The biology and pathogenesis of vivax malaria.

Plasmodium vivax contributes significantly to global malaria morbidity. Key advances include the discovery of pathways facilitating invasion by P. vivax merozoites of nascent reticulocytes, crucial for vaccine development. Humanized mouse models and hepatocyte culture systems have enhanced understanding of hypnozoite biology. The spleen has emerged as a major reservoir for asexual vivax parasites, replicating in an endosplenic life cycle, and contributing to recurrent and chronic infections, systemic inflammation, and anemia. Splenic accumulation of uninfected red cells is the predominant cause of anemia. Recurring and chronic infections cause progressive anemia, malnutrition, and death in young children in high-transmission regions. Endothelial activation likely contributes to vivax-associated organ dysfunction. The many recent advances in vivax pathobiology should help guide new approaches to prevention and management.

Extreme mortality during a historical measles outbreak on Rotuma is consistent with measles immunosuppression.

Until the early twentieth century, populations on many Pacific Islands had never experienced measles. As travel to the Pacific Islands by Europeans became more common, the arrival of measles and other pathogens had devastating consequences. In 1911, Rotuma in Fiji was hit by a measles epidemic, which killed 13% of the island population. Detailed records show two mortality peaks, with individuals reported as dying solely from measles in the first and from measles and diarrhoea in the second. Measles is known to disrupt immune system function. Here, we investigate whether the pattern of mortality on Rotuma in 1911 was a consequence of the immunosuppressive effects of measles. We use a compartmental model to simulate measles infection and immunosuppression. Whilst immunosuppressed, we assume that individuals are vulnerable to dysfunctional reactions triggered by either (i) a newly introduced infectious agent arriving at the same time as measles or (ii) microbes already present in the population in a pre-existing equilibrium state. We show that both forms of the immunosuppression model provide a plausible fit to the data and that the inclusion of immunosuppression in the model leads to more realistic estimates of measles epidemiological parameters than when immunosuppression is not included.

The early history of dengue in Australia.

Although reports of outbreaks of dengue-like diseases in the Asia Pacific region were frequent from about 1870, the disease probably did not become endemic in Australia until about 1885. Several seminal discoveries about this disease were made in Queensland and later in Sydney. These included a refined case definition for dengue, identification of the mosquito vector, demonstration of a viraemia and its duration, quantification of the incubation time, demonstration of immunity after experimental infection and recognition that the virus could cause a fatal haemorrhagic fever, and this was more frequent in second or subsequent infections. Australian research was foundational to the modern understanding of dengue.

Why Did Black Soldiers Historically Have More Pneumonia Than White Soldiers in the U.S. Army?

Black U.S. Army soldiers had four times as much bacterial pneumonia as White U.S. Army soldiers during both the U.S. Civil War and World War I (WWI). Pneumonia case fatality rates were a third greater in Black soldiers during the U.S. Civil War, but were the same between the racial groups by WWI. During WWII, the use of antibiotics decreased bacterial pneumonia mortality rates 100-fold and apparently erased racial differences. Similar differences in bacterial pneumonia rates by racial group were observed in African colonial soldiers of the French and British Armies during WWI. Pneumonia rates in Indian, Filipino, and Puerto Rican soldiers suggested that genetic polymorphisms were not a decisive factor determining Black pneumonia mortality. Postmeasles pneumonias did not suggest an immune deficit in Black soldiers. Geographic focus of pneumonia in Black soldiers from the southern U.S. states and other tropical regions raises the possibility that increased bacterial pneumonia rates were related indirectly to malaria infections. Malaria remains a difficult-to-measure but potentially important mortality risk factor in pneumonia.

Pernicious Plasmodium vivax as a Historical Cause of Malarial Cachexia?

