Moving targets: The challenges of studying infectious diseases among pregnant women in resource limited settings.

Conducting clinical trials to prevent and treat infectious diseases in pregnancy is essential to saving maternal and newborn lives, though it is fraught with challenges. We have been conducting research in malaria treatment and prevention in children and pregnant women in Blantyre, Malawi for over a decade. Here, we review some of the unique challenges that we have faced in leading research studies that with rigor and integrity and maintaining the highest ethical standard. We conclude with concrete strategies to overcome some of the apparent obstacles that frequently focus on building trust through bidirectional communication with local health workers and communities. We also highlight the key role of local and international investigators to advocate for the health of the communities in which they work

Utility of broad-spectrum antibiotics for diagnosing pulmonary tuberculosis in adults : a systematic review and meta-analysis

Funding: Helse Nord RHF, Wellcome Trust, and the UK Commonwealth Scholarship Commission.Suboptimal diagnostics for pulmonary tuberculosis drive the use of the so-called trial of antibiotics, a course of broad-spectrum antibiotics without activity against Mycobacterium tuberculosis that is given to patients who are mycobacteriology negative but symptomatic, with the aim of distinguishing pulmonary tuberculosis from bacterial lower respiratory tract infection. The underlying assumption—that patients with lower respiratory tract infection will improve, whereas those with pulmonary tuberculosis will not—has an unclear evidence base for such a widely used intervention (at least 26·5 million courses are prescribed per year). We aimed to collate available evidence on the diagnostic performance of the trial of antibiotics.Publisher PDFPeer reviewe

Incidence and Seasonality of Influenza-Like Illnesses Among Pregnant Women in Blantyre, Malawi.

Pregnant women with influenza infection are at increased risk of developing complications compared with other adults. Information about burden of influenza in pregnant women in Africa is limited. To determine incidence and seasonality of influenza-like illness (ILI) in pregnant women in Blantyre, Malawi, we recruited a cohort of 450 pregnant women and conducted surveillance for ILI and malaria infection. We recorded gestational age and birthweight. We accrued 157 person-years of observation (PYO) and detected 37 episodes of ILI (24/100 PYO) and 83 episodes of malaria infection (including all new episodes of parasitemia) (53/100 PYO). ILI was the most common cause of fever, but was not associated with adverse pregnancy outcomes. ILI incidence peaked during the hot dry season. These results indicate that ILI is a significant burden among Malawian pregnant women and it is somewhat seasonal. Studies with molecular diagnostics are needed to establish influenza-specific burden and the potential role of vaccination

Sensitivity and specificity of using trial-of-antibiotics versus sputum mycobacteriology for diagnosis of tuberculosis : protocol for a systematic literature review

TD is funded by the Commonwealth Scholarship Commission and the Helse Nord RHF. This review is part of his PhD work at London School of Hygiene & Tropical Medicine.Background:  Suboptimal diagnostics for pulmonary tuberculosis (PTB) drives use of ‘trial-of-antibiotics (non-tuberculosis)’ in an attempt to distinguish PTB patients from those with bacterial lower respiratory tract infection (LRTI). The underlying assumption—that patients with LRTI will report ‘response’ to broad-spectrum antibiotics, while those with PTB will not—has minimal evidence base for such a widely used intervention. Numerous potential causes of misclassification include bacterial super-infection of active PTB, placebo effect, and antimicrobial resistance (AMR). The main aim of this systematic review is to collate available evidence on the performance of trial-of-antibiotics as a diagnostic test and to explore the timing, interpretation, and decision-making process. Methods:  We will search MEDLINE, Embase, and Global Health using the Ovid platform for published studies that recruited adults being investigated for PTB, performed trial-of-antibiotics accompanied by mycobacteriological investigations, and reported both diagnostic test outcomes at the individual level. Following article selection, two authors will independently review titles and abstracts against eligibility criteria then perform full-text screening and extraction into a spreadsheet. We will conduct a risk of bias assessment at the level of the study using QUADAS-2 (University of Bristol) tool that assesses diagnostic evaluation work in four domains: (1) patient selection, (2) the index test, (3) the reference standard, and (4) patient flow and timing of tests. We will perform a narrative synthesis and, where possible, meta-analyses addressing our primary outcome. Our protocol adheres to the standards recommended by the PRISMA-P. Discussion:  Pooling all available evidence on the accuracy, approach, and interpretation of results of trial-of-antibiotics in the context of PTB diagnosis will meet an urgent need, considering the widespread utilisation and potential for antimicrobial resistance. We therefore believe that our findings will have impact on policy and that they will inform the design of future detailed investigations into this important diagnostic approach.Publisher PDFPeer reviewe

Effect of the duration of antimicrobial exposure on the development of antimicrobial resistance (AMR) for macrolide antibiotics: protocol for a systematic review with a network meta-analysis

