Adherence to national guidelines for the diagnosis and management of severe malaria: a nationwide, cross-sectional survey in Malawi, 2012
Monica P. ShahMelissa Briggs‐HagenJobiba ChinkhumbaAndy BauleniAlfred ChaliraDubulao MoyoWilfred DodoliMisheck LuhangaJohn SandeDoreen AliJulie GutmanDon P. MathangaKim A. Lindblade
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Abstract:
Severe malaria has a case fatality rate of 10-20 %; however, few studies have addressed the quality of severe malaria case management. This study evaluated the diagnostic and treatment practices of malaria patients admitted to inpatient health facilities (HF) in Malawi. In July–August 2012, a nationwide, cross-sectional survey of severe malaria management was conducted in 36 HFs selected with equal probability from all eligible public sector HFs in Malawi. Patient records from all admissions during October 2011 and April 2012 (low and high season, respectively) were screened for an admission diagnosis of malaria or prescription of any anti-malarial. Eligible records were stratified by age (< 5 or ≥ 5 years). A maximum of eight records was randomly selected within each age and month stratum. Severe malaria was defined by admission diagnosis or documentation of at least one sign or symptom of severe malaria. Treatment with intravenous (IV) quinine or artesunate was considered correct. Patients without documentation of severe malaria were analysed as uncomplicated malaria patients; treatment with an artemisinin-based combination therapy (ACT) or oral quinine based on malaria test results was considered correct. All analyses accounted for HF level clustering and sampling weights. The analysis included 906 records from 35 HFs. Among these, 42 % (95 % confidence interval [CI] 35–49) had a severe malaria admission diagnosis and 50 % (95 % CI 44–57) had at least one severe malaria sign or symptom documented. Severe malaria patients defined by admission diagnosis (93, 95 % CI 86–99) were more likely to be treated correctly compared to patients defined by a severe sign (82, 95 % CI 75–89) (p < 0.0001). Among uncomplicated malaria patients, 26 % (95 % CI 18–35) were correctly treated and 53 % (95 % CI 42–64) were adequately treated with IV quinine alone or in combination with an ACT or oral quinine. A majority of patients diagnosed with severe malaria received the recommended IV therapy in accordance with national treatment guidelines. However, the inconsistencies between diagnosis of severe malaria and documentation of severe signs and symptoms highlight the need to improve healthcare worker recognition and documentation of severe signs and symptoms.Keywords:
Case fatality rate
Tropical Medicine
Cross-sectional study
Quinine
Artesunate
Rapid diagnostic test
Since 2006, following publication of the South East Asian Quinine verus Artesunate Malaria Trial (SEAQUAMAT) [1] involving 1461 patients, mainly adults, WHO recommends parenteral artesunate (for IV or IM use) as frst choice treatment in areas of low-malaria transmission. The African Quinine versus Artesunate Malaria Trial (AQUAMAT) has now proved that parenteral artesunate is superior to quinine also in children with severe malaria [2]. The AQUAMAT trial represents the largest trial on hospitalized patients with severe malaria ever completed, with 5425 patients, equally divided in two treatment groups exposed to artesunate and quinine, respectively. Two thirds of the patients in each group were treated via intravenous route, while the remaining one third received their treatment by intramuscular administration. The overall case fatality rate was 22.5% lower in the artesunate group compared to the quinine group; moreover, the clinical profle was superior in the artesunate group. Based on this evidence, WHO revised guidelines for the treatment of Malaria [3], placing parenteral artesunate as frst choice treatment for all malaria endemic areas. This evidence is further confrmed by a recent Cochrane meta-analysis that found an overall mortality reduction of 39% among adults and 24% among children treated with artesunate compared to quinine [4]. It is interesting to note that one of the early randomized controlled trials conducted in Africa to compare an artemisinin with quinine was reported from Sudan in 2002 [5]. A total of 77 children with cerebral malaria were randomly allocated to receive either artemether or quinine. The response to artemether was found to be slightly better than that of quinine, but the differences between the two groups were not statistically signifcant. The outcome in terms of cure rate, neurological sequalae and case fatality was also comparable. The fndings are in line with the current WHO guidelines which regards quinine and artemether as comparable alternatives to artesunate.
