A Case Report of Quinine-Induced Thrombotic Microangiopathy Successfully Treated With Eculizumab.

Drug-induced thrombotic microangiopathy (DITMA) is a life-threatening condition which may be immune or nonimmune mediated. Quinine is the most implicated drug in immune-mediated DITMA. However, the optimal treatment is unclear. Complement inhibition by eculizumab has demonstrated success in many DITMA (e.g., carfilzomib, gemcitabine, and tacrolimus), but there are limited data in DITMA, including quinine-associated cases. A 55-year-old female was diagnosed with quinine-associated thrombotic microangiopathy (TMA), as confirmed by a positive quinine-dependent platelet-associated antibody. This was successfully treated with eculizumab with complete resolution of thrombocytopenia and anemia by 1 and 6 weeks. She required hemodialysis for a month and gained full recovery of renal function. We discuss various challenges with the diagnosis and management of DITMA. We also review published data on the use of eculizumab in various DITMA. Our case demonstrates successful treatment of quinine-induced TMA with eculizumab. We recommend further studies to assess the efficacy of complement inhibition in quinine and other DITMA.

Physiopathology and clinical management of blackwater fever: a scoping review.

BACKGROUND: Blackwater fever (BWF) is a severe syndrome occurring in patients with malaria upon antimalarial treatment, characterized by massive intravascular haemolysis and haemoglobinuria. BWF is a neglected condition and management recommendations are unavailable. OBJECTIVES: We performed a scoping review to appraise available data on clinical picture, treatment and physiopathology of BWF, which could guide rationally its clinical management. METHODS: MEDLINE, EMBASE, LILACS, Web of Science, and Scopus databases, and the reference list of relevant publications, were searched. Papers reporting original data on BWF cases or investigating the physiopathology of BWF were eligible. Data regarding case characteristics, trigger event, clinical management and outcome were extracted. For papers investigating the physiopathology of BWF, study design and principal findings were extracted. No quality assessment was performed. Data are presented as numbers and percentages, and summary of findings, grouped by paper focus (clinical description or physiopathology). RESULTS: 101 papers were included. The majority of BWF cases were observed in autochthonous children (75.7%) and adults (15.3%), in contrast with historical perception that BWF patients were typically expatriates. Clinical management was described for 794 cases; corticosteroids were used in 23. Outcome was reported for 535 patients, with 18.1% mortality. The trigger was reported for 552 (47.5%) cases; in 70.4% identified as quinine. However, two RCT comparing artesunate and quinine for falciparum malaria treatment did not find significant difference in BWF occurrence after their administration. Two case-control studies did not find significant difference in G6PDH deficiency between malaria patients with and without BWF. CONCLUSIONS: The physiopathology and optimal treatment of BWF remain similarly unknown as they were over a century ago. Empirical supporting treatment approach seems reasonable, while change of antimalarial drug and use of corticosteroids remain object of debate.

[A drink with an unexpected ending... Adverse reaction by tonic water: A case report]. / Una copa con final inesperado... Reacción adversa por agua tónica: reporte de un caso.

BACKGROUND: Quinine is an alkaloid with antipyretic and anti-infective properties, and also an ingredient in tonic waters. Adverse reactions have been reported with this product, such as photosensitivity, vasculitis, and contact dermatitis. CASE REPORT: A 31-year-old male patient who, after 3-4 hours of consuming "Schweppes®" gin with tonic water, manifested ulcers on the lips and oral cavity, and a fixed erythematous lesion on the second phalanx of the hand, 24 hours later. Skin tests with aeroallergens and food were negative, and 48-hour patch tests were positive (quinine [++] and "Schweppes®" [++]). Based on the test findings, the diagnosis of an adverse reaction to quinine, contained in the tonic water, will be established. CONCLUSIONS: Quinine can be found in other types of foods or medications, so it is important to establish an accurate diagnosis and offer adequate recommendations to the patient with the consumption of this product.

