John R. MacArthur

An Outbreak of Cryptosporidiosis Linked to a Foodhandler

In September and October 1998, a cryptosporidiosis outbreak occurred on a Washington, DC, university campus. In a case-control study of 88 case patients and 67 control subjects, eating in 1 of 2 cafeterias was associated with diarrheal illness (P<.001). Morbidity was associated with eating dinner on 22 September (odds ratio, 8.1; 95% confidence interval, 3.4-19.5); weaker associations were found for 6 other meals. Cryptosporidium parvum was detected in stool specimens of 16 (70%) of 23 ill students and 2 of 4 ill employees. One ill foodhandler with laboratory-confirmed C. parvum prepared raw produce on 20-22 September. All 25 Cryptosporidium isolates submitted for DNA analysis, including 3 from the ill foodhandler, were genotype 1. This outbreak illustrates the potential for cryptosporidiosis to cause foodborne illness. Epidemiologic and molecular evidence indicate that an ill foodhandler was the likely outbreak source.

Efficacy of Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine for Treatment of Uncomplicated Malaria in Children in Zaire and Uíge Provinces, Angola

ABSTRACT The development of resistance to antimalarials is a major challenge for global malaria control. Artemisinin-based combination therapies, the newest class of antimalarials, are used worldwide but there have been reports of artemisinin resistance in Southeast Asia. In February through May 2013, we conducted open-label, nonrandomized therapeutic efficacy studies of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) in Zaire and Uíge Provinces in northern Angola. The parasitological and clinical responses to treatment in children with uncomplicated Plasmodium falciparum monoinfection were measured over 28 days, and the main outcome was a PCR-corrected adequate clinical and parasitological response (ACPR) proportion on day 28. Parasites from treatment failures were analyzed for the presence of putative molecular markers of resistance to lumefantrine and artemisinins, including the recently identified mutations in the K13 propeller gene. In the 320 children finishing the study, 25 treatment failures were observed: 24 in the AL arms and 1 in the DP arm. The PCR-corrected ACPR proportions on day 28 for AL were 88% (95% confidence interval [CI], 78 to 95%) in Zaire and 97% (91 to 100%) in Uíge. For DP, the proportions were 100% (95 to 100%) in Zaire, and 100% (96 to 100%) in Uíge. None of the treatment failures had molecular evidence of artemisinin resistance. In contrast, 91% of AL late-treatment failures had markers associated with lumefantrine resistance on the day of failure. The absence of molecular markers for artemisinin resistance and the observed efficacies of both drug combinations suggest no evidence of artemisinin resistance in northern Angola. There is evidence of increased lumefantrine resistance in Zaire, which should continue to be monitored.

Malaria in pregnant women in an area with sustained high coverage of insecticide-treated bed nets

BackgroundSince 2000, the World Health Organization has recommended a package of interventions to prevent malaria during pregnancy and its sequelae that includes the promotion of insecticide-treated bed nets (ITNs), intermittent preventive treatment in pregnancy (IPTp), and effective case management of malarial illness. It is recommended that pregnant women in malaria-endemic areas receive at least two doses of sulphadoxine-pyrimethamine in the second and third trimesters of pregnancy. This study assessed the prevalence of placental malaria at delivery in women during 1st or 2nd pregnancy, who did not receive intermittent preventive treatment for malaria (IPTp) in a malaria-endemic area with high bed net coverage.MethodsA hospital-based cross-sectional study was done in Ifakara, Tanzania, where bed net coverage is high. Primi- and secundigravid women, who presented to the labour ward and who reported not using IPTp were included in the study. Self-report data were collected by questionnaire; whereas neonatal birth weight and placenta parasitaemia were measured directly at the time of delivery.ResultsOverall, 413 pregnant women were enrolled of which 91% reported to have slept under a bed net at home the previous night, 43% reported history of fever and 62% were primigravid. Malaria parasites were detected in 8% of the placenta samples; the geometric mean (95%CI) placental parasite density was 3,457 (1,060–11,271) parasites/μl in primigravid women and 2,178 (881–5,383) parasites/μl in secundigravid women. Fifteen percent of newborns weighed <2,500 g at delivery. Self-reported bed net use was statistically associated with lower risk for low birth weight [OR 0.34 (95% CI: 0.16–0.74) and OR 0.22 (95% CI: 0.08–0.59) for untreated and treated bed nets, respectively], but was not associated with placental parasitaemia [OR 0.74 (0.21–2.68) and OR 1.64 (0.44–6.19) for untreated and treated bed nets, respectively].ConclusionThe observed incidence of LBW and prevalence of placental parasitaemia at delivery suggests that malaria remains a problem in pregnancy in this area with high bed net coverage when eligible women do not receive IPTp. Delivery of IPTp should be emphasized at all levels of implementation to achieve maximum community coverage.

