Anu Kantele, T Sakari Jokiranta
Review of cases with the emerging fifth human malaria parasite, Plasmodium knowlesi.
Clin Infect Dis. 2011 Jun;52(11):1356-62. doi: 10.1093/cid/cir180.
Abstract/Text
Human malaria has been known to be caused by 4 Plasmodium species, with Plasmodium falciparum causing the most-severe disease. Recently, numerous reports have described human malaria caused by a fifth Plasmodium species, Plasmodium knowlesi, which usually infects macaque monkeys. Hundreds of human cases have been reported from Malaysia, several cases have been reported in other Southeast Asian countries, and a few cases have been reported in travelers visiting these areas. Similarly to P. falciparum, P. knowlesi can cause severe and even fatal cases of disease that are more severe than those caused by the other Plasmodium species. Polymerase chain reaction is of value for diagnosis because P. knowlesi infection is easily misdiagnosed as less dangerous Plasmodium malariae infection with conventional microscopy. P. knowlesi infection should be suspected in patients who are infected with malaria in Southeast Asia. If human-mosquito-human transmission were to occur, the disease could spread to new areas where the mosquito vectors live, such as the popular tourist areas in western India.
Antoine Berry, Xavier Iriart, Nathalie Wilhelm, Alexis Valentin, Sophie Cassaing, Benoit Witkowski, Françoise Benoit-Vical, Sandie Menard, David Olagnier, Judith Fillaux, Stephane Sire, Alain Le Coustumier, Jean-François Magnaval
Imported Plasmodium knowlesi malaria in a French tourist returning from Thailand.
Am J Trop Med Hyg. 2011 Apr;84(4):535-8. doi: 10.4269/ajtmh.2011.10-0622.
Abstract/Text
We report a case of imported Plasmodium knowlesi malaria in a French tourist following a vacation in Thailand. This case shows, first, tourists may contract knowlesi malaria even only staying on the beach and second, the diagnosis remains difficult, even with polymerase chain reaction methods.
田中誠二: 日本内地の土着マラリアに関する研究 ―「マラリア五県」の発生状況を解明する―, （財）国土地理協会 研究助成 研究活動実施報告書．2011．.
大友弘士: 日本におけるマラリア. 化学療法の領域 1998;14: 789-794．.
Anna M Checkley, Adrian Smith, Valerie Smith, Marie Blaze, David Bradley, Peter L Chiodini, Christopher J M Whitty
Risk factors for mortality from imported falciparum malaria in the United Kingdom over 20 years: an observational study.
BMJ. 2012 Mar 27;344:e2116. Epub 2012 Mar 27.
Abstract/Text
OBJECTIVES: To determine which travellers with malaria are at greatest risk of dying, highlighting factors which can be used to target health messages to travellers.
DESIGN: Observational study based on 20 years of UK national data.
SETTING: National register of malaria cases.
PARTICIPANTS: 25,054 patients notified with Plasmodium falciparum malaria, of whom 184 died, between 1987 and 2006.
MAIN OUTCOME MEASURES: Comparison between those with falciparum malaria who died and non-fatal cases, including age, reason for travel, country of birth, time of year diagnosed, malaria prophylaxis used.
RESULTS: Mortality increased steadily with age, with a case fatality of 25/548 (4.6%) in people aged >65 years, adjusted odds ratio 10.68 (95% confidence interval 6.4 to 17.8), P<0.001 compared with 18-35 year olds. There were no deaths in the ≤ 5 year age group. Case fatality was 3.0% (81/2740 cases) in tourists compared with 0.32% (26/8077) in travellers visiting friends and relatives (adjusted odds ratio 8.2 (5.1 to 13.3), P<0.001). Those born in African countries with endemic malaria had a case fatality of 0.4% (36/8937) compared with 2.4% (142/5849) in others (adjusted odds ratio 4.6 (3.1 to 9.9), P<0.001). Case fatality was particularly high from the Gambia. There was an inverse correlation in mortality between region of presentation and number of cases seen in the region (R(2) = 0.72, P<0.001). Most delay in fatal cases was in seeking care.
CONCLUSIONS: Most travellers acquiring malaria are of African heritage visiting friends and relatives. In contrast the risks of dying from malaria once acquired are highest in the elderly, tourists, and those presenting in areas in which malaria is seldom seen. Doctors often do not think of these as high risk groups for malaria; for this reason they are important groups to target in pre-travel advice.
Wim Van Bortel, Bea Van den Poel, Greet Hermans, Marleen Vanden Driessche, Helmut Molzahn, Isra Deblauwe, Katrien De Wolf, Anna Schneider, Nick Van Hul, Ruth Müller, Leen Wilmaerts, Sophie Gombeer, Nathalie Smitz, Johanna Helena Kattenberg, Pieter Monsieurs, Anna Rosanas-Urgell, Marjan Van Esbroeck, Emmanuel Bottieau, Ula Maniewski-Kelner, Javiera Rebolledo
Two fatal autochthonous cases of airport malaria, Belgium, 2020.
Euro Surveill. 2022 Apr;27(16). doi: 10.2807/1560-7917.ES.2022.27.16.2100724.
Abstract/Text
We report an outbreak investigation of two fatal cases of autochthonous Plasmodium falciparum malaria that occurred in Belgium in September 2020. Various hypotheses of the potential source of infection were investigated. The most likely route of transmission was through an infectious exotic Anopheles mosquito that was imported via the international airport of Brussels or the military airport Melsbroek and infected the cases who lived at 5 km from the airports. Based on genomic analysis of the parasites collected from the two cases, the most likely origin of the Plasmodium was Gabon or Cameroon. Further, the parasites collected from the two Belgian patients were identical by descent, which supports the assumption that the two infections originated from the bite of the same mosquito, during interrupted feeding. Although airport malaria remains a rare event, it has significant implications, particularly for the patient, as delayed or missed diagnosis of the cause of illness often results in complications and mortality. Therefore, to prevent such severe or fatal outcomes, we suggest a number of public health actions including increased awareness among health practitioners, especially those working in the vicinity of airports, and increased surveillance of exotic mosquito species at airports.
Imke Wieters, Philip Eisermann, Frauke Borgans, Katharina Giesbrecht, Udo Goetsch, Gudrun Just-Nübling, Johanna Kessel, Simone Lieberknecht, Birgit Muntau, Dennis Tappe, Joscha Schork, Timo Wolf
Two cases of airport-associated falciparum malaria in Frankfurt am Main, Germany, October 2019.
Euro Surveill. 2019 Dec;24(49). doi: 10.2807/1560-7917.ES.2019.24.49.1900691.
Abstract/Text
Two cases of presumably airport-acquired falciparum malaria were diagnosed in Frankfurt in October 2019. They were associated with occupation at the airport, and Plasmodium falciparum parasites from their blood showed genetically identical microsatellite and allele patterns. Both had severe malaria. It took more than a week before the diagnosis was made. If symptoms are indicative and there is a plausible exposure, malaria should be considered even if patients have not travelled to an endemic area.
J Whitworth, D Morgan, M Quigley, A Smith, B Mayanja, H Eotu, N Omoding, M Okongo, S Malamba, A Ojwiya
Effect of HIV-1 and increasing immunosuppression on malaria parasitaemia and clinical episodes in adults in rural Uganda: a cohort study.
Lancet. 2000 Sep 23;356(9235):1051-6. doi: 10.1016/S0140-6736(00)02727-6.
Abstract/Text
BACKGROUND: An association between HIV-1 and malaria is expected in theory, but has not been convincingly shown in practice. We studied the effects of HIV-1 infection and advancing immunosuppression on falciparum parasitaemia and clinical malaria.
