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Article ; Online: Estimating the burden of severe malarial anaemia and access to hospital care in East Africa.

Winskill, Peter / Dhabangi, Aggrey / Kwambai, Titus K / Mori, Amani Thomas / Mousa, Andria / Okell, Lucy C

2023 Volume 14, Issue 1, Page(s) 5691

Abstract: Severe malarial anaemia can be fatal if not promptly treated. Hospital studies may under-represent the true burden because cases often occur in settings with poor access to healthcare. We estimate the relationship of community prevalence of malaria ... ...

Abstract	Severe malarial anaemia can be fatal if not promptly treated. Hospital studies may under-represent the true burden because cases often occur in settings with poor access to healthcare. We estimate the relationship of community prevalence of malaria infection and severe malarial anaemia with the incidence of severe malarial anaemia cases in hospital, using survey data from 21 countries and hospital data from Kenya, Tanzania and Uganda. The estimated percentage of severe malarial anaemia cases that were hospitalised is low and consistent for Kenya (21% (95% CrI: 7%, 47%)), Tanzania (18% (95% CrI: 5%, 52%)) and Uganda (23% (95% CrI: 9%, 48%)). The majority of severe malarial anaemia cases remain in the community, with the consequent public health burden being contingent upon the severity of these cases. Alongside health system strengthening, research to better understand the spectrum of disease associated with severe malarial anaemia cases in the community is a priority.
MeSH term(s)	Humans ; Kenya/epidemiology ; Tanzania/epidemiology ; Anemia/epidemiology ; Malaria/complications ; Malaria/epidemiology ; Hospitals
Language	English
Publishing date	2023-09-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-41275-w
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Article ; Online: Asymptomatic recrudescence after artemether-lumefantrine treatment for uncomplicated falciparum malaria: a systematic review and meta-analysis.

Mumtaz, Rida / Okell, Lucy C / Challenger, Joseph D

Malaria journal

2020 Volume 19, Issue 1, Page(s) 453

Abstract: Background: In clinical trials of therapy for uncomplicated Plasmodium falciparum, there are usually some patients who fail treatment even in the absence of drug resistance. Treatment failures, which can be due to recrudescence or re-infection, are ... ...

Abstract	Background: In clinical trials of therapy for uncomplicated Plasmodium falciparum, there are usually some patients who fail treatment even in the absence of drug resistance. Treatment failures, which can be due to recrudescence or re-infection, are categorized as 'clinical' or 'parasitological' failures, the former indicating that symptoms have returned. Asymptomatic recrudescence has public health implications for continued malaria transmission and may be important for the spread of drug-resistant malaria. As the number of recrudescences in an individual trial is often low, it is difficult to assess how commonplace asymptomatic recrudescence is, and with what factors it is associated. Methods: A systematic literature review was carried out on clinical trials of artemether-lumefantrine (AL) in patients seeking treatment for symptomatic uncomplicated falciparum malaria, and information on symptoms during treatment failure was recorded. Only treatment failures examined by polymerase chain reaction (PCR) were included, so as to exclude re-infections. A multivariable Bayesian regression model was used to explore factors potentially explaining the proportion of recrudescent infections which are symptomatic across the trials included in the study. Results: Across 60 published trials, including 9137 malaria patients, 37.8% [95% CIs (26.6-49.4%)] of recrudescences were symptomatic. A positive association was found between transmission intensity and the observed proportion of recrudescences that were asymptomatic. Symptoms were more likely to return in trials that only enrolled children aged < 72 months [odds ratio = 1.62, 95% CIs (1.01, 2.59)]. However, 84 studies had to be excluded from this analysis, as recrudescences were not specified as symptomatic or asymptomatic. Conclusions: AL, the most widely used treatment for uncomplicated P. falciparum in Africa, remains a highly efficacious drug in most endemic countries. However in the small proportion of patients where AL does not clear parasitaemia, the majority of patients do not develop symptoms again and thus would be unlikely to seek another course of treatment. This continued asymptomatic parasite carriage in patients who have been treated may have implications for drug-resistant parasites being introduced into high-transmissions settings.
MeSH term(s)	Antimalarials/adverse effects ; Antimalarials/therapeutic use ; Artemether, Lumefantrine Drug Combination/adverse effects ; Artemether, Lumefantrine Drug Combination/therapeutic use ; Asymptomatic Infections ; Child ; Child, Preschool ; Humans ; Infant ; Infant, Newborn ; Malaria, Falciparum/drug therapy ; Malaria, Falciparum/epidemiology ; Recurrence ; Treatment Failure
Chemical Substances	Antimalarials ; Artemether, Lumefantrine Drug Combination
Language	English
Publishing date	2020-12-09
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Systematic Review
ISSN	1475-2875
ISSN (online)	1475-2875
DOI	10.1186/s12936-020-03520-1
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Article: Selection of artemisinin partial resistance Kelch13 mutations in Uganda in 2016-22 was at a rate comparable to that seen previously in South-East Asia.