ANTECEDENTES: La quinina es un alcaloide con propiedades antipiréticas, antiinfecciosas y, además, un ingrediente del agua tónica. Se han descrito reacciones adversas con este producto, como fotosensibilidad, vasculitis y dermatitis de contacto. REPORTE DE CASO: Paciente masculino de 31 años, que luego de 3-4 horas de consumir ginebra con agua tónica "Schweppes®" manifestó úlceras en los labios y la cavidad bucal, y una lesión eritematosa fija en la segunda falange de la mano, 24 horas después. Las pruebas cutáneas con aeroalérgenos y alimentos resultaron negativas, y las pruebas epicutáneas de 48 horas positivas (quinina [++] y "Schweppes®" [++]). Con base en los hallazgos de las pruebas, se estableció el diagnóstico de reacción adversa por quinina, contenida en el agua tónica. CONCLUSIÓN: La quinina puede encontrarse en diferentes alimentos o medicamentos, por lo que es importante establecer el diagnóstico preciso y ofrecer recomendaciones adecuadas por el consumo de este producto.

Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis.

BACKGROUND: Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy. METHODS: For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371. FINDINGS: We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49-1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47-1·17), stillbirth (aHR=0·71, 0·32-1·57), and major congenital anomalies (aHR=0·60, 0·13-2·87). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36-0·92). INTERPRETATION: We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted. FUNDING: Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.

Comparative efficacy and safety of the artemisinin derivatives compared to quinine for treating severe malaria in children and adults: A systematic update of literature and network meta-analysis.

BACKGROUND: The artemisinin derivatives are the preferred antimalaria drugs for treating severe Plasmodium falciparum malaria. However, their clinical effectiveness compared to each other is unknown. Our objective, therefore, was to evaluate the efficacy and safety of the artemisinin derivatives and quinine for treating severe P. falciparum malaria in children and adults using a network meta-analysis. METHODS AND FINDINGS: Review protocol was registered with PROSPERO, CRD42020218190. We updated the search strategies of three Cochrane systematic reviews which included published and unpublished randomised control trials (RCTs) that have compared specific artemisinin derivatives to quinine in treating severe malaria. Search included CENTRAL, MEDLINE, Embase, LILACS, ISI Web of Science and trial registries up to February 2021. We screened studies, extracted data, assessed risk of bias, and quality of evidence in duplicate. Separate network meta-analyses in the frequentist framework, using a random effects model, with quinine as reference, were conducted for adults and children, and rankings were produced using p-scores to assess mortality, parasite clearance, coma recovery, fever clearance, neurological sequela and adverse events. Searches identified 818 citations, 33 RCTs were eligible. We pooled 7795 children and 3182 adults. The networks involved artesunate, artemether, rectal artemisinin, arteether and quinine. Compared to quinine, artesunate reduced mortality in children (risk ratio (RR), 0.76; 95%CI [0.65 to 0.89], moderate quality), adults (RR, 0.55; 95%CI [0.40 to 0.75], moderate quality) and in cerebral malaria (RR, 0.72; 95%CI [0.55 to 0.94], moderate quality). Compared to rectal artemisinin and intramuscular arteether, the efficacy and safety of parenteral artesunate, and intramuscular artemether in treating severe malaria are not clear. Rankings showed that none of the artemisinin drugs were consistently superior in all the outcomes assessed. Indirect evidence produced were of very low ratings due to suspected publication bias and imprecision. CONCLUSIONS: Artesunate reduces mortality compared to quinine for both adults and children in Asia and Africa including cerebral malaria. The artemisinin derivatives remain the best treatment for severe malaria but their comparative clinical effectiveness is yet to be fully explored.

Efficacy of 3-day low dose quinine plus clindamycin versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children (CLINDAQUINE): an open-label randomized trial.

BACKGROUND: The World Health Organization recommends quinine plus clindamycin as first-line treatment of malaria in the first trimester of pregnancy and as a second-line treatment for uncomplicated falciparum malaria when artemisinin-based drug combinations are not available. The efficacy of quinine plus clindamycin was compared with that of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in children below 5 years of age. METHODS: An open-label, phase 3, randomized trial was conducted in western Kenya. Children aged 6-59 months with uncomplicated falciparum malaria were randomly assigned (1:1) via a computer-generated randomization list to receive 3 days of twice a day treatment with either oral quinine (20 mg/kg/day) plus clindamycin (20 mg/kg/day) or artemether-lumefantrine (artemether 20 mg, lumefantrine 120 mg) as one (for those weighing 5-14 kg) or two (for those weighing 15-24 kg) tablets per dose. The primary outcome was a PCR-corrected rate of adequate clinical and parasitological response (ACPR) on day 28 in the per-protocol population. RESULTS: Of the 384 children enrolled, 182/192 (94.8%) receiving quinine plus clindamycin and 171/192 (89.1%) receiving artemether-lumefantrine completed the study. The PCR-corrected ACPR rate was 44.0% (80 children) in the quinine plus clindamycin group and 97.1% (166 children) in the artemether-lumefantrine group (treatment difference - 53.1%, 95% CI - 43.5% to - 62.7%). At 72 h after starting treatment, 50.3% (94 children) in the quinine plus clindamycin group were still parasitaemic compared with 0.5% (1 child) in the artemether-lumefantrine group. Three cases of severe malaria were recorded as serious adverse events in the quinine plus clindamycin group. CONCLUSIONS: The study found no evidence to support the use of a 3-day low dose course of quinine plus clindamycin in the treatment of uncomplicated falciparum malaria in children under 5 years of age in Kenya, where artemether-lumefantrine is still effective. TRIAL REGISTRATION: This trial is registered with the Pan-African Clinical Trials Registry, PACTR20129000419241.

