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ABSTRACT: In Vietnam, the artemisinin-based combination therapy (ACT) of dihydroartemisinin-piperaquine is currently used for first-line treatment of uncomplicated Plasmodium falciparum malaria. However, limited efficacy and tolerability data are available on alternative forms of ACT in Vietnam in case there is a reduction in the susceptibility of dihydroartemisinin-piperaquine. A study was conducted to compare the efficacy and tolerability of two fixed-dose formulations of ACT, artemisinin-piperaquine (Artequick®, ARPQ) and artesunate-amodiaquine (Coarsucam™, ASAQ) for the treatment of P. falciparum malaria in south-central Vietnam.
A randomized, open-label trial was conducted comparing the efficacy of a two-day regimen of ARPQ (~2.8 mg/kg artemisinin plus ~17.1 mg/kg of piperaquine per day) and a three-day regimen of ASAQ (~4.7 mg/kg of artesunate plus ~12.6 mg/kg of amodiaquine per day) for the treatment of children and adults with uncomplicated falciparum malaria. Primary efficacy endpoint was day 42, PCR-corrected, parasitological cure rate. Secondary endpoints were parasite and fever clearance times and tolerability.
Of 128 patients enrolled, 63 were administered ARPQ and 65 ASAQ. Of the patients who completed the 42 days follow-up period or had a recurrence of malaria, 55 were on ARPQ (30 children, 25 adults) and 59 were on ASAQ (31 children, 28 adults). Recrudescent parasitaemia was PCR-confirmed for one patient in each treatment group, with cure rates at day 42 of 98% (95% CI: 88-100) for both forms of ACT. The median parasite clearance time was significantly slower in the ARPQ group compared with the ASAQ group (48 h vs. 36 h, P<0.001) and fever clearance times were shorter in the ASAQ group (12 h vs. 24 h, P=0.07). The two forms of ACT were well tolerated with no serious adverse events.
Both forms of ACT were highly efficacious in the treatment of uncomplicated P. falciparum malaria. Although the two-day course of ARPQ was equally as effective as the three-day course of ASAQ, parasite and fever clearance times were shorter with ASAQ. Further studies are warranted in different regions of Vietnam to determine the nationwide efficacy of ASAQ.
Australian New Zealand Clinical Trials Registry Number, ACTRN12609000816257.
Malaria Journal 06/2012; 11:217. · 3.19 Impact Factor
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ABSTRACT: Of the unexplained characteristics of the 1918-19 influenza pandemic, the extreme mortality rate among young adults (W-shaped mortality curve) is the foremost. Lack of a coherent explanation of this and other epidemiologic and clinical manifestations of the pandemic contributes to uncertainty in preparing for future pandemics. Contemporaneous records suggest that immunopathologic responses were a critical determinant of the high mortality rate among young adults and other high-risk subgroups. Historical records and findings from laboratory animal studies suggest that persons who were exposed to influenza once before 1918 (e.g., A/H3Nx 1890 pandemic strain) were likely to have dysregulated, pathologic cellular immune responses to infections with the A/H1N1 1918 pandemic strain. The immunopathologic effects transiently increased susceptibility to ultimately lethal secondary bacterial pneumonia. The extreme mortality rate associated with the 1918-19 pandemic is unlikely to recur naturally. However, T-cell-mediated immunopathologic effects should be carefully monitored in developing and using universal influenza vaccines.
