Ron H. Behrens

Imported Falciparum Malaria in Europe: Sentinel Surveillance Data from the European Network on Surveillance of Imported Infectious Diseases

Malaria continues to have a high morbidity rate associated among European travelers. Thorough recording of epidemiological and clinical aspects of imported malaria has been helpful in the detection of new outbreaks and areas of developing drug resistance. Sentinel surveillance of data collected prospectively since 1999 has begun within TropNetEurop, a European network focusing on imported infectious diseases. TropNetEurop appears to cover approximately 10% of all patients with malaria seen in Europe. Reports of 1659 immigrants and European patients with Plasmodium falciparum malaria were analyzed for epidemiological information and data on clinical features. Regional data were quite diverse, reflecting local patterns of immigration and international travel. By far, the most infections were imported from West Africa. Europeans had more clinical complications; consequently, all deaths occurred in this group. Compared with European standards, the mortality rate was low (0.6% in Europeans). Data from TropNetEurop member sites can contribute to our understanding of the epidemiological and clinical findings regarding imported falciparum malaria.

Atovaquone-Proguanil versus Mefloquine for Malaria Prophylaxis in Nonimmune Travelers: Results from a Randomized, Double-Blind Study

Concerns about the tolerability of mefloquine highlight the need for new drugs to prevent malaria. Atovaquone-proguanil (Malarone; GlaxoSmithKline) was safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but experience in nonimmune people is limited. In a randomized, double-blind study, nonimmune travelers received malaria prophylaxis with atovaquone-proguanil (493 subjects) or mefloquine (483 subjects). Information about adverse events (AEs) and potential episodes of malaria was obtained 7, 28, and 60 days after travel. AEs were reported by an equivalent proportion of subjects who had received atovaquone-proguanil or mefloquine (71.4% versus 67.3%; difference, 4.1%; 95% confidence interval, -1.71 to 9.9). Subjects who received atovaquone-proguanil had fewer treatment-related neuropsychiatric AEs (14% versus 29%; P=.001), fewer AEs of moderate or severe intensity (10% versus 19%; P=.001), and fewer AEs that caused prophylaxis to be discontinued (1.2% versus 5.0%; P=.001), compared with subjects who received melfoquine. No confirmed diagnoses of malaria occurred in either group. Atovaquone-proguanil was better tolerated than was mefloquine, and it was similarly effective for malaria prophylaxis in nonimmune travelers.

Assessment of the incidence of substandard drugs in developing countries

In a number of developing countries there is reportedly a high incidence of the availability of substandard drugs. The majonty of these reports do not contain quantitative data to support these claims, nor do they describe the methodology employed for the quality assessment. Many assume counterfeiting as the reason for the poor quality and in some cases this is not justified. We collected 96 samples of chloroquine and selected antibacterials from Nigeria and Thailand in a controlled and methodical manner and analysed them using appropriately validated methods based on high‐performance liquid chromatography capable of detecting drug‐related impurities and quantifying active drug(s). The results indicate that 36.5% of the samples were substandard with respect to pharmacopoeial limits. Decomposition was the cause of poor quality in a number of the samples but overall, poor manufacturing appeared to be prevalent. The analyses generated little evidence to indicate fraudulent manufacturing. Treatment failure and drug‐resistance are possible consequences of the use of substandard drugs.

Pharmacopoeial quality of drugs supplied by Nigerian pharmacies

BACKGROUND The quality of medicines available in some less-developed countries is inadequate in terms of content of active ingredient. Reasons for the poor quality of drugs include widespread counterfeiting of medicines in less-developed countries, excessive decomposition of active ingredient as a result of high temperature and humidity, and poor quality assurance during the manufacture of medicinal products. Our aim was to investigate the quality of different drugs obtained from retail pharmacies in two urban areas of Nigeria, and, in instances of poor quality, to ascertain the reason why. METHODS We randomly collected 581 samples of 27 different drugs from 35 pharmacies in Lagos and Abuja in Nigeria. We analysed the medicines for drug content by validated chromatographic methods, and compared our results with pharmacopoeial requirements. FINDINGS 279 (48%) samples did not comply with set pharmacopoeial limits, and this proportion was uniform for the various types of drugs tested. Although some preparations contained no active ingredient, most had amounts just outside the pharmacopoeial limits. We identified samples with both too much and too little active drug content. INTERPRETATION The most probable cause of the poor quality of drugs is absence of adequate quality assurance during manufacture. Substandard drugs sold in the pharmacies of less-developed countries could contribute to global microbial resistance and therapeutic failure of infectious diseases.