METHODS: HIV-1-positive and HIV-1-negative adults selected from a population-based cohort in rural Uganda were invited to attend a clinic every 3 months (routine visits) and whenever they were sick (interim visits). At each visit, information was collected on recent fever, body temperature, and malaria parasites. Participants were assigned a clinical stage at each routine visit and had regular CD4-cell measurements.
FINDINGS: 484 participants made 7220 routine clinic visits between 1990 and 1998. Parasitaemia was more common at visits by HIV-1-positive individuals (328 of 2788 [11.8%] vs 231 of 3688 [6.3%], p<0.0001). At HIV-1-positive visits, lower CD4-cell counts were associated with higher parasite densities, compared with HIV-1-negative visits (p=0.0076). Clinical malaria was significantly more common at HIV-1-positive visits (55 of 2788 [2.0%] vs 26 of 3688 [0.7%], p=0.0003) and the odds of having clinical malaria increased with falling CD4-cell count (p=0.0002) and advancing clinical stage (p=0.0024). Participants made 3377 interim visits. The risk of clinical malaria was significantly higher at visits by HIV-1-positive individuals than HIV-1-negative individuals (4.0% vs 1.9%, p=0.009). The risk of clinical malaria tended to increase with falling CD4-cell counts (p=0.052).
INTERPRETATION: HIV-1 infection is associated with an increased frequency of clinical malaria and parasitaemia. This association tends to become more pronounced with advancing immunosuppression, and could have important public-health implications for sub-Saharan Africa.
Cheryl Cohen, Alan Karstaedt, John Frean, Juno Thomas, Nelesh Govender, Elizabeth Prentice, Leigh Dini, Jacky Galpin, Heather Crewe-Brown
Increased prevalence of severe malaria in HIV-infected adults in South Africa.
Clin Infect Dis. 2005 Dec 1;41(11):1631-7. doi: 10.1086/498023. Epub 2005 Oct 26.
Abstract/Text
BACKGROUND: Conflicting reports exist regarding the impact of human immunodeficiency virus (HIV) infection on the risk of severe malaria. We aimed to assess the effect of HIV infection status, advancing immunosuppression, and antimalarial immunity on the severity of malaria.
METHODS: A prospective cohort study was conducted. Consecutive hospitalized adult patients with falciparum malaria were tested for HIV antibodies and to determine CD4+ T cell count. Immunity to malaria was assessed by obtaining a history of childhood residence in an area where malaria is endemic. Patients were assessed for features of severe malaria.
RESULTS: Three hundred thirty-six patients were enrolled in the study, of whom 32 (10%) had severe malaria. The prevalence of HIV infection was 33%, and 111 patients (33%) were nonimmune to malaria. HIV-infected patients complained more frequently about respiratory and abdominal symptoms and less frequently about rigors and headache. Risk factors for severe malaria determined by multivariate analysis included being nonimmune to malaria, having a positive HIV serostatus, having an elevated parasite count, and having an increased white blood cell count. Risk of severe malaria was increased in HIV-infected patients with a CD4+ T cell count of < 200 x 10(6) cells/L (P < or = .001). Nonimmune HIV-infected patients were significantly more likely to have severe malaria (13 [36%] of 36 patients) than were nonimmune non-HIV-infected patients (9 [12%] of 75 patients; odds ratio, 4.15 [95% confidence interval, 1.57-10.97]; P = .003). HIV serostatus did not affect risk of severe malaria in the group from an area with endemicity (5 [7%] of 74 HIV-infected patients had severe malaria, and 5 [3%] of 151 non-HIV-infected patients had malaria; P = .248).
CONCLUSIONS: HIV-infected nonimmune adults are at increased risk of severe malaria. This risk is associated with a low CD4+ T cell count. This interaction is of great public health importance.
Robert Steffen, Isis Amitirigala, Margot Mutsch
Health risks among travelers--need for regular updates.
J Travel Med. 2008 May-Jun;15(3):145-6. doi: 10.1111/j.1708-8305.2008.00198.x.
Abstract/Text
Karin Leder, Jim Black, Dan O'Brien, Zoe Greenwood, Kevin C Kain, Eli Schwartz, Graham Brown, Joseph Torresi
Malaria in travelers: a review of the GeoSentinel surveillance network.
Clin Infect Dis. 2004 Oct 15;39(8):1104-12. doi: 10.1086/424510. Epub 2004 Sep 27.
Abstract/Text
BACKGROUND: Malaria is a common and important infection in travelers.
METHODS: We have examined data reported to the GeoSentinel surveillance network to highlight characteristics of malaria in travelers.
RESULTS: A total of 1140 malaria cases were reported (60% of cases were due to Plasmodium falciparum, 24% were due to Plasmodium vivax). Male subjects constituted 69% of the study population. The median duration of travel was 34 days; however, 37% of subjects had a travel duration of < or =4 weeks. The majority of travellers did not have a pretravel encounter with a health care provider. Most cases occurred in travelers (39%) or immigrants/refugees (38%). The most common reasons for travel were to visit friends/relatives (35%) or for tourism (26%). Three-quarters of infections were acquired in sub-Saharan Africa. Severe and/or complicated malaria occurred in 33 cases, with 3 deaths. Compared with others in the GeoSentinel database, patients with malaria had traveled to sub-Saharan Africa more often, were more commonly visiting friends/relatives, had traveled for longer periods, presented sooner after return, were more likely to have a fever at presentation, and were less likely to have had a pretravel encounter. In contrast to immigrants and visitors of friends or relatives, a higher proportion (73%) of the missionary/volunteer group who developed malaria had a pretravel encounter with a health care provider. Travel to sub-Saharan Africa and Oceania was associated with the greatest relative risk of acquiring malaria.
CONCLUSIONS: We have used a global database to identify patient and travel characteristics associated with malaria acquisition and characterized differences in patient type, destinations visited, travel duration, and malaria species acquired.
Steve M Taylor, Malcolm E Molyneux, David L Simel, Steven R Meshnick, Jonathan J Juliano
Does this patient have malaria?
JAMA. 2010 Nov 10;304(18):2048-56. doi: 10.1001/jama.2010.1578. Epub 2010 Nov 5.
Abstract/Text
CONTEXT: Malaria commonly infects residents of and travelers to tropical regions. The clinical features of infection are notoriously nonspecific but have not been comprehensively evaluated.
OBJECTIVE: To systematically review and synthesize data related to the predictive value of clinical findings for the diagnosis of malaria in endemic areas and in travelers returning from endemic areas.
DATA SOURCES, STUDY SELECTION, AND DATA EXTRACTION: The databases of MEDLINE and EMBASE (1950-July 2010) were searched to identify studies published in the English language of endemic and "imported" (acquired during travel) malaria. Additional studies were identified from reference lists. Studies were included that had patients suspected of having acute malaria (usually because of fever) and compared the presence or absence of clinical findings with blood smear confirmation. Two authors independently identified studies, appraised study quality, and extracted data on the patient population, outcome assessment, and clinical findings. Differences between reviewers were resolved by consensus.
DATA SYNTHESIS: Fourteen studies for endemic malaria were identified that met review criteria. Individual symptoms are of limited diagnostic utility but presence of splenomegaly (summary likelihood ratio [LR], 3.3; 95% confidence interval [CI], 2.0-4.7) or hepatomegaly (summary LR, 2.4; 95% CI, 1.6-3.6) make malaria more likely. Combinations of findings can affect the likelihood of malaria, but their performance varies by setting. Seven studies of imported malaria were identified. The presence of fever (LR, 5.1; 95% CI, 4.9-5.3), splenomegaly (summary LR, 6.5; 95% CI, 3.9-11.0), hyperbilirubinemia (LR, 7.3; 95% CI, 5.5-9.6), or thrombocytopenia (summary LR, 5.6; 95% CI, 4.1-7.5) make malaria more likely.