Prior to the understanding of malaria as a parasitic disease, malaria cachexia was a loosely defined syndrome consisting of severe anemia and splenomegaly in a chronically wasted individual living in a malarious area. Entire rural populations in diverse areas such as the Thames estuary, Marseilles marshes, and the Mississippi valley were said to have cachexia on the basis of chronic malaria "poisoning," which accounted for their poor socioeconomic health. Malaria cachexia appeared to disappear as the marshes were drained, agriculture improved, and quinine or iron treatments were administered. Malaria cachexia's association with plasmodia in the blood was uncertain once blood smears were examined in the twentieth century. Modern studies have raised the question of chronic Plasmodium vivax in the spleen as a possible etiology; historical specimens could be examined to clarify malaria cachexia.

Malaria Paradoxes of the U.S. Civil War.

The U.S. Civil War (1861-1865) pre-dated modern understanding of malaria. Yet, malarial diseases (remittent fever, intermittent fever, typho-malarial fever) were frequently reported as causes of morbidity and mortality in soldiers. Modern readers find Civil War-era descriptions of malaria contradictory or paradoxical. For example, although the concept of race-specific immunity to tropical diseases was widely accepted, malaria mortality rates were reportedly more than three times higher among Black than White Union soldiers (16/1,000/year versus 5/1,000/year). Also, malaria rates were reportedly lower among prisoners of war at the infamous Andersonville, GA, prison camp than among Confederate soldiers in the same area. Literally tons of quinine were given prophylactically to Union soldiers deployed in the southern United States, but blackwater fever was not reported by medical officers. All three paradoxes have reasonable modern explanations that give credence to the astute clinical observations of our scientific predecessors during the U.S. Civil War.

Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum.

BACKGROUND: The long-acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood-stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD)-deficient individuals. METHODS: Healthy adults with normal levels of G6PD were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48 ± 2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. RESULTS: Twelve participants were inoculated and administered 200 mg (n = 3), 300 mg (n = 4), 400 mg (n = 2), or 600 mg (n = 3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 hours and 4.2 hours, respectively) was faster than with 200 mg or 300 mg (11.8 hours and 9.6 hours, respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants) but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 106 and 109, respectively, in a 60-kg adult. CONCLUSIONS: Although a single dose of tafenoquine exhibits potent P. falciparum blood-stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency. Clinical Trials Registration. Australian and New Zealand Clinical Trials Registry (ACTRN12620000995976).

Casualties during Australian military operations in New Guinea 1914-1919.

Casualties during the occupation of German New Guinea by the Australian Naval and Military Expeditionary Force starting in September 1914 were limited to six dead during a few initial armed clashes and the loss of RAN submarine AE-1, followed by a few years of tropical disease exposures. A dengue epidemic affected most soldiers within a month of their arrival in Rabaul. Subsequently, a malaria epidemic swept through the occupation forces in January 1915 infecting a majority of the soldiers and killing five. Malaria was eventually controlled by daily draughts of quinine solution. Diarrhoea/dysentery was a particular concern among the local contract labour force. Skin diseases were a major chronic problem of tropical service. Twenty-seven non-combat deaths over 4 years (<1%/year) were considered a 'healthy' outcome for the occupation force which consisted largely of men unfit for active service in the Australian Imperial Force. No one should under-estimate the modern requirement to protect non-immune soldiers or travellers going to Papua New Guinea for extended periods.

Transmission Blocking Activity of Low-dose Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum.

BACKGROUND: Blocking the transmission of parasites from humans to mosquitoes is a key component of malaria control. Tafenoquine exhibits activity against all stages of the malaria parasite and may have utility as a transmission blocking agent. We aimed to characterize the transmission blocking activity of low-dose tafenoquine. METHODS: Healthy adults were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Piperaquine was administered on days 9 and 11 to clear asexual parasitemia while allowing gametocyte development. A single 50-mg oral dose of tafenoquine was administered on day 25. Transmission was determined by enriched membrane feeding assays predose and at 1, 4, and 7 days postdose. Artemether-lumefantrine was administered following the final assay. Outcomes were the reduction in mosquito infection and gametocytemia after tafenoquine and safety parameters. RESULTS: Six participants were enrolled, and all were infective to mosquitoes before tafenoquine, with a median 86% (range, 22-98) of mosquitoes positive for oocysts and 57% (range, 4-92) positive for sporozoites. By day 4 after tafenoquine, the oocyst and sporozoite positivity rate had reduced by a median 35% (interquartile range [IQR]: 16-46) and 52% (IQR: 40-62), respectively, and by day 7, 81% (IQR 36-92) and 77% (IQR 52-98), respectively. The decline in gametocyte density after tafenoquine was not significant. No significant participant safety concerns were identified. CONCLUSIONS: Low-dose tafenoquine (50 mg) reduces P. falciparum transmission to mosquitoes, with a delay in effect.