Imported malaria and high risk groups: observational study using UK surveillance data 1987-2006

Objective To examine temporal, geographic, and sociodemographic trends in case reporting and case fatality of malaria in the United Kingdom. Setting National malaria reference laboratory surveillance data in the UK. Design Observational study using prospectively gathered surveillance data and data on destinations from the international passenger survey. Participants 39 300 cases of proved malaria in the UK between 1987 and 2006. Main outcome measures Plasmodium species; sociodemographic details (including age, sex, and country of birth and residence); mortality; destination, duration, and purpose of international travel; and use of chemoprophylaxis. Results Reported cases of imported malaria increased significantly over the 20 years of the study; an increasing proportion was attributable to Plasmodium falciparum (P falciparum/P vivax reporting ratio 1.3:1 in 1987-91 and 5.4:1 in 2002-6). P vivax reports declined from 3954 in 1987-91 to 1244 in 2002-6. Case fatality of reported P falciparum malaria did not change over this period (7.4 deaths per 1000 reported cases). Travellers visiting friends and relatives, usually in a country in Africa or Asia from which members of their family migrated, accounted for 13 215/20 488 (64.5%) of all malaria reported, and reports were geographically concentrated in areas where migrants from Africa and South Asia to the UK have settled. People travelling for this purpose were at significantly higher risk of malaria than other travellers and were less likely to report the use of any chemoprophylaxis (odds ratio of reported chemoprophylaxis use 0.23, 95% confidence interval 0.21 to 0.25). Conclusions Despite the availability of highly effective preventive measures, the preventable burden from falciparum malaria has steadily increased in the UK while vivax malaria has decreased. Provision of targeted and appropriately delivered preventive messages and services for travellers from migrant families visiting friends and relatives should be a priority.

NK Cells as Effectors of Acquired Immune Responses: Effector CD4+ T Cell-Dependent Activation of NK Cells Following Vaccination

We characterized vaccine-induced cellular responses to rabies virus in naive adult volunteers. Contrary to current paradigms, we observed potent and prolonged in vitro NK cell cytokine production and degranulation responses after restimulation of PBMCs with inactivated rabies virus in vaccinated, but not in unvaccinated, individuals. This “recall” NK cell response was absolutely dependent on Ag-specific IL-2 from CD45RO+ CD4+ T cells as well as IL-12 and IL-18 from accessory cells. Importantly, NK cells represented over 70% of all IFN-γ–secreting and degranulating cells in the first 12–18 h after virus rechallenge indicating they may be required for rapid control of infection after vaccination. Activation of NK cells may be a critical function of IL-2–secreting effector memory T cells. Although IL-2–dependent postvaccination NK cell activation has been reported previously, this is the first time the magnitude of this effect and its contribution to the overall vaccine-induced response has been appreciated and the mechanisms of NK activation postvaccination have been elucidated. Our data will allow standard protocols for evaluating vaccine-induced immunity to be adapted to assess NK cell effector responses.

Epidemiology and clinical features of vivax malaria imported to Europe: Sentinel surveillance data from TropNetEurop

BackgroundPlasmodium vivax is the second most common species among malaria patients diagnosed in Europe, but epidemiological and clinical data on imported P. vivax malaria are limited. The TropNetEurop surveillance network has monitored the importation of vivax malaria into Europe since 1999.ObjectivesTo present epidemiological and clinical data on imported P. vivax malaria collected at European level.Material and methodsData of primary cases of P. vivax malaria reported between January 1999 and September 2003 were analysed, focusing on disease frequency, patient characteristics, place of infection, course of disease, treatment and differences between network-member countries.ResultsWithin the surveillance period 4,801 cases of imported malaria were reported. 618 (12.9%) were attributed to P. vivax. European travellers and immigrants were the largest patient groups, but their proportion varied among the reporting countries. The main regions of infection in descending order were the Indian subcontinent, Indonesia, South America and Western and Eastern Africa, as a group accounting for more than 60% of the cases. Regular use of malaria chemoprophylaxis was reported by 118 patients. With 86 (inter-quartile range 41–158) versus 31 days (inter-quartile range 4–133) the median symptom onset was significantly delayed in patients with chemoprophylaxis (p < 0.0001). Common complaints were fever, headache, fatigue, and musculo-skeletal symptoms. All patients survived and severe clinical complications were rare. Hospitalization was provided for 60% and primaquine treatment administered to 83.8% of the patients, but frequencies varied strongly among reporting countries.ConclusionsTropNetEurop data can contribute to the harmonization of European treatment policies.

