G. Dennis Shanks

Deaths from bacterial pneumonia during 1918-19 influenza pandemic.

A sequential-infection hypothesis is consistent with characteristics of this pandemic.

A large proportion of asymptomatic Plasmodium infections with low and sub-microscopic parasite densities in the low transmission setting of Temotu Province, Solomon Islands: challenges for malaria diagnostics in an elimination setting

BackgroundMany countries are scaling up malaria interventions towards elimination. This transition changes demands on malaria diagnostics from diagnosing ill patients to detecting parasites in all carriers including asymptomatic infections and infections with low parasite densities. Detection methods suitable to local malaria epidemiology must be selected prior to transitioning a malaria control programme to elimination. A baseline malaria survey conducted in Temotu Province, Solomon Islands in late 2008, as the first step in a provincial malaria elimination programme, provided malaria epidemiology data and an opportunity to assess how well different diagnostic methods performed in this setting.MethodsDuring the survey, 9,491 blood samples were collected and examined by microscopy for Plasmodium species and density, with a subset also examined by polymerase chain reaction (PCR) and rapid diagnostic tests (RDTs). The performances of these diagnostic methods were compared.ResultsA total of 256 samples were positive by microscopy, giving a point prevalence of 2.7%. The species distribution was 17.5% Plasmodium falciparum and 82.4% Plasmodium vivax. In this low transmission setting, only 17.8% of the P. falciparum and 2.9% of P. vivax infected subjects were febrile (≥38°C) at the time of the survey. A significant proportion of infections detected by microscopy, 40% and 65.6% for P. falciparum and P. vivax respectively, had parasite density below 100/μL. There was an age correlation for the proportion of parasite density below 100/μL for P. vivax infections, but not for P. falciparum infections. PCR detected substantially more infections than microscopy (point prevalence of 8.71%), indicating a large number of subjects had sub-microscopic parasitemia. The concordance between PCR and microscopy in detecting single species was greater for P. vivax (135/162) compared to P. falciparum (36/118). The malaria RDT detected the 12 microscopy and PCR positive P. falciparum, but failed to detect 12/13 microscopy and PCR positive P. vivax infections.ConclusionAsymptomatic malaria infections and infections with low and sub-microscopic parasite densities are highly prevalent in Temotu province where malaria transmission is low. This presents a challenge for elimination since the large proportion of the parasite reservoir will not be detected by standard active and passive case detection. Therefore effective mass screening and treatment campaigns will most likely need more sensitive assays such as a field deployable molecular based assay.

Hot topic or hot air? Climate change and malaria resurgence in East African highlands

Climate has a significant impact on malaria incidence and we have predicted that forecast climate changes might cause some modifications to the present global distribution of malaria close to its present boundaries. However, it is quite another matter to attribute recent resurgences of malaria in the highlands of East Africa to climate change. Analyses of malaria time-series at such sites have shown that malaria incidence has increased in the absence of co-varying changes in climate. We find the widespread increase in resistance of the malaria parasite to drugs and the decrease in vector control activities to be more likely driving forces behind the malaria resurgence.

A New Primaquine Analogue, Tafenoquine (WR 238605), for Prophylaxis against Plasmodium falciparum Malaria

We tested tafenoquine (WR 238605), a new long-acting 8-aminoquinoline, for its ability to prevent malaria in an area that is holoendemic for Plasmodium falciparum. In a double-blinded, placebo-controlled, randomized clinical trial in western Kenya, adult volunteers received a treatment course of 250 mg halofantrine per day for 3 days, to effect clearance of preexisting parasites. The volunteers were then assigned to 1 of 4 drug regimens: placebo throughout; 3 days of 400 mg (base) of tafenoquine per day, followed by placebo weekly; 3 days of 200 mg of tafenoquine per day, followed by 200 mg per week; and 3 days of 400 mg of tafenoquine per day, followed by 400 mg per week. Prophylaxis was continued for up to 13 weeks. Of the evaluable subjects (223 of 249 randomized subjects), volunteers who received 400 mg tafenoquine for only 3 days had a protective efficacy of 68% (95% confidence interval [CI], 53%-79%), as compared with placebo recipients; those who received 200 mg per day for 3 days followed by 200 mg per week had a protective efficacy of 86% (95% CI, 73%-93%); and those who received 400 mg for 3 days followed by 400 mg per week had a protective efficacy of 89% (95% CI, 77%-95%). A similar number of volunteers in the 4 treatment groups reported adverse events. Prophylactic regimens of 200 mg or 400 mg of tafenoquine, taken weekly for < or =13 weeks, are highly efficacious in preventing falciparum malaria and are well tolerated.