Reflections on quinine and its importance in dermatology today.

Quinine and its D-isomer quinidine have been used medically in Europe since the 1600s. They were originally found within the bark of the cinchona tree in the jungle of the Andes. They were recognized to have multiple beneficial medical properties, ranging from a combined antipyretic and analgesic effect to the first effective treatment for malaria and later atrial fibrillation. With the development of other medications and the recognition of the potential life-threatening toxic reactions to these drugs, their medical use declined. Quinine is available without a prescription in many countries and is present in tonic water. Quinine has an extensive following of users who believe it is salutary and harmless, considering it a food supplement. In the past, dermatologists were frequently the first to recognize disease caused by these drugs owing to early findings of dermatitis or petechiae. Even though the medical use of these drugs has markedly decreased, drug eruptions may still be due to quinine, and patients may even be unaware they are taking this medication.

Efficacy and safety of dual intravenous artesunate plus quinine compared to intravenous artesunate for cerebral malaria in a triple blinded parallel multisite randomized controlled trial in Nigerian children: DUAL PAQ TRIAL Protocol.

BACKGROUND: Evidence exists as to the criticality of the first 24 h in the management of cerebral malaria. The morbidity and the mortality rate (35%) with the current intravenous monotherapy for the initial treatment of cerebral malaria are unacceptably high. Combination therapy and a shorter course of effective medication have been shown to improve outcomes in human participants in the treatment of other diseases. This study outlines a protocol to conduct a triple blinded parallel randomized controlled trial on cerebral malaria using dual intravenous medications compared to the current standard of monotherapy. METHODS: This is a parallel multi-site randomized controlled superiority triple blinded trial consisting of intravenous artesunate plus quinine and a control arm of intravenous artesunate only. Eligible and assenting children aged 6 months to 17 years will be recruited from 4 tertiary hospitals by random selection from the list of tertiary hospitals in Nigeria. Participants will be randomized and assigned in parallel into two arms using random numbers generated from GraphPad Prism (version 9) by a clinical pharmacologist who has no link with the investigators, the patients, or the statistician. The primary measurable outcome is survival at 12, 24, and 48 h post-randomization. A composite secondary outcome consists of the number of children that regained consciousness, parasitaemia and defervescence at 12 and 24 h post-randomization and haematological and inflammatory markers at 24 and 48 h post-randomization. Adverse events both solicited and unsolicited are recorded all through the study post-randomization. The study is approved by the State Research Ethics Review Committee. Data analysis will be performed in GraphPad Prism version 9. DISCUSSION: The outcome of this analysis will give insight into the efficacy and safety of dual intravenous antimalaria in the treatment of cerebral malaria among Nigerian children compared with the standard of care. The safety profile of this intervention will also be highlighted. This may help inform physicians on the optimal treatment for cerebral malaria to improve outcomes and reduce recrudescence and treatment failure. TRIAL REGISTRATION: Pan Africa Clinical Trial Registry PACTR202102893629864 . 23/02/2021.

Ototoxic hearing loss from antimalarials: A systematic narrative review.