THD is funded by the Commonwealth Scholarship Commission and the Helse Nord RHF. This review is part of his PhD work at LSHTM. ELC is funded by a Wellcome Trust Senior Research Fellowship in Clinical Science: WT200901. HRS is supported by the Medical Research Council [MR/R008345/1].Background: Antimicrobial resistance generates a huge health and economic burden and has the potential to become the leading cause of death globally, but its underlying drivers are yet to be fully described. The association between a microbe’s exposure to antimicrobials and subsequent development of, or selection for, resistance is well documented, as are the exacerbating microbial and human factors. However, the nature and extent of this risk, and how it varies by antimicrobial class and duration of treatment, is poorly defined. The goal of our systematic review and network meta-analysis is to determine the relationship between the duration of antimicrobial exposure and selection for resistance. We will use macrolides as the antimicrobial class of interest and Streptococcus pneumoniae carriage as an indicator organism. Our secondary outcomes include duration of symptoms, risk of treatment failure and recurrence, and descriptions of resistance mechanisms. Methods:  We will conduct a systematic review, selecting studies if they are published randomised controlled trials (RCTs) which report the relationship between taking a macrolide for any indication and incidence of resistant Streptococcus pneumoniae in patients of any age group. We will use a predefined search strategy to identify studies meeting these eligibility criteria in MEDLINE, Embase, Global Health and the Cochrane Central Register of RCTs. Two authors will independently screen titles and abstracts, review the full texts and undertake data extraction. We will use the Cochrane Collaboration’s tool to assess the quality of included RCTs. If feasible, we will perform pair-wise meta-analysis modelling to determine the relationship between the duration of macrolide treatment and development of macrolide resistant Streptococcus pneumoniae. If the identified studies meet the assumptions for a network meta-analysis (NMA), we will additionally model this relationship using indirect comparisons. Our protocol utilises reporting guidance by Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and the extensions for protocols (PRISMA-P) and network meta-analyses (PRISMA for NMA). Our review will also report to these standards. Discussion:  Establishing the relationship between the duration of antimicrobial exposure and development of, or selection for, resistance will inform the design of antimicrobial prescriptions, treatment guidelines and the behaviour of both physicians and patients. This work will therefore be a strong contribution towards the full realisation of current antimicrobial resistance stewardship strategies.Publisher PDFPeer reviewe

Tuberculosis diagnosis cascade in Blantyre, Malawi : a prospective cohort study

Wellcome Trust. PM is funded by Wellcome (206575/Z/17/Z). ELC is funded by Wellcome (200901/Z/16/Z). ELW received salary funding from the UK Medical Research Council (grant number MR/K012126/1), this award is jointly funded by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the EDCTP2 programme supported by the European Union.Background Tuberculosis (TB) control relies on early diagnosis and treatment. International guidelines recommend systematic TB screening at health facilities, but implementation is challenging. We investigated completion of recommended TB screening steps in Blantyre, Malawi. Methods A prospective cohort recruited adult outpatients attending Bangwe primary clinic. Entry interviews were linked to exit interviews. The proportion of participants progressing through each step of the diagnostic pathway were estimated. Factors associated with request for sputum were investigated using multivariable logistic regression. Results Of 5442 clinic attendances 2397 (44%) had exit interviews. In clinically indicated participants (n = 445) 256 (57.5%) were asked about cough, 36 (8.1%) were asked for sputum, 21 (4.7%) gave sputum and 1 (0.2%) received same-day results. Significant associations with request for sputum were: any TB symptom (aOR:3.20, 95%CI:2.02–5.06), increasing age (aOR:1.02, 95%CI:1.01–1.04 per year) and for HIV-negative participants only, a history of previous TB (aOR:3.37, 95%CI:1.45–7.81). Numbers requiring sputum tests (26/day) outnumbered diagnostic capacity (8–12/day). Conclusions Patients were lost at every stage of the TB care cascade, with same day sputum submission following all steps of the diagnosis cascade achieved in only 4.7% if clinically indicated. Infection control strategies should be implemented, with reporting on early steps of the TB care cascade formalised. High-throughput screening interventions, such as digital CXR, that can achieve same-day TB diagnosis are urgently needed to meet WHO End TB goals.Peer reviewe

Frequent malaria illness episodes in two Malawian patients on antiretroviral therapy soon after stopping cotrimoxazole preventive therapy

We describe two Malawian adults on successful antiretroviral therapy who experienced frequent malaria episodes after stopping cotrimoxazole prophylaxis. We argue that, in addition to stopping cotrimoxazole, diminished malaria immunity and drug interactions between efavirenz and artemether–lumefantrine may have played a causative role in the recurrent malaria our patients experienced