Quantification of Tafenoquine and 5,6-Orthoquinone Tafenoquine by UHPLC-MS/MS in Blood, Plasma, and Urine, and Application to a Pharmacokinetic Study.

Analytical methods for the quantification of the new 8-aminoquinoline antimalarial tafenoquine (TQ) in human blood, plasma and urine, and the 5,6-orthoquinone tafenoquine metabolite (5,6-OQTQ) in human plasma and urine have been validated. The procedure involved acetonitrile extraction of samples followed by ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Chromatography was performed using a Waters Atlantis T3 column with a gradient of 0.1% formic acid and acetonitrile at a flow rate of 0.5 mL per minute for blood and plasma. Urine analysis was the same but with methanol containing 0.1% formic acid replacing acetonitrile mobile phase. The calibration range for TQ and 5,6-OQTQ in plasma was 1 to 1200 ng/mL, and in urine was 10 to 1000 ng/mL. Blood calibration range for TQ was 1 to 1200 ng/mL. Blood could not be validated for 5,6-OQTQ due to significant signal suppression. The inter-assay precision (coefficient of variation %) was 9.9% for TQ at 1 ng/mL in blood (n = 14) and 8.2% for TQ and 7.1% for 5,6-OQTQ at 1 ng/mL in plasma (n = 14). For urine, the inter-assay precision was 8.2% for TQ and 6.4% for 5,6-OQTQ at 10 ng/mL (n = 14). TQ and 5,6-OQTQ are stable in blood, plasma and urine for at least three months at both -80 °C and -20 °C. Once validated, the analytical methods were applied to samples collected from healthy volunteers who were experimentally infected with Plasmodium falciparum to evaluate the blood stage antimalarial activity of TQ and to determine the therapeutic dose estimates for TQ, the full details of which will be published elsewhere. In this study, the measurement of TQ and 5,6-OQTQ concentrations in samples from one of the four cohorts of participants is reported. Interestingly, TQ urine concentrations were proportional to parasite recrudescence times post dosing To our knowledge, this is the first description of a fully validated method for the measurement of TQ and 5,6-OQTQ quantification in urine.

Plasmodium vivax Relapse Rates in Allied Soldiers during the Second World War: Importance of Hypnozoite Burden.

Allied soldiers suffered repeated relapses of Plasmodium vivax malaria during and immediately after the Second World War. This surprised many military medical officers who had underestimated the huge casualties produced by P. vivax malaria. Tropical (Philippines) strains of P. vivax were known to relapse more frequently than those from temperate regions (the United States). Intense exposure to mosquito infection likely increased the absolute number of hypnozoites in soldiers' livers. Both quinine and quinacrine were used as chemosuppressive agents, but their inconsistent use until at least 1943 promoted intermittent parasitological failures. Fear of hemolytic reactions after a mass casualty event in 1943 engendered fear and avoidance of the only 8-aminoquinoline pamaquine then available to cure relapses. Variable chemosuppression likely prevented acquisition of effective parasitological immunity. Unexpectedly high relapse rates in soldiers were likely an indirect measure of the high hypnozoite burden and suggest how difficult it will be to eliminate P. vivax malaria from endemic areas.

Emergency typhoid immunisation after the fall of Singapore 1942.