BACKGROUND: Drugs used in curative and prophylactic antimalarial treatment may be ototoxic and lead to permanent hearing loss, but there is no consensus regarding prevalence and permanence of ototoxic hearing loss caused by antimalarials. The purpose of this systematic narrative review was to synthesize current evidence on antimalarial ototoxicity in human populations. METHOD: Studies published between 2005 and 2018 that reported prevalence of post-treatment hearing loss in individuals treated for malaria were included. RESULTS: Twenty-two studies including data from 21 countries were included. Primary themes of the included studies were to evaluate drug safety and/or efficacy (n = 13) or ototoxic effects of drugs (n = 9). Hearing data were measured objectively in 9 studies. Five studies focused on quinine (or derivates), 10 focused on artemisinin combination therapies, and 7 considered multiple drug combinations. There is a paucity of evidence that thoroughly reports potentially permanent ototoxic effects of antimalarials. CONCLUSIONS: Antimalarial drugs may be ototoxic in some cases. More research in human populations is needed to describe ototoxicity of current antimalarials and of future drugs that will be used/developed in response to antimalarial resistance. It is recommended that randomized trials evaluating drug safety objectively measure and report ototoxic hearing loss as an adverse event.

[Hip necrosis. A severe complication after intragluteal injection of quinine salt in Bangui, Central African Republic]. / La nécrose de la hanche : Une complication grave de l'injection intrafessière de sels de quinine à Bangui, République centrafricaine.

Introduction: Intramuscular injection of quinine has been for long the most common treatment for malaria in children in endemic areas of Africa, especially sub-Saharan Africa, and remains too often used. However, it is frequently wrongly performed by unqualified people. When administered in a poorly developed or malnourished child, the injection can be done too deeply in the hip joint instead of the gluteus muscle area. Materials and Methods: The files of 3012 children examined in out-patient clinics in Bangui, Central African Republic, between 2011 and 2020 were reviewed. Sequelae of intramuscular injections were observed in 307 cases, including intraquadricipital injection in 170 cases (56%) and intragluteal injection in 137 cases (44%). The latter included 115 sciatic paralysis and 22 hip sequelae with stiffness, shortening of the limb, limping and pain at walking. In these 22 cases, an intragluteal injection was incriminated by the families. However, 16 files were considered as insufficient because of imprecise history or because poor quality or no radiograph was available. Although suspected of being hip necrosis, these files were excluded. Six cases presented specific clinical pictures and interpretable radiographs and were included in this study. Results: The clinical and the radiographic aspects of this severe complication apparently not documented in the literature are analyzed. The well-known toxicity of quinine may be responsible of a necrosis involving both the femoral head and the acetabular roof, resulting in a painful joint, stiff in adduction, with limping and with an apparent marked shortening of the lower limb. Radiographs show a subtotal femoral head necrosis associated to an acetabular roof necrosis with an upward displacement of the epiphyseo-metaphysal femoral stump, the latter keeping a roughly spherical aspect and remaining well-covered and fitted in a relatively deep neo-acetabulum. Discussion: In the African background, this picture of coxopathy occurring in childhood may suggest an avascular necrosis of the femoral head complicating a sickle-cells disease, or above all sequelae of septic osteoarthritis. Treatments are limited to the prescription of a partial weight bearing of the hip. Conclusion: Although no irrefutable arguments are existing, the observed clinical and radiographic pictures are sufficiently clear and typical to individualize this severe iatrogenic complication which should be avoided by a good technic or by using the intravenous way when necessary.

Quinine in Otology and Neurotology: Ototoxicity and Historic Role in Therapy.

OBJECTIVES/HYPOTHESIS: Quinine, a cinchona bark-derived antimalarial alkaloid, is a known ototoxic. Isolated and named in 1820 by the French scientists Pierre-Joseph Pelletier and Joseph-Bienaimé Caventou, it has since been employed in the treatment of different maladies. Quinine was also recommended as a local anesthetic in surgical procedures in the early 20th century. This article aims to identify early ototoxicity reports regarding quinine and to investigate if quinine was previously used in otology as an anesthetic agent or as an actual therapy. METHOD: Historical review of medical and pharmaceutical literature from the 19th and 20th centuries in databases (PubMed; Web of Science), as well as medical books on ototoxic drugs, quinine, and therapies in otology. RESULTS: The first identified reference of quinine ototoxicity was from 1824. Quinine also had a therapeutic role in otology and neurotology and was employed for its analgesic properties. It was used in Menière's disease, vertigo, otalgia, purulent otitis media, neuralgia of the plexus tympani, furuncles in the auditory canal, and herpes zoster in the auricle. CONCLUSION: Quinine was acknowledged as an ototoxic drug in the 19th century. Quinine was used in several otologic disorders, both as an analgesic (for herpes zoster, otalgia) and as a therapeutic agent (Menière's disease, vertigo, purulent otitis media, furuncles in the auditory canal). This research demonstrates that, analogously to gentamicin, quinine was used in Menière's disease specifically due to its ototoxic effects.