CONCLUSIONS: In endemic areas, the likelihood of malaria is increased by the presence of splenomegaly and hepatomegaly but individual findings are of limited utility and cannot reliably exclude malaria; combinations of findings may be useful to stratify risk in patients. In returning travelers, the clinical assessment can provide substantial diagnostic benefit, although all patients still require laboratory testing because malaria can be rapidly fatal.
Aubrey J Cunnington, J Brian de Souza, Michael Walther, Eleanor M Riley
Malaria impairs resistance to Salmonella through heme- and heme oxygenase-dependent dysfunctional granulocyte mobilization.
Nat Med. 2011 Dec 18;18(1):120-7. doi: 10.1038/nm.2601. Epub 2011 Dec 18.
Abstract/Text
In sub-Saharan Africa, invasive nontyphoid Salmonella (NTS) infection is a common and often fatal complication of Plasmodium falciparum infection. Induction of heme oxygenase-1 (HO-1) mediates tolerance to the cytotoxic effects of heme during malarial hemolysis but might impair resistance to NTS by limiting production of bactericidal reactive oxygen species. We show that co-infection of mice with Plasmodium yoelii 17XNL (Py17XNL) and Salmonella enterica serovar Typhimurium 12023 (Salmonella typhimurium) causes acute, fatal bacteremia with high bacterial load, features reproduced by phenylhydrazine-induced hemolysis or hemin administration. S. typhimurium localized predominantly in granulocytes. Py17XNL, phenylhydrazine and hemin caused premature mobilization of granulocytes from bone marrow with a quantitative defect in the oxidative burst. Inhibition of HO by tin protoporphyrin abrogated the impairment of resistance to S. typhimurium by hemolysis. Thus, a mechanism of tolerance to one infection, malaria, impairs resistance to another, NTS. Furthermore, HO inhibitors may be useful adjunctive therapy for NTS infection in the context of hemolysis.
Elizabeth A Reddy, Andrea V Shaw, John A Crump
Community-acquired bloodstream infections in Africa: a systematic review and meta-analysis.
Lancet Infect Dis. 2010 Jun;10(6):417-32. doi: 10.1016/S1473-3099(10)70072-4.
Abstract/Text
Data on the prevalence and causes of community-acquired bloodstream infections in Africa are scarce. We searched three databases for studies that prospectively studied patients admitted to hospital with at least a blood culture, and found 22 eligible studies describing 58 296 patients, of whom 2051 (13.5%) of 15 166 adults and 3527 (8.2%) of 43 130 children had bloodstream infections. 1643 (29.1%) non-malaria bloodstream infections were due to Salmonella enterica (58.4% of these non-typhoidal Salmonella), the most prevalent isolate overall and in adults, and 1031 (18.3% overall) were due to Streptococcus pneumoniae, the most common isolate in children. Other common isolates included Staphylococcus aureus (531 infections; 9.5%) and Escherichia coli (412; 7.3%). Mycobacterium tuberculosis complex accounted for 166 (30.7%) of 539 isolates in seven studies that used mycobacterial culture techniques. HIV infection was associated with any bloodstream infection, particularly with S enterica and M tuberculosis complex bacteraemia. Where recorded, patients with bloodstream infections had an in-hospital case fatality of 18.1%. Our results show that bloodstream infections are common and associated with high mortality. Improved clinical microbiology services and reassessment of empirical treatment guidelines that account for the epidemiology of bloodstream infections might contribute to better outcomes.
2010 Elsevier Ltd. All rights reserved.
Gordon C Cook, and Alimuddin I Zumla: Manson’s Tropical Diseases 22nd Edition, 2009 , Saunders Ltd.;2008.
Meghna Desai, Feiko O ter Kuile, François Nosten, Rose McGready, Kwame Asamoa, Bernard Brabin, Robert D Newman
Epidemiology and burden of malaria in pregnancy.
Lancet Infect Dis. 2007 Feb;7(2):93-104. doi: 10.1016/S1473-3099(07)70021-X.
Abstract/Text
We reviewed evidence of the clinical implications and burden of malaria in pregnancy. Most studies come from sub-Saharan Africa, where approximately 25 million pregnant women are at risk of Plasmodium falciparum infection every year, and one in four women have evidence of placental infection at the time of delivery. P falciparum infections during pregnancy in Africa rarely result in fever and therefore remain undetected and untreated. Meta-analyses of intervention trials suggest that successful prevention of these infections reduces the risk of severe maternal anaemia by 38%, low birthweight by 43%, and perinatal mortality by 27% among paucigravidae. Low birthweight associated with malaria in pregnancy is estimated to result in 100,000 infant deaths in Africa each year. Although paucigravidae are most affected by malaria, the consequences for infants born to multigravid women in Africa may be greater than previously appreciated. This is because HIV increases the risk of malaria and its adverse effects, particularly in multigravidae, and recent observational studies show that placental infection almost doubles the risk of malaria infection and morbidity in infants born to multigravidae. Outside Africa, malaria infection rates in pregnant women are much lower but are more likely to cause severe disease, preterm births, and fetal loss. Plasmodium vivax is common in Asia and the Americas and, unlike P falciparum, does not cytoadhere in the placenta, yet, is associated with maternal anaemia and low birthweight. The effect of infection in the first trimester, and the longer term effects of malaria beyond infancy, are largely unknown and may be substantial. Better estimates are also needed of the effects of malaria in pregnancy outside Africa, and on maternal morbidity and mortality in Africa. Global risk maps will allow better estimation of potential impact of successful control of malaria in pregnancy.
Bertrand Lell, Peter G Kremsner
Clindamycin as an antimalarial drug: review of clinical trials.
Antimicrob Agents Chemother. 2002 Aug;46(8):2315-20.
Abstract/Text
R N Brogden, T M Speight, G S Avery
Minocycline: A review of its antibacterial and pharmacokinetic properties and therapeutic use.
Drugs. 1975;9(4):251-91.
Abstract/Text
Minocycline is a semi-synthetic tetracycline derivative which is well absorbed and distributed in body tissues and is suitable for twice daily administration. It appears to be as generally effective as other tetracyclines and analogues, but also to be effective in infections due to tetracycline-resistant staphylococci. Side-effects are typical of those of other tetracyclines, but minocycline has been associated with a high incidence of vertigo in some studies. On the other hand, minocycline appears to have little or no photosensitising potential. It is not yet clear whether minocycline can be safely used in patients with moderate or severe impairment of renal function, but if used in renal failure, the plasma urea concentration should be monitored.
Guidelines for treatment of malaria in the united states (updated September 23, 2011), Center for disease prevention and control, 2011．.
David G Lalloo, Delane Shingadia, Geoffrey Pasvol, Peter L Chiodini, Christopher J Whitty, Nicholas J Beeching, David R Hill, David A Warrell, Barbara A Bannister, HPA Advisory Committee on Malaria Prevention in UK Travellers
UK malaria treatment guidelines.
J Infect. 2007 Feb;54(2):111-21. doi: 10.1016/j.jinf.2006.12.003. Epub 2007 Jan 9.
