Antibiotic-Resistant Arcobacter spp. in commercial and smallholder farm animals in Asante Akim North Municipality, Ghana and Korogwe Town Council, Tanzania: a cross-sectional study.

BACKGROUND: Arcobacter species are considered emerging foodborne pathogens that can potentially cause serious infections in animals and humans. This cross-sectional study determined the frequency of potentially pathogenic Arcobacter spp. in both commercial and smallholder farm animals in Ghana and Tanzania. A total of 1585 and 1047 (poultry and livestock) samples were collected in Ghana and Tanzania, respectively. Selective enrichment media, along with oxidase and Gram testing, were employed for isolation of suspected Arcobacter spp. and confirmation was done using MALDI-TOF MS. Antibiotic susceptibility was assessed through disk diffusion method and ECOFFs were generated, for interpretation, based on resulting inhibition zone diameters. RESULTS: The overall Arcobacter frequency was higher in Ghana (7.0%, n = 111) than in Tanzania (2.0%, n = 21). The frequency of Arcobacter in commercial farms in Ghana was 10.3% (n/N = 83/805), while in Tanzania, it was 2.8% (n/N = 12/430). Arcobacter was detected in only 3.6% (n/N = 28/780) of the samples from smallholder farms in Ghana and 1.5% (n/N = 9/617) of the samples from Tanzania. For commercial farms, in Ghana, the presence of Arcobacter was more abundant in pigs (45.1%, n/N = 37/82), followed by ducks (38.5%, n/N = 10/26) and quails (35.7%, n/N = 10/28). According to MALDI-TOF-based species identification, Arcobacter butzleri (91.6%, n/N = 121/132), Arcobacter lanthieri (6.1%, n/N = 8/132), and Arcobacter cryaerophilus (2.3%, n/N = 3/132) were the only three Arcobacter species detected at both study sites. Almost all of the Arcobacter from Ghana (98.2%, n/N = 109/111) were isolated during the rainy season. The inhibition zone diameters recorded for penicillin, ampicillin, and chloramphenicol allowed no determination of an epidemiological cut-off value. However, the results indicated a general resistance to these three antimicrobials. Multidrug resistance was noted in 57.1% (n/N = 12/21) of the Arcobacter isolates from Tanzania and 45.0% (n/N = 50/111) of those from Ghana. The type of farm (commercial or smallholder) and source of the sample (poultry or livestock) were found to be associated with multi-drug resistance. CONCLUSIONS: The high levels of MDR Arcobacter detected from farms in both countries call for urgent attention and comprehensive strategies to mitigate the spread of antimicrobial resistance in these pathogens.

Comparing the roles of community health workers for malaria control and elimination in Cambodia and Tanzania.

The reduction of deaths from malaria in sub-Saharan Africa (SSA) is stalling, whereas many countries in Southeast Asia are approaching malaria elimination. We reviewed the role of community health worker (CHW) programmes in malaria control and elimination between regions, with a more detailed description of the programmes in Tanzania and Cambodia. Compared with Tanzania, Cambodia has a much more developed CHW network, which has been pivotal in the near elimination of malaria. In Tanzania, the malaria burden has remained similar over the last decade and treatment continues to rely on healthcare facilities, which provide more limited access to early diagnosis and treatment. Overall, the proportion of malaria cases treated by CHWs is substantially lower in SSA than in Southeast Asia. Even though networks of CHWs are resource intensive and malaria epidemiology differs substantially between countries, there is a strong case for expanding CHW networks in rural SSA to improve early access to effective malaria treatment and reduce the malaria burden.

Medicinal plants for treatment of diarrhoeal diseases among under-five children: experience from traditional healers in North-eastern Tanzania.

BACKGROUND: Right through history, humans have relied heavily on plants for sustenance and the healing of different ailments. One of the long-standing traditions that communities have inherited from earlier generations is the use of herbal medicines for the treatment of paediatric ailments, including diarrhoea. This study showcased medicinal plants used by traditional healers for the treatment of diarrhoeal diseases among under-five children in North-eastern Tanzania. METHODS AND DESIGN: A qualitative research approach and a narrative research design were employed. The research was carried out in the districts of Korogwe and Handeni in North-eastern Tanzania, with 52 in-depth interviews performed with participants (traditional healers). Purposive sampling method was used to select participants, and a thematic analysis framework was used to analyze the data. RESULTS: Study results indicate that traditional healers had enormous insights and were well informed about medicinal plants that were perceived to be efficacious in treating diarrhoeal diseases among under-five children. A total of 54 medicinal plants were reported by the participants to be effective in healing diarrhoeal diseases among under-five children. However, out of 54 medicinal plants, 15 were predominantly disclosed by the majority of participants. Those medicinal plants include Psidium guajava, Rhus natalensis, Ozoroa insignis, Tamarindus indica, Ocimum suave, Combretum molle, Zanha africana, Solanum incanum, and Ximenia americana. Other medicinal plants mentioned by most participants include, Ochna holstii, Elaeodendron schlechterianum, Albizia anthelmintica, Commiphora pteleifolia, Salacia stuhlmanniana, and Zenkerella grotei. CONCLUSION: All traditional healers seemed to have a clear understanding regarding the medicinal plants that were used to treat diarrhoeal diseases among under-five children. The participants acknowledged to treating under-five children with diarrhoeal diseases using herbal medications on multiple occasions. The findings of this study should inspire more in-depth botanical research to determine whether the medicinal plants reported in this study have anti-diarrhoeal properties.

Community perceptions on the effectiveness of herbal medicines and factors associated with their use in managing diarrhoea among under-five children in North-eastern Tanzania.