Quinine is still the main anti-malarial treatment used for the management of severe malaria in the majority of endemic countries, and will continue to be used in many settings, as the availability of parenteral artesunate is still limited. Quinine requires multiple daily dose administrations, may induce hypoglycemia especially in pregnant women, and is associated with side effects. WHO has prequalifed artesunate manufactured by Guilin Pharmaceutical Co. Ltd, Guangxi, China. This is the frst injectable artemisinin-based formulation manufactured in China which has been prequalifed. It is expected that following the change in the recommendations by WHO the demand for IV artesunate will progressively increase.
Some countries would prefer to have their own evidence before changing national treatment policies. While it is understandable that health professionals may want to make an evaluation in their own context, it is clear that the available evidence points to superiority of parenteral artesunate compared to quinine in severe malaria. Operational research is encouraged to guide implementation of the new policy. In rare condition like severe malaria recruitment of large numbers of cases requires multicentre and perhaps multicountry involvement as in SEAQUAMAT and AQUAMAT studies. Moreover, based on the international ethical guidelines [6] it could be unethical to delay implementation of the new guidelines and subject patients to further drug effectiveness trials.
By 2004 there was a general consensus among international experts about the need to switch from chloroquine as frst-line treatment against falciparum malaria to the extent that organizations providing chloroquine for endemic countries were accused of medical malpractice in a famous letter published in The Lancet [7]. This lead to drastic revisions of the malaria treatment policies and practices of WHO and the Global Fund. In spite of the earlier and overwhelming evidence of chloroquine resistance in Sudan, the change of the frst-line treatment was implemented as late as 2004–2006 [8]. The health consequences of this lag before switching to an effective treatment for a potentially fatal disease are obvious. We hope that the lesson has been learnt.
Artesunate
Quinine
Artemether
Case fatality rate
Cerebral Malaria
Severe Malaria
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Quinine
Severe Malaria
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Artesunate
Combination therapy
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Aims To investigate whether coadministration of the antimalarials artesunate and artemisinin alters the clearance of either drug. Methods Ten healthy Vietnamese males (Group AS) were randomized to receive a single dose of 100 mg oral artesunate (pro‐drug of dihydroartemisinin) on day −5 and then once daily for 5 consecutive days (days 1–5). Oral artemisinin (500 mg) was coadministered on days 1 and 5. Another 10 subjects (Group AM) were given 500 mg oral artemisinin on day −5 and then further doses on days 1–5. Artesunate 100 mg was given on days 1 and 5. Artemisinin and dihydroartemisinin plasma concentrations on days −5, 1 and 5 were quantified by h.p.l.c. with on‐line postcolumn derivatization and u.v. detection. Results In Group AS, dihydroartemisinin oral clearance values (mean (95% CI)) were similar on day 1 (32 (22, 47)) l h −1 and day 5 (38 (28, 51)) l h −1 of daily artesunate administration but these mean values were approximately three fold higher compared with day −5 after a single dose (95 (56, 159)). In this group, artemisinin oral clearance increased from 196 (165, 232) l h −1 on day 1–315 (241, 410) l h −1 on day 5. In Group AM, dihydroartemisinin oral clearance on day 1 was 39 (34, 46) l h −1 and increased 1.6 fold to 64 (48, 85) l h −1 on day 5. In this group, artemisinin oral clearance increased sequentially (1.5 and 4.7 fold, respectively) from 207 (151, 285) l h −1 on day −5–308 (257, 368) l h −1 on day 1 and to 981 (678, 1420) l h −1 on day 5. The increase in artemisinin oral clearance between days −5 and 1 (in the absence of artesunate) was similar to that between days 1 and 5 in Group AS subjects who took daily artesunate. Dihydroartemisinin was not a significant metabolite of artemisinin. Conclusions Artesunate (dihydroartemisinin) did not alter the elimination of artemisinin. However, dihydroartemisinin elimination was inhibited by artemisinin. Artemisinin induced its own elimination even 5 days after a single oral dose. There was no evidence for the formation of dihydroartemisinin from artemisinin.
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Artemisia annua
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A study on efficacy and effectiveness of artemisinin (total dose of 60 mg/kg) and artesunate (total dose of 12 mg/kg over five days) in treatment of uncomplicated malaria was conducted in highly malaria transmitted areas in Vietnam. 126 uncomplicated malaria cases finished 14 day follow-up. 100% cure rate achieved at day 14 in patients of the efficacy groups received either artemisinin or artesunate, while it was 83% and 93% in patients treated respectively with artemisinin and artesunate of the effectiveness groups. Compliance of the treatment regimens was discussed.
