Historical epidemics of scrub typhus in Queensland and Papua New Guinea.

Undifferentiated febrile diseases (e.g., Mossman fever) from northern Queensland were eventually partially attributed to mite-transmitted rickettsial infections known as scrub typhus or tsutsugamushi fever. Scrub typhus became a major medical threat to military operations in Papua New Guinea during the Second World War and killed more Australian soldiers than malaria in the pre-antibiotic era. Further investigations showed scrub typhus to be an occupational disease of rural workers in north Queensland especially around Cairns and Innisfail. Occasional small epidemics of scrub typhus still occur during military exercises in Queensland, but as scrub typhus is not a reportable disease, its presence in the civilian community is largely unknown. Increased use of serological testing in patients with fever and rash illnesses after exposure in northern Queensland is likely to show that scrub typhus is a modern infection that remains treatable with antibiotics once it is identified.

Rapid mortality transition of Pacific Islands in the 19th century.

The depopulation of Pacific islands during the 16th to 19th centuries is a striking example of historical mass mortality due to infectious disease. Pacific Island populations have not been subject to such cataclysmic infectious disease mortality since. Here we explore the processes which could have given rise to this shift in infectious disease mortality patterns. We show, using mathematical models, that the population dynamics exhibited by Pacific Island populations are unlikely to be the result of Darwinian evolution. We propose that extreme mortality during first-contact epidemics is a function of epidemiological isolation, not a lack of previous selection. If, as pathogens become established in populations, extreme mortality is rapidly suppressed by herd immunity, Pacific Island population mortality patterns can be explained with no need to invoke genetic change. We discuss the mechanisms by which this could occur, including (i) a link between the proportion of the population transmitting infectious agents and case-fatality rates, and (ii) the course of infection with pathogens such as measles and smallpox being more severe in adults than in children. Overall, we consider the present-day risk of mass mortality from newly emerging infectious diseases is unlikely to be greater on Pacific islands than in other geographical areas.

Enhanced risk of illness during the 1918 influenza pandemic after previous influenza-like illnesses in three military populations.

The reasons for the unprecedented mortality during the 1918 influenza pandemic remain poorly understood. We examined morbidity records from three military cohorts from years prior to and during the 1918 pandemic period to assess the effects of previous respiratory illnesses on experiences during the pandemic. Clinical registers and morbidity lists were examined to identify all medical encounters for acute respiratory illnesses in students at two U.S. military officer training academies and Australian soldiers deployed in Europe. Influenza-like illness prior to the major pandemic wave of 1918 predisposed Australian soldiers [relative risk (RR) 1·37, 95% confidence interval (CI) 1·18-1·60, P < 0·0001] and US officer trainees at West Point (RR 3·10, 95% CI 2·13-4·52, P < 0·0001) and Annapolis (RR 2·03, 95% CI 1·65-2·50, P < 0·0001) to increased risks of medically treated illnesses in late 1918. The findings suggest that susceptibility to and/or clinical expressions of the 1918 pandemic influenza virus depended on previous experiences with respiratory infectious agents. The findings are consistent with observations during the 2009 pandemic in Canada and may reflect antibody-dependent enhancement of influenza infection.

Age-specific measles mortality during the late 19th-early 20th centuries.

Measles mortality fell prior to the introduction of vaccines or antibiotics. By examining historical mortality reports we sought to determine how much measles mortality was due to epidemiological factors such as isolation from major population centres or increased age at time of infection. Age-specific records were available from Aberdeen; Scotland; New Zealand and the states of Australia at the end of the 19th and beginning of the 20th centuries. Despite the relative isolation of Australia, measles mortality was concentrated in very young children similar to Aberdeen. In the more isolated states of Tasmania, Western Australia and Queensland adults made up 14-15% of measles deaths as opposed to 8-9% in Victoria, South Australia and New South Wales. Mortality in Iceland and Faroe Islands during the 1846 measles epidemic was used as an example of islands isolated from respiratory pathogens. The transition from crisis mortality across all ages to deaths concentrated in young children occurred prior to the earliest age-specific mortality data collected. Factors in addition to adult age of infection and epidemiological isolation such as nutritional status and viral virulence may have contributed to measles mortality outcomes a century ago.

Spatio-temporal investigation of the 1918 influenza pandemic in military populations indicates two different viruses.