BACKGROUND: The demand for herbal medicines continues to increase globally. However, community perceptions on their effectiveness and factors influencing their use have not been extensively investigated, notably in the Tanga Region, North-eastern Tanzania, where their use in treating various diseases, including paediatric diarrhoea, has flourished. According to studies, Tanga Region has a high prevalence of diarrhoea among under-five children. This study explored community perceptions on the effectiveness of herbal medicines and factors associated with their use in managing diarrhoea among under-five children in North-eastern Tanzania. METHODS: A qualitative approach and a narrative design were employed by the present study since they had the potential to reveal unrecognized or unreported research problems. Focus group discussions and in-depth interviews were used to facilitate data collection from June 2022 to February 2023. The methods were chosen since they are the most common sources of qualitative data in health research. Purposive sampling method was used to select 247 participants, which included 171 caretakers, 52 traditional healers, and 24 paediatric health workers. Interviews were conducted until the saturation point was reached. The purposive technique was considered since it was a method that enabled the researcher to select participants who were knowledgeable about the study topic. Data analysis was performed using thematic analysis. RESULTS: Economic hardship, culture and heritage, superstitious beliefs, failure to recover after receiving hospital medication, easy accessibility of herbal medicines, and long distance to the health facility were the factors perceived to be potentially associated with persistent use of herbal medicines among caretakers. The majority of participants believed that herbal treatments were harmless and effective in treating diarrhoea. CONCLUSION: Superstitious beliefs, culture, and heritage were the primary justifications for using herbal medicines. It is vital for the relevant authority to educate the community on the risk of using unproven herbal medicines in order to diminish the effects that may arise from using uninvestigated herbs. As things stand, the use of herbal medications will continue owing to their relevance to the lives of people in the study setting.

Prostration and the prognosis of death in African children with severe malaria.

OBJECTIVES: Malaria is still one of the main reasons for hospitalization in children living in sub-Saharan Africa. Rapid risk stratification at admission is essential for optimal medical care and improved prognosis. Whereas coma, deep breathing, and, to a lesser degree, severe anemia are established predictors of malaria-related death, the value of assessing prostration for risk stratification is less certain. METHODS: Here we used a retrospective multi-center analysis comprising over 33,000 hospitalized children from four large studies, including two observational studies from the Severe Malaria in African Children network, a randomized controlled treatment study, and the phase-3-clinical RTS,S-malaria vaccine trial, to evaluate known risk factors of mortality and with a specific emphasis on the role of prostration. RESULTS: Despite comparable age profiles of the participants, we found significant inter- and intra-study variation in the incidence of fatal malaria as well as in the derived risk ratios associated with the four risk factors: coma, deep breathing, anemia, and prostration. Despite pronounced variations, prostration was significantly associated with an increased risk of mortality (P <0.001) and its consideration resulted in improved predictive performance, both in a multivariate model and a univariate model based on the Lambaréné Organ Dysfunction Score. CONCLUSION: Prostration is an important clinical criterion to determine severe pediatric malaria with possible fatal outcomes.

Fetal growth and birth weight are independently reduced by malaria infection and curable sexually transmitted and reproductive tract infections in Kenya, Tanzania, and Malawi: A pregnancy cohort study.

OBJECTIVES: Malaria and sexually transmitted and reproductive tract infections (STIs/RTIs) are highly prevalent in sub-Saharan Africa and associated with poor pregnancy outcomes. We investigated the individual and combined effects of malaria and curable STIs/RTIs on fetal growth in Kenya, Tanzania, and Malawi. METHODS: This study was nested within a randomized trial comparing monthly intermittent preventive treatment for malaria in pregnancy with sulfadoxine-pyrimethamine vs dihydroartemisinin-piperaquine, alone or combined with azithromycin. Fetal weight gain was assessed by serial prenatal ultrasound. Malaria was assessed monthly, and Treponema pallidum, Neisseria gonorrhoeae, Trichomonas vaginalis, Chlamydia trachomatis, and bacterial vaginosis at enrollment and in the third trimester. The effect of malaria and STIs/RTIs on fetal weight/birthweight Z-scores was evaluated using mixed-effects linear regression. RESULTS: In total, 1435 pregnant women had fetal/birth weight assessed 3950 times. Compared to women without malaria or STIs/RTIs (n = 399), malaria-only (n = 267), STIs/RTIs only (n = 410) or both (n = 353) were associated with reduced fetal growth (adjusted mean difference in fetal/birth weight Z-score [95% confidence interval]: malaria = -0.18 [-0.31,-0.04], P = 0.01; STIs/RTIs = -0.14 [-0.26,-0.03], P = 0.01; both = -0.20 [-0.33,-0.07], P = 0.003). Paucigravidae experienced the greatest impact. CONCLUSION: Malaria and STIs/RTIs are associated with poor fetal growth especially among paucigravidae women with dual infections. Integrated antenatal interventions are needed to reduce the burden of both malaria and STIs/RTIs.

Prescription patterns and compliance with World Health Organization recommendations for the management of uncomplicated and severe malaria: A prospective, real-world study in sub-Saharan Africa.

BACKGROUND: This study aimed to evaluate the gap between guidelines and local clinical practice for diagnosis and treatment of uncomplicated and severe malaria, the patient characteristics, diagnostic approach, treatment, and compliance to standard guideline recommendations. METHODS: This was a multicentre, observational study conducted between October 2020 and March 2021 in which patients of all ages with symptoms suggestive of malaria and who visited a healthcare facility were prospectively enrolled in six countries in sub-Saharan Africa (The Democratic Republic of the Congo, Mozambique, Nigeria, Rwanda, The United Republic of Tanzania, and Zambia). RESULTS: Of 1001 enrolled patients, 735 (73.4%) patients had confirmed malaria (based on overall judgment by investigator) at baseline (uncomplicated malaria: 598 [81.4%] and severe malaria: 137 [18.6%]). Of the confirmed malaria patients, 533 (72.5%) were administered a malaria rapid diagnostic test. The median age of patients was 11 years (range: 2 weeks-91 years) with more patients coming from rural (44.9%) than urban (30.6%) or suburban areas (24.5%). At the community level, 57.8% of patients sought advice or received treatment for malaria and 56.9% of patients took one or more drugs for their illness before coming to the study site. In terms of early access to care, 44.1% of patients came to the study site for initial visit ≥ 48 h after symptom onset. In patients with uncomplicated malaria, the most prescribed treatments were artemisinin-based combination therapy (ACT; n = 564 [94.3%]), primarily using artemether-lumefantrine (82.3%), in line with the World Health Organization (WHO) treatment guidelines. In addition, these patients received antipyretics (85.6%) and antibiotics (42.0%). However, in those with severe malaria, only 66 (48.2%) patients received parenteral treatment followed by oral ACT as per WHO guidelines, whereas 62 (45.3%) received parenteral treatment only. After receiving ambulatory care, 88.6% of patients with uncomplicated malaria were discharged and 83.2% of patients with severe malaria were discharged after hospitalization. One patient with uncomplicated malaria having multiple co-morbidities and three patients with severe malaria died. CONCLUSIONS: The findings of this study suggest that the prescribed treatment in most patients with uncomplicated malaria, but not of those with severe malaria, was in alignment with the WHO recommended guidelines.