Effects of coronavirus disease pandemic on tuberculosis notifications, Malawi

The coronavirus disease (COVID-19) pandemic might affect tuberculosis (TB) diagnosis and patient care. We analyzed a citywide electronic TB register in Blantyre, Malawi and interviewed TB officers. Malawi did not have an official COVID-19 lockdown but closed schools and borders on March 23, 2020. In an interrupted time series analysis, we noted an immediate 35.9% reduction in TB notifications in April 2020; notifications recovered to near prepandemic numbers by December 2020. However, 333 fewer cumulative TB notifications were received than anticipated. Women and girls were affected more (30.7% fewer cases) than men and boys (20.9% fewer cases). Fear of COVID-19 infection, temporary facility closures, inadequate personal protective equipment, and COVID-19 stigma because of similar symptoms to TB were mentioned as reasons for fewer people being diagnosed with TB. Public health measures could benefit control of both TB and COVID-19, but only if TB diagnostic services remain accessible and are considered safe to attend.Peer reviewe

Chloroquine as weekly chemoprophylaxis or intermittent treatment to prevent malaria in pregnancy in Malawi: a randomised controlled trial.

BACKGROUND: Sulfadoxine-pyrimethamine resistance threatens efficacy of intermittent preventive treatment of malaria during pregnancy, and alternative regimens need to be identified. With the return of chloroquine efficacy in southern Africa, we postulated that chloroquine either as an intermittent therapy or as weekly chemoprophylaxis would be more efficacious than intermittent sulfadoxine-pyrimethamine for prevention of malaria in pregnancy and associated maternal and newborn adverse outcomes. METHODS: We did an open-label, single-centre, randomised controlled trial at Ndirande Health Centre, Blantyre, in southern Malawi. We enrolled pregnant women (first or second pregnancy) at 20-28 weeks' gestation who were HIV negative. Participants were randomly assigned in a 1:1:1 ratio using a computer-generated list to either intermittent sulfadoxine-pyrimethamine (two doses of 1500 mg sulfadoxine and 75 mg pyrimethamine, 4 weeks apart), intermittent chloroquine (two doses of 600 mg on day 1, 600 mg on day 2, and 300 mg on day 3), or chloroquine prophylaxis (600 mg on day 1 then 300 mg every week). The primary endpoint was placental malaria in the modified intent-to-treat population, which consisted of participants who contributed placental histopathology data at birth. Secondary outcomes included clinical malaria, maternal anaemia, low birthweight, and safety. This trial is registered with ClinicalTrials.gov, number NCT01443130. FINDINGS: Between February, 2012, and May, 2014, we enrolled and randomly allocated 900 women, of whom 765 contributed histopathological data and were included in the primary analysis. 108 (14%) women had placental malaria, which was lower than the anticipated prevalence of placental malaria infection. Protection from placental malaria was not improved by chloroquine as either prophylaxis (30 [12%] of 259 had positive histopathology; relative risk [RR] 0·75, 95% CI 0·48-1·17) or intermittent therapy (39 [15%] of 253; RR 1·00, 0·67-1·50) compared with intermittent sulfadoxine-pyrimethamine (39 [15%] of 253). In protocol-specified analyses adjusted for maternal age, gestational age at enrolment, bednet use the night before enrolment, anaemia at enrolment, and malaria infection at enrolment, women taking chloroquine as prophylaxis had 34% lower placental infections than did those allocated intermittent sulfadoxine-pyrimethamine (RR 0·66, 95% CI 0·46-0·95). Clinical malaria was reported in nine women assigned intermittent sulfadoxine-pyrimethamine, four allocated intermittent chloroquine (p=0·26), and two allocated chloroquine prophylaxis (p=0·063). Maternal anaemia was noted in five women assigned intermittent sulfadoxine-pyrimethamine, 15 allocated intermittent chloroquine (p=0·038), and six assigned chloroquine prophylaxis (p>0·99). Low birthweight was recorded for 31 babies born to women allocated intermittent sulfadoxine-pyrimethamine, 29 assigned intermittent chloroquine (p=0·78), and 41 allocated chloroquine prophylaxis (p=0·28). Four women assigned intermittent sulfadoxine-pyrimethamine had adverse events possibly related to study product compared with 94 women allocated intermittent chloroquine (p<0·0001) and 26 allocated chloroquine prophylaxis (p<0·0001). Three women had severe or life-threatening adverse events related to study product, of whom all were assigned intermittent chloroquine (p=0·25). INTERPRETATION: Chloroquine administered as intermittent therapy did not provide better protection from malaria and related adverse effects compared with intermittent sulfadoxine-pyrimethamine in a setting of high resistance to sulfadoxine-pyrimethamine. Chloroquine chemoprophylaxis might provide benefit in protecting against malaria during pregnancy, but studies with larger sample sizes are needed to confirm these results. FUNDING: US National Institutes of Health