Emerging Infectious Diseases 02/2012; 18(2):201-7. · 6.79 Impact Factor
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ABSTRACT: Please cite this paper as: Shanks et al. (2012) Epidemiological isolation causing variable mortality in Island populations during the 1918-1920 influenza pandemic. Influenza and Other Respiratory Viruses 6(6), 417-423. Background During the 1918 pandemic period, influenza-related mortality increased worldwide; however, mortality rates varied widely across locations and demographic subgroups. Islands are isolated epidemiological situations that may elucidate why influenza pandemic mortality rates were so variable in apparently similar populations. Objectives Our objectives were to determine and compare the patterns of pandemic influenza mortality on islands. Methods We reviewed historical records of mortality associated with the 1918-1920 influenza pandemic in various military and civilian groups on islands. Results and Conclusions Mortality differed more than 50-fold during pandemic-related epidemics on Pacific islands [range: 0·4% (Hawaii) to 22% (Samoa)], and on some islands, mortality sharply varied among demographic subgroups of island residents such as Saipan: Chamorros [12%] and Caroline Islanders [0·4%]. Among soldiers from island populations who had completed initial military training, influenza-related mortality rates were generally low, for example, Puerto Rico (0·7%) and French Polynesia (0·13%). The findings suggest that among island residents, those who had been exposed to multiple, antigenically diverse respiratory pathogens prior to infection with the 1918 pandemic strain (e.g., less isolated) experienced lower mortality. The continuous circulation of antigenically diverse influenza viruses and other respiratory infectious agents makes widespread high mortality during future influenza pandemics unlikely.
Influenza and Other Respiratory Viruses 01/2012; 6(6):417-23. · 4.16 Impact Factor
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ABSTRACT: Purulent bronchitis was a distinctive and apparently new lethal respiratory infection in British and American soldiers during the First World War. Mortality records suggest that purulent bronchitis caused localized outbreaks in the midst of a broad epidemic wave of lethal respiratory illness in 1916-1917. Probable purulent bronchitis deaths in the Australian Army showed an epidemic wave that moved from France to England. Purulent bronchitis may have been the clinical expression of infection with a novel influenza virus which also could have been a direct precursor of the 1918 pandemic strain.
Influenza and Other Respiratory Viruses 11/2011; 6(4):235-9. · 4.16 Impact Factor
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ABSTRACT: In 1918, two waves of epidemic influenza arose with very different clinical phenotypes. During the first wave, infection rates were high but mortality was low. During the second wave, high numbers of deaths occurred and mortality differed 30-100 times among seemingly similar groups of affected adults, but the reason for this variation is unclear. In 1918, the crews of most warships and some island populations were affected by influenza during both waves of infection and had no or very few deaths during the second wave. However, some warships and island populations were not affected during the first wave of infection and had high mortality during the second wave. These findings suggest that infection during the first wave protected against death, but not infection, during the second wave. If so, the two waves of infection were probably caused by antigenically distinct influenza viruses--not by one virus that suddenly increased in pathogenicity between the first and second waves. These findings are relevant to modern concerns that the 2009 influenza A H1N1 virus could suddenly increase in lethality.
The Lancet Infectious Diseases 10/2011; 11(10):793-9. · 17.39 Impact Factor
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ABSTRACT: The safety and tolerability of primaquine (PQ) administered as a short higher-dose (30mg twice daily for 7 days) regimen in 203 Australian Defence Force personnel was evaluated in an open-label presumptive anti-relapse therapy study. No clinically significant differences were measured in the subjects' haematological and biochemical indices before and after PQ treatment. The most common adverse events were nausea, abdominal pain, headache and insomnia, many of which were mild in severity (30%; 60/203) and transient; 19% of subjects (39/203) experienced moderate (with some interference with daily duties requiring no or minimal medical therapy) adverse events. Two subjects (1%) had severe gastrointestinal adverse events requiring cessation of medication, but neither was seriously ill. Ten subjects (5%) had peripheral cyanosis (blueness of the lips), but none reported any respiratory compromise. These findings suggest that the short higher-dose PQ regimen is safe and well tolerated, which could improve PQ compliance and effectiveness.