Effectiveness and safety of intermittent preventive treatment with dihydroartemisinin-piperaquine or artesunate-amodiaquine for reducing malaria and related morbidities in schoolchildren in Tanzania: a randomised controlled trial.

BACKGROUND: In high transmission settings, most school-aged children harbour malaria parasites without showing symptoms, often leading to anaemia and possibly impaired psychomotor and cognitive abilities. We aimed to assess the effectiveness and safety of intermittent preventive treatment for malaria in school-aged children (IPTsc) living in highly endemic areas. METHODS: We did an open-label randomised controlled trial in seven primary schools in northeastern Tanzania. Schoolchildren aged 5-15 years were individually randomly assigned (1:1:1) to receive dihydroartemisinin-piperaquine, artesunate-amodiaquine, or standard of care (control) using a balanced block design. Drugs were administered by schoolteachers, with supervision from study nurses, at months 0 (baseline), 4, and 8, and were given in line with manufacturer's recommendations with dose based on the child's bodyweight. The primary endpoints were change from baseline in mean haemoglobin concentration at months 12 and 20, and clinical incidence of malaria and prevalence of parasitaemia at months 12 and 20 in the intervention groups versus the control group. The outcome data were collected through longitudinal surveys conducted every 4 months. Data were analysed on the basis of intention to treat (including all randomised participants) and per protocol (comprising children who completed the full 3-day regimen of all three IPTsc treatment rounds as assigned). This study is registered with ClinicalTrials.gov (NCT03640403). FINDINGS: Of the 1797 children scheduled for clinical screening, 1566 were enrolled and randomly allocated (526 to receive dihydroartemisinin-piperaquine, 527 to receive artesunate-amodiaquine, and 513 to receive standard of care). Due to COVID-19-related school closures, only two schools were visited at month 12 (135 children in the dihydroartemisinin-piperaquine group, 131 in the artesunate-amodiaquine group, and 118 in the control group). At month 12, compared with the control group, the change from baseline in mean haemoglobin concentration was increased by 0·5 g/dL (95% CI 0·2 to 0·8; p<0·0001) in the dihydroartemisinin-piperaquine group and 0·5 g/dL (0·2 to 0·7; p=0·0020) in the artesunate-amodiaquine group in the intention-to-treat analysis (with similar findings in the per protocol analysis). In the same period, in the intention-to-treat analysis, the prevalence of malaria parasitaemia increased from 28·5% (138 of 485 participants) to 33·6% (39 of 116) in the control group, but decreased from 28·0% (139 of 497) to 12·0% (15 of 125) in the dihydroartemisinin-piperaquine group (-21·6 percentage points [95% CI -31·9 to -11·3], p=0·0001 vs control at month 12) and from 24·7% (124 of 502) to 16·0% (20 of 125) in the artesunate-amodiaquine group (-17·6 percentage points [-28·4 to -6·9], p=0·0015). The decrease for artesunate-amodiaquine was larger in the per protocol analysis (-25·3 percentage points [-36·3 to -14·2], p<0·0001). The protective effect of IPTsc against malaria parasitaemia was 64% (95% CI 39 to 79; p<0·0001) for dihydroartemisinin-piperaquine and 52% (23 to 70; p=0·0015) for artesunate-amodiaquine in the intention-to-treat analysis, and was slightly higher on per protocol analysis. The protective effect against clinical malaria at month 12 was 20% (95% CI 9 to 29; p=0·0002) for dihydroartemisinin-piperaquine and 19% (8 to 28; p=0·0004) for artesunate-amodiaquine. No significant differences in any primary outcomes between the intervention and control groups were noted at month 20. Dihydroartemisinin-piperaquine and artesunate-amodiaquine were associated with a small number of mild adverse events, and there were no treatment-related serious adverse events or deaths. INTERPRETATION: IPTsc with dihydroartemisinin-piperaquine or artesunate-amodiaquine is a safe and effective approach to reducing malaria parasitaemia, clinical malaria, and related morbidities, and is feasible to implement through programmes delivered by schoolteachers. FUNDING: Flemish Interuniversity Council (VLIRUOS), EU EDCTP2 programme (MaReCa project), and Global Minds 2019. TRANSLATION: For the Swahili translation of the abstract see Supplementary Materials section.

Effect of monthly intermittent preventive treatment with dihydroartemisinin-piperaquine with and without azithromycin versus monthly sulfadoxine-pyrimethamine on adverse pregnancy outcomes in Africa: a double-blind randomised, partly placebo-controlled trial.