Meteorologic Influences on Plasmodium falciparum Malaria in the Highland Tea Estates of Kericho, Western Kenya

Recent epidemics of Plasmodium falciparum malaria have been observed in high-altitude areas of East Africa. Increased malaria incidence in these areas of unstable malaria transmission has been attributed to a variety of changes including global warming. To determine whether the reemergence of malaria in western Kenya could be attributed to changes in meteorologic conditions, we tested for trends in a continuous 30-year monthly malaria incidence dataset (1966–1995) obtained from complete hospital registers at a Kenyan tea plantation. Contemporary monthly meteorologic data (1966–1995) that originated from the tea estate meteorologic station and from global climatology records were also tested for trends. We found that total hospital admissions (malaria and nonmalaria) remained unchanged while malaria admissions increased significantly during the period. We also found that all meteorologic variables showed no trends for significance, even when combined into a monthly suitability index for malaria transmission. We conclude that climate changes have not caused the highland malaria resurgence in western Kenya.

Global warming and malaria:a call for accuracy

For more than a decade, malaria has held a prominent place in speculations on the impacts of global climate change. Mathematical models that “predict” increases in the geographic distribution of malaria vectors and the prevalence of the disease have received wide publicity. Efforts to put the issue into perspective1–5 are rarely quoted and have had little influence on the political debate. The model proposed by Frank C Tanser and colleagues6 in The Lancet and the accompanying Commentary by Simon Hales and Alistair Woodward7 are typically misleading examples. The relation between climate and malaria transmission is complex and varies according to location,2 yet Tanser et al base their projections on thresholds derived from a mere 15 African locations. Slight adjustments of values assigned to such thresholds and rules can influence spatial predictions strongly.8 The authors invest considerable effort in assessing the sensitivity of their model to climate change scenarios but do not report the internal sensitivities to thresholds and rules. The predictive skill of their model is low (63% sensitivity, 95% CI 61–65%) but they consider projections acceptable if prevalence is projected “to within a month” (presumably +/− 1 month?), thereby biasing their model towards success. A model covering an entire year in a parasite-positive site would always be correct, although in such areas it would be relatively insensitive to climate. By contrast, sites in which transmission is seasonal would provide a more reliable test of accuracy, but estimation is more difficult because climate sensitivity is greater. Furthermore, because parasite clearance in communities is not instantaneous,9 spot samples of parasitaemia on survey dates are not a suitable indicator of the duration of the transmission season. Lastly, “person/months” are unsuitable as a measure of transmission: an extension of season from 1 to 4 months will have more impact than from 10 to 12 months. According to their model, an extension of transmission from 11 to 12 months results in 106 more person/months in a population of 106 people, whereas an extension from 1 to 5 months gives the same increase in a population of 250 000. What Tanser and colleagues have modelled is merely the duration of the transmission season, which they interpret as “heightened transmission” and increased incidence. A greater failing is their reliance on “parasite-ratio studies”. The relations between transmission season and parasite prevalence, and parasite prevalence and clinical disease, are unclear but unlikely to be linear. Moreover, they use 1995 data for human populations, although these are projected to double by 2030. In addition, the proportion living in urban areas—with a specific climate10 and orders of magnitude less malaria transmission11,12—is projected to rise from 37% to 53%.13 For all these reasons, we do not accept the model as a “baseline against which interventions can be planned”. It is regrettable that many involved in this debate ignore the rich heritage of literature on the subject. For example, in 1937, in his classic textbook,14 L W Hackett stated: “Everything about malaria is so moulded and altered by local conditions that it becomes a thousand different diseases and epidemiological puzzles. Like chess, it is played with a few pieces, but is capable of an infinite variety of situations”. A pressing question in Hackett’s time was the changing distribution of the disease in Europe. On the role of climate, he wrote: “Certainly, climate lays down the broad lines of malaria distribution … Nevertheless, although this is a very simple and plausible explanation … even the early malariologists felt that there was something unsatisfactory about it … malaria has not so much receded as it has contracted, oftentimes toward the north … Thus in Germany it is the northern coast which is still malarious, the south is free … There is, therefore, no climatic reason why (malaria) should have abandoned south Germany or the French Riviera”. We quote Hackett because we feel that the classic components of science—unbiased observation and systematic experimentation—cannot be sidestepped with models that omit many of his chess pieces. Yet Hales and Woodward7 begin by stating: “The present geographical distribution of malaria is explained by a combination of environmental factors (especially climate) and social factors (such as disease-control measures)”. In our opinion, “even the early malariologists” would surely disagree: much of the decline of malaria in Europe took place without control measures during a period when the climate was warming. The text by Hales and Woodward that follows displays a lack of knowledge. Thus, “Most people at risk of malaria live in areas of stable transmission … ” is simply wrong. It is true that in many parts of the world malaria is termed “stable” because transmission remains relatively constant from year to year, the disease is endemic, the collective immunity is high, and epidemics are uncommon. However, in many other regions, the disease is endemic but “unstable” because annual transmission varies considerably, and the potential for epidemics is great. Climatic factors, particularly rainfall, are sometimes, but by no means always, relevant.15 Again, “On the fringes of endemic zones, where transmission is limited by rainfall … there are strong seasonal patterns, and occasional major epidemics” is also wrong. In many regions, far from any “fringes”, malaria is endemic, stable, but highly seasonal. For example, in semi-arid regions of Mali, transmission is restricted to the rainy season, from July to September. The same 3 months constituted the transmission season for Plasmodium falciparum in Italy before it was eliminated.16 Paradoxically, in parts of the Sudan, rainfall is restricted to a month at most, but malaria is transmitted throughout the year. Female Anopheles gambiae survive drought and heat by resting in dwellings and other sheltered places.17 Blood feeding and transmission continue, but the mosquitoes do not develop eggs until the rains return. This phenomenon, termed gonotrophic dissociation, is remarkably similar to the winter survival strategy of Anopheles atroparvus, the principal vector of malaria in Holland until the mid 20th century.16 By contrast, malaria is unstable in many regions that normally have abundant rainfall, and epidemics occur during periods of drought. An illustrative example is the catastrophic 1934–35 epidemic in Ceylon (now Sri Lanka), estimated to have killed 100 000 people.18 Worst hit was the south-western quadrant of the country, where average annual rainfall is greater than 250 cm, and malaria was endemic, but unstable and relatively infrequent. The dominant vector, Anopheles culicifacies, breeds along the banks of rivers and tends to be scarce in normal years. In the years 1928–33 there was abundant rainfall, river flow was high, A culicifacies was rare, and the human population was exceptionally malaria-free. However, after failure of two successive monsoons, the drying rivers produced colossal numbers of A culicifacies, and the resulting epidemic was exacerbated by the low collective immunity. In the drier parts of the island, where A culicifacies was dominant but transmission was more stable, immunity protected the population from the worst ravages of the disease. Hales and Woodward state that “the underlying problem” of the future “extension of seasonality” of malaria is “pollution of the atmosphere”, and call for rich countries to “recognise their obligations to the poorest by substantially reducing fossil-fuel consumption”. We understand public anxiety about climate change, but are concerned that many of these much-publicised predictions are ill informed and misleading. We urge those involved to pay closer attention to the complexities of this challenging subject.