Efficacy and tolerability of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: a systematic review and individual patient data meta-analysis.

BACKGROUND: Malaria in pregnancy affects both the mother and the fetus. However, evidence supporting treatment guidelines for uncomplicated (including asymptomatic) falciparum malaria in pregnant women is scarce and assessed in varied ways. We did a systematic literature review and individual patient data (IPD) meta-analysis to compare the efficacy and tolerability of different artemisinin-based or quinine-based treatments for malaria in pregnant women. METHODS: We did a systematic review of interventional or observational cohort studies assessing the efficacy of artemisinin-based or quinine-based treatments in pregnancy. Seven databases (MEDLINE, Embase, Global Health, Cochrane Library, Scopus, Web of Science, and Literatura Latino Americana em Ciencias da Saude) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrials.gov) were searched. The final search was done on April 26, 2019. Studies that assessed PCR-corrected treatment efficacy in pregnancy with follow-up of 28 days or more were included. Investigators of identified studies were invited to share data from individual patients. The outcomes assessed included PCR-corrected efficacy, PCR-uncorrected efficacy, parasite clearance, fever clearance, gametocyte development, and acute adverse events. One-stage IPD meta-analysis using Cox and logistic regression with random-effects was done to estimate the risk factors associated with PCR-corrected treatment failure, using artemether-lumefantrine as the reference. This study is registered with PROSPERO, CRD42018104013. FINDINGS: Of the 30 studies assessed, 19 were included, representing 92% of patients in the literature (4968 of 5360 episodes). Risk of PCR-corrected treatment failure was higher for the quinine monotherapy (n=244, adjusted hazard ratio [aHR] 6·11, 95% CI 2·57-14·54, p<0·0001) but lower for artesunate-amodiaquine (n=840, 0·27, 95% 0·14-0·52, p<0·0001), artesunate-mefloquine (n=1028, 0·56, 95% 0·34-0·94, p=0·03), and dihydroartemisinin-piperaquine (n=872, 0·35, 95% CI 0·18-0·68, p=0·002) than artemether-lumefantrine (n=1278) after adjustment for baseline asexual parasitaemia and parity. The risk of gametocyte carriage on day 7 was higher after quinine-based therapy than artemisinin-based treatment (adjusted odds ratio [OR] 7·38, 95% CI 2·29-23·82). INTERPRETATION: Efficacy and tolerability of artemisinin-based combination therapies (ACTs) in pregnant women are better than quinine. The lower efficacy of artemether-lumefantrine compared with other ACTs might require dose optimisation. FUNDING: The Bill & Melinda Gates Foundation, ExxonMobil Foundation, and the University of Oxford Clarendon Fund.

Pregnancy outcomes and risk of placental malaria after artemisinin-based and quinine-based treatment for uncomplicated falciparum malaria in pregnancy: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.

