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.

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.

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.

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.

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.

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 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.

Malaria chemoprophylaxis using proguanil/dapsone combinations on the Thai-Cambodian border.

The Thai-Cambodian border is a difficult area in which to provide adequate malaria chemoprophylaxis because of multiple drug-resistant Plasmodium falciparum. In 1990-1991, Thai soldiers were randomly selected to receive proguanil (200 mg/day) combined with dapsone (4 mg or 12.5 mg/day) (n = 184) or pyrimethamine/dapsone (12.5 mg and 100 mg/week) (n = 177). Doxycycline (100 mg/day) was given to men with glucose-6-phosphate dehydrogenase deficiency (n = 77). Falciparum malaria attack rates were the same whether proguanil/dapsone (10.3%) or pyrimethamine/dapsone (11.3%) was used. However, proguanil/dapsone was more effective than pyrimethamine/dapsone in preventing vivax malaria (1.6% versus 12.4%). Men receiving doxycycline had falciparum malaria (3.9%) and vivax malaria (1.3%) at low rates. Adjusting the dapsone component from 4 mg to 12.5 mg did not improve the prophylactic effectiveness. Hematologic toxicity was not observed with the proguanil/dapsone combination. We conclude that proguanil/dapsone is not a useful alternative for malaria chemoprophylaxis on the Thai-Cambodian border.

A comparative study of gastrointestinal infections in United States soldiers receiving doxycycline or mefloquine for malaria prophylaxis.

A double blind study of daily doxycycline (100 mg) vs. weekly mefloquine (250 mg) was performed on United States soldiers training in Thailand to assess the effect of doxycycline malaria prophylaxis on the incidence of gastrointestinal infections. During a 5 week period, 49% (58/119) of soldiers receiving doxycycline and 48% (64/134) of soldiers receiving mefloquine reported an episode of diarrhea. Infection with bacterial enteric pathogens was identified in 39% (47/119) of soldiers taking doxycycline and 46% (62/134) of soldiers taking mefloquine. Forty-four percent (59/134) of soldiers receiving mefloquine and 36% (43/119) of soldiers receiving doxycycline were infected with enterotoxigenic Escherichia coli (ETEC), while 9% (12/134) of soldiers receiving mefloquine and 4% of soldiers receiving doxycycline were infected with Campylobacter. Side effects from either medication were minimal. After 5 weeks in Thailand, the percent of non-ETEC strains resistant to greater than or equal to 2 antibiotics increased from 65% (77/119) to 86% (95/111) in soldiers on mefloquine and from 79% (84/106) to 93% (88/95) in soldiers on doxycycline. Doxycycline prophylaxis did not prevent or increase diarrheal disease in soldiers deployed to Thailand where ETEC and other bacterial pathogens are often resistant to tetracyclines.

Causal prophylactic and radical curative activity of WR182393 (a guanylhydrazone) against Plasmodium cynomolgi in Macaca mulatta.

Primaquine is the only currently available drug effective against persistent tissue stages of relapsing malaria in humans. Causal prophylactic and radical curative properties of WR182393 (a guanylhydrazone) were investigated as part of an effort to evaluate alternatives to primaquine in the rhesus monkey (Macaca mulatta)/Plasmodium cynomolgi test model. The drug was suspended in dimethylsulfoxide for intramuscular (im) injection. A pilot study indicated causal prophylactic activity in a regimen of 40 mg base/kg/day im for three days beginning the day before intravenous challenge with 1 x 10(6) P. cynomolgi sporozoites. Regimens of 31, 10, 3.1, and 0 mg base/kg/day im for three days were then tested in groups of two monkeys given a similar challenge. The two animals given 31 mg base/kg/day remained parasite-free. Average time to parasitemia for the lower dosage groups was 38, 18, and 8 days respectively. Groups of two monkeys with sporozoite-induced P. cynomolgi infections were also treated for seven days with 31, 10, 3.1, and 0 mg base/kg/day im in combination with 10 mg base/kg/day of chloroquine orally. Both monkeys given 31 mg base/kg/day did not relapse. The average time to relapse following treatment was 48, 29, and 8 days, respectively, for the lower dosage groups. Compound WR182393 is the first non-8-aminoquinoline class of drug to exhibit both causal prophylactic and radical curative properties against a relapsing primate, vivax-like malaria.