Routine delivery of artemisinin-based combination treatment at fixed health facilities reduces malaria prevalence in Tanzania: an observational study

BackgroundArtemisinin-based combination therapy (ACT) has been promoted as a means to reduce malaria transmission due to their ability to kill both asexual blood stages of malaria parasites, which sustain infections over long periods and the immature derived sexual stages responsible for infecting mosquitoes and onward transmission. Early studies reported a temporal association between ACT introduction and reduced malaria transmission in a number of ecological settings. However, these reports have come from areas with low to moderate malaria transmission, been confounded by the presence of other interventions or environmental changes that may have reduced malaria transmission, and have not included a comparison group without ACT. This report presents results from the first large-scale observational study to assess the impact of case management with ACT on population-level measures of malaria endemicity in an area with intense transmission where the benefits of effective infection clearance might be compromised by frequent and repeated re-infection.MethodsA pre-post observational study with a non-randomized comparison group was conducted at two sites in Tanzania. Both sites used sulphadoxine-pyrimethamine (SP) monotherapy as a first-line anti-malarial from mid-2001 through 2002. In 2003, the ACT, artesunate (AS) co-administered with SP (AS + SP), was introduced in all fixed health facilities in the intervention site, including both public and registered non-governmental facilities. Population-level prevalence of Plasmodium falciparum asexual parasitaemia and gametocytaemia were assessed using light microscopy from samples collected during representative household surveys in 2001, 2002, 2004, 2005 and 2006.FindingsAmong 37,309 observations included in the analysis, annual asexual parasitaemia prevalence in persons of all ages ranged from 11% to 28% and gametocytaemia prevalence ranged from <1% to 2% between the two sites and across the five survey years. A multivariable logistic regression model was fitted to adjust for age, socioeconomic status, bed net use and rainfall. In the presence of consistently high coverage and efficacy of SP monotherapy and AS + SP in the comparison and intervention areas, the introduction of ACT in the intervention site was associated with a modest reduction in the adjusted asexual parasitaemia prevalence of 5 percentage-points or 23% (p < 0.0001) relative to the comparison site. Gametocytaemia prevalence did not differ significantly (p = 0.30).InterpretationThe introduction of ACT at fixed health facilities only modestly reduced asexual parasitaemia prevalence. ACT is effective for treatment of uncomplicated malaria and should have substantial public health impact on morbidity and mortality, but is unlikely to reduce malaria transmission substantially in much of sub-Saharan Africa where individuals are rapidly re-infected.

The challenge of artemisinin resistance can only be met by eliminating Plasmodium falciparum malaria across the Greater Mekong subregion

Artemisinin-based combinations are currently the most effective anti-malarials and, in addition to vector control, have led to significant declines in malaria morbidity and mortality. However, foci of artemisinin drug resistance have been identified in the Greater Mekong subregion (GMS) of the Asia Pacific, threatening the major gains made in malaria control and potentially creating a parasite pool that is more difficult to treat and eliminate. Efforts are underway to halt the spread of artemisinin resistance, including coordination of activities and funding, and identification of areas of suspected artemisinin resistance, now using a newly identified molecular marker. However, targeting resources to the containment of resistant parasites is likely inefficient and monitoring impact is challenging. A more sustainable solution is the rapid elimination of all Plasmodium falciparum parasites from the GMS. This strategy is more efficient for several reasons. First, a subregional strategy is in line with current commitment to elimination and will build upon the existing national political support for elimination as well as enhancing collaboration among countries. Second, the challenge of human mobility in the GMS is subregional in scope and requires a harmonized elimination strategy. Third, countries will need to improve and intensify malaria operations to reach elimination, and this will be a singular goal across the subregion. Rallying around the goal of P. falciparum elimination will not only utilize existing regional bodies to catalyze political and funding support, but will also leverage the funding already in place to achieve this subregional goal.

New global estimates of malaria deaths

www.thelancet.com Vol 380 August 11, 2012 559 Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/ 4 Kahama-Maro J, D’Acremont V, Mtasiwa D, Genton B, Lengeler C. Low quality of routine microscopy for malaria at diff erent levels of the health system in Dar es Salaam. Malaria J 2011; 10: 332. 5 Makani J, Matuja W, Liyombo E, Snow RW, Marsh K, Warrell DA. Admission diagnosis of cerebral malaria in adults in an endemic area of Tanzania: implications and clinical description. QJM 2003; 96: 355–62. New global estimates of malaria deaths

Extensive Drug Resistance in Malaria and Tuberculosis

Emergence of artemisinin resistance is reason to revise the definition of drug resistance for malaria.

Probable locally acquired mosquito-transmitted malaria in Georgia, 1999.