SAFETY AND EFFICACY OF HIGH-DOSE SODIUM STIBOGLUCONATE THERAPY OF AMERICAN CUTANEOUS LEISHMANIASIS

40 patients with American cutaneous leishmaniasis caused primarily by Leishmania braziliensis panamensis were treated with sodium stibogluconate in a double-blind, randomised controlled trial. Nine weeks after starting treatment, all 19 patients treated with 20 mg Sb/kg per day for twenty days were cured but 5 of 21 patients treated with 10 mg Sb/kg per day for twenty days had persistent active disease (p less than 0.05). Both treatment regimens were well tolerated and they were associated with a similar incidence of reversible toxic effects. Existing recommendations for therapy of American cutaneous leishmaniasis with sodium stibogluconate are inadequate for some patients, and higher doses are both safe and efficacious.

Malaria chemoprophylaxis in the age of drug resistance. I. Currently recommended drug regimens

As international travel becomes increasingly common and resistance to antimalarial drugs escalates, a growing number of travelers are at risk for contracting malaria. Parasite resistance to chloroquine and proguanil and real or perceived intolerance among patients to standard prophylactic agents such as mefloquine have highlighted the need for new antimalarial drugs. Promising new regimens include atovaquone and proguanil, in combination; primaquine; and a related 8-aminoquinoline, tafenoquine. These agents are active against the liver stage of the malaria parasite and therefore can be discontinued shortly after the traveler leaves an area where malaria is endemic, which encourages adherence to the treatment regimen. Part 1 of this series reviews currently recommended chemoprophylactic drug regimens, and part 2 will focus on 8-aminoquinoline drugs.

Malaria in Kenya's Western Highlands

Reemergence of epidemics in tea plantations will likely result in antimalarial-drug resistance.

Malaria early warning in Kenya

Kenya displays large spatiotemporal diversity in its climate and ecology. It follows that malaria transmission will reflect this environmental heterogeneity in both space and time. In this article, we discuss how such heterogeneity, and its epidemiological consequences, should be considered in the development of early warning systems for malaria epidemics.