WR 238605, chloroquine, and their combinations as blood schizonticides against a chloroquine-resistant strain of Plasmodium vivax in Aotus monkeys.

The compound WR 238605 is a primaquine analog being developed by the U.S. Army as an antimalarial drug. Currently, there is no established treatment for Plasmodium vivax parasitemias that are not cured by chloroquine. This study tested WR 238605, chloroquine, and their combinations against a chloroquine-resistant strain of P. vivax (AMRU 1) in Aotus monkeys. A total dose of 3 mg/kg of WR 238605 given at a dosage of 1 mg/kg/day for three days cleared patent parasites in all eight monkeys but recrudescence of parasitemia occurred 15-25 days after initiation of treatment. A total dose of 9 mg/kg of WR 238605 over a three-day period cured all three monkeys of their infections. A total dose of 30 mg/kg of chloroquine did not clear patent infections in three monkeys, whereas a total dose of 60 mg/kg generally (two of three) cleared patent parasitemia but did not cure. Whereas total doses of 30 mg/kg of chloroquine or 3 mg/kg of WR 238605 given alone failed to cure, both drugs given in combination at these dosages cured two of three infections. These results indicate that WR 238605 may be an alternative treatment for chloroquine-resistant vivax malaria.

Halofantrine for the treatment of mefloquine chemoprophylaxis failures in Plasmodium falciparum infections.

Thai soldiers who became slide-positive for malaria while receiving mefloquine chemoprophylaxis were treated with halofantrine to study its efficacy against mefloquine-resistant falciparum malaria. Thirty-two patients received three doses of 500 mg (1,500 mg total) of halofantrine at six-hr intervals, and were then observed for four weeks. Parasite recrudescence following treatment (median 21 days) occurred in seven of 23 patients (30%) who had mefloquine serum concentrations indicative of regular prophylaxis (greater than 500 ng/ml). Serum concentrations of mefloquine in all 32 patients averaged 950 ng/ml (range 26-2,515) prior to halofantrine treatment. The halofantrine serum concentrations were higher in patients cured by halofantrine than in patients with drug failure, but this was not statistically significant. Patients who were cured by halofantrine had parasites that were more sensitive in in vitro testing to mefloquine (mean [inhibitory concentration] IC50 = 12.5 ng/ml) than in patients whose parasitemias recrudesced (mean IC50 = 23.8 ng/ml) (P less than 0.01, by Wilcoxon rank sum test). These observations suggest that the current formulation and regimen of halofantrine are not optimal for the treatment of multiple drug-resistant falciparum malaria from Thailand.

Evaluation of WR250417 (a proguanil analog) for causal prophylactic activity in the Plasmodium cynomolgi-Macaca mulatta model.

The Plasmodium cynomolgi-Macaca mulatta model has been used to test the antimalarial activity of new drugs for both radical cure and casual prophylaxis. The proguanil analog WR250417 (also known as PS-15) was evaluated for causal prophylactic activity in rhesus monkeys infected with P. cynomolgi bastianelli. Four monkeys were orally dosed with 40 mg/kg/day of WR250417 over three days (-1, 0, and +1). Sporozoite-induced infection of P. cynomolgi was initiated on day 0 with 1 x 10(6) sporozoites to each monkey. Compound WR250417 extended the prepatent period from an average of 8.5 days for controls (n = 2) to a mean of 18.3 days (range 18-19 days, n = 4) for drug-treated monkeys. Analysis of plasma drug concentrations by high-performance liquid chromatography showed that the monkeys converted the WR250417 to its putative principal active metabolite WR99210 (a dihydrotriazine). These findings demonstrate that WR250417 and its principal metabolite do not prevent primary infection by P. cynomolgi.