In July 1999, the Centers for Disease Control and Prevention received notification of a case of malaria in a 32-year-old female native of Colquitt County, Georgia, who had no history of travel into an area where malaria transmission is endemic. An epidemiological investigation confirmed the absence of risk factors, such as blood transfusion, organ transplantation, malariotherapy, needle sharing, or past malaria infection. Active case finding revealed no other infected persons in Colquitt County. Light trapping and larvae-dipping failed to identify adult or larval anophelines; however, Colquitt County is known to be inhabited by Anopheles quadrimaculatus, a competent malaria vector. The patients home was located near housing used by seasonal migrant workers from regions of southern Mexico and Central America where malaria is endemic, one of whom may have been the infection source. The occurrence of malaria in this patient with no risk factors, except for proximity to potentially gametocytemic hosts, suggests that this illness probably was acquired through the bite of an Anopheles species mosquito.

Delayed Plasmodium falciparum clearance following artesunate-mefloquine combination therapy in Thailand, 1997-2007.

BackgroundThere is concern that artesunate resistance is developing in Southeast Asia. The purpose of this study is to investigate the prevalence of parasitaemia in the few days following treatment with artesunate-mefloquine (AM), which is an indirect measure of decreased artesunate susceptibility.MethodsThis is a retrospective analysis of 31 therapeutic efficacy studies involving 1,327 patients treated with AM conducted by the Thai National Malaria Control Programme from 1997–2007.ResultsThe prevalence of patients with parasitaemia on day 2 was higher in the east compared to the west (east: 20%, west: 9%, OR 2.47, 95% CI: 1.77, 3.45). In addition, the prevalence of day-2 parasitaemia increased over time (OR for each year = 1.10, 95% CI: 1.03, 1.19). After controlling for initial parasitaemia and age, year and region remained important determinants of day-2 parasitaemia (OR for region = 3.98, 95%CI 2.63, 6.00; OR for year = 1.28, 95%CI: 1.17, 1.39). The presence of parasitaemia on day 2 and day 3 were specific, but not sensitive predictors of treatment failure.DiscussionDelayed resolution of parasitaemia after AM treatment increased in eastern Thailand between 1997 and 2007, which may be an early manifestation of decreased artesunate susceptibility. However, clinical and parasitological treatment failure after 28 days (which is related to both mefloquine and artesunate decreased susceptibility) is not changing over time. The presence of parasitaemia on day 2 is a poor indicator of AM 28-day treatment failure.

A call to action: addressing the challenge of artemisinin-resistant malaria

Malaria continues to exert an enormous toll globally. In 2008, there were an estimated 243 million clinical cases and 863,000 deaths [101]. More than 80% of these cases and approximately 90% of the deaths occur in sub-Saharan Africa, mainly among children less than 5 years of age. Despite these staggering figures, the past decade has seen a resurgence of optimism regarding progress in malaria control. Although much remains to be done, there are now well-documented examples of success achieved through scale-up of key interventions. Reduced malaria infection and associated reductions in child morbidity and mortality have been reported in Equatorial Guinea [1], Zanzibar [2], São Tomé and Principe [3], Rwanda and Ethiopia [4]. As scale-up and coverage continue to progress in other countries, especially those with a very high malaria burden, it is expected that similar gains will be achieved. The strategy to reduce malaria morbidity and mortality in sub-Saharan Africa is predicated on achieving rapid, high-level population coverage with four key inter ventions: long-lasting insecticide-treated nets (ITNs), indoor residual spraying (where appropriate), intermittent preventive treatment in pregnancy, and prompt and effective treatment with artemisinin-containing combination therapies (ACTs) [102]. ACTs have been shown to be highly effective in the treatment of uncomplicated malaria [5]. All 42 countries in Africa with endemic Plasmodium falciparum transmission have adopted ACTs as a first-line treatment, replacing older, less effective choices such as chloroquine or sulfadoxine–pyrimethamine [101]. These older regimens were greatly compromised by high levels of parasite drug resistance and were associated with an alarming deterioration in child survival [6]. While programmatic roll out of ACTs has lagged somewhat behind that seen with ITNs [101], major efforts are underway to increase access to these antimalarials through the public and private sectors, and through facility and community-based delivery systems. High ACT coverage is expected to substantially contribute to further reductions in child mortality in Africa over the next 5–10 years. To date, in Africa there has been no evidence of a decreased response of P. falciparum to artemisinin. Recent reports from Southeast Asia suggest that falciparum parasites now show early signs of resistance to ACTs and artemisinin monotherapies [7]. These reports sparked a call for containment of the resistant parasite and/or elimination of malaria transmission from the subregion [103]. Scientists have yet to uncover the bio logical basis for this development. Southeast Asia has been, historically, the crucible in which biological, pharmaco logical, cultural, political and economic factors have catalyzed the emergence of parasites resistant to one antimalarial compound after another. If artemisinin-resistant parasites make their way from the forests and swidden farms in the Mekong Basin to the East African Coast – just as chloroquineand sulfonamideresistant parasites have done [8,9] – many fear the remarkable achievements just getting underway in many African countries will be short-lived. The immediate call to contain or eliminate ACT-resistant malaria in Southeast Asia has implications for the rest of the Stephen P Kachur Malaria Branch, US Centers for Disease Control and Prevention, Mailstop F-22, 4770 Buford Highway, NE, Atlanta, GA 30341, USA