BACKGROUND: Intermittent preventive treatment in pregnancy (IPTp) with dihydroartemisinin-piperaquine is more effective than IPTp with sulfadoxine-pyrimethamine at reducing malaria infection during pregnancy in areas with high-grade resistance to sulfadoxine-pyrimethamine by Plasmodium falciparum in east Africa. We aimed to assess whether IPTp with dihydroartemisinin-piperaquine, alone or combined with azithromycin, can reduce adverse pregnancy outcomes compared with IPTp with sulfadoxine-pyrimethamine. METHODS: We did an individually randomised, double-blind, three-arm, partly placebo-controlled trial in areas of high sulfadoxine-pyrimethamine resistance in Kenya, Malawi, and Tanzania. HIV-negative women with a viable singleton pregnancy were randomly assigned (1:1:1) by computer-generated block randomisation, stratified by site and gravidity, to receive monthly IPTp with sulfadoxine-pyrimethamine (500 mg of sulfadoxine and 25 mg of pyrimethamine for 1 day), monthly IPTp with dihydroartemisinin-piperaquine (dosed by weight; three to five tablets containing 40 mg of dihydroartemisinin and 320 mg of piperaquine once daily for 3 consecutive days) plus a single treatment course of placebo, or monthly IPTp with dihydroartemisinin-piperaquine plus a single treatment course of azithromycin (two tablets containing 500 mg once daily for 2 consecutive days). Outcome assessors in the delivery units were masked to treatment group. The composite primary endpoint was adverse pregnancy outcome, defined as fetal loss, adverse newborn baby outcomes (small for gestational age, low birthweight, or preterm), or neonatal death. The primary analysis was by modified intention to treat, consisting of all randomised participants with primary endpoint data. Women who received at least one dose of study drug were included in the safety analyses. This trial is registered with ClinicalTrials.gov, NCT03208179. FINDINGS: From March-29, 2018, to July 5, 2019, 4680 women (mean age 25·0 years [SD 6·0]) were enrolled and randomly assigned: 1561 (33%; mean age 24·9 years [SD 6·1]) to the sulfadoxine-pyrimethamine group, 1561 (33%; mean age 25·1 years [6·1]) to the dihydroartemisinin-piperaquine group, and 1558 (33%; mean age 24·9 years [6.0]) to the dihydroartemisinin-piperaquine plus azithromycin group. Compared with 335 (23·3%) of 1435 women in the sulfadoxine-pyrimethamine group, the primary composite endpoint of adverse pregnancy outcomes was reported more frequently in the dihydroartemisinin-piperaquine group (403 [27·9%] of 1442; risk ratio 1·20, 95% CI 1·06-1·36; p=0·0040) and in the dihydroartemisinin-piperaquine plus azithromycin group (396 [27·6%] of 1433; 1·16, 1·03-1·32; p=0·017). The incidence of serious adverse events was similar in mothers (sulfadoxine-pyrimethamine group 17·7 per 100 person-years, dihydroartemisinin-piperaquine group 14·8 per 100 person-years, and dihydroartemisinin-piperaquine plus azithromycin group 16·9 per 100 person-years) and infants (sulfadoxine-pyrimethamine group 49·2 per 100 person-years, dihydroartemisinin-piperaquine group 42·4 per 100 person-years, and dihydroartemisinin-piperaquine plus azithromycin group 47·8 per 100 person-years) across treatment groups. 12 (0·2%) of 6685 sulfadoxine-pyrimethamine, 19 (0·3%) of 7014 dihydroartemisinin-piperaquine, and 23 (0·3%) of 6849 dihydroartemisinin-piperaquine plus azithromycin treatment courses were vomited within 30 min. INTERPRETATION: Monthly IPTp with dihydroartemisinin-piperaquine did not improve pregnancy outcomes, and the addition of a single course of azithromycin did not enhance the effect of monthly IPTp with dihydroartemisinin-piperaquine. Trials that combine sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine for IPTp should be considered. FUNDING: European & Developing Countries Clinical Trials Partnership 2, supported by the EU, and the UK Joint-Global-Health-Trials-Scheme of the Foreign, Commonwealth and Development Office, Medical Research Council, Department of Health and Social Care, Wellcome, and the Bill-&-Melinda-Gates-Foundation.

Implementation research of a cluster randomized trial evaluating the implementation and effectiveness of intermittent preventive treatment for malaria using dihydroartemisinin-piperaquine on reducing malaria burden in school-aged children in Tanzania: methodology, challenges, and mitigation.

BACKGROUND: It has been more than 20 years since the malaria epidemiologic shift to school-aged children was noted. In the meantime, school-aged children (5-15 years) have become increasingly more vulnerable with asymptomatic malaria prevalence reaching up to 70%, making them reservoirs for subsequent transmission of malaria in the endemic communities. Intermittent Preventive Treatment of malaria in schoolchildren (IPTsc) has proven to be an effective tool to shrink this reservoir. As of 3rd June 2022, the World Health Organization recommends IPTsc in moderate and high endemic areas. Even so, for decision-makers, the adoption of scientific research recommendations has been stifled by real-world implementation challenges. This study presents methodology, challenges faced, and mitigations used in the evaluation of the implementation of IPTsc using dihydroartemisinin-piperaquine (DP) in three councils (Handeni District Council (DC), Handeni Town Council (TC) and Kilindi DC) of Tanga Region, Tanzania so as to understand the operational feasibility and effectiveness of IPTsc on malaria parasitaemia and clinical malaria incidence. METHODS: The study deployed an effectiveness-implementation hybrid design to assess feasibility and effectiveness of IPTsc using DP, the interventional drug, against standard of care (control). Wards in the three study councils were the randomization unit (clusters). Each ward was randomized to implement IPTsc or not (control). In all wards in the IPTsc arm, DP was given to schoolchildren three times a year in four-month intervals. In each council, 24 randomly selected wards (12 per study arm, one school per ward) were chosen as representatives for intervention impact evaluation. Mixed design methods were used to assess the feasibility and acceptability of implementing IPTsc as part of a more comprehensive health package for schoolchildren. The study reimagined an existing school health programme for Neglected Tropical Diseases (NTD) control include IPTsc implementation. RESULTS: The study shows IPTsc can feasibly be implemented by integrating it into existing school health and education systems, paving the way for sustainable programme adoption in a cost-effective manner. CONCLUSIONS: Through this article other interested countries may realise a feasible plan for IPTsc implementation. Mitigation to any challenge can be customized based on local circumstances without jeopardising the gains expected from an IPTsc programme. Trial registration clinicaltrials.gov, NCT04245033. Registered 28 January 2020, https://clinicaltrials.gov/ct2/show/NCT04245033.