Knowledge of Malaria, Risk Perception, and Compliance with Prophylaxis and Personal and Environmental Preventive Measures in Travelers Exiting Zimbabwe from Harare and Victoria Falls International Airport

BACKGROUND Travel associated malaria is a major health risk for visitors to malaria endemic destinations. To examine the knowledge of malaria prevention, risk perception, current prophylactic behavior, and compliance with chemoprophylaxis and personal and environmental protection measures we conducted a study in a cohort of travelers exiting Zimbabwe from two international airports during a peak malaria transmission period. METHODS Data were collected by pretested self-administered questionnaires from 595 adults in the departure lounges of Harare and Victoria Falls International airports. Excluded were children and travelers from the African continent. A multilingual research assistant supervised data collection. RESULTS The majority of travelers obtained health advice prior to travel. Patterns of protective behavior and compliance with prophylaxis were inconsistent with a high perception of malaria threat and good knowledge. About 23% of travelers failed to use chemoprophylaxis during their visit. In the group of travelers who used chemoprophylaxis, 18% were noncompliant. Fifteen drug combinations were in use. Full compliance with medication plus use of personal preventive measures always was estimated as 13%. Forgetfulness was the main cause of noncompliance, followed by deliberate omission due to side effects. Of 57 travelers who reported side effects from current medication, over half used mefloquine. CONCLUSIONS There is a need to examine how people process personal risk and communications about risk. We must recognize the competition between precautionary measures against malaria and other life demands that are imposed by travel, especially in young long stay travelers and persons visiting primarily for business purposes. Mediating a protective response will also depend on judgments about the effectiveness of the action, strengthening travelers intentions toward adherence, and increasing efficacy perception by individuals and their peers. Conflicts in prophylactic recommendations need to be resolved. As ecotourism develops in Zimbabwe and other malaria regions, stakeholders in this rapidly growing industry must be made aware of the important role they can play in protecting clients from malaria.

Age as a Risk Factor for Severe Manifestations and Fatal Outcome of Falciparum Malaria in European Patients: Observations from TropNetEurop and SIMPID Surveillance Data

Previous studies have indicated that age is a risk factor for severe falciparum malaria in nonimmune patients. The objectives of this study were to reevaluate previous findings with a larger sample and to find out how strongly clinical outcomes for elderly patients differ from those for younger patients. Results of adjusted analyses indicated that the risks of death due to falciparum malaria, of experiencing cerebral or severe disease in general, and of hospitalization increased significantly with each decade of life. The case-fatality rate was almost 6 times greater among elderly patients than among younger patients, and cerebral complications occurred 3 times more often among elderly patients. Antimalarial chemoprophylaxis was significantly associated with a lower case-fatality rate and a lower frequency of cerebral complications. Women were more susceptible to cerebral complications than were men. Our study provides evidence that falciparum malaria is more serious in older patients and demonstrates that clinical surveillance networks are capable of providing quality data for investigation of rare events or diseases.

Malaria:: An Update for Physicians

Malaria remains the most important parasitic infection in humans. There have been significant advances in the treatment of both nonsevere and severe malaria with the advent of artemisinin combination therapies and parenteral artesunate, but the optimum supportive management of severe malaria is unclear. A broadly acceptable therapy for the prevention of relapses in Plasmodium vivax infection has not been discovered. Globally, the priority remains to prevent infection in the vulnerable, to move toward elimination where feasible, and to ensure that effective treatment is available to all. In developed settings, prevention of infection and its early recognition are crucial.