Singapore surrendered to the Japanese invasion in February 1942 after its water supply collapsed. At the suggestion of the colonial medical authorities, an emergency typhoid immunisation campaign was then begun using locally manufactured vaccine from extemporary materials; within 3 months, >600 000 had been immunised. Comparison with prewar statistics suggests that a postsurrender typhoid fever epidemic was prevented despite an increase in other enteric infections. Public health crises with disrupted supply chains may make locally manufactured vaccines of increasing importance in the future.

Historical 8-Aminoquinoline Combinations: Not All Antimalarial Drugs Work Well Together.

Since their first use in the 1920s, 8-aminoquinolines have been known to have important toxicities such as methemoglobinemia and hemolysis. An empiric pamaquine (plasmochin) combination with quinine was widely used in the British military with relatively little toxicity. Attempts to use pamaquine with a new synthetic antimalarial drug (atabrine, quinacrine) in the 1930-1940s, however, resulted in hemolytic reactions and some deaths from renal failure. An improved 8-aminoquinoline, primaquine, was particularly effective against Plasmodium vivax relapses when combined with either quinine or chloroquine. When used in reduced daily doses (15 mg) over 2 weeks, it was safely given to many thousands of U.S. soldiers returning from Korea. CP tablets (chloroquine 300 mg, primaquine 45 mg weekly) were widely used during the Vietnam War with few hemolytic reactions and no known deaths. Efficacy and toxicity of 8-aminoquinolines is determined in part by the selection of appropriate partner drugs.

Historical gold mining infectious disease epidemics.

Lethal infectious disease epidemics have historically occurred in military, refugee and mining camps where crowded conditions promote the spread of enteric, respiratory and insect-borne infections. The early history of gold mines around Palmer River, Queensland in the 1870s, Kalgoorlie, Western Australia in the 1890s and Papua on the island of New Guinea in the 1910s are recounted specifically as it relates to infectious disease deaths. Despite large diagnostic gaps, it is likely that malaria was the predominant problem in Palmer River, typhoid in Kalgoorlie and bacillary dysentery in Papua. Nearly two-thirds of all recorded deaths in the Palmer River district from 1873 to 1883 were due to infections, predominately 'fevers'. Typhoid fever likely killed >2000 Australians in the early phases of the Western Australian goldfields in the 1890s. Severe dysentery outbreaks killed up to a majority of the local workforce in the Lakekema goldfields of Papua resulting in the colonial authorities stopping mining activity in the second decade of the 20th century. In the absence of public health measures and specific chemotherapy, large mortality rates in miners reflected the over-riding economic drivers of gold miners and their lack of any understanding of microbial disease and its interruption by public health measures. Similar infectious disease epidemics are likely to reoccur when large numbers of impoverished miners use low-technology methods to work alluvial gold deposits in conflict areas as has been seen in modern Africa.

Mystery of blackwater fever from an Australian perspective.

Blackwater fever is a haemolytic syndrome associated with malaria that coincided with the use of quinine chemoprophylaxis. Once quinine was no longer chronically used to prevent malaria, blackwater fever largely disappeared and its aetiology remains poorly understood. Blackwater fever is representative of classical tropical medicine and its history was reflected in Australia's colonial development of Papua New Guinea particularly as reported in the Australian medical literature.

Malaria Relapses Following Parasite-Free Blood Transfusions in the U.S. Army during the Korean War.

Latent Plasmodium vivax parasites in the liver known as hypnozoites activate causing malaria relapses months after the original infection. The putative initiation signal is unknown. Plasmodium falciparum infections appear to trigger P. vivax relapses and initiation of relapse may be triggered by hemolysis or fever. The U.S. Army hospital records from the Korean War (> 500,000 individual records) were used to determine whether there was an association between blood transfusion and vivax malaria relapse. Importantly, blood for transfusion was collected in the United States, so the risk of transmission of malaria parasites was minimal. Blood transfusion (largely for combat trauma) was a risk factor for subsequent vivax malaria (relative risk 2.54, 95% CI 2.15-2.99, P < 0.0001). As expected, blood transfusion was not a risk factor for subsequent dysentery, but transfusion was a risk factor for subsequent hepatitis. Blood transfusion causing an increased heme delivery to the liver and a subsequent redox signal within hepatocytes may partially explain hypnozoite activation leading to relapses of vivax malaria.