High anti-SARS-CoV-2 seroprevalence among unvaccinated mother-child pairs from a rural setting in north-eastern Tanzania during the second wave of COVID-19.

Background: The reported infection rates and burden of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in low- and middle-income countries, including those in sub-Saharan Africa, are relatively low compared to the rates and burden in Europe and America, partly due to limited testing capability. Unlike many countries, Tanzania has implemented neither mass screening nor restrictive measures such as lockdowns to date. The prevalence of SARS-CoV-2 infection in rural mainland Tanzania is largely unknown. Methods: A cross-sectional study was conducted between April and October 2021 to assess the anti-SARS-CoV-2 seroprevalence among mother-child pairs (n = 634 children, n = 518 mothers) in a rural setting in north-eastern Tanzania. Results: A very high prevalence of anti-SARS-CoV-2 antibody titres was found, with seroprevalence rates ranging from 29% among mothers and 40% among children, with a dynamic peak in seropositivity incidence at the end of July/early August being revealed. Significant differences in age, socioeconomic status, and body composition were associated with seropositivity in mothers and children. No significant associations were observed between seropositivity and comorbidities, including anaemia, diabetes, malaria, and HIV. Conclusions: The transmission of SARS-CoV-2 in a rural region of Tanzania during 2021 was high, indicating a much higher infection rate in rural Tanzania compared to that reported in the UK and USA during the same period. Ongoing immune surveillance may be vital to monitoring the burden of viral infection in rural settings without access to molecular genotyping, where the load of communicable diseases may mask COVID-19. Surveillance could be implemented in tandem with the intensification of vaccination strategies.

Seroprevalence of SARS-CoV-2 antibodies among children and adolescents recruited in a malariometric survey in north-eastern Tanzania July 2021.

BACKGROUND: African countries stand out globally as the region seemingly least affected by the COVID-19 pandemic, caused by the virus SARS-CoV-2. Besides a younger population and potential pre-existing immunity to a SARS-CoV-2-like virus, it has been hypothesized that co-infection or recent history of Plasmodium falciparum malaria may be protective of COVID-19 severity and mortality. The number of COVID-19 cases and deaths, however, may be vastly undercounted. Very little is known about the extent to which the Tanzanian population has been exposed to SARS-CoV-2. Here, we investigated the seroprevalence of IgG to SARS-CoV-2 spike protein in two Tanzanian rural communities 1½ years into the pandemic and the association of coinciding malaria infection and exposure. METHODS: During a malariometric survey in July 2021 in two villages in north-eastern Tanzania, blood samples were taken from 501 participants (0-19 years old). Malaria was detected by mRDT and microscopy. Levels of IgG against the spike protein of SARS-CoV-2 were measured by ELISA as well as IgG against five different antigens of P. falciparum; CIDRα1.1, CIDRα1.4 and CIDRα1.5 of PfEMP1 and GLURP and MSP3. RESULTS: The seroprevalence of SARS-CoV-2 IgG was 39.7% (106/267) in Kwamasimba and 32.5% (76/234) in Mkokola. In both villages the odds of being seropositive increased significantly with age (AOR = 1.12, 95% CI 1.07-1.17, p < 0.001). P. falciparum malaria prevalence by blood smear microscopy was 7.9% in Kwamasimba and 2.1% in Mkokola. 81.3% and 70.5% in Kwamasimba and Mkokola, respectively, showed recognition of minimum one malaria antigen. Residing in Kwamasimba was associated with a broader recognition (AOR = 1.91, 95% CI 1.34-2.71, p < 0.001). The recognition of malaria antigens increased significantly with age in both villages (AOR = 1.12; 95% CI 1.08-1.16, p < 0.001). Being SARS-CoV-2 seropositive did not associate with the breadth of malaria antigen recognition when adjusting for age (AOR = 0.99; 95% CI 0.83-1.18; p = 0.91). CONCLUSION: More than a third of the children and adolescents in two rural communities in Tanzania had antibodies to SARS-CoV-2. In particular, the adolescents were seropositive but being seropositive did not associate with the status of coinciding malaria infections or previous exposure. In Tanzania, natural immunity may have developed fast, potentially protecting a substantial part of the population from later variants.

The choice of reference chart affects the strength of the association between malaria in pregnancy and small for gestational age: an individual participant data meta-analysis comparing the Intergrowth-21 with a Tanzanian birthweight chart.

BACKGROUND: The prevalence of small for gestational age (SGA) may vary depending on the chosen weight-for-gestational-age reference chart. An individual participant data meta-analysis was conducted to assess the implications of using a local reference (STOPPAM) instead of a universal reference (Intergrowth-21) on the association between malaria in pregnancy and SGA. METHODS: Individual participant data of 6,236 newborns were pooled from seven conveniently identified studies conducted in Tanzania and Malawi from 2003-2018 with data on malaria in pregnancy, birthweight, and ultrasound estimated gestational age. Mixed-effects regression models were used to compare the association between malaria in pregnancy and SGA when using the STOPPAM and the Intergrowth-21 references, respectively. RESULTS: The 10th percentile for birthweights-for-gestational age was lower for STOPPAM than for Intergrowth-21, leading to a prevalence of SGASTOPPAM of 14.2% and SGAIG21 of 18.0%, p < 0.001. The association between malaria in pregnancy and SGA was stronger for STOPPAM (adjusted odds ratio (aOR) 1.30 [1.09-1.56], p < 0.01) than for Intergrowth-21 (aOR 1.19 [1.00-1.40], p = 0.04), particularly among paucigravidae (SGASTOPPAM aOR 1.36 [1.09-1.71], p < 0.01 vs SGAIG21 aOR 1.21 [0.97-1.50], p = 0.08). CONCLUSIONS: The prevalence of SGA may be overestimated and the impact of malaria in pregnancy underestimated when using Intergrowth-21. Comparing local reference charts to global references when assessing and interpreting the impact of malaria in pregnancy may be appropriate.