Transactions of the Royal Society of Tropical Medicine and Hygiene 09/2011; 105(10):568-73. · 2.16 Impact Factor
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ABSTRACT: Rotuma is an isolated Polynesian island. In January 1911, most residents of Rotuma (population approximately 2,600) were exposed to measles virus for the first time. The official mortality register documented 491 deaths due to all causes among Rotumans during 1911 (cumulative measles-related mortality: 12.8%); most deaths occurred in April-May and were attributed to measles and its sequelae. Measles-related mortality rates were higher among young children (23.4 per 100 person-years) and young adults (17.1 per 100 person-years) than among adolescents (11.0 per 100 person-years) and older adults (5.6 per 100 person-years); females (16.2 per 100 person-years) died at a higher rate than males (13.2 per 100 person-years). Gastrointestinal complications (75%), not respiratory complications, were the predominant clinical manifestations of fatal measles cases; tuberculosis mortality was unusually high during the year of the epidemic. In 1911, measles-related mortality varied by nearly 3-fold across geographic districts (range, 7.4%-21.6%). The extreme mortality due to measles on Rotuma typifies the experiences of isolated populations after first encounters with measles; it suggests that prior exposures to a narrow range of microbes and genetic homogeneity predispose isolated populations to lethal outcomes when they are first exposed to highly contagious and pathogenic viruses (e.g., measles, influenza).
American journal of epidemiology 05/2011; 173(10):1211-22. · 5.59 Impact Factor
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ABSTRACT: During the 1918-1919 influenza pandemic, nurses and physicians were intensively exposed to the pandemic A/H1N1 strain. There are few published summaries of the mortality experiences of nurses and physicians during the pandemic.
Mortality records from U.S. and British Armies during the First World War and obituary notices in national medical association journals were reviewed to ascertain death notices of nurses and physicians likely to have died of influenza.
Illness-related mortality among U.S. military nurses (1·05%) was one and one-half times higher than among U.S. medical officers (0·68%), nearly two times higher than among British medical officers (0·55%), and nine times higher than among British nurses (0·12%). Among U.S. nursing officers, mortality was approximately twice as high among those assigned in the United States than in Europe. Among civilian physicians, mortality during the influenza pandemic was markedly increased in Canada, New Zealand, South Africa and the United States but not Australia.
During the 1918 pandemic, mortality among nurses and physicians was relatively low compared to their patients and significantly varied across locations and settings. Medical-care providers (particularly U.S. nursing officers) who were new to their assignments when pandemic-related epidemics occurred may have had higher risk of influenza-related mortality because of occupational exposures to bacterial respiratory pathogens that they had not previously encountered.
Influenza and Other Respiratory Viruses 05/2011; 5(3):213-9. · 4.16 Impact Factor
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The Journal of Infectious Diseases 04/2011; 203(7):1034-5. · 6.41 Impact Factor
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ABSTRACT: There has been considerable debate on the existence of trends in climate in the highlands of East Africa and hypotheses about their potential effect on the trends in malaria in the region. We apply a new robust trend test to mean temperature time series data from three editions of the University of East Anglia's Climatic Research Unit database (CRU TS) for several relevant locations. We find significant trends in the data extracted from newer editions of the database but not in the older version for periods ending in 1996. The trends in the newer data are even more significant when post-1996 data are added to the samples. We also test for trends in the data from the Kericho meteorological station prepared by Omumbo et al. We find no significant trend in the 1979-1995 period but a highly significant trend in the full 1979-2009 sample. However, although the malaria cases observed at Kericho, Kenya rose during a period of resurgent epidemics (1994-2002) they have since returned to a low level. A large assembly of parasite rate surveys from the region, stratified by altitude, show that this decrease in malaria prevalence is not limited to Kericho.