Meier-Scherling, Cecile P G / Watson, Oliver J / Asua, Victor / Ghinai, Isaac / Katairo, Thomas / Garg, Shreeya / Conrad, Melissa / Rosenthal, Philip J / Okell, Lucy C / Bailey, Jeffrey A

medRxiv : the preprint server for health sciences

2024

Abstract: Background: Artemisinin partial resistance, mediated by mutations in the : Methods: We investigated K13 mutation prevalence at 16 sites in Uganda (2016-2022, 6586 samples), and five sites in SEA (2003-2018, 5465 samples) by calculating selection ... ...

Abstract	Background: Artemisinin partial resistance, mediated by mutations in the Methods: We investigated K13 mutation prevalence at 16 sites in Uganda (2016-2022, 6586 samples), and five sites in SEA (2003-2018, 5465 samples) by calculating selection coefficients using Bayesian mixed-effect linear models. We then tested whether SEA K13 mutation prevalence could have been forecast accurately using up to the first five years of available data and forecast future K13 mutation prevalence in Uganda. Findings: The selection coefficient for the prevalence of relevant K13 mutations (441L, 469F/Y, 561H, 675V) was estimated at s=0·383 (95% CrI: 0·247 - 0·528) per year, a 38% relative prevalence increase. Selection coefficients across Uganda were s=0·968 (0·463 - 1·569) for 441L, s=0·153 (-0·445 - 0·727) for 469F, s=0·222 (-0·011 - 0·398) for 469Y, and s=0·152 (-0·023 - 0·312) for 675V. In SEA, the selection coefficient was s=-0·005 (-0·852 - 0·814) for 539T, s=0·574 (-0·092 - 1·201) for 580Y, and s=0·308 (0·089 - 0·536) for all validated K13 mutations. Forecast prevalences for Uganda assuming constant selection neared fixation (>95% prevalence) within a decade (2028-2033) for combined K13 mutations. Interpretation: The selection of K13 mutations in Uganda was at a comparable rate to that observed in SEA, suggesting K13 mutations may continue to increase quickly in Uganda. Funding: NIH R01AI156267, R01AI075045, and R01AI089674.
Language	English
Publishing date	2024-02-04
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.03.24302209
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Article ; Online: Asymptomatic recrudescence after artemether–lumefantrine treatment for uncomplicated falciparum malaria

Rida Mumtaz / Lucy C. Okell / Joseph D. Challenger

Malaria Journal, Vol 19, Iss 1, Pp 1-

a systematic review and meta-analysis

2020 Volume 9

Abstract: Abstract Background In clinical trials of therapy for uncomplicated Plasmodium falciparum, there are usually some patients who fail treatment even in the absence of drug resistance. Treatment failures, which can be due to recrudescence or re-infection, ... ...