Efficacy and tolerance of extended-dose halofantrine for drug-resistant falciparum malaria in Thailand.

New treatments for malaria are urgently needed in areas such as Thailand where highly drug-resistant strains of Plasmodium falciparum are prevalent. Mefloquine is rapidly losing efficacy and conventional doses of halofantrine are infective. We therefore used pharmacokinetic stimulation to design an extended-dose halofantrine regimen and tested it in 26 soldiers stationed along the Thai-Cambodian border. Halofantrine was given after meals as three doses of 500 mg each at 4-hr intervals on the first day, followed by 500 mg a day for six days (total dose 4.5 g). Twenty-six soldiers treated with quinine-tetracycline for seven days (Q7T7) served as controls. There were no significant differences in efficacy between halofantrine and Q7T7 (P > 0.1) as assessed by cure rate (92% versus 85%), mean parasite clearance time (82 hr versus 81 hr), or mean fever clearance time (93 hr versus 99 hr). Halofantrine was better tolerated than Q7T7. The side effects score was lower (2 versus 11; P < 0.001), there were less days on which side effects occurred (2.0 days versus 5.5 days; P < 0.001), and fewer patients had adverse effects on every treatment day (4% versus 42%; P < 0.01). High-dose halofantrine is as effective and better tolerated than quinine-tetracycline for multidrug-resistant falciparum malaria.

Proguanil plus sulfamethoxazole is not causally prophylactic in the Macaca mulatta--Plasmodium cynomolgi model.

New drugs for causal prophylaxis of malaria are needed. A proguanil/sulfamethoxazole combination was investigated using a rhesus monkey model (Macaca mulatta infected with Plasmodium cynomolgi) to determine whether causal prophylaxis could be achieved. When a five-day regimen of proguanil (40 mg/kg/day) combined with sulfamethoxazole (100 mg/kg/day) was used, infection of all animals (6 of 6) was observed, with an extended prepatent period (median 40 days). Two control animals became infected on days 9 and 23 following sporozoite inoculation. Plasma concentrations indicated that proguanil and sulfamethoxazole were adequately absorbed and metabolized to cycloguanil and N4-acetylsulfamethoxazole, respectively. Analysis of liver biopsy specimens demonstrated that the drugs were present two days following sporozoite inoculation but were not detectable one week later. Proguanil plus sulfamethoxazole does not eliminate exoerythrocytic-stage parasites in the rhesus monkey--P. cynomolgi model.

Quinine with tetracycline for the treatment of drug-resistant falciparum malaria in Thailand.

Reports of deteriorating quinine efficacy prompted us to investigate the ability of quinine-tetracycline to clear parasites and fever from patients with multiple drug-resistant Plasmodium falciparum infections. Past and present treatment results were compared at two study sites along the Thai-Cambodian border. In northeastern Thailand, quinine-tetracycline cleared parasites more quickly in 1990 than in 1987 (mean 3.4 and 4.0 days, respectively; P = 0.006). In southeastern Thailand, there were no significant differences between 1990 (n = 26) and 1981-1983 (n = 42) in the time taken to clear either parasites (median 96 and 93 hr, respectively; P = 0.35) or fever (mean 74 and 66 hr, respectively; P = 0.30). In vitro drug sensitivity testing revealed a two-fold decrease in susceptibility to quinine between 1983 and 1990 in isolates from the southeastern Thai-Cambodian border (mean inhibitory concentration 166 ng/ml and 320 ng/ml, respectively; P less than 0.001). We conclude that oral quinine-tetracycline continues to reliably clear parasites and fever from falciparum malaria patients infected in eastern Thailand. Periodic re-evaluations are warranted, however, since the decrease in vitro susceptibility to quinine may be followed by an in vivo decay in the treatment response.