Attributable risk factors for asymptomatic malaria and anaemia and their association with cognitive and psychomotor functions in schoolchildren of north-eastern Tanzania.

In Africa, children aged 5 to 15 years (school age) comprises more than 50% (>339 million) of the under 19 years population, and are highly burdened by malaria and anaemia that impair cognitive development. For the prospects of improving health in African citizens, understanding malaria and its relation to anaemia in school-aged children, it is crucial to inform targeted interventions for malaria control and accelerate elimination efforts as part of improved school health policy. We conducted a study to determine the risk factors for asymptomatic malaria and their association to anaemia. We explored the prevalence of antimalarial drug resistance as well as the association of asymptomatic malaria infection and anaemia on cognitive and psychomotor functions in school-aged children living in high endemic areas. This study was a comprehensive baseline survey, within the scope of a randomised, controlled trial on the effectiveness and safety of antimalarial drugs in preventing malaria and its related morbidity in schoolchildren. We enrolled 1,587 schoolchildren from 7 primary schools located in Muheza, north-eastern Tanzania. Finger-pricked blood samples were collected for estimation of malaria parasitaemia using a microscope, haemoglobin concentration using a haemoglobinometer, and markers of drug resistance processed from dried blood spots (DBS). Psychomotor and Cognitive functions were assessed using a '20 metre Shuttle run' and a test of everyday attention for children (TEA-Ch), respectively. The prevalence of asymptomatic malaria parasitaemia, anaemia and stunting was 26.4%, 49.8%, and 21.0%, respectively with marked variation across schools. In multivariate models, asymptomatic malaria parasitaemia attributed to 61% of anaemia with a respective population attribution fraction of 16%. Stunting, not sleeping under a bednet and illiterate parent or guardian were other factors attributing to 7%, 9%, and 5% of anaemia in the study population, respectively. Factors such as age group (10-15 years), not sleeping under a bednet, low socioeconomic status, parents' or guardians' with a low level of education, children overcrowding in a household, and fewer rooms in a household were significantly attributed to higher malaria infection. There was no significant association between malaria infection or anaemia and performance on tests of cognitive function (sustained attention) or psychomotor function (VO2 max). However, a history of malaria in the past one month was significantly associated with decreased cognitive scores (aOR = -4.1, 95% CI -7.7-0.6, p = 0.02). Furthermore, stunted children had significantly lower VO2max scores (aOR = -1.9, 95% CI -3.0-0.8, p = 0.001). Regarding the antimalarial drug resistance markers, the most prevalent Pfmdr1 86-184-1034-1042-1246 haplotypes were the NFSND in 47% (n = 88) and the NYSND in 52% (n = 98). The wild type Pfcrt haplotypes (codons 72-76, CVMNK) were found in 99.1% (n = 219) of the samples. Malaria, stunting and parents' or guardians' illiteracy were the key attributable factors for anaemia in schoolchildren. Given malaria infection in schoolchildren is mostly asymptomatic; an addition of interventional programmes such as intermittent preventive treatment of malaria in schoolchildren (IPTsc) would probably act as a potential solution while calling for an improvement in the current tools such as bednet use, school food programme, and community-based (customised) health education with an emphasis on nutrition and malaria control.

Weight change during the first week of life and a new method for retrospective prediction of birthweight among exclusively breastfed newborns.

INTRODUCTION: Identification of low birthweight and small for gestational age is pivotal in clinical management and many research studies, but in low-income countries, birthweight is often unavailable within 24 h of birth. Newborn weights measured within days after birth and knowledge of the growth patterns in the first week of life can help estimate the weight at birth retrospectively. This study aimed to generate sex-specific prediction maps and weight reference charts for the retrospective estimation of birthweight for exclusively breastfed newborns in a low-resource setting. MATERIAL AND METHODS: This was a prospective cohort study nested in a clinical trial of intermittent preventive treatment in pregnancy for malaria with either dihydroartemisinin-piperaquine with/without azithromycin or sulfadoxine-pyrimethamine in Korogwe District, north-eastern Tanzania (Clinicaltrials.gov: NCT03208179). Newborns were weighed at birth or in the immediate hours after birth and then daily for 1 week. Reference charts, nadir, time to regain weight, and prediction maps were generated using nonlinear mixed-effects models fitted to the longitudinal data, incorporating interindividual variation as random effects. Predictions and prediction standard deviations were computed using a linear approximation approach. RESULTS: Between March and December 2019, 513 live newborns with birthweights measured within 24 h of delivery were weighed daily for 1 week. Complete datasets were available from 476 exclusively breastfed newborns. There was a rapid decline in weight shortly after delivery. The average weight loss, time of nadir, and time to regain weight were 4.3% (95% confidence interval [CI] 3.8-4.9) at 27 h (95% CI 24-30) and 105 h (95% CI 91-120) in boys and 4.9% (95% CI 4.2-5.6) at 28 h (95% CI 23-33) and 114 h (95% CI 93-136) in girls, respectively. The data were used to generate prediction maps with 1-h time intervals and 0.05 kg weight increments showing the predicted birthweights and weight-for-age and weight-change-for-age reference charts depicting variation in weight loss from <1 to >10%. CONCLUSIONS: The prediction maps and reference charts can be used by researchers in low-resource settings to retrospectively estimate birthweights using weights collected up to 168 h after delivery, thereby maximizing data utilization. Clinical practitioners can also use the prediction maps to retrospectively classify newborns as low birthweight or small for gestational age.

Comparative genomics revealed adaptive admixture in Cryptosporidium hominis in Africa.