Abstract/Text
Malaria is the tropical disease most commonly imported into the UK, with 1500-2000 cases reported each year, and 10-20 deaths. Approximately three-quarters of reported malaria cases in the UK are caused by Plasmodium falciparum, which is capable of invading a high proportion of red blood cells and rapidly leading to severe or life-threatening multi-organ disease. Most non-falciparum malaria cases are caused by Plasmodium vivax; a few cases are caused by the other two species of Plasmodium: Plasmodium ovale or Plasmodium malariae. Mixed infections with more than 1 species of parasite can occur; they commonly involve P. falciparum with the attendant risks of severe malaria. Management of malaria depends on awareness of the diagnosis and on performing the correct diagnostic tests: the diagnosis cannot be excluded until 3 blood specimens have been examined by an experienced microscopist. There are no typical clinical features of malaria, even fever is not invariably present. The optimum diagnostic procedure is examination of thick and thin blood films by an expert to detect and speciate the malarial parasites; P. falciparum malaria can be diagnosed almost as accurately using rapid diagnostic tests (RDTs) which detect plasmodial antigens or enzymes, although RDTs for other Plasmodium species are not as reliable. The treatment of choice for non-falciparum malaria is a 3-day course of oral chloroquine, to which only a limited proportion of P. vivax strains have gained resistance. Dormant parasites (hypnozoites) persist in the liver after treatment of P. vivax or P. ovale infection: the only currently effective drug for eradication of hypnozoites is primaquine. This must be avoided or given with caution under expert supervision in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD), in whom it may cause severe haemolysis. Uncomplicated P. falciparum malaria can be treated orally with quinine, atovaquone plus proguanil (Malarone) or co-artemether (Riamet); quinine is highly effective but poorly tolerated in prolonged dosage and is always supplemented by additional treatment, usually with oral doxycycline. ALL patients treated for P. falciparum malaria should be admitted to hospital for at least 24 h, since patients can deteriorate suddenly, especially early in the course of treatment. Severe falciparum malaria, or infections complicated by a relatively high parasite count (more than 2% of red blood cells parasitized), should be treated with intravenous therapy until the patient is well enough to continue with oral treatment. In the UK, the treatment of choice for severe or complicated malaria is currently an infusion of intravenous quinine. This may exacerbate hypoglycaemia that can occur in malaria; patients treated with intravenous quinine therefore require careful monitoring. Intravenous artesunate reduces high parasite loads more rapidly than quinine and is more effective in treating severe malaria in selected situations. It can also be used in patients with contra-indications to quinine. Intravenous artesunate is unlicensed in the EU. Assistance in obtaining artesunate may be sought from specialist tropical medicine centres, on consultation, for named patients. Patients with severe or complicated malaria should be managed in a high dependency or intensive care environment. They may require haemodynamic support and management of acute respiratory distress syndrome, disseminated intravascular coagulation, renal impairment/failure, seizures, and severe intercurrent infections including gram-negative bacteraemia/septicaemia. Falciparum malaria in pregnancy is more likely to be severe and complicated: the placenta contains high levels of parasites. Stillbirth or early delivery may occur and diagnosis can be difficult if parasites are concentrated in the placenta and scanty in the blood. The treatment of choice for falciparum malaria in pregnancy is quinine; doxycycline is contraindicated in pregnancy but clindamycin can be substituted for it, and is equally effective. Primaquine (for eradication of P. vivax or P. ovale hypnozoites) is contraindicated in pregnancy; after treatment for these infections a pregnant woman should take weekly chloroquine prophylaxis until after delivery when hypnozoite eradication can be considered. Children are over-represented in the incidence of malaria in the UK, probably because completely susceptible UK-born children accompany their overseas-born parents on visits to family and friends in endemic areas. Malaria in children (and sometimes in adults) may present with misleading symptoms such as gastrointestinal features, sore throat or lower respiratory complaints; the diagnosis must always be sought in a feverish or very sick child who has visited malaria-endemic areas. Children can be treated with most of the antimalarial regimens which are effective in adults, with appropriate dosage adjustment. Doxycycline plus quinine should not be given to children under 12 years as doxycycline is contraindicated in this age group, but clindamycin can be substituted for doxycycline, and pyrimethamine-sulfadoxine (Fansidar) may also be an effective substitute. An acute attack of malaria does not confer protection from future attacks: individuals who have had malaria should take effective anti-mosquito precautions and chemoprophylaxis during future visits to endemic areas.
Klara Sondén, Katja Wyss, Irina Jovel, Antero Vieira da Silva, Anton Pohanka, Muhammad Asghar, Manijeh Vafa Homann, Lars L Gustafsson, Urban Hellgren, Anna Färnert
High Rate of Treatment Failures in Nonimmune Travelers Treated With Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria in Sweden: Retrospective Comparative Analysis of Effectiveness and Case Series.
Clin Infect Dis. 2017 Jan 15;64(2):199-206. doi: 10.1093/cid/ciw710. Epub 2016 Oct 24.
Abstract/Text
BACKGROUND: Artemisinin-based combination therapy (ACT) is the first-line treatment of Plasmodium falciparum malaria. Since the introduction of artemether-lumefantrine (AL) for treatment of uncomplicated malaria in Sweden, treatment failures have been reported in adults.
METHODS: A retrospective comparative analysis of treatment regimen for P. falciparum malaria in adults in Stockholm during 2000-2015 was performed to evaluate the effectiveness of AL. Parasite genotyping and drug concentrations were investigated in the AL treatment failures.
RESULTS: Among the total 397 P. falciparum episodes, 310 were treated with oral regimen only (95 AL, 162 mefloquine, 36 atovaquone-proguanil [AP], and 17 others), and 87 were administered initial intravenous therapy (38 artesunate and 49 quinine) followed by oral treatments. Five late treatment failures were detected after AL and one slow response to AP. The effectiveness of AL alone was 94.7% (95% confidence interval [CI], 88.1%-98.3%), compared with 99.5% for other oral regimens (P = .003). All AL failures occurred in European men and the effectiveness in this group was only 73.7% (95% CI, 48.8%-90.0%). Genotyping confirmed recrudescence of the initial parasite populations and drug resistance markers revealed no clinically significant resistance patterns. Lumefantrine concentrations suggested subtherapeutic concentrations in at least 2 cases.
CONCLUSIONS: Our findings indicate a high rate of symptomatic late treatment failures after 6-dose AL regime in nonimmune adults, especially in men. Our report warrants the need to establish optimal dosing of AL in adults and to alert clinicians about the importance of informing patients regarding the risk of parasites reappearing weeks after AL treatment.
© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.
Elizabeth A Ashley, Mehul Dhorda, Rick M Fairhurst, Chanaki Amaratunga, Parath Lim, Seila Suon, Sokunthea Sreng, Jennifer M Anderson, Sivanna Mao, Baramey Sam, Chantha Sopha, Char Meng Chuor, Chea Nguon, Siv Sovannaroth, Sasithon Pukrittayakamee, Podjanee Jittamala, Kesinee Chotivanich, Kitipumi Chutasmit, Chaiyaporn Suchatsoonthorn, Ratchadaporn Runcharoen, Tran Tinh Hien, Nguyen Thanh Thuy-Nhien, Ngo Viet Thanh, Nguyen Hoan Phu, Ye Htut, Kay-Thwe Han, Kyin Hla Aye, Olugbenga A Mokuolu, Rasaq R Olaosebikan, Olaleke O Folaranmi, Mayfong Mayxay, Maniphone Khanthavong, Bouasy Hongvanthong, Paul N Newton, Marie A Onyamboko, Caterina I Fanello, Antoinette K Tshefu, Neelima Mishra, Neena Valecha, Aung Pyae Phyo, Francois Nosten, Poravuth Yi, Rupam Tripura, Steffen Borrmann, Mahfudh Bashraheil, Judy Peshu, M Abul Faiz, Aniruddha Ghose, M Amir Hossain, Rasheda Samad, M Ridwanur Rahman, M Mahtabuddin Hasan, Akhterul Islam, Olivo Miotto, Roberto Amato, Bronwyn MacInnis, Jim Stalker, Dominic P Kwiatkowski, Zbynek Bozdech, Atthanee Jeeyapant, Phaik Yeong Cheah, Tharisara Sakulthaew, Jeremy Chalk, Benjamas Intharabut, Kamolrat Silamut, Sue J Lee, Benchawan Vihokhern, Chanon Kunasol, Mallika Imwong, Joel Tarning, Walter J Taylor, Shunmay Yeung, Charles J Woodrow, Jennifer A Flegg, Debashish Das, Jeffery Smith, Meera Venkatesan, Christopher V Plowe, Kasia Stepniewska, Philippe J Guerin, Arjen M Dondorp, Nicholas P Day, Nicholas J White, Tracking Resistance to Artemisinin Collaboration (TRAC)
Spread of artemisinin resistance in Plasmodium falciparum malaria.