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Quinine was the drug of choice for severe malaria until 2005 and was used extensively in South Africa for this purpose. As discussed in this issue of the SAJCC by Mathiba et al . from Chris Hani Baragwanath Hospital (CHBH), two large randomised controlled trials (SEAQUAMAT (South East Asian Quinine Artesunate Malaria Trial) and AQUAMAT (African Quinine v. Artesunate Malaria Trial)) conducted in adults and children, respectively found that mortality was significantly lower with intravenous artesunate and as such it became the recommended agent for severe malaria.
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A monoclonal antibody (MAb) 1C1 against artemisinin was prepared by a cell fusion with splenocytes and aminopterin-sensitive myeloma cells, SP2/0. An artesunate-BSA conjugate was used as immunogen to raise antibodies specific to artemisinin. The prepared anti-artemisinin MAb-1C1 have a novel characteristic which shows a specificity to compounds that are structurally related to artemisinin such as artesunate (630 %) and dihydroartemisinin (29.9 %). By using MAb-1C1, a specific and reliable ELISA was developed for the detection of compounds structurally related to artemisinin. The system shows a full measuring range from 2 to 20 μg/mL in the case of artemisinin and from 4 to 125 ng/mL in the case of artesunate in the competitive ELISA, and was validated to be of use for surveying and breeding of Artemisia annua containing a high amount of artemisinin as well as for the characterization of the pharmacokinetics of artemisinin and its derivatives.
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Immunogen
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Background: In Multi drug resistant falciparum malaria anti-malarial combinations are frequently used i.e. Quinine and IV Artesunate. Quinine is associated with electrocardiographic disturbances. Artesunate in high dose produce QTC prolongation in animal models, so the electrocardiogram (ECG) is thoroughly studied.Methods: Severe falciparum malaria cases 15 to 60 years were randomly allocated into 3 treatment regimens i.e. Artesunate, Quinine alone and their combination. Electrocardiographic recordings were taken periodically in 3 groups and compared statistically.Results: The mean QTC interval is significantly prolonged in combination treatment group from 0.40+0.02 to 0.49+0.09 (P<0.05) ECG disturbance (44%). QTC prolongation was commonest (i.e. 27%) with electrolyte imbalance could produce life threatening cardiac arrhythmia (Polymorphic VT with Sr K+ 2.9). Artesunate alone was list prone (i.e. only 6%) Quinine though has comparatively more (i.e. 25%) but there is no life-threatening cardiac arrhythmia in artesunate and Quinine.
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The study compared the clinical efficacy and safety of oral artemisinin and oral artesunate as well as artemisinin pharmacokinetics during and after resolution of falciparum malaria. Forty adults with symptomatic falciparum malaria were allocated at random to treatment with either oral artemisinin (500 mg single dose on day 1 followed by 250 mg twice daily for 4 d and then another 500 mg single dose on day 6) or with oral artesunate (100 mg single dose on day 1 followed by 50 mg twice daily for 5 d). Patients were admitted to hospital at the Kibaha Designated District Hospital, Kibaha, Tanzania for the duration of treatment. The patients were seen once weekly for 3 more weeks. The time to parasite clearance (PCT) after oral artesunate (26·4 ± 3·6 h) was shorter (P = 0·002) than after artemisinin (31 ± 3·6 h). The fever subsidence time (FST) after oral artesunate (18·9 ± 4·0 h) was also shorter (P = 0.04) than after artemisinin (21·8±4·6 h). Parasites were detected in 4 (20%) and 7 (35%) patients after completing treatment with artesunate and artemisinin respectively. In these patients the parasitaemia reappeared at the 3rd or 4th week of follow-up. Standard haematology, blood biochemistry and urinanalysis, performed before drug intake and again on days 6 and 14, were normal. No clinical abnormality was observed during the study period. Artemisinin plasma concentrations, determined by high performance liquid chromatography with post-column derivatization and detection by ultraviolet light, were followed up to 8 h after drug administration on days 1 and 6. Artemisinin absorption was rapid, the maximum plasma concentrations Cmax) being attained at about 3 h. Artemisinin areas under the plasma concentration-time curve (AUC) and the Cmax values were about 6 times higher after the first dose on day 1 than on day 6. This decrease in artemisinin plasma concentration is suggestive of an increase in metabolic capacity due to pronounced autoinduction.
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