Cryptosporidiosis is a major cause of diarrhoeal illness among African children, and is associated with childhood mortality, malnutrition, cognitive development and growth retardation. Cryptosporidium hominis is the dominant pathogen in Africa, and genotyping at the glycoprotein 60 (gp60) gene has revealed a complex distribution of different subtypes across this continent. However, a comprehensive exploration of the metapopulation structure and evolution based on whole-genome data has yet to be performed. Here, we sequenced and analysed the genomes of 26 C. hominis isolates, representing different gp60 subtypes, collected at rural sites in Gabon, Ghana, Madagascar and Tanzania. Phylogenetic and cluster analyses based on single-nucleotide polymorphisms showed that isolates predominantly clustered by their country of origin, irrespective of their gp60 subtype. We found a significant isolation-by-distance signature that shows the importance of local transmission, but we also detected evidence of hybridization between isolates of different geographical regions. We identified 37 outlier genes with exceptionally high nucleotide diversity, and this group is significantly enriched for genes encoding extracellular proteins and signal peptides. Furthermore, these genes are found more often than expected in recombinant regions, and they show a distinct signature of positive or balancing selection. We conclude that: (1) the metapopulation structure of C. hominis can only be accurately captured by whole-genome analyses; (2) local anthroponotic transmission underpins the spread of this pathogen in Africa; (3) hybridization occurs between distinct geographical lineages; and (4) genetic introgression provides novel substrate for positive or balancing selection in genes involved in host-parasite coevolution.

Effectiveness and safety of intermittent preventive treatment for malaria using either dihydroartemisinin-piperaquine or artesunate-amodiaquine in reducing malaria related morbidities and improving cognitive ability in school-aged children in Tanzania: A study protocol for a controlled randomised trial.

BACKGROUND: In high transmission settings, up to 70% of school-aged children harbour malaria parasites without showing any clinical symptoms. Thus, epidemiologically, school aged children act as a substantial reservoir for malaria transmission. Asymptomatic Plasmodium infections induce inflammation leading to iron deficiency anaemia. Consequently, anaemia retards child growth, predisposes children to other diseases and reduces cognitive potential that could lead to poor academic performance. School aged children become increasingly more vulnerable as compared to those aged less than five years due to delayed acquisition of protective immunity. None of the existing Intermittent Preventive Treatment (IPT) strategies is targeting school-aged children. Here, we describe the study protocol of a clinical trial conducted in north-eastern Tanzania to expand the IPT by assessing the effectiveness and safety of two antimalarial drugs, Dihydroartemisinin-Piperaquine (DP) and Artesunate-Amodiaquine (ASAQ) in preventing malaria related morbidities in school-aged children (IPTsc) living in a high endemic area. METHODS/DESIGN: The trial is a phase IIIb, individual randomized, open label, controlled trial enrolling school children aged 5-15 years, who receive either DP or ASAQ or control (no drug), using a "balanced block design" with the "standard of care" arm as reference. The interventional treatments are given three times a year for the first year. A second non-interventional year will assess possible rebound effects. Sample size was estimated to 1602 school children (534 per group) from selected primary schools in an area with high malaria endemicity. Thick and thin blood smears (to measure malaria parasitaemia using microscope) were obtained prior to treatment at baseline, and will be obtained again at month 12 and 20 from all participants. Haemoglobin concentration using a haemoglobinometer (HemoCue AB, Sweden) will be measured four monthly. Finger-prick blood (dried bloodspot-DBS) prepared on Whatman 3 M filter paper, will be used for sub-microscopic malaria parasite detection usingPCR, detect markers of drug resistance (using next generation sequencing (NGS) technology), and malaria serological assays (using enzyme-linked immunosorbent assay, ELISA). To determine the benefit of IPTsc on cognitive and psychomotor ability test of everyday attention for children (TEA-Ch) and a '20 m Shuttle run' respectively, will be conducted at baseline, month 12 and 20. The primary endpoints are change in mean haemoglobin from baseline concentration and reduction in clinical malaria incidence at month 12 and 20 of follow up. Mixed design methods are used to assess the acceptability, cost-effectiveness and feasibility of IPTsc as part of a more comprehensive school children health package. Statistical analysis will be in the form of multilevel modelling, owing to repeated measurements and clustering effect of participants. DISCUSSION: Malaria intervention using IPTsc strategy may be integrated in the existing national school health programme. However, there is limited systematic evidence to assess the effectiveness and operational feasibility of this approach. School-aged children are easily accessible in most endemic malaria settings. The evidence from this study will guide the implementation of the strategy to provide complementary approach to reduce malaria related morbidity, anaemia and contribute to the overall burden reduction. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03640403, registered on Aug 21, 2018, prospectively registered.Url https://www.clinicaltrials.gov/ct2/show/NCT03640403?term=NCT03640403&rank=1.

Safety and immunogenicity of the RTS,S/AS01 malaria vaccine in infants and children identified as HIV-infected during a randomized trial in sub-Saharan Africa.

BACKGROUND: We assessed the safety and immunogenicity of the RTS,S/AS01 malaria vaccine in a subset of children identified as HIV-infected during a large phase III randomized controlled trial conducted in seven sub-Saharan African countries. METHODS: Infants 6-12 weeks and children 5-17 months old were randomized to receive 4 RTS,S/AS01 doses (R3R group), 3 RTS,S/AS01 doses plus 1 comparator vaccine dose (R3C group), or 4 comparator vaccine doses (C3C group) at study months 0, 1, 2 and 20. Infants and children with WHO stage III/IV HIV disease were excluded but HIV testing was not routinely performed on all participants; our analyses included children identified as HIV-infected based on medical history or clinical suspicion and confirmed by polymerase chain reaction or antibody testing. Serious adverse events (SAEs) and anti-circumsporozoite (CS) antibodies were assessed. RESULTS: Of 15459 children enrolled in the trial, at least 1953 were tested for HIV and 153 were confirmed as HIV-infected (R3R: 51; R3C: 54; C3C: 48). Among these children, SAEs were reported for 92.2% (95% CI: 81.1-97.8) in the R3R, 85.2% (72.9-93.4) in the R3C and 87.5% (74.8-95.3) in the C3C group over a median follow-up of 39.3, 39.4 and 38.3 months, respectively. Fifteen HIV-infected participants in each group (R3R: 29.4%, R3C: 27.8%, C3C: 31.3%) died during the study. No deaths were considered vaccination-related. In a matched case-control analysis, 1 month post dose 3 anti-CS geometric mean antibody concentrations were 193.3 EU/mL in RTS,S/AS01-vaccinated HIV-infected children and 491.5 EU/mL in RTS,S/AS01-vaccinated immunogenicity controls with unknown or negative HIV status (p = 0.0001). CONCLUSIONS: The safety profile of RTS,S/AS01 in HIV-infected children was comparable to that of the comparator (meningococcal or rabies) vaccines. RTS,S/AS01 was immunogenic in HIV-infected children but antibody concentrations were lower than in children with an unknown or negative HIV status. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT00866619.