N Engl J Med. 2014 Jul 31;371(5):411-23. doi: 10.1056/NEJMoa1314981.
Abstract/Text
BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies.
METHODS: Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined.
RESULTS: The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days.
CONCLUSIONS: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).
S Looareesuwan, P Wilairatana, K Chalermarut, Y Rattanapong, C J Canfield, D B Hutchinson
Efficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand.
Am J Trop Med Hyg. 1999 Apr;60(4):526-32.
Abstract/Text
The increasing frequency of therapeutic failures in falciparum malaria underscores the need for novel, rapidly effective antimalarial drugs or drug combinations. Atovaquone and proguanil are blood schizonticides that demonstrate synergistic activity against multi-drug-resistant Plasmodium falciparum in vitro. In an open-label, randomized, controlled clinical trial conducted in Thailand, adult patients with acute P. falciparum malaria were randomly assigned to treatment with atovaquone and proguanil/hydrochloride (1,000 mg and 400 mg, respectively, administered orally at 24-hr intervals for three doses) or mefloquine (750 mg administered orally, followed 6 hr later by an additional 500-mg dose). Efficacy was assessed by cure rate (the percentage of patients in whom parasitemia was eliminated and did not recur during 28 days of follow-up), parasite clearance time (PCT), and fever clearance time (FCT). Safety was assessed by sequential clinical and laboratory assessments for 28 days. Atovaquone/proguanil was significantly more effective than mefloquine (cure rate 100% [79 of 79] vs. 86% [68 of 79]; P < 0.002). The atovaquone/proguanil and mefloquine treatments did not differ with respect to PCT (mean = 65 hr versus 74 hr) or FCT (mean = 59 hr versus 51 hr). Adverse events were generally typical of malaria symptoms and each occurred in < 10% of the patients in either group, with the exception of increased vomiting found in the atovaquone/proguanil group. Transient elevations of liver enzyme levels occurred more frequently in patients treated with atovaquone/proguanil than with mefloquine, but the differences were not significant and values returned to normal by day 28 in most patients. The combination of atovaquone and proguanil was well tolerated and more effective than mefloquine in the treatment of acute uncomplicated multidrug-resistant falciparum malaria in Thailand.
Mary EW and Eli S: Fever. Travel Medicine second edition. ed by Jay SK, Phyllis EK, David OF, et al.Philadelphia: Mosby, 2008.
T H Nguyen, N P Day, V C Ly, D Waller, N T Mai, D B Bethell, T H Tran, N J White
Post-malaria neurological syndrome.
Lancet. 1996 Oct 5;348(9032):917-21.
Abstract/Text
BACKGROUND: Neurological signs and symptoms are common in malaria, but observations in Vietnam and Thailand have pointed to a discrete transient neurological syndrome after recovery from severe infections.
METHODS: A prospective study of the post-malaria neurological syndrome (PMNS) was conducted at two centres in Vietnam over four years. Criteria for inclusion were recent symptomatic malaria infection with parasites cleared from blood (and in cases of cerebral malaria full recovery of consciousness), and development of neurological or psychiatric symptoms within two months after the acute illness. Half of the patients with severe falciparum malaria had been taking part in a randomised trial of antimalarials.
FINDINGS: Of 18,124 patients with falciparum malaria treated (1176 of whom had severe infections) 19 adults and three children had subsequent PMNS; in one patient it followed uncomplicated malaria and in 21 it followed severe malaria. The overall incidence (95% confidence interval) of PMNS after falciparum malaria at the main study centre was 1.2 per 1000 (0.7 to 1.8 per 1000) and relative risk (95% CI) for developing PMNS after severe versus uncomplicated falciparum malaria was 299 (40 to 2223). 13 patients had an acute confusional state or psychosis, six had one or more generalised convulsions, two had generalised convulsions followed by a long period of acute confusion, and one developed a fine tremor. At the time of PMNS diagnosis all patients were aparasitaemic. The syndrome was self-limiting, median duration 60 h (range 24-240). PMNS was associated with the use of oral mefloquine. In the randomised trial 4.4% (10/228) of patients with severe malaria who received mefloquine after parenteral treatment developed PMNS compared with 0.5% (1/210) of those who received quinine; relative risk 9.2 (95% CI 1.2 to 71.3, p = 0.012).
INTERPRETATION: Mefloquine is not the only risk factor for PMNS but it is a strong one. Where an effective alternative drug is available, mefloquine should not be used after treatment of severe malaria.
C Luxemburger, F O ter Kuile, F Nosten, G Dolan, J H Bradol, L Phaipun, T Chongsuphajaisiddhi, N J White
Single day mefloquine-artesunate combination in the treatment of multi-drug resistant falciparum malaria.
Trans R Soc Trop Med Hyg. 1994 Mar-Apr;88(2):213-7.
Abstract/Text
The therapeutic efficacy and toxicity of a combination of low dose mefloquine (15 mg/kg) plus artesunate 10 mg/kg in one day (MA) was compared with the currently used regimen of high dose mefloquine (25 mg/kg) (MQ) in 552 patients with uncomplicated falciparum malaria in an area of multi-drug resistance on the Thai-Burmese border. MA gave faster clinical and parasitological responses and prevented early treatment failure; 15 patients in the MQ group (6%) were early failures (< 9 d) compared with none receiving MA (P = 0.0001). Overall failure rates by day 28 were 19% in the MA group and 24% in with MQ group (relative risk (RR) = 0.78, 95% confidence interval (CI) 0.54-1.12). In the subgroup of patients who required re-treatment, MA proved significantly more effective than MQ; failure rates were 25% and 52% respectively (RR = 0.49, 95% CI = 0.29-0.83). Treatment failures were associated with mefloquine treatment in the previous month (RR = 1.72, 95% CI = 1.09-2.70) and diarrhoea (RR = 1.55, 95% CI = 1.05-2.28). Gastrointestinal side-effects and dizziness were more likely in the MQ group. There was no evident adverse effect associated with artesunate. A single day's treatment with artesunate augments the antimalarial efficacy of mefloquine.
Jason D Maguire, Krisin, Hariyani Marwoto, Thomas L Richie, David J Fryauff, J Kevin Baird
Mefloquine is highly efficacious against chloroquine-resistant Plasmodium vivax malaria and Plasmodium falciparum malaria in Papua, Indonesia.
Clin Infect Dis. 2006 Apr 15;42(8):1067-72. doi: 10.1086/501357. Epub 2006 Mar 13.
Abstract/Text
BACKGROUND: During the period of 1996-1999, we prospectively monitored 243 Javanese adults and children after arriving in Papua, Indonesia, and microscopically documented each new case of malaria by active surveillance.
METHODS: In a randomized, open-label, comparative malaria treatment trial, 72 adults and 50 children received chloroquine for each incident case of malaria, and 74 adults and 47 children received mefloquine.
RESULTS: Among 975 primary treatment courses, the cumulative 28-day curative efficacies were 26% and 82% for chloroquine against Plasmodium falciparum malaria and Plasmodium vivax malaria, respectively. Mefloquine cure rates were far superior (96% against P. falciparum malaria and 99.6% against P. vivax malaria).
