promising opportunities to collect and disseminate surveillance data in a timely way. High quality malaria surveillance in Ethiopia remains a resource intensive activity and extending the generalizability of sentinel surveillance findings to other contexts remains a major limitation of these strategies.

Perspectives from Ethiopia regarding U.S. military humanitarian assistance: how to build a better medical civil action project (MEDCAP).

Assuming that budgetary constraints continue over the next several years, the U.S. military's overseas medical activities including medical civic action projects (MEDCAPs) and humanitarian assistance projects could comprise an increasing proportion of the contributions of U.S. government (USG) to improving global health. We have identified several issues with MEDCAPs in Ethiopia since 2009 that resulted in delays or project cancellations. These were mostly related to lack of a plan to develop sustainable capacities. Although there are many obvious medical needs for civilian populations in Ethiopia, the provision of sustainable development assistance involving these Ethiopian populations on behalf of the USG is a complex undertaking involving coordination with many partners and coordination with several other USG agencies. Military medical professionals planning MEDCAPs and other cooperative global health projects would benefit from consultation and close coordination with U.S. Centers for Disease Control and Prevention (CDC) and U.S. Agency of International Development (USAID) experts who are involved in supporting medium- and long-term health projects in Ethiopia. The establishment of durable military medical academic relationships and involvement of overseas military medical research units could also help promote sustainable projects and build robust professional relationships in global health.

In vivo efficacy of artemether-lumefantrine and chloroquine against Plasmodium vivax: a randomized open label trial in central Ethiopia.

BACKGROUND: In vivo efficacy assessments of antimalarials are essential for ensuring effective case management. In Ethiopia, chloroquine (CQ) without primaquine is the first-line treatment for Plasmodium vivax in malarious areas, but artemether-lumefantrine (AL) is also commonly used. METHODS AND FINDINGS: In 2009, we conducted a 42-day efficacy study of AL or CQ for P. vivax in Oromia Regional State, Ethiopia. Individuals with P. vivax monoinfection were enrolled. Primary endpoint was day 28 cure rate. In patients with recurrent parasitemia, drug level and genotyping using microsatellite markers were assessed. Using survival analysis, uncorrected patient cure rates at day 28 were 75.7% (95% confidence interval (CI) 66.8-82.5) for AL and 90.8% (95% CI 83.6-94.9) for CQ. During the 42 days of follow-up, 41.6% (47/113) of patients in the AL arm and 31.8% (34/107) in the CQ arm presented with recurrent P. vivax infection, with the median number of days to recurrence of 28 compared to 35 days in the AL and CQ arm, respectively. Using microsatellite markers to reclassify recurrent parasitemias with a different genotype as non-treatment failures, day 28 cure rates were genotype adjusted to 91.1% (95% CI 84.1-95.1) for AL and to 97.2% (91.6-99.1) for CQ. Three patients (2.8%) with recurrent parasitemia by day 28 in the CQ arm were noted to have drug levels above 100 ng/ml. CONCLUSIONS: In the short term, both AL and CQ were effective and well-tolerated for P. vivax malaria, but high rates of recurrent parasitemia were noted with both drugs. CQ provided longer post-treatment prophylaxis than AL, resulting in delayed recurrence of parasitemia. Although the current policy of species-specific treatment can be maintained for Ethiopia, the co-administration of primaquine for treatment of P. vivax malaria needs to be urgently considered to prevent relapse infections. TRIAL REGISTRATION: ClinicalTrials.gov NCT01052584.

In vivo efficacy of artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria in Central Ethiopia.