BACKGROUND: Malaria in pregnancy, including asymptomatic infection, has a detrimental impact on foetal development. Individual patient data (IPD) meta-analysis was conducted to compare the association between antimalarial treatments and adverse pregnancy outcomes, including placental malaria, accompanied with the gestational age at diagnosis of uncomplicated falciparum malaria infection. METHODS: A systematic review and one-stage IPD meta-analysis of studies assessing the efficacy of artemisinin-based and quinine-based treatments for patent microscopic uncomplicated falciparum malaria infection (hereinafter uncomplicated falciparum malaria) in pregnancy was conducted. The risks of stillbirth (pregnancy loss at ≥ 28.0 weeks of gestation), moderate to late preterm birth (PTB, live birth between 32.0 and < 37.0 weeks), small for gestational age (SGA, birthweight of < 10th percentile), and placental malaria (defined as deposition of malaria pigment in the placenta with or without parasites) after different treatments of uncomplicated falciparum malaria were assessed by mixed-effects logistic regression, using artemether-lumefantrine, the most used antimalarial, as the reference standard. Registration PROSPERO: CRD42018104013. RESULTS: Of the 22 eligible studies (n = 5015), IPD from16 studies were shared, representing 95.0% (n = 4765) of the women enrolled in literature. Malaria treatment in this pooled analysis mostly occurred in the second (68.4%, 3064/4501) or third trimester (31.6%, 1421/4501), with gestational age confirmed by ultrasound in 91.5% (4120/4503). Quinine (n = 184) and five commonly used artemisinin-based combination therapies (ACTs) were included: artemether-lumefantrine (n = 1087), artesunate-amodiaquine (n = 775), artesunate-mefloquine (n = 965), and dihydroartemisinin-piperaquine (n = 837). The overall pooled proportion of stillbirth was 1.1% (84/4361), PTB 10.0% (619/4131), SGA 32.3% (1007/3707), and placental malaria 80.1% (2543/3035), and there were no significant differences of considered outcomes by ACT. Higher parasitaemia before treatment was associated with a higher risk of SGA (adjusted odds ratio [aOR] 1.14 per 10-fold increase, 95% confidence interval [CI] 1.03 to 1.26, p = 0.009) and deposition of malaria pigment in the placenta (aOR 1.67 per 10-fold increase, 95% CI 1.42 to 1.96, p < 0.001). CONCLUSIONS: The risks of stillbirth, PTB, SGA, and placental malaria were not different between the commonly used ACTs. The risk of SGA was high among pregnant women infected with falciparum malaria despite treatment with highly effective drugs. Reduction of malaria-associated adverse birth outcomes requires effective prevention in pregnant women.

Post-malarial anemia in Mozambican children treated with quinine or artesunate: A retrospective observational study.

OBJECTIVES: This retrospective analysis performed in Manhiça, Southern Mozambique, aimed to describe the frequency of post-malarial anemia (measured as a decrease of hematocrit ≥10%) and the need for blood transfusions in children with severe malaria treated with intravenous quinine or parenteral artesunate. METHODS: All children <15 years admitted with a parasitologically-confirmed diagnosis of malaria from 1st January 2003 to 31st December 2017, alive at hospital discharge, and with at least one measurement of hematocrit within 28 days after hospital discharge, detected by passive case detection, were included. RESULTS: The overall prevalence of post-malarial anemia observed in the study was 23.13%, with an estimated incidence rate of 288.84 episodes/1,000 children-month at risk in the follow-up period (28 days after discharge). There were no differences between treatment groups, although the study showed a higher association between blood transfusions and artesunate treatment. CONCLUSIONS: In this setting, children with severe malaria frequently present a meaningful decrease of hematocrit (>=10%) in the first weeks after their episode, sometimes requiring blood transfusions. Because of the high underlying prevalence of anemia in malaria-endemic settings, all children with severe malaria need to be actively followed up, irrespective of the treatment received.

Quinine exposure and the risk of acute kidney injury: a population-based observational study of older people.

OBJECTIVES: to establish and quantify any observable association between the exposure to community prescriptions for quinine and acute kidney injury (AKI) events in a population of older adults. DESIGN: two observational studies using the same dataset, a retrospective longitudinal cohort study and a self-controlled case series (SCCS). SETTING: NHS health board in Scotland. PARTICIPANTS: older adults (60+ years) who received quinine prescriptions in Tayside, Scotland, between January 2004 and December 2015. The first study included 12,744 individuals. The SCCS cohort included 5,907 people with quinine exposure and more than or equal to one AKI event. MAIN OUTCOME MEASURED: in the first study, multivariable logistic regression was used to calculate odds ratios (ORs) for AKI comparing between episodes with and without recent quinine exposure after adjustment for demographics, comorbidities and concomitant medications. The SCCS study divided follow-up for each individual into periods 'on' and 'off' quinine, calculating incidence rate ratios (IRRs) for AKI adjusting for age. RESULTS: during the study period, 273,596 prescriptions for quinine were dispensed in Tayside. A total of 13,616 AKI events occurred during follow-up (crude incidence 12.5 per 100 person-years). In the first study, exposure to quinine before an episode of care was significantly associated with an increased probability of AKI (adjusted OR = 1.27, 95% confidence interval (CI) 1.21-1.33). In the SCCS study, exposure to quinine was associated with an increased relative incidence of AKI compared to unexposed periods (IRR = 1.20, 95% CI 1.15-1.26), with the greatest risk observed within 30 days following quinine initiation (IRR = 1.48, 95% CI 1.35-1.61). CONCLUSION: community prescriptions for quinine in an older adult population are associated with an increased risk of AKI.