PLoS ONE 01/2011; 6(9):e24524. · 4.09 Impact Factor
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G Dennis Shanks
The Lancet 11/2010; 376(9753):1621-2. · 38.28 Impact Factor
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Timothy J Whitman,
Philip E Coyne,
Alan J Magill,
David L Blazes,
Michael D Green,
Wilbur K Milhous,
Timothy H Burgess,
Daniel Freilich,
Sybil A Tasker,
Ramzy G Azar,
Timothy P Endy,
Christopher D Clagett,
Gregory A Deye, G Dennis Shanks,
Gregory J Martin
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ABSTRACT: In 2003, 44 U.S. Marines were evacuated from Liberia with either confirmed or presumed Plasmodium falciparum malaria. An outbreak investigation showed that only 19 (45%) used insect repellent, 5 (12%) used permethrin-treated clothing, and none used bed netting. Adherence with weekly mefloquine (MQ) was reported by 23 (55%). However, only 4 (10%) had serum MQ levels high enough to correlate with protection (> 794 ng/mL), and 9 (22%) had evidence of steady-state kinetics (MQ carboxy metabolite/MQ > 3.79). Tablets collected from Marines met USP identity and dissolution specifications for MQ. Testing failed to identify P. falciparum isolates with MQ resistance. This outbreak resulted from under use of personal protective measures and inadequate adherence with chemophrophylaxis. It is essential that all international travelers make malaria prevention measures a priority, especially when embarking to regions of the world with high transmission intensity such as west Africa..
The American journal of tropical medicine and hygiene 08/2010; 83(2):258-65. · 2.59 Impact Factor
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ABSTRACT: Understanding the risk of mortality during the 1918-1919 influenza pandemic could inform preparations for a future pandemic.
Prospectively collected demographic, hospitalization, and death data from all individuals who served in the Australian Imperial Force from 1914 through 1919 in Europe and the Middle East were abstracted from archived records. Analyses were conducted to determine mortality risk factors.
Hospitalization with a respiratory illness during the spring-summer of 1918 protected soldiers from death (odds ratio, 0.37 [95% confidence interval, 0.25-0.53]; P < .001) but not from hospitalization during the fall-winter of 1918-1919. During the fall-winter of 1918-1919, there was a strong inverse relationship between risk of dying of pneumonia-influenza and time in military service. The pneumonia-influenza death rate among men who enlisted in 1918 (6.33 deaths per 100 person-years) was 9 times higher than that among the 1917 enlistment cohort (0.72 deaths per 100 person-years) and >14 times higher than that among the 1916 cohort (0.43 deaths per 100 person-years), 1915 cohort (0.29 deaths per 100 person-years), and 1914 cohort (0.28 deaths per 100 person-years).
There was a strong inverse relationship between length of service in the Australian Imperial Force and mortality risk from pneumonia-influenza during the fall-winter of 1918-1919. The protective effect of increased service likely reflected increased acquired immunity to influenza viruses and endemic bacterial strains that caused secondary pneumonia and most of the deaths during the 1918-1919 influenza pandemic.
The Journal of Infectious Diseases 06/2010; 201(12):1880-9. · 6.41 Impact Factor
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G Dennis Shanks
Clinical Infectious Diseases 01/2010; 50(2):282-3. · 9.15 Impact Factor
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ABSTRACT: Malaria was the major cause of morbidity and a leading cause of mortality in the Andaman Islands Penal Colony from 1858 to 1945. Besides annual malaria incidence peaks coinciding with the arrival of the monsoon, multi-year cycles (administrative in nature) of 10-15 years are also discernable. The size of the previous year's prisoner intake was associated (r(2)=0.21, n=57) with increased malaria. The positive relationship (r(2)=0.33, n=47) between the total number of Buddhist prisoners and malaria may have been due to prisoners of Burmese ethnicity introducing new malaria strains to the otherwise isolated islands. Well-meaning but ultimately disastrous attempts were made to drain the mangrove swamps around the penal colony. Because of the brackish-water breeding habits of the main vector, Anopheles sundaicus, engineering works along the shoreline often increased malaria. Malaria morbidity approximately trebled from 1928 to 1929 and doubled again in the next year with increases in all-cause mortality from 20/1000 in 1929 to 51/1000 in 1930, coincident with a major dredging operation for a new port. The history of malaria control in the Andaman Islands Penal Colony is a cautionary tale that well-meaning and well-funded efforts can fail spectacularly if local epidemiological reality is not well understood.