BACKGROUND: In vivo efficacy assessments of the first-line treatments for Plasmodium falciparum malaria are essential for ensuring effective case management. In Ethiopia, artemether-lumefantrine (AL) has been the first-line treatment for uncomplicated P. falciparum malaria since 2004. METHODS: Between October and November 2009, we conducted a 42-day, single arm, open label study of AL for P. falciparum in individuals >6 months of age at two sites in Oromia State, Ethiopia. Eligible patients who had documented P. falciparum mono-infection were enrolled and followed according to the standard 2009 World Health Organization in vivo drug efficacy monitoring protocol. The primary and secondary endpoints were PCR uncorrected and corrected cure rates, as measured by adequate clinical and parasitological response on days 28 and 42, respectively. RESULTS: Of 4426 patients tested, 120 with confirmed falciparum malaria were enrolled and treated with AL. Follow-up was completed for 112 patients at day 28 and 104 patients at day 42. There was one late parasitological failure, which was classified as undetermined after genotyping. Uncorrected cure rates at both day 28 and 42 for the per protocol analysis were 99.1% (95% CI 95.1-100.0); corrected cure rates at both day 28 and 42 were 100.0%. Uncorrected cure rates at day 28 and 42 for the intention to treat analysis were 93.3% (95% CI 87.2-97.1) and 86.6% (95% CI 79.1-92.1), respectively, while the corrected cure rates at day 28 and 42 were 94.1% (95% CI 88.2-97.6) and 87.3% (95% CI 79.9-92.7), respectively. Using survival analysis, the unadjusted cure rate was 99.1% and 100.0% adjusted by genotyping for day 28 and 42, respectively. Eight P. falciparum patients (6.7%) presented with Plasmodium vivax infection during follow-up and were excluded from the per protocol analysis. Only one patient had persistent parasitaemia at day 3. No serious adverse events were reported, with cough and nausea/vomiting being the most common adverse events. CONCLUSIONS: AL remains a highly effective and well-tolerated treatment for uncomplicated falciparum malaria in the study setting after several years of universal access to AL. A high rate of parasitaemia with P. vivax possibly from relapse or new infection was observed. TRIAL REGISTRATION: NCT01052584.

Telephone survey to assess influenza-like illness, United States, 2006.

Although current national response plans assume that most influenza-infected patients would stay home during a pandemic, surveillance systems might be overwhelmed and unable to monitor their health status. We explored the feasibility of using a nationwide telephone survey to monitor at-home patients. Of randomly selected adults surveyed during low influenza activity months (April-October 2006, surveillance weeks 17-41), 86% (7,268/8,449) agreed to answer questions about health status and influenza-like illness symptoms. Three percent (230/7,628) self-reported "flu." A subset (0.9%, 68/230) self-reported fever. In comparison, the Centers for Disease Control and Prevention's Sentinel Provider Network reported clinical influenza-like illness rates of 1.2%, 0.9%, and 1.2% for weeks 17, 20, and 41, respectively. The consistency between information obtained by telephone and surveillance data warrants further studies to determine whether telephone surveys can accurately monitor health status during seasonal influenza peaks and to augment current surveillance systems during a pandemic.

Multiple sclerosis prevalence and possible lead exposure.

This study was conducted to estimate the current prevalence of multiple sclerosis (MS) in Jefferson County, Missouri, USA, and to address community concerns about a perceived excess of MS around an active lead smelter. The study population consisted of the residents of Jefferson County, Missouri between 1998 and 2002. An aggressive MS case finding with capture-recapture analysis was used. The spatial clustering was examined using a spatial scan statistic. The capture-recapture analysis showed the case ascertainment to be 95%. The crude five-year period prevalence of MS in Jefferson County was 105 per 100,000 population (95% confidence interval [CI], 91-121), and 107 per 100,000 (95% CI, 95-119) when age-standardized to the 2000 U.S. population. No significant spatial clusters of MS cases were identified in the study area. The estimates of MS prevalence in Mid-western community of USA appeared to be comparable to estimates from other areas of similar latitude in the United States and Western Europe. The MS cases did not appear to cluster around the lead smelter.

An epidemiologic investigation of amyotrophic lateral sclerosis in Jefferson County, Missouri, 1998-2002.

Amyotrophic lateral sclerosis (ALS) cases diagnosed between 1998 and 2002 were identified to study ALS prevalence and spatial clustering in Jefferson County, Missouri, where an active lead smelter is located. The study used the El Escorial criteria for ALS diagnosis, the capture-recapture analysis for ALS case ascertainment, and the spatial scan statistic for cluster analysis. The estimated crude prevalence of ALS in Jefferson County was 3.9 per 100,000 population (95% CI, 1.7-7.7) at the time point on December 31, 2002. After age-adjustment to the 2002 U.S. population, the prevalence was 4.2 per 100,000 (95% CI, 1.9-6.6). This prevalence estimate was comparable to recent prevalence estimates from Western Europe. A small but significant cluster (p=0.04) was detected around the smelter area. An ALS registry utilizing outpatient, inpatient, and death certificate data is needed to provide comprehensive information for ALS case ascertainment. Etiologic studies are needed to assess whether living in proximity to a lead smelter is associated with the development of ALS.

Department of Defense Global Emerging Infections Surveillance and Response System Indian Ocean tsunami response.