Abstract	Abstract Background In clinical trials of therapy for uncomplicated Plasmodium falciparum, there are usually some patients who fail treatment even in the absence of drug resistance. Treatment failures, which can be due to recrudescence or re-infection, are categorized as ‘clinical’ or ‘parasitological’ failures, the former indicating that symptoms have returned. Asymptomatic recrudescence has public health implications for continued malaria transmission and may be important for the spread of drug-resistant malaria. As the number of recrudescences in an individual trial is often low, it is difficult to assess how commonplace asymptomatic recrudescence is, and with what factors it is associated. Methods A systematic literature review was carried out on clinical trials of artemether-lumefantrine (AL) in patients seeking treatment for symptomatic uncomplicated falciparum malaria, and information on symptoms during treatment failure was recorded. Only treatment failures examined by polymerase chain reaction (PCR) were included, so as to exclude re-infections. A multivariable Bayesian regression model was used to explore factors potentially explaining the proportion of recrudescent infections which are symptomatic across the trials included in the study. Results Across 60 published trials, including 9137 malaria patients, 37.8% [95% CIs (26.6–49.4%)] of recrudescences were symptomatic. A positive association was found between transmission intensity and the observed proportion of recrudescences that were asymptomatic. Symptoms were more likely to return in trials that only enrolled children aged < 72 months [odds ratio = 1.62, 95% CIs (1.01, 2.59)]. However, 84 studies had to be excluded from this analysis, as recrudescences were not specified as symptomatic or asymptomatic. Conclusions AL, the most widely used treatment for uncomplicated P. falciparum in Africa, remains a highly efficacious drug in most endemic countries. However in the small proportion of patients where AL does not clear parasitaemia, the majority of patients do not develop symptoms again and thus would be unlikely to seek another course of treatment. This continued asymptomatic parasite carriage in patients who have been treated may have implications for drug-resistant parasites being introduced into high-transmissions settings.
Keywords	Malaria ; Plasmodium falciparum ; Artemisinin-based combination therapy ; Artemether–lumefantrine ; Clinical trials ; Treatment failure ; Arctic medicine. Tropical medicine ; RC955-962 ; Infectious and parasitic diseases ; RC109-216
Subject code	610
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: Does integrated community case management (iCCM) target health inequities and treatment delays? Evidence from an analysis of Demographic and Health Surveys data from 21 countries in the period 2010 to 2018.

Winskill, Peter / Mousa, Andria / Oresanya, Olusola / Counihan, Helen / Okell, Lucy C / Walker, Patrick G

Journal of global health

2021 Volume 11, Page(s) 4013

Abstract: Background: Integrated community case management (iCCM) is a programme that can, via community health workers (CHWs), increase access to timely and essential treatments for children. As well as improving treatment coverage, iCCM has an additional equity- ...

Abstract	Background: Integrated community case management (iCCM) is a programme that can, via community health workers (CHWs), increase access to timely and essential treatments for children. As well as improving treatment coverage, iCCM has an additional equity-focus with the aim of targeting underserved populations. To assess the success of iCCM programmes it is important that we understand the contribution they are making to equitable health coverage. Methods: We analysed demographic and health survey data from 21 countries over 9 years to assess evidence and evaluate iCCM programmes. We summarise the contribution CHWs are making relative to other health care provider groups and what treatment combinations CHWs are commonly prescribing. We assessed the ability of CHWs to target treatment delays and health inequities by evaluating time to treatment following fever onset and relationships between CHWs and wealth, rurality and remoteness. Results: There was good evidence that CHWs are being successfully targeted to improve inequities in health care coverage. There is a larger contribution of CHWs in areas with higher poverty, rurality and remoteness. In six surveys CHWs were associated with significantly shorter average time between fever onset and advice or treatment seeking, whilst in one they were associated with significantly longer times. In areas with active CHW programmes, the contribution of CHWs relative to other health care provider groups varied between 11% to 45% of treatment visits. The distribution of types of treatment provided by CHWs was also very variable between countries. Conclusions: The success of an iCCM programme depends not only on increasing treatment coverage but addressing inequities in access to timely health care. Whilst much work is still needed to attain universal health care targets, and despite incomplete data, there is evidence that iCCM is successfully addressing treatment delays and targeting underserved populations.
MeSH term(s)	Case Management ; Child ; Community Health Workers ; Demography ; Humans ; Rural Population ; Time-to-Treatment
Language	English
Publishing date	2021-03-01
Publishing country	Scotland
Document type	Journal Article
ZDB-ID	2741629-X
ISSN	2047-2986 ; 2047-2986
ISSN (online)	2047-2986
ISSN	2047-2986
DOI	10.7189/jogh.11.04013
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Article ; Online: Mapping sulphadoxine-pyrimethamine-resistant Plasmodium falciparum malaria in infected humans and in parasite populations in Africa.

Okell, Lucy C / Griffin, Jamie T / Roper, Cally

Scientific reports

2017 Volume 7, Issue 1, Page(s) 7389

Abstract: Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine in vulnerable populations reduces malaria morbidity in Africa, but resistance mutations in the parasite dhps gene (combined with dhfr mutations) threaten its efficacy. We update a ... ...