There were multiple waves of influenza-like illness in 1918, the last of which resulted in a highly lethal pandemic killing 50 million people. It is difficult to study the initial waves of influenza-like illness in early 1918 because few deaths resulted and few morbidity records exist. Using extant military mortality records, we constructed mortality maps based on location of burial in France and Belgium in the British Army, and on home town in Vermont and New York in the USA Army. Differences between early and more lethal later waves in late 1918 were consistent with historical descriptions in France. The maps of Vermont and New York support the hypothesis that previous exposure may have conferred a degree of protection against subsequent infections; soldiers from rural areas, which were likely to have experienced less mixing than soldiers from urban areas, were at higher risk of mortality. Differences between combat and disease mortality in 1918 were consistent with limited influenza virus circulation during the early 1918 wave. We suggest that it is likely that more than one influenza virus was circulating in 1918, which might help explain the higher mortality rates in those unlikely to have been infected in early 1918.

Spatiotemporal patterns of pandemic influenza-related deaths in Allied naval forces during 1918.

This paper draws on the mortality records of the French, US and UK Royal navies to reconstruct the spatiotemporal evolution of the 1918­1919 influenza pandemic in global Allied naval forces. For a total of 7658 deaths attributed to respiratory diseases (French and US navies) and all diseases (UK Royal Navy) at 514 locations worldwide, techniques of spatial point pattern analysis were used to generate weekly maps of global mortality intensity in 1918. The map sequence for the main period of pandemic mortality, mid-August to mid-November 1918, revealed a near-simultaneous development of mutiple foci of high disease intensity in three distant locations (Europe, North America, West Africa). Given the relatively slow speed of naval ships in convoy at this time (<12 knots), our findings suggest that the pandemic influenza virus was circulating on three continents at the observed onset of the main mortality wave.

Pacific islands which escaped the 1918-1919 influenza pandemic and their subsequent mortality experiences.

Very few Pacific islands escaped the 1918-1919 influenza pandemic. Subsequent influenza epidemics in the established colonial outposts of American Samoa and New Caledonia infected many but killed very few persons whereas the extraordinarily isolated Niue, Rotuma, Jaliut and Yule islands experienced high mortality influenza epidemics (>3% of population) following 1918. These dichotomous outcomes indicate that previous influenza exposure and degree of epidemiological isolation were important mortality risk factors during influenza epidemics on Pacific islands.

Host and environmental factors reducing mortality during the 1918-1919 influenza pandemic.

Mortality from influenza and pneumonia during the 1918-1919 pandemic was compared between subgroups of civilian and military populations from states in Australia and the USA. Exposures to crowded environments before and during the pandemic were used as proxies for exposure to respiratory infections. In three separate datasets, civilian mortality from influenza and pneumonia was higher in urban than rural populations. In contrast soldiers from these same urban backgrounds had significantly lower mortality than their rural counterparts. This suggests the lower mortality in rural civilians was due to the rural environment, probably due to the relative social isolation in rural areas. This is encouraging for pandemic planning, as it suggests social distancing interventions have the potential to reduce mortality in future pandemics. Soldiers recruited before 1918 had significantly lower mortality than those recruited in 1918, and this effect was separate from the protection given by urban origin to soldiers. Both these effects substantially reduced mortality in soldiers. Further research to identify the mechanisms of these separate protective effects may yield important evidence to inform pandemic planning strategies.

Treatment of falciparum malaria in the age of drug resistance.

The growing problem of drug resistance has greatly complicated the treatment for falciparum malaria. Whereas chloroquine and sulfadoxine/pyrimethamine could once cure most infections, this is no longer true and requires examination of alternative regimens. Not all treatment failures are drug resistant and other issues such as expired antimalarials and patient compliance need to be considered. Continuation of a failing treatment policy after drug resistance is established suppresses infections rather than curing them, leading to increased transmission of malaria, promotion of epidemics and loss of public confidence in malaria control programs. Antifolate drug resistance (i.e. pyrimethamine) means that new combinations are urgently needed particularly because addition of a single drug to an already failing regimen is rarely effective for very long. Atovaquone/proguanil and mefloquine have been used against multiple drug resistant falciparum malaria with resistance to each having been documented soon after drug introduction. Drug combinations delay further transmission of resistant parasites by increasing cure rates and inhibiting formation of gametocytes. Most currently recommended drug combinations for falciparum malaria are variants of artemisinin combination therapy where a rapidly acting artemisinin compound is combined with a longer half-life drug of a different class. Artemisinins used include dihydroartemisinin, artesunate, artemether and companion drugs include mefloquine, amodiaquine,sulfadoxine/pyrimethamine, lumefantrine, piperaquine, pyronaridine, chlorproguanil/dapsone. The standard of care must be to cure malaria by killing the last parasite. Combination antimalarial treatment is vital not only to the successful treatment of individual patients but also for public health control of malaria.

