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In malaria-endemic areas of Sub-Saharan Africa, overlap of clinical symptoms between malarial and non-malarial febrile illnesses can lead to empiric use of antibiotics among children. Our study aimed to illustrate the potential impact of decreasing malaria prevalence from malaria control efforts on antibiotic use. We constructed a probabilistic decision tree model representing antibiotic prescription in febrile children < 5 years. This model was used to predict change in absolute antibiotic use compared to baseline under levels of decreasing malaria prevalence. Model parameters were based on data from a hospital study in Ghana and validated via literature review. The baseline prevalence of malaria diagnoses was 52% among all hospitalized children. For our main results, we reported outcomes for a scenario representing a 50% decrease in malaria prevalence. Compared to baseline, absolute antibiotic prescription decreased from a baseline of 639 doses (95% CI 574-694) to 575 (95% CI 502-638). This reflected a 10% (95% CI 7%-13%) decrease in absolute antibiotic use. Our findings demonstrate that effective malaria control can reduce pediatric antibiotic use. However, until substantial progress is made in developing accurate diagnostics for non-malarial febrile illnesses, further reductions in antibiotic use will remain a challenge., (© 2024. The Author(s).)

Background: Healthcare resources are often limited in areas of sub-Saharan Africa. This makes accurate and timely diagnoses challenging and delays treatment of childhood febrile illness. We explored longitudinal characteristics related to symptoms, diagnosis and treatment of hospitalised febrile children in a rural area of Ghana highly endemic for malaria., Methods: Febrile children under 15 years, admitted to the study hospital paediatric ward, were recruited to the study and clinical data were collected throughout hospitalisation. Descriptive statistics were reported for all cases; for longitudinal analyses, a subset of visits with limited missing data was used., Results: There were 801 hospitalised children included in longitudinal analyses. Malaria (n = 581, 73%) and sepsis (n = 373, 47%) were the most prevalent suspected diagnoses on admission. One-third of malaria suspected diagnoses (n = 192, 33%) were changed on the discharge diagnosis, compared to 84% (n = 315) of sepsis suspected diagnoses. Among malaria-only discharge diagnoses, 98% (n/N = 202/207) received an antimalarial and 33% (n/N = 69/207) an antibiotic; among discharge diagnoses without malaria, 28% (n/N = 108/389) received an antimalarial and 83% (n/N = 324/389) an antibiotic., Conclusions: Suspected diagnoses were largely based on clinical presentation and were frequently changed; changed diagnoses were associated with lingering symptoms, underscoring the need for faster and more accurate diagnostics. Medications were over-prescribed regardless of diagnosis stability, possibly because of a lack of confidence in suspected diagnoses. Thus, better diagnostic tools are needed for childhood febrile illnesses to enhance the accuracy of and confidence in diagnoses, and to cut down unjustified medication use, reducing the risk of antimicrobial and malaria resistance., (© 2023 The Authors Tropical Medicine & International Health Published by John Wiley & Sons Ltd.)