Abstract	Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine in vulnerable populations reduces malaria morbidity in Africa, but resistance mutations in the parasite dhps gene (combined with dhfr mutations) threaten its efficacy. We update a systematic review to map the prevalence of K540E and A581G mutations in 294 surveys of infected humans across Africa from 2004-present. Interpreting these data is complicated by multiclonal infections in humans, especially in high transmission areas. We extend statistical methods to estimate the frequency, i.e. the proportion of resistant clones in the parasite population at each location, and so standardise for varying transmission levels. Both K540E and A581G mutations increased in prevalence and frequency in 60% of areas after 2008, highlighting the need for ongoing surveillance. Resistance measures within countries were similar within 300 km, suggesting an appropriate spatial scale for surveillance. Spread of the mutations tended to accelerate once their prevalence exceeded 10% (prior to fixation). Frequencies of resistance in parasite populations are the same or lower than prevalence in humans, so more areas would be classified as likely to benefit from IPT if similar frequency thresholds were applied. We propose that the use of resistance frequencies as well as prevalence measures for policy decisions should be evaluated.
MeSH term(s)	Africa/epidemiology ; Animals ; Antimalarials/pharmacology ; Dihydropteroate Synthase/genetics ; Drug Combinations ; Drug Resistance ; Humans ; Malaria, Falciparum/epidemiology ; Malaria, Falciparum/parasitology ; Malaria, Falciparum/veterinary ; Models, Statistical ; Mutation ; Plasmodium falciparum/drug effects ; Plasmodium falciparum/genetics ; Population Surveillance ; Prevalence ; Protozoan Proteins/genetics ; Pyrimethamine/pharmacology ; Sulfadoxine/pharmacology ; Tetrahydrofolate Dehydrogenase/genetics
Chemical Substances	Antimalarials ; Drug Combinations ; Protozoan Proteins ; fanasil, pyrimethamine drug combination (37338-39-9) ; Sulfadoxine (88463U4SM5) ; DHFR protein, Plasmodium falciparum (EC 1.5.1.3) ; Tetrahydrofolate Dehydrogenase (EC 1.5.1.3) ; Dihydropteroate Synthase (EC 2.5.1.15) ; Pyrimethamine (Z3614QOX8W)
Language	English
Publishing date	2017-08-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Systematic Review
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-017-06708-9
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Article ; Online: Global patterns of submicroscopic

Whittaker, Charles / Slater, Hannah / Nash, Rebecca / Bousema, Teun / Drakeley, Chris / Ghani, Azra C / Okell, Lucy C

The Lancet. Microbe

2021 Volume 2, Issue 8, Page(s) e366–e374

Abstract: Background: Adoption of molecular techniques to detect : Methods: In this systematic review and meta-analysis we searched PubMed and Web of Science from Jan 1, 2010, until Oct 11, 2020, for cross-sectional studies reporting data on asexual : ... ...

Abstract	Background: Adoption of molecular techniques to detect Methods: In this systematic review and meta-analysis we searched PubMed and Web of Science from Jan 1, 2010, until Oct 11, 2020, for cross-sectional studies reporting data on asexual Findings: Of 4893 identified studies, we retained 121 after screening and removal of duplicates. 45 studies from a previous systematic review were included giving 166 studies containing 551 cross-sectional survey microscopy and PCR prevalence pairs. Our results show that submicroscopic infections predominate in low-transmission settings across all regions, but also reveal marked geographical variation, with the proportion of infections that are submicroscopic being highest in South American surveys and lowest in west African surveys. Although current transmission levels partly explain these results, we find that historical transmission intensity also represents a crucial determinant of the size of the submicroscopic reservoir, as does the demographic structure of the infected population (with submicroscopic infection more likely to occur in adults than in children) and the PCR or microscopy methodology used. We also observed a small yet significant influence of seasonality, with fewer submicroscopic infections observed in the wet season than the dry season. Integrating these results with estimates of infectivity in relation to parasite density suggests the contribution of submicroscopic infections to transmission across different settings is likely to be highly variable. Interpretation: Significant variation in the prevalence of submicroscopic infection exists even across settings characterised by similar current levels of transmission. These differences in submicroscopic epidemiology potentially warrant different approaches to targeting this infected subgroup across different settings to eliminate malaria. Funding: Bill & Melinda Gates Foundation, The Royal Society, and the UK Medical Research Council.
MeSH term(s)	Adult ; Bayes Theorem ; Child ; Cross-Sectional Studies ; Female ; Humans ; Malaria/diagnosis ; Malaria, Falciparum/epidemiology ; Plasmodium falciparum/genetics ; Pregnancy
Language	English
Publishing date	2021-08-11
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't ; Systematic Review
ISSN	2666-5247
ISSN (online)	2666-5247
DOI	10.1016/S2666-5247(21)00055-0
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Article ; Online: Mathematical Modelling to Guide Drug Development for Malaria Elimination.