Travel as a risk factor for uncomplicated Plasmodium falciparum malaria in the highlands of western Kenya.

In the 1980s, highland malaria returned to the tea estates of western Kenya after an absence of nearly a generation. In order to determine the importance of travel for the spread of malaria in this region, we prospectively collected blood films and travel, demographic and geographic information on well persons and outpatients on tea estates near the western rim of the Rift Valley. Risk factors for malaria asexual parasitaemia included: tribal/ethnic group, home province and home district malaria endemicity. Travel away from the Kericho tea estates within the previous two months showed an odds ratio (OR) for parasitaemia of 1.59 for well persons and 2.38 for outpatients. Sexual stages of malaria parasites (gametocytes) had an OR of 3.14 (well persons) and 2.22 (outpatients) for those who had travelled. Increased risk of malaria parasitaemia with travel was concentrated in children aged <5 years. An increase in population gametocytaemia is possibly due to increased chloroquine resistance and suppressed infections contracted outside of the tea estates.

Epidemiology of highland malaria in western Kenya.

OBJECTIVES: To investigate the epidemiology of falciparum malaria in workers from a highland tea plantation in western Kenya with very seasonally limited malaria transmission to determine what factors are associated with increased risk of malaria transmission in the Kenyan highlands. DESIGN: A cross-sectional study with rolling, random subject enrollment from April 1998 through October 1999. SETTING: Highland tea plantation located at 0 degrees 22' south and 35' 17' east in the Rift Valley highlands of western Kenya, an area with seasonally limited malaria transmission. SUBJECTS: The data for the study were obtained from enrollment of outpatients from the healthcare system of a major tea company, which has 18 estates with 22,000 workers and approximately 50,000 persons eligible for health care. Of the 2796 patients evaluated during the study period, 798 cases of malaria were confirmed by positive peripheral blood smear; 1998 smear-negative patients were pressured to be non-infected and served as controls (Ratio: 2.52: 1). INTERVENTIONS: Tea estate workers do not receive malaria chemoprophylaxis, but were given easily available free treatment for any symptomatic infections. MAIN OUTCOME MEASURES: Smear-positive cases were compared with smear-negative patients for multiple demographic and disease variables, including sex, age, travel history, ethnic origin, home district transmission risk index and length of residence. Disease characteristics, including parasite types, counts and clinical symptoms, and treatments administered were described. RESULTS: Malaria was predominantly P. falciparum (>99%); asexual parasite counts ranged from 1-10,440 per mm3, with a mean of 803.6 (95% confidence interval: 695.2, 912.0). Gametocytemia was present in 7.5% of smear-positive malaria cases, but was rare in the absence of blood asexual forms (0.5%). Prior use of a variety of antimalarial drugs was extremely common and negatively predictive of parasitemia in patients presenting for clinical treatment (Pearson Chi-square 50.81, p < 0.001), as was a subjective history of previous malaria infection in the past year (F = 26.65, 14 df, p < 0.001; univariate ANOVA). Amodiaquine was the most commonly used drug to treat cases of either smear-proven or clinically suspected malaria, accounting for 56% of therapy; pyrimethamine/sulfadoxine was used to treat 27%, artemesinin 8% and chloroquine was administered to only 3%, while combination therapy was used in 5% of cases, and only a single treatment (0.1 %) was recorded using quinine. Subjects with a prior history of treatment for malaria were statistically less likely to be infected again (Pearson Chi-square 50.81, p < 0.001). Presenting with symptoms suggestive of malaria was statistically associated with parasitemia, particularly fever, headache and dizziness, (p <0.001 for all, univariate ANOVA), but in general, clinical symptoms were not an effective discriminator of malarial disease. Ethnic group predicted malaria infection with groups traditionally from the Lake Victoria lowland regions having a greater prevalence of parasitemia (F = 2.04, 4. df, p = 0.002, univariate ANOVA). Parasitemia was significantly associated with age less than ten years (Pearson Chi-Square 145.99, p < 0.001), with a history of travel more than twenty kilometers from site within six weeks (Pearson Chi-square 58.28, p < 0.001) and with time since arrival on the plantation of one year or less (Pearson Chi-square 185.12, p <0.001) CONCLUSION: Lower infection rates in persons with a history of prior infection implies a protective effect; the predilection of malaria for young and immunologically naive victims was confirmed. The proclivity in some ethnic groups for travel to holoendemic areas also accounts for the strong associations between recent travel, lowland ethnic group and infection. These findings taken together suggest that importation of malaria to the highlands, as well as travel away from the highlands, are important sources of new infections among persons living and working there.