Controlled human malaria infections (CHMI) are a valuable tool to study parasite gene expression in vivo under defined conditions. In previous studies, virulence gene expression was analyzed in samples from volunteers infected with the Plasmodium falciparum (Pf) NF54 isolate, which is of African origin. Here, we provide an in-depth investigation of parasite virulence gene expression in malaria-naïve European volunteers undergoing CHMI with the genetically distinct Pf 7G8 clone, originating in Brazil. Differential expression of var genes, encoding major virulence factors of Pf, PfEMP1s, was assessed in ex vivo parasite samples as well as in parasites from the in vitro cell bank culture that was used to generate the sporozoites (SPZ) for CHMI (Sanaria PfSPZ Challenge (7G8)). We report broad activation of mainly B-type subtelomeric located var genes at the onset of a 7G8 blood stage infection in naïve volunteers, mirroring the NF54 expression study and suggesting that the expression of virulence-associated genes is generally reset during transmission from the mosquito to the human host. However, in 7G8 parasites, we additionally detected a continuously expressed single C-type variant, Pf7G8&#95;040025600, that was most highly expressed in both pre-mosquito cell bank and volunteer samples, suggesting that 7G8, unlike NF54, maintains expression of some previously expressed var variants during transmission. This suggests that in a new host, the parasite may preferentially express the variants that previously allowed successful infection and transmission. Trial registration: ClinicalTrials.gov - NCT02704533; 2018-004523-36., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright: © 2023 Wichers-Misterek et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Perceived adverse effects of antimalarial chemoprophylaxis can be difficult to distinguish from travel-related illness and are often cited as important reasons for non-adherence or refusal of antimalarial chemoprophylaxis. We aimed to investigate the occurrence of symptoms of illness in travellers with and without chemoprophylaxis in a cross-sectional study after travel and to identify risk factors for non-adherence to prophylaxis., Methods: We enrolled 458 travellers to Africa and South America during their pre-travel medical consultation at the travel clinic of the University Medical Centre Hamburg-Eppendorf and conducted post-travel interviews on symptoms of illness and intake of malaria prophylaxis., Results: Eleven percent (49/437) of the participants reported symptoms of illness during travel. In total, 36% (160/448) of the participants reported prescription of chemoprophylaxis, the vast majority of these travelled to Africa (98%) and received atovaquone/proguanil (93%). Frequency of symptoms did not differ significantly between participants without prophylaxis and those taking atovaquone/proguanil. Non-adherence to prophylaxis was frequent (20%), but only 3% (4/149) of the participants stopped the medication early because of perceived side effects. Risk factors associated with non-adherence to prophylaxis included age under 30 years, travel to West or Central Africa and travel duration greater than 14 days., Conclusions: Symptoms of illness during travel occurred at similar frequencies irrespective of intake of chemoprophylaxis. Travellers should be informed about chemoprophylaxis in a balanced way, without raising fear of side effects, especially among groups at higher risk for incorrect use of prophylaxis., (© International Society of Travel Medicine 2023. Published by Oxford University Press.)

Background: Aim of our study was to identify conditions under which malaria transmission caused by imported infectious mosquitoes or travellers could occur at large central European airports, and if such transmission could be sustained by indigenous mosquitoes., Methods: We developed a deterministic and a stochastic compartmental Susceptible-Exposed-Infectious-Recovered-Susceptible (humans)/Susceptible-Exposed-Infectious (mosquitoes) model with two mosquito (imported Anopheles gambiae, indigenous A. plumbeus) and three human (travellers, airport personnel exposed/not exposed to imported A. gambiae) populations. We assessed various scenarios to identify combinations of model parameters leading to ongoing malaria transmission at the airport., Results: The number of infected airport personnel was low (five infected employees/six months) under assumptions reflecting possible future climatic conditions, current passenger mobility and no desinsection of airports/aircraft. Almost all infections among airport personnel were directly due to bites by imported A. gambiae. Indigenous mosquitoes would need to have comparable transmission parameters to A. gambiae to sustain disease transmission. Incoming infectious passengers play only a minor role in malaria transmission. Use of aircraft/airport desinsection led to no transmission events in the model., Conclusion: Our study shows that sustainable air travel-induced malaria transmission in central Europe is unlikely under current conditions or conditions which might become realistic in the next century., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The epidemiology of pediatric febrile illness is shifting in sub-Saharan Africa, but malaria remains a major cause of childhood morbidity and mortality. The present study describes causes of febrile illness in hospitalized children in Ghana and aims to determine the burden of malaria coinfections and their association with parasite densities., Methods: In a prospective study, children (aged ≥30 days and ≤15 years) with fever ≥38.0°C were recruited after admission to the pediatric ward of a primary hospital in Ghana. Malaria parasitemia was determined and blood, stool, urine, respiratory, and cerebrospinal fluid specimens were screened for parasitic, bacterial, and viral pathogens. Associations of Plasmodium densities with other pathogens were calculated., Results: From November 2013 to April 2015, 1238 children were enrolled from 4169 admissions. A clinical/microbiological diagnosis could be made in 1109/1238 (90%) patients, with Plasmodium parasitemia (n = 728/1238 [59%]) being predominant. This was followed by lower respiratory tract infections/pneumonia (n = 411/1238 [34%]; among detected pathogens most frequently Streptococcus pneumoniae, n = 192/299 [64%]), urinary tract infections (n = 218/1238 [18%]; Escherichia coli, n = 21/32 [66%]), gastrointestinal infections (n = 210 [17%]; rotavirus, n = 32/97 [33%]), and invasive bloodstream infections (n = 62 [5%]; Salmonella species, n = 47 [76%]). In Plasmodium-infected children the frequency of lower respiratory tract, gastrointestinal, and bloodstream infections increased with decreasing parasite densities., Conclusions: In a hospital setting, the likelihood of comorbidity with a nonmalarial disease is inversely correlated with increasing blood levels of malaria parasites. Hence, parasite densities provide important information as an indicator for the probability of coinfection, in particular to guide antimicrobial medication.