The Department of Defense (DoD) Global Emerging Infections Surveillance and Response System (DoD-GEIS) identifies and addresses DoD vulnerabilities to emerging infections through a global network of partners. Following the Indian Ocean tsunami of December 26, 2004, DoD-GEIS facilitated the DoD medical response and coordination with the Centers for Disease Control and Prevention and the World Health Organization. DoD-GEIS partners in Southeast Asia (U.S. Naval Medical Research Unit 2, Jakarta, Indonesia; and Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand) rapidly conducted health assessments and established surveillance for communicable diseases that threatened survivors. Preexisting collaboration with the Centers for Disease Control and Prevention, the World Health Organization, and host countries was critical for the DoD-GEIS tsunami response.

A veterinarian's experience of the spring 2004 avian influenza outbreak in Laos.

Since it was first reported in December 2003, the outbreak of avian influenza A/H5N1 has spread to at least nine countries in Asia, affected multiple species of animals, and caused at least 42 human deaths. The magnitude and extent of this zoonotic outbreak are unprecedented, continue to grow, and threaten the start of a global human influenza pandemic. Control of the H5N1 outbreak has required the implementation of integrated human and veterinary health surveillance and response efforts. These efforts have also necessitated an unprecedented level of bilateral and multilateral international communication and cooperation. This report describes the contribution of one public-health veterinarian to the H5N1 outbreak response effort in Laos, and emphasises the value of multidisciplinary approaches to addressing this and future emerging infectious disease outbreaks.

Investigation of healthcare-associated transmission of Mycobacterium tuberculosis among patients with malignancies at three hospitals and at a residential facility.

BACKGROUND: Immunocompromised patients have an increased risk of experiencing progression of latent Mycobacterium tuberculosis infection (LTBI) to active tuberculosis (TB) disease. In January 2002, 2 patients with leukemia (Patients 1 and 2) developed pulmonary TB after recent exposure at 3 hospitals (Hospital A, Hospital B, and Hospital C) and at a residential facility for patients with cancer. Neither was known to have LTBI. Within 1 year, 3 other patients with malignancy and TB disease had been identified at these facilities, prompting an investigation of healthcare facility-associated transmission of M. tuberculosis. METHODS: The authors performed genotypic analysis of the five available M. tuberculosis isolates from patients with malignancies at these facilities, reviewed medical records, interviewed individuals who had identical M. tuberculosis genotypic patterns, and performed tuberculin skin testing (TST) and case finding for possible exposed contacts. RESULTS: Only Patients 1 and 2 had identical genotypic patterns. Neither patient had baseline TST results available. Patient 1 had clinical evidence of infectiousness 3 months before the diagnosis of TB was ascertained. Among employee contacts of Patient 1, TST conversions occurred in 1 of 59 (2%), 2 of 34 (6%), 2 of 32 (6%), and 0 of 8 who were tested at Hospitals A, B, and C and at the residential facility, respectively. Among the others who were exposed to Patient 1, 1 of 31 (3%), 1 of 30 (3%), 0 of 40 (0%), and 12 of 136 (9%) who were tested had positive TSTs at Hospitals A, B, and C and at the residential facility, respectively. CONCLUSIONS: Delayed TB diagnosis in 2 patients with leukemia resulted in the transmission of M. tuberculosis to 19 patients and staff at 3 hospitals and a residential facility. Baseline TB screening and earlier clinical recognition of active disease could reduce healthcare facility-associated transmission of M. tuberculosis among patients with malignancy.

Trends of multiple-drug resistance among Salmonella serotype Typhi isolates during a 14-year period in Egypt.

A total of 853 isolates of Salmonella serotype Typhi recovered from patients with typhoid fever who were admitted to a major infectious disease hospital in Cairo, Egypt, from 1987 through 2000 underwent antibiotic susceptibility testing to determine multiple-drug resistance. The observed resurgence of chloramphenicol susceptibility (P=.002) may suggest reuse of this drug for the treatment of typhoid fever in Egypt.

Evaluation of dipstick serologic tests for diagnosis of brucellosis and typhoid Fever in egypt.

Two dipstick assays for the detection of Brucella- and typhoid-specific immunoglobulin M, recently developed by the Royal Tropical Institute of The Netherlands, were evaluated by use of 85 plasma samples from Egyptian patients. Both dipsticks were simple and accurate rapid diagnostic assays, and they can be useful adjuncts for the diagnosis of typhoid fever and brucellosis.