Back to the future: lethal respiratory pandemics in New Guinea.

Lethal respiratory epidemics have torn through Papua New Guinea (PNG) since records began in the 19th century. Such historical epidemics were likely caused by influenza but often exacerbated by secondary bacterial pneumonias. Although PNG largely escaped the 1918-1919 influenza pandemic, major lethal waves were recorded in 1921, 1925, 1931 and 1964. As recently as 1969, thousands died in the PNG highlands from H3N2 influenza and subsequent pneumococcal pneumonias. This pre-independence crisis was met by a major deployment of the Australian Defence Force personnel and aircraft. Currently, vaccination efforts aided by the Australian Government are trying to cope with the COVID-19 crisis.

Mining-Associated Malaria Epidemics.

Tropical alluvial gold and gem miners are often an especially at-risk population for malaria infection. Geographical areas of mining-associated malaria epidemics in the recent past include Southeast Asia (Cambodia, Thailand, and Myanmar); the Amazon basin (Brazil, French Guyana, Suriname, Columbia, and Peru); and tropical Africa. Mobile populations of young adult men engaged in the hard labor of mining may experience severe malaria especially if they lack preexisting immunity and are irregularly consuming antimalarial drugs. Particular problems occur because much of this informal mining activity is illegal and done in isolated areas without access to health services and with evidence of emerging antimalarial drug resistance. Concentrating vulnerable populations in an ecologically disturbed landscape is often conducive to epidemics, which can then spread as these highly mobile workers return to their homes. Mining-associated malaria endangers malaria elimination efforts and miners need to be addressed as a group of particular concern.

Epidemiological Isolation May Explain Differences in Historical Respiratory Infectious Disease Mortality.

Indigenous and aboriginal peoples of the Americas and Pacific died at enormous rates soon after joining the global pathogen pool in the seventeenth to nineteenth centuries from respiratory infections such as smallpox, measles, and influenza. It was widely assumed that this represented a selection process against primitive societies. Darwinian selection for specific genetic resistance factors seems an unlikely hypothesis given that some populations stabilized quickly over two to three generations. European-origin populations whose childhood was marked by epidemiological isolation also suffered high infectious disease mortality from respiratory pathogens. American soldiers with smallpox, South African (Boer) children with measles, and New Zealand soldiers with influenza suggest that epidemiological isolation resulting in few previous respiratory infections during childhood may be a consistent mortality risk factor. Modern studies of innate immunity following Bacillus Calmette-Guérin (BCG) in infancy point toward rapid immune adaptation rather than evolutionary selection as an explanation for excessive first contact epidemic mortality from respiratory pathogens.

Influenza Outbreak During Exercise Talisman Sabre, Queensland, Australia, July 2019.

Influenza appeared in Queensland, Australia during Exercise Talisman Sabre (TS-19) in July 2019 with an early focus within the New Zealand Defence Force members arriving in Australia aboard HMNZS Canterbury. A total of 76 cases of influenza-like illness (ILI) were reported, of which 43 were confirmed by rapid diagnostic tests to be influenza A (n=32) and B (n=11). Australia's influenza season (starting in March, peaked in July 2019) exposed large numbers of military members to a virus for which they had been suboptimally immunized either because of low uptake of the Southern Hemisphere vaccine by Australians/New Zealanders who were not mandated to be immunized, or because U.S. soldiers had received only the Northern Hemisphere vaccine for the 2018-2019 season. A low-intensity clinical unit separate from the main exercise was used as a means of isolating ILI cases both to facilitate their treatment and limit disease spread. Despite disease rates of <1%, influenza still had a major impact on TS-19 mostly in terms of the considerable medical resources required to manage ILI.