Background: A unit of the European Mobile Laboratory (EMLab) consortium was deployed to the Ebola virus disease (EVD) treatment unit in Guéckédou, Guinea, from March 2014 through March 2015., Methods: The unit diagnosed EVD and malaria, using the RealStar Filovirus Screen reverse transcription-polymerase chain reaction (RT-PCR) kit and a malaria rapid diagnostic test, respectively., Results: The cleaned EMLab database comprised 4719 samples from 2741 cases of suspected EVD from Guinea. EVD was diagnosed in 1231 of 2178 hospitalized patients (57%) and in 281 of 563 who died in the community (50%). Children aged <15 years had the highest proportion of Ebola virus-malaria parasite coinfections. The case-fatality ratio was high in patients aged <5 years (80%) and those aged >74 years (90%) and low in patients aged 10-19 years (40%). On admission, RT-PCR analysis of blood specimens from patients who died in the hospital yielded a lower median cycle threshold (Ct) than analysis of blood specimens from survivors (18.1 vs 23.2). Individuals who died in the community had a median Ct of 21.5 for throat swabs. Multivariate logistic regression on 1047 data sets revealed that low Ct values, ages of <5 and ≥45 years, and, among children aged 5-14 years, malaria parasite coinfection were independent determinants of a poor EVD outcome., Conclusions: Virus load, age, and malaria parasite coinfection play a role in the outcome of EVD., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: There is growing evidence for a positive association between malaria and invasive nontyphoidal Salmonella (iNTS) disease. However, case-control studies conducted within healthcare facilities also report inverse associations. This may be due to Berkson's bias, a selection bias that acts when both exposure and outcome are associated with hospital attendance and study participants are selected among attendees only. This study describes the effect of Berkson's bias on the malaria-iNTS association and provides a less biased effect estimate., Methods: Data collected in 2 Ghanaian hospitals were analyzed using 2 case-control approaches. In both approaches, cases were defined as iNTS-positive children, and concomitant malaria infection was the exposure of interest. In the first conventional sampling approach, children without any febrile bloodstream infection served as controls. In the second control-disease approach, children with non-iNTS bacteremia were used as controls., Results: Data from 6746 children were suitable for the analyses. One hundred sixty children with iNTS infection were study cases. In the conventional case-control approach 6301 children were controls, and in the control-disease approach 285 children were controls. In the conventional case-control study, malaria was estimated to protect against iNTS disease (odds ratio [OR], 0.4; 95% confidence interval [CI], .3-.7), whereas in the control-disease approach, malaria was identified to be a risk factor for iNTS disease (OR, 1.9; 95% CI, 1.1-3.3)., Conclusions: The study highlights how a selection bias may reverse results if an unsuitable control group is used and adds further evidence on the malaria-iNTS disease association., (© 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.)