Transactions of the Royal Society of Tropical Medicine and Hygiene 10/2009; 104(3):185-90. · 2.16 Impact Factor
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G Dennis Shanks
Clinical Infectious Diseases 09/2009; 49(6):850-1. · 9.15 Impact Factor
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ABSTRACT: Artesunate-amodiaquine (AAQ) is efficacious for the treatment of uncomplicated Plasmodium falciparum malaria in Africa, but little is known about its efficacy in Southeast Asia. We compared the efficacy of dihydroartemisinin-piperaquine (DHP) and AAQ against falciparum malaria in central Vietnam.
Open, randomized clinical trial of 116 patients (36 children aged 6-14 years, 80 adults aged 15-60 years) were randomly allocated a 3-day course of either DHP (approximately 2.3 mg/kg dihydroartemisinin plus approximately 18.5 mg/kg of piperaquine per day) or AAQ (approximately 4.4 mg/kg of artesunate plus approximately 10.6 mg/kg of amodiaquine per day). The follow-up period was 42 days.
The two drug combinations were well tolerated by all age groups with no obvious drug associated adverse events. Of the patients who completed 42 days of follow-up, 49 were on DHP (15 children, 34 adults) and 49 were on AAQ (14 children, 35 adults). The 42 day cure rates adjusted for reinfection identified by PCR genotyping for the two groups were similar [100% (49/49) and 98% (48/49) for DHP and AAQ, respectively]. With fewer reinfections, DHP appears to possess greater post-treatment prophylactic activity than AAQ.
AAQ, an inexpensive artemisinin-based combination, could be an additional option to DHP for the treatment of multidrug-resistant falciparum malaria in Vietnam.
Tropical Medicine & International Health 04/2009; 14(5):504-11. · 2.80 Impact Factor
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ABSTRACT: Deaths during the 1918-19 influenza pandemic have been attributed to a hypervirulent influenza strain. Hence, preparations for the next pandemic focus almost exclusively on vaccine prevention and antiviral treatment for infections with a novel influenza strain. However, we hypothesize that infections with the pandemic strain generally caused self-limited (rarely fatal) illnesses that enabled colonizing strains of bacteria to produce highly lethal pneumonias. This sequential-infection hypothesis is consistent with characteristics of the 1918-19 pandemic, contemporaneous expert opinion, and current knowledge regarding the pathophysiologic effects of influenza viruses and their interactions with respiratory bacteria. This hypothesis suggests opportunities for prevention and treatment during the next pandemic (e.g., with bacterial vaccines and antimicrobial drugs), particularly if a pandemic strain-specific vaccine is unavailable or inaccessible to isolated, crowded, or medically underserved populations.
Emerging Infectious Diseases 09/2008; 14(8):1193-9. · 6.79 Impact Factor
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ABSTRACT: Malaria has a substantial secondary effect on other causes of mortality. From the 19th century, malaria epidemics in the Andaman Islands' penal colony were initiated by the brackish swamp-breeding malaria vector Anopheles sundaicus and fuelled by the importation of new prisoners. Malaria was a major determinant of the highly variable all-cause mortality rate (correlation coefficient r(2)=0.60, n=68, p<0.0001) from 1872 to 1939. Directly attributed malaria mortality based on post-mortem examinations rarely exceeded one-fifth of total mortality. Infectious diseases such as pneumonia, tuberculosis, dysentery, and diarrhoea, which combined with malaria made up the majority of all-cause mortality, were positively correlated with malaria incidence over several decades. Deaths secondary to malaria (indirect malaria mortality) were at least as great as mortality directly attributed to malaria infections.
The Lancet Infectious Diseases 07/2008; 8(9):564-70. · 17.39 Impact Factor
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The Journal of Infectious Diseases 01/2008; 196(11):1717-8; author reply 1718-9. · 6.41 Impact Factor