Long-term incidence of severe malaria following RTS,S/AS01 vaccination in children and infants in Africa: an open-label 3-year extension study of a phase 3 randomised controlled trial.

BACKGROUND: Results from a previous phase 3 study showed efficacy of the RTS,S/AS01 vaccine against severe and clinical malaria in children (in 11 sites in Africa) during a 3-4-year follow-up. We aimed to investigate malaria incidence up to 7 years postvaccination in three of the sites of the initial study. METHODS: In the initial phase 3 study, infants aged 6-12 weeks and children aged 5-17 months were randomly assigned (1:1:1) to receive four RTS,S/AS01 doses (four-dose group), three RTS,S/AS01 doses and a comparator dose (three-dose group), or four comparator doses (control group). In this open-label extension study in Korogwe (Tanzania), Kombewa (Kenya), and Nanoro (Burkina Faso), we assessed severe malaria incidences as the primary outcome for 3 additional years (January, 2014, to December, 2016), up to 6 years (younger children) or 7 years (older children) postprimary vaccination in the modified intention-to-treat population (ie, participants who received at least one dose of the study vaccine). As secondary outcomes, we evaluated clinical malaria incidences and serious adverse events. This trial is registered with ClinicalTrials.gov, number NCT02207816. FINDINGS: We enrolled 1739 older children (aged 5-7 years) and 1345 younger children (aged 3-5 years). During the 3-year extension, 66 severe malaria cases were reported, resulting in severe malaria incidence of 0·004 cases per person-years at risk (PPY; 95% CI 0-0·033) in the four-dose group, 0·007 PPY (0·001-0·052) in the three-dose group, and 0·009 PPY (0·001-0·066) in the control group in the older children category and a vaccine efficacy against severe malaria that did not contribute significantly to the overall efficacy (four-dose group 53·7% [95% CI -13·7 to 81·1], p=0·093; three-dose group 23·3% [-67·1 to 64·8], p=0·50). In younger children, severe malaria incidences were 0·007 PPY (0·001-0·058) in the four-dose group, 0·007 PPY (0·001-0·054) in the three-dose group, and 0·011 PPY (0·001-0·083) in the control group. Vaccine efficacy against severe malaria also did not contribute significantly to the overall efficacy (four-dose group 32·1% [-53·1 to 69·9], p=0·35; three-dose group 37·6% [-44·4 to 73·0], p=0·27). Malaria transmission was still occurring as evidenced by an incidence of clinical malaria ranging from 0·165 PPY to 3·124 PPY across all study groups and sites. In older children, clinical malaria incidence was 1·079 PPY (95% CI 0·152-7·662) in the four-dose group, 1·108 PPY (0·156-7·868) in the three-dose group, and 1·016 PPY (0·14-7·213) in the control group. In younger children, malaria incidence was 1·632 PPY (0·23-11·59), 1·563 PPY (0·22-11·104), and 1·686 PPY (0·237-11·974), respectively. In the older age category in Nanoro, clinical malaria incidence was higher in the four-dose (2·444 PPY; p=0·011) and three-dose (2·411 PPY; p=0·034) groups compared with the control group (1·998 PPY). Three cerebral malaria episodes and five meningitis cases, but no vaccine-related severe adverse events, were reported. INTERPRETATION: Overall, severe malaria incidence was low in all groups, with no evidence of rebound in RTS,S/AS01 recipients, despite an increased incidence of clinical malaria in older children who received RTS,S/AS01 compared with the comparator group in Nanoro. No safety signal was identified. FUNDING: GlaxoSmithKline Biologicals SA.

Safety profile of the RTS,S/AS01 malaria vaccine in infants and children: additional data from a phase III randomized controlled trial in sub-Saharan Africa.

A phase III, double-blind, randomized, controlled trial (NCT00866619) in sub-Saharan Africa showed RTS,S/AS01 vaccine efficacy against malaria. We now present in-depth safety results from this study. 8922 children (enrolled at 5-17 months) and 6537 infants (enrolled at 6-12 weeks) were 1:1:1-randomized to receive 4 doses of RTS,S/AS01 (R3R) or non-malaria control vaccine (C3C), or 3 RTS,S/AS01 doses plus control (R3C). Aggregate safety data were reviewed by a multi-functional team. Severe malaria with Blantyre Coma Score ≤2 (cerebral malaria [CM]) and gender-specific mortality were assessed post-hoc. Serious adverse event (SAE) and fatal SAE incidences throughout the study were 24.2%-28.4% and 1.5%-2.5%, respectively across groups; 0.0%-0.3% of participants reported vaccination-related SAEs. The incidence of febrile convulsions in children was higher during the first 2-3 days post-vaccination with RTS,S/AS01 than with control vaccine, consistent with the time window of post-vaccination febrile reactions in this study (mostly the day after vaccination). A statistically significant numerical imbalance was observed for meningitis cases in children (R3R: 11, R3C: 10, C3C: 1) but not in infants. CM cases were more frequent in RTS,S/AS01-vaccinated children (R3R: 19, R3C: 24, C3C: 10) but not in infants. All-cause mortality was higher in RTS,S/AS01-vaccinated versus control girls (2.4% vs 1.3%, all ages) in our setting with low overall mortality. The observed meningitis and CM signals are considered likely chance findings, that - given their severity - warrant further evaluation in phase IV studies and WHO-led pilot implementation programs to establish the RTS,S/AS01 benefit-risk profile in real-life settings.