Background: Country-specific studies in Africa have indicated that Plasmodium falciparum is associated with invasive nontyphoidal Salmonella (iNTS) disease. We conducted a multicenter study in 13 sites in Burkina Faso, Ethiopia, Ghana, Guinea-Bissau, Kenya, Madagascar, Senegal, South Africa, Sudan, and Tanzania to investigate the relationship between the occurrence of iNTS disease, other systemic bacterial infections, and malaria., Methods: Febrile patients received a blood culture and a malaria test. Isolated bacteria underwent antimicrobial susceptibility testing, and the association between iNTS disease and malaria was assessed., Results: A positive correlation between frequency proportions of malaria and iNTS was observed (P = .01; r = 0.70). Areas with higher burden of malaria exhibited higher odds of iNTS disease compared to other bacterial infections (odds ratio [OR], 4.89; 95% CI, 1.61-14.90; P = .005) than areas with lower malaria burden. Malaria parasite positivity was associated with iNTS disease (OR, 2.44; P = .031) and gram-positive bacteremias, particularly Staphylococcus aureus, exhibited a high proportion of coinfection with Plasmodium malaria. Salmonella Typhimurium and Salmonella Enteritidis were the predominant NTS serovars (53/73; 73%). Both moderate (OR, 6.05; P = .0001) and severe (OR, 14.62; P < .0001) anemia were associated with iNTS disease., Conclusions: A positive correlation between iNTS disease and malaria endemicity, and the association between Plasmodium parasite positivity and iNTS disease across sub-Saharan Africa, indicates the necessity to consider iNTS as a major cause of febrile illness in malaria-holoendemic areas. Prevention of iNTS disease through iNTS vaccines for areas of high malaria endemicity, targeting high-risk groups for Plasmodium parasitic infection, should be considered., (© 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.)

Background: Malaria incidence has declined considerably over the last decade. This is partly due to a scale-up of control measures but is also attributed to increasing urbanization. This study aimed to analyse the association between malaria and urbanization and the effect of urbanicity on the acquisition of semi-immunity., Methods: In 2012, children with fever presenting to St Michael's Hospital Pramso/Ghana were recruited. The malaria-positive-fraction (MPF) of fever cases was calculated on community-level to approximate the malaria risk. The mean age of malaria cases was calculated for each community to estimate the acquisition of semi-immunity. The level of urbanicity for the communities was calculated and associations between MPF, urbanicity and immunity were modelled using linear regression., Results: Twenty-six villages were included into the study with a mean MPF of 35 %. A linear decrease of 5 % (95 % CI: 4-6 %) in MPF with every ten-point increase in urbanicity was identified. The mean age of malaria patients increased by 2.9 months (95 % CI: 1.0-4.8) with every ten-point increase in urbanicity., Discussion: The results confirm an association between an increase in urbanicity and declining malaria risk and demonstrate that the acquisition of semi-immunity is heterogeneous on a micro-epidemiological scale and is associated with urbanicity.

Background: Previous studies on the association of malaria and stunted growth delivered inconsistent results. These conflicting results may be due to different levels of confounding and to considerable difficulties in elucidating a causal relationship. Randomized experiments are impractical and previous observational studies have not fully controlled for potential confounding including nutritional deficiencies, breastfeeding habits, other infectious diseases and socioeconomic status., Methods: This study aims to estimate the causal effect between malaria episodes and stunted growth by applying a combination of Mendelian randomization, using the sickle cell trait, and matching. We demonstrate the method on a cohort of children in the Ashanti Region, Ghana., Results: We found that the risk of stunting increases by 0.32 (P-value: 0.004, 95% CI: 0.09, 1.0) for every malaria episode. The risk estimate based on Mendelian randomization substantially differs from the multiple regression estimate of 0.02 (P-value: 0.02, 95% CI: 0.003, 0.03). In addition, based on the sensitivity analysis, our results were reasonably insensitive to unmeasured confounders., Conclusions: The method applied in this study indicates a causal relationship between malaria and stunting in young children in an area of high endemicity and demonstrates the usefulness of the sickle cell trait as an instrument for the analysis of conditions that might be causally related to malaria.