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.

Malaria chemoprophylaxis in the age of drug resistance. II. Drugs that may be available in the future.

All current regimens of malaria chemoprophylaxis have serious drawbacks as a result of either suboptimal efficacy, difficulty with medication compliance, or adverse events. Two 8-aminoquinolines may be approaching registration, with primaquine having completed its prophylactic field testing and tafenoquine having begun advanced field testing at the end of 2000. Primaquine has long been used for management of relapses of malaria, but in the past decade, it has been reexamined for use in malaria prevention in order to stop infection in the liver. In field trials performed in Indonesia and Colombia, the efficacy of primaquine for malaria prevention was approximately 90%, compared with that of placebo. Because of its short half-life, primaquine requires daily administration. For adults, the prevention regimen is 30 mg base daily (0.5 mg base/kg/day), and it can probably be discontinued soon after departure from an area where malaria is endemic. To kill parasites that already exist in the liver, terminal prophylaxis is given after exposure to relapses of malaria infection; for adults, such prophylaxis usually consists of 15 mg base (0.3 mg base/kg/day) given daily for 2 weeks. Primaquine-induced gastrointestinal disturbances can be minimized if the drug is taken with food. Neither primaquine nor tafenoquine should be given to persons with glucose-6-phosphate dehydrogenase deficiency, to avoid the development of potentially severe drug-induced hemolysis. Tafenoquine is an analogue of primaquine that is more potent than the parent drug. Field trials in Kenya, Ghana, Gabon, and Southeast Asia have demonstrated an efficacy rate of approximately 90% for tafenoquine. Its long half-life allows for infrequent dosing (currently tested at 200 mg base/week), and its effect on parasites at the liver stage may allow for drug discontinuation at the time of departure from the area of endemicity.

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 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.

Changing patterns of clinical malaria since 1965 among a tea estate population located in the Kenyan highlands.

The changing epidemiology of clinical malaria since 1965 among hospitalized patients was studied at a group of tea estates in the western highlands of Kenya. These data indicate recent dramatic increases in the numbers of malaria admissions (6.5 to 32.5% of all admissions), case fatality (1.3 to 6%) and patients originating from low-risk, highland areas (34 to 59%). Climate change, environmental management, population migration, and breakdown in health service provision seem unlikely explanations for this changing disease pattern. The coincident arrival of chloroquine resistance during the late 1980s in the subregion suggests that drug resistance is a key factor in the current pattern and burden of malaria among this highland population.

Etiology of interepidemic periods of mosquito-borne disease.

Dengue viruses and malaria protozoa are of increasing global concern in public health. The diseases caused by these pathogens often show regular seasonal patterns in incidence because of the sensitivity of their mosquito vectors to climate. Between years in endemic areas, however, there can be further significant variation in case numbers for which public health systems are generally unprepared. There is an acute need for reliable predictions of within-year and between-year epidemic events. The prerequisite for developing any system of early warning is a detailed understanding of the factors involved in epidemic genesis. In this report we discuss the potential causes of the interepidemic periods in dengue hemorrhagic fever in Bangkok and of Plasmodium falciparum malaria in a highland area of western Kenya. The alternative causes are distinguished by a retrospective analysis of two unique and contemporaneous 33-year time series of epidemiological and associated meteorological data recorded at these two sites. We conclude that intrinsic population dynamics offer the most parsimonious explanation for the observed interepidemic periods of disease in these locations.