CONCLUSIONS: Mefloquine is a useful alternative treatment for P. vivax malaria and P. falciparum malaria in areas such as Papua, where chloroquine is still recommended as the first-line therapeutic agent.
G N L Galappaththy, A A A Omari, P Tharyan
Primaquine for preventing relapses in people with Plasmodium vivax malaria.
Cochrane Database Syst Rev. 2007 Jan 24;(1):CD004389. doi: 10.1002/14651858.CD004389.pub2. Epub 2007 Jan 24.
Abstract/Text
BACKGROUND: Plasmodium vivax infections contribute to a significant proportion of the malaria infections in many countries. Primaquine is the most widely used drug for treating the dormant liver stage. Different primaquine dosing regimens are in use.
OBJECTIVES: To compare primaquine regimens for preventing relapses in people with P. vivax malaria.
SEARCH STRATEGY: In 2006, we searched the Cochrane Infectious Diseases Group's Specialized Register (January), CENTRAL (The Cochrane Library 2006, Issue 3), MEDLINE (October), EMBASE (January), LILACS (January). We also checked conference proceedings and reference lists, and contacted researchers, the World Health Organization (WHO), malaria mailing lists, and pharmaceutical companies.
SELECTION CRITERIA: Randomized and quasi-randomized controlled trials comparing primaquine plus chloroquine with chloroquine alone, and the standard primaquine regimen (15 mg/day for 14 days) with other primaquine-containing regimens in people with vivax malaria.
DATA COLLECTION AND ANALYSIS: All authors independently assessed trial eligibility and quality, and extracted data. We calculated odds ratios (OR) with 95% confidence intervals (CI) for dichotomous data, and used the random-effects model if there was significant heterogeneity.
MAIN RESULTS: Nine trials (3423 participants) met the inclusion criteria. Compared with chloroquine alone, five-day primaquine plus chloroquine was no better at preventing relapses (OR 1.04, 95% CI 0.64 to 1.69, random-effects model; 2104 participants; 3 trials), while 14-day primaquine plus chloroquine was significantly better (OR 0.24, 95% CI 0.12 to 0.45, random-effects model; 1071 participants, 6 trials). Limited data suggest the advantage for the 14-day primaquine regimen persisted for over six months (OR 0.41, 95% CI 0.29 to 0.60; 585 participants, 2 trials). Direct comparisons of the 14-day and five-day primaquine plus chloroquine regimens also confirm the superiority of the longer course (OR 13.33, 95% CI 3.45 to 51.44; 186 participants, 2 trials). Adverse effects were poorly reported, with three trials reporting skin rash, vertigo, headache, abdominal pain and/or nausea, and two trials reporting that primaquine was well tolerated.
AUTHORS' CONCLUSIONS: Primaquine (15 mg/kg/day for 14 days) plus chloroquine is more effective than chloroquine alone or primaquine (15 mg/kg for 5 days) plus chloroquine in preventing relapses of vivax malaria. Primaquine (five days) plus chloroquine appears no better than chloroquine. Countries should follow the WHO's recommendation for 14-day primaquine plus chloroquine regimen. Alternative regimens need to be evaluated in randomized controlled trials, which should also consider variations in regional P. vivax strains and the possibility of primaquine resistance, reinfection, and adherence in those who relapse.
Nicola Townell, David Looke, David McDougall, James S McCarthy
Relapse of imported Plasmodium vivax malaria is related to primaquine dose: a retrospective study.
Malar J. 2012 Jun 22;11:214. doi: 10.1186/1475-2875-11-214. Epub 2012 Jun 22.
Abstract/Text
BACKGROUND: Relapsing Plasmodium vivax infection results in significant morbidity for the individual and is a key factor in transmission. Primaquine remains the only licensed drug for prevention of relapse. To minimize relapse rates, treatment guidelines have recently been revised to recommend an increased primaquine dose, aiming to achieve a cumulative dose of ≥6 mg/kg, i.e. ≥420 mg in a 70 kg patient. The aims of this study were to characterize the epidemiology of P. vivax infection imported into Queensland Australia, to determine the rates of relapse, to investigate the use of primaquine therapy, and its efficacy in the prevention of relapse.
METHODS: A retrospective study was undertaken of laboratory confirmed P. vivax infection presenting to the two major tertiary hospitals in Queensland, Australia between January 1999 and January 2011.Primaquine dosing was classified as no dose, low dose (<420 mg), high dose (≥420 mg), or unknown. The dose of primaquine prescribed to patients who subsequently relapsed that prescribed to patients who did not relapse.
RESULTS: Twenty relapses occurred following 151 primary episodes of P. vivax infection (13.2%). Relapses were confirmed among 3/21 (14.2%), 9/50 (18.0%), 1/54 (1.9%) and 7/18 (38.9%) of patients administered no dose, low dose, high dose and unknown primaquine dose respectively. High dose primaquine therapy was associated with a significantly lower rate of relapse compared to patients who were prescribed low dose therapy (OR 11.6, 95% CI 1.5-519, p = 0.005).
CONCLUSIONS: Relapse of P. vivax infection is more likely in patients who received low dose primaquine therapy. This study supports the recommendations that high dose primaquine therapy is necessary to minimize relapse of P. vivax malaria.
Jane Achan, James K Tibenderana, Daniel Kyabayinze, Fred Wabwire Mangen, Moses R Kamya, Grant Dorsey, Umberto D'Alessandro, Philip J Rosenthal, Ambrose O Talisuna
Effectiveness of quinine versus artemether-lumefantrine for treating uncomplicated falciparum malaria in Ugandan children: randomised trial.
BMJ. 2009 Jul 21;339:b2763. Epub 2009 Jul 21.
Abstract/Text
OBJECTIVE: To compare the effectiveness of oral quinine with that of artemether-lumefantrine in treating uncomplicated malaria in children.
DESIGN: Randomised, open label effectiveness study.
SETTING: Outpatient clinic of Uganda's national referral hospital in Kampala.
PARTICIPANTS: 175 children aged 6 to 59 months with uncomplicated malaria.
INTERVENTIONS: Participants were randomised to receive oral quinine or artemether-lumefantrine administered by care givers at home.
MAIN OUTCOME MEASURES: Primary outcomes were parasitological cure rates after 28 days of follow-up unadjusted and adjusted by genotyping to distinguish recrudescence from new infections. Secondary outcomes were adherence to study drug, presence of gametocytes, recovery of haemoglobin concentration from baseline at day 28, and safety profiles.
RESULTS: Using survival analysis the cure rate unadjusted by genotyping was 96% for the artemether-lumefantrine group compared with 64% for the quinine group (hazard ratio 10.7, 95% confidence interval 3.3 to 35.5, P=0.001). In the quinine group 69% (18/26) of parasitological failures were due to recrudescence compared with none in the artemether-lumefantrine group. The mean adherence to artemether-lumefantrine was 94.5% compared with 85.4% to quinine (P=0.0008). Having adherence levels of 80% or more was associated with a decreased risk of treatment failure (0.44, 0.19 to 1.02, P=0.06). Adverse events did not differ between the two groups.
CONCLUSIONS: The effectiveness of a seven day course of quinine for the treatment of uncomplicated malaria in Ugandan children was significantly lower than that of artemether-lumefantrine. These findings question the advisability of the recommendation for quinine therapy for uncomplicated malaria in Africa.
TRIAL REGISTRATION: ClinicalTrials.gov NCT00540202.
https://www.fda.gov/news-events/press-announcements/fda-approves-only-drug-us-treat-severe-malaria FDA Approves Only Drug in U.S. to Treat Severe Malaria].