Slater, Hannah C / Okell, Lucy C / Ghani, Azra C

Trends in parasitology

2016 Volume 33, Issue 3, Page(s) 175–184

Abstract: Mathematical models of the dynamics of a drug within the host are now frequently used to guide drug development. These generally focus on assessing the efficacy and duration of response to guide patient therapy. Increasingly, antimalarial drugs are used ... ...

Abstract	Mathematical models of the dynamics of a drug within the host are now frequently used to guide drug development. These generally focus on assessing the efficacy and duration of response to guide patient therapy. Increasingly, antimalarial drugs are used at the population level, to clear infections, provide chemoprevention, and to reduce onward transmission of infection. However, there is less clarity on the extent to which different drug properties are important for these different uses. In addition, the emergence of drug resistance poses new threats to longer-term use and highlights the need for rational drug development. Here, we argue that integrating within-host pharmacokinetic and pharmacodynamic (PK/PD) models with mathematical models for the population-level transmission of malaria is key to guiding optimal drug design to aid malaria elimination.
MeSH term(s)	Antimalarials/pharmacology ; Antimalarials/therapeutic use ; Disease Eradication ; Drug Design ; Drug Resistance ; Humans ; Malaria, Falciparum/drug therapy ; Models, Theoretical ; Plasmodium falciparum
Chemical Substances	Antimalarials
Language	English
Publishing date	2016-10-07
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2036227-4
ISSN	1471-5007 ; 1471-4922
ISSN (online)	1471-5007
ISSN	1471-4922
DOI	10.1016/j.pt.2016.09.004
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Article ; Online: Author Correction: Using mortuary and burial data to place COVID-19 in Lusaka, Zambia within a global context.

Sheppard, Richard J / Watson, Oliver J / Pieciak, Rachel / Lungu, James / Kwenda, Geoffrey / Moyo, Crispin / Chanda, Stephen Longa / Barnsley, Gregory / Brazeau, Nicholas F / Gerard-Ursin, Ines C G / Olivera Mesa, Daniela / Whittaker, Charles / Gregson, Simon / Okell, Lucy C / Ghani, Azra C / MacLeod, William B / Del Fava, Emanuele / Melegaro, Alessia / Hines, Jonas Z /

Mulenga, Lloyd B / Walker, Patrick G T / Mwananyanda, Lawrence / Gill, Christopher J

Nature communications

2024 Volume 15, Issue 1, Page(s) 2213

Language	English
Publishing date	2024-03-12
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-44940-w
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Article ; Online: Mapping sulphadoxine-pyrimethamine-resistant Plasmodium falciparum malaria in infected humans and in parasite populations in Africa

Lucy C. Okell / Jamie T. Griffin / Cally Roper

Scientific Reports, Vol 7, Iss 1, Pp 1-

2017 Volume 15

Abstract: Abstract Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine in vulnerable populations reduces malaria morbidity in Africa, but resistance mutations in the parasite dhps gene (combined with dhfr mutations) threaten its efficacy. We ... ...

Abstract	Abstract Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine in vulnerable populations reduces malaria morbidity in Africa, but resistance mutations in the parasite dhps gene (combined with dhfr mutations) threaten its efficacy. We update a systematic review to map the prevalence of K540E and A581G mutations in 294 surveys of infected humans across Africa from 2004-present. Interpreting these data is complicated by multiclonal infections in humans, especially in high transmission areas. We extend statistical methods to estimate the frequency, i.e. the proportion of resistant clones in the parasite population at each location, and so standardise for varying transmission levels. Both K540E and A581G mutations increased in prevalence and frequency in 60% of areas after 2008, highlighting the need for ongoing surveillance. Resistance measures within countries were similar within 300 km, suggesting an appropriate spatial scale for surveillance. Spread of the mutations tended to accelerate once their prevalence exceeded 10% (prior to fixation). Frequencies of resistance in parasite populations are the same or lower than prevalence in humans, so more areas would be classified as likely to benefit from IPT if similar frequency thresholds were applied. We propose that the use of resistance frequencies as well as prevalence measures for policy decisions should be evaluated.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2017-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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