Kassoum Kayentao, Aissata Ongoiba, Anne C Preston, Sara A Healy, Safiatou Doumbo, Didier Doumtabe, Abdrahamane Traore, Hamadi Traore, Adama Djiguiba, Shanping Li, Mary E Peterson, Shinyi Telscher, Azza H Idris, Neville K Kisalu, Kevin Carlton, Leonid Serebryannyy, Sandeep Narpala, Adrian B McDermott, Martin Gaudinski, Siriman Traore, Hamidou Cisse, Mamadou Keita, Jeff Skinner, Zonghui Hu, Amatigué Zéguimé, Adama Ouattara, M'Bouye Doucoure, Amagana Dolo, Abdoulaye Djimdé, Boubacar Traore, Robert A Seder, Peter D Crompton, Mali Malaria mAb Trial Team
Safety and Efficacy of a Monoclonal Antibody against Malaria in Mali.
N Engl J Med. 2022 Nov 17;387(20):1833-1842. doi: 10.1056/NEJMoa2206966. Epub 2022 Oct 31.
Abstract/Text
BACKGROUND: CIS43LS is a monoclonal antibody that was shown to protect against controlled Plasmodium falciparum infection in a phase 1 clinical trial. Whether a monoclonal antibody can prevent P. falciparum infection in a region in which the infection is endemic is unknown.
METHODS: We conducted a phase 2 trial to assess the safety and efficacy of a single intravenous infusion of CIS43LS against P. falciparum infection in healthy adults in Mali over a 6-month malaria season. In Part A, safety was assessed at three escalating dose levels. In Part B, participants were randomly assigned (in a 1:1:1 ratio) to receive 10 mg of CIS43LS per kilogram of body weight, 40 mg of CIS43LS per kilogram, or placebo. The primary efficacy end point, assessed in a time-to-event analysis, was the first P. falciparum infection detected on blood-smear examination, which was performed at least every 2 weeks for 24 weeks. At enrollment, all the participants received artemether-lumefantrine to clear possible P. falciparum infection.
RESULTS: In Part B, 330 adults underwent randomization; 110 were assigned to each trial group. The risk of moderate headache was 3.3 times as high with 40 mg of CIS43LS per kilogram as with placebo. P. falciparum infections were detected on blood-smear examination in 39 participants (35.5%) who received 10 mg of CIS43LS per kilogram, 20 (18.2%) who received 40 mg of CIS43LS per kilogram, and 86 (78.2%) who received placebo. At 6 months, the efficacy of 40 mg of CIS43LS per kilogram as compared with placebo was 88.2% (adjusted 95% confidence interval [CI], 79.3 to 93.3; P<0.001), and the efficacy of 10 mg of CIS43LS per kilogram as compared with placebo was 75.0% (adjusted 95% CI, 61.0 to 84.0; P<0.001).
CONCLUSIONS: CIS43LS was protective against P. falciparum infection over a 6-month malaria season in Mali without evident safety concerns. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04329104.).
Copyright © 2022 Massachusetts Medical Society.
Richard L Wu, Azza H Idris, Nina M Berkowitz, Myra Happe, Martin R Gaudinski, Christian Buettner, Larisa Strom, Seemal F Awan, LaSonji A Holman, Floreliz Mendoza, Ingelise J Gordon, Zonghui Hu, Andrezza Campos Chagas, Lawrence T Wang, Lais Da Silva Pereira, Joseph R Francica, Neville K Kisalu, Barbara J Flynn, Wei Shi, Wing-Pui Kong, Sarah O'Connell, Sarah H Plummer, Allison Beck, Adrian McDermott, Sandeep R Narpala, Leonid Serebryannyy, Mike Castro, Rosa Silva, Marjaan Imam, Iris Pittman, Somia P Hickman, Andrew J McDougal, Ashly E Lukoskie, Jittawadee R Murphy, Jason G Gall, Kevin Carlton, Patricia Morgan, Ellie Seo, Judy A Stein, Sandra Vazquez, Shinyi Telscher, Edmund V Capparelli, Emily E Coates, John R Mascola, Julie E Ledgerwood, Lesia K Dropulic, Robert A Seder, VRC 614 Study Team
Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria.
N Engl J Med. 2022 Aug 4;387(5):397-407. doi: 10.1056/NEJMoa2203067.
Abstract/Text
BACKGROUND: New approaches for the prevention and elimination of malaria, a leading cause of illness and death among infants and young children globally, are needed.
METHODS: We conducted a phase 1 clinical trial to assess the safety and pharmacokinetics of L9LS, a next-generation antimalarial monoclonal antibody, and its protective efficacy against controlled human malaria infection in healthy adults who had never had malaria or received a vaccine for malaria. The participants received L9LS either intravenously or subcutaneously at a dose of 1 mg, 5 mg, or 20 mg per kilogram of body weight. Within 2 to 6 weeks after the administration of L9LS, both the participants who received L9LS and the control participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying Plasmodium falciparum (3D7 strain).
RESULTS: No safety concerns were identified. L9LS had an estimated half-life of 56 days, and it had dose linearity, with the highest mean (±SD) maximum serum concentration (Cmax) of 914.2±146.5 μg per milliliter observed in participants who had received 20 mg per kilogram intravenously and the lowest mean Cmax of 41.5±4.7 μg per milliliter observed in those who had received 1 mg per kilogram intravenously; the mean Cmax was 164.8±31.1 in the participants who had received 5 mg per kilogram intravenously and 68.9±22.3 in those who had received 5 mg per kilogram subcutaneously. A total of 17 L9LS recipients and 6 control participants underwent controlled human malaria infection. Of the 17 participants who received a single dose of L9LS, 15 (88%) were protected after controlled human malaria infection. Parasitemia did not develop in any of the participants who received 5 or 20 mg per kilogram of intravenous L9LS. Parasitemia developed in 1 of 5 participants who received 1 mg per kilogram intravenously, 1 of 5 participants who received 5 mg per kilogram subcutaneously, and all 6 control participants through 21 days after the controlled human malaria infection. Protection conferred by L9LS was seen at serum concentrations as low as 9.2 μg per milliliter.
CONCLUSIONS: In this small trial, L9LS administered intravenously or subcutaneously protected recipients against malaria after controlled infection, without evident safety concerns. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 614 ClinicalTrials.gov number, NCT05019729.).
Copyright © 2022 Massachusetts Medical Society.
David Sinclair, Sarah Donegan, Rachel Isba, David G Lalloo
Artesunate versus quinine for treating severe malaria.
Cochrane Database Syst Rev. 2012 Jun 13;6:CD005967. doi: 10.1002/14651858.CD005967.pub4. Epub 2012 Jun 13.
Abstract/Text
BACKGROUND: Severe malaria results in over a million deaths every year, most of them in children aged under five years and living in sub-Saharan Africa. This review examines whether treatment with artesunate, instead of the standard treatment quinine, would result in fewer deaths and better treatment outcomes.
OBJECTIVES: To compare artesunate with quinine for treating severe malaria.
SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE, LILACS, ISI Web of Science, the metaRegister of Controlled trials (mRCT), conference proceedings, and reference lists of articles to November 2010.
SELECTION CRITERIA: Randomized controlled trials comparing intravenous, intramuscular, or rectal artesunate with intravenous or intramuscular quinine for treating adults and children with severe malaria who are unable to take medication by mouth.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed the eligibility and risk of bias of trials, and extracted and analysed data. The primary outcome was all-cause death. Dichotomous outcomes were summarized using risk ratios (RR) and continuous outcomes by mean differences (MD). Where appropriate, we combined data in meta-analyses.
MAIN RESULTS: Eight trials enrolling 1664 adults and 5765 children are included in this review.Treatment with artesunate significantly reduced the risk of death both in adults (RR 0.61, 95% Confidence Interval (CI) 0.50 to 0.75; 1664 participants, five trials) and children (RR 0.76, 95% CI 0.65 to 0.90; 5765 participants, four trials)In children, treatment with artesunate increased the incidence of neurological sequelae at the time of hospital discharge. The majority of these sequelae were transient and no significant difference between treatments was seen at later follow up.
AUTHORS' CONCLUSIONS: The evidence clearly supports the superiority of parenteral artesunate over quinine for the treatment of severe malaria in both adults and children and in different regions of the world.
F Bruneel, B Gachot, M Wolff, B Régnier, M Danis, F Vachon, Corresponding Group
Resurgence of blackwater fever in long-term European expatriates in Africa: report of 21 cases and review.
Clin Infect Dis. 2001 Apr 15;32(8):1133-40. doi: 10.1086/319743. Epub 2001 Apr 2.
Abstract/Text
Blackwater fever (BWF) is a severe clinical syndrome, characterized by intravascular hemolysis, hemoglobinuria, and acute renal failure that is classically seen in European expatriates chronically exposed to Plasmodium falciparum and irregularly taking quinine. BWF virtually disappeared after 1950, when chloroquine superseded quinine. We report 21 cases of BWF seen in France from 1990 through 1999 in European expatriates who lived in sub-Saharan Africa. All patients had macroscopic hemoglobinuria, jaundice, and anemia. Acute renal failure occurred in 15 patients (71%), 7 of whom required dialysis. The presumed triggers of BWF were halofantrine (38%), quinine (24%), mefloquine (24%), and halofantrine or quinine (14%). Glucose-6-phosphate dehydrogenase (G6PD) activity was normal in the 14 patients who underwent this test. Low-level P. falciparum parasitemia was found in 8 patients. All 21 patients survived. Our data and 13 cases reported in the literature suggest a resurgence of classic BWF among Europeans living in Africa and a need to discuss attendant therapeutic implications.
Victor Mung'Ala-Odera, Robert W Snow, Charles R J C Newton
The burden of the neurocognitive impairment associated with Plasmodium falciparum malaria in sub-saharan Africa.
Am J Trop Med Hyg. 2004 Aug;71(2 Suppl):64-70.
Abstract/Text
The burden of Plasmodium falciparum malaria has been estimated traditionally in terms of infections and mortality. Neurocognitive sequelae have recently been identified that add to the burden caused by this parasite. We have attempted to provide estimates of the neurocognitive burden based upon more recent estimates of the population at risk and a detailed review of published studies in sub-Saharan Africa. There is little data on which to estimate the burden, and considerable limitations in extracting the data from the published studies to provide these estimates. However, we estimate that at least 1,300-7,800 children will have neurologic sequelae following cerebral malaria in stable endemic areas per year. The figure is likely to be considerably higher, since these estimates do not include neurocognitive impairment following non-cerebral malaria in children or adults in stable endemic areas, or populations in low stable or epidemic areas.
Copyright 2004 The American Society of Tropical Medicine and Hygiene
Mark S Riddle, Jeffrey L Jackson, John W Sanders, David L Blazes
Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis.
Clin Infect Dis. 2002 May 1;34(9):1192-8. doi: 10.1086/339810. Epub 2002 Apr 3.
Abstract/Text
The efficacy of exchange transfusion as an adjunct treatment for severe falciparum malaria is controversial. No sufficiently powered, randomized, controlled study has been reported. We analyzed 8 studies that compared survival rates associated with adjunct exchange transfusion with those associated with antimalarial chemotherapy alone. Exchange transfusion was not associated with a higher survival rate than was antimalarial chemotherapy alone (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.7-2.1). However, patients who received transfusions had higher levels of parasitemia and more-severe malaria. Sensitivity analysis found that survival rates were higher among patients with partial immunity to malaria (OR, 0.5; 95% CI, 0.2-1.2) than they were among patients with no immunity (OR, 2.1; 95% CI, 0.9-4.8; P=.007). Exchange transfusion does not appear to increase the survival rate; however, there were significant problems with the comparability of treatment groups in the studies reviewed, and a randomized controlled trial is necessary to determine whether exchange transfusion is beneficial.
Jung-Yeon Kim, Jeong-Su Kim, Mi-Hyun Park, Young-A Kang, Jun-Wook Kwon, Shin-Hyeong Cho, Byeong-Chul Lee, Tong-Soo Kim, Jong-Koo Lee
A locally acquired falciparum malaria via nosocomial transmission in Korea.
Korean J Parasitol. 2009 Sep;47(3):269-73. doi: 10.3347/kjp.2009.47.3.269. Epub 2009 Aug 28.
Abstract/Text
A 57-year old man who was admitted to an emergency room of a tertiary hospital with hemoptysis developed malarial fever 19 days later and then died from severe falciparum malaria 2 days later. He had not traveled outside of Korea for over 30 years. Through intensive interviews and epidemiological surveys, we found that a foreign patient with a recent history of travel to Africa was transferred to the same hospital with severe falciparum malaria. We confirmed through molecular genotyping of the MSP-1 gene that Plasmodium falciparum genotypes of the 2 patients were identical. It is suggested that a breach of standard infection control precautions resulted in this P. falciparum transmission between 2 patients in a hospital environment. This is the first report of a nosocomial transmission of falciparum malaria in Korea.
Sanjay K Jain, Deborah Persaud, Trish M Perl, Margaret A Pass, Kathleen M Murphy, John M Pisciotta, Peter F Scholl, James F Casella, David J Sullivan
Nosocomial malaria and saline flush.
Emerg Infect Dis. 2005 Jul;11(7):1097-9. doi: 10.3201/eid1107.050092.
Abstract/Text
An investigation of malaria in a US patient without recent travel established Plasmodium falciparum molecular genotype identity in 2 patients who shared a hospital room. P. falciparum can be transmitted in a hospital environment from patient to patient by blood inoculum if standard precautions are breached.
H A Abulrahi, E A Bohlega, R E Fontaine, S M al-Seghayer, A A al-Ruwais
Plasmodium falciparum malaria transmitted in hospital through heparin locks.
Lancet. 1997 Jan 4;349(9044):23-5.
Abstract/Text
BACKGROUND: After a community investigation had implicated hospital admission as a shared feature of a cluster of acute Plasmodium falciparum malaria (AFM) cases in Riyadh, Saudi Arabia, we began an in-hospital investigation to determine the method of transmission.
METHODS: We investigated all AFM patients admitted to one paediatric hospital for any reason from December, 1991, to April, 1992. We classified AFM as locally acquired (LAFM) if during the month before AFM onset the patient had not visited a malarious area, and as hospital acquired (HAFM) if the LAFM patient had been admitted to hospital during that month. We compared exposures of HAFM cases with those of other patients sampled from the same wards. We observed nursing practices and investigated by anonymous questionnaire how nurses administered parenteral drugs.
FINDINGS: Of 21 LAFM cases, 20 (95%) had a previous hospital admission (exposure admission) compared with 15 (25%) of 61 other patients (p < 0.001; chi 2 test). During the exposure admission, all HAFM patients had occupied the same room as, or a room adjacent to, an AFM patient; 14 (23%) of 60 other patients occupied the same room or rooms adjacent to an AFM patient (p < 0.001, chi 2). 90% of HAFM patients received infusions through a heparin lock during the exposure admission, compared with 49% of 120 general patients (p < 0.001, chi 2). 10% of nurses admitted to using one syringe for more than one heparin lock and 50% filled syringes with enough heparin for three to ten heparin locks.
INTERPRETATION: P falciparum was transmitted between patients when single syringes were used on heparin locks of sequential patients. This practice would easily transmit other blood-borne agents.
