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A review of new challenges and solutions to the timely and effective implementation of clinical research responses to high priority diseases of epidemic and pandemic potential: A scoping review protocol
Background: Conducting and implementing clinical research response during pandemic and epidemic diseases outbreaks are often fraught with challenges due to their unprecedented nature. In previous research, challenges to the implementation of clinical research responses during pandemic and epidemic outbreaks were identified and solutions suggested. While the emergence of the Covid-19 pandemic has, on one hand, highlighted new and unresolved challenges, several novel solutions such as the Randomised Evaluation of Covid-19 Therapy (RECOVERY) trial were also implemented and reported in the literature. This scoping review, therefore, aims to synthesise and update solutions to the barriers affecting the implementation of clinical research responses during new, emerging or re-emerging diseases of pandemic and epidemic potential, to further inform strategies that would enhance pandemic and epidemic preparedness and response. Methods: This scoping review will be conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analysis- Extension for Scoping Reviews (PRISMA-ScR). Search will be conducted in six scientific databases: Ovid MEDLINE, Ovid Global Health, OVID PsycINFO, Ovid Embase, Scopus Epistemonikos, and complemented by a grey literature search in Google Scholar. Terms related to clinical trial, high consequence infectious diseases and the PEARLES domains will be used in the search. Two reviewers will independently screen retrieved articles in Rayyan software. Descriptive data of studies will be extracted into a pre-developed Microsoft Excel template while qualitative data related to the PEARLES solutions or barriers will be coded in NVivo. Results will be synthesised thematically and presented in a narrative style. Conclusions: This scoping review will synthesise new and updated solutions to the PEARLES challenges encountered during the implementation of clinical research responses to high consequence epidemics and pandemics. Furthermore, it will examine how challenges and proposed solutions identified prior to the emergence of Covid-19 have been addressed and tested in real time.
Distinct patterns of vital sign and inflammatory marker responses in adults with suspected bloodstream infection.
ObjectivesTo identify patterns in inflammatory marker and vital sign responses in adult with suspected bloodstream infection (BSI) and define expected trends in normal recovery.MethodsWe included patients ≥16y from Oxford University Hospitals with a blood culture taken between 01-January-2016 to 28-June-2021. We used linear and latent class mixed models to estimate trajectories in C-reactive protein (CRP), white blood count, heart rate, respiratory rate and temperature and identify CRP response subgroups. Centile charts for expected CRP responses were constructed via the lambda-mu-sigma method.ResultsIn 88,348 suspected BSI episodes; 6,908(7.8%) were culture-positive with a probable pathogen, 4,309(4.9%) contained potential contaminants, and 77,131(87.3%) were culture-negative. CRP levels generally peaked 1-2 days after blood culture collection, with varying responses for different pathogens and infection sources (p<0.0001). We identified five CRP trajectory subgroups: peak on day-1 (36,091;46.3%) or 2 (4,529;5.8%), slow recovery (10,666;13.7%), peak on day-6 (743;1.0%), and low response (25,928;33.3%). Centile reference charts tracking normal responses were constructed from those peaking on day-1/2.ConclusionsCRP and other infection response markers rise and recover differently depending on clinical syndrome and pathogen involved. However, centile reference charts, that account for these differences, can be used to track if patients are recovering line as expected and to help personalise infection.
Obesity Differs from Diabetes Mellitus in Antibody and T Cell Responses Post COVID-19 Recovery.
Obesity and type 2 diabetes (DM) are risk factors for severe COVID-19 outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with obesity and DM in Bangladesh. In this cross-sectional study, SARS-CoV-2-specific antibody and T cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020. In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T cell responses, which correlated with disease severity. After adjusting for age, sex, DM status, disease severity, and time since onset of symptoms, obesity was associated with decreased neutralising antibody titers, and increased SARS-CoV-2 spike-specific IFN-γ response along with increased proliferation and IL-2 production by CD8+ T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T cell responses after adjustment for obesity and other confounders. Obesity is associated with lower neutralising antibody levels and higher T cell responses to SARS-CoV-2 post COVID-19 recovery, while antibody or T cell responses remain unaltered in DM.
Paediatric meningitis in the conjugate vaccine era and a novel clinical decision model to predict bacterial aetiology.
ObjectivesThe aims of this study were to assess aetiology and clinical characteristics in childhood meningitis, and develop clinical decision rules to distinguish bacterial meningitis from other similar clinical syndromes.MethodsChildren aged <16 years hospitalised with suspected meningitis/encephalitis were included, and prospectively recruited at 31 UK hospitals. Meningitis was defined as identification of bacteria/viruses from cerebrospinal fluid (CSF) and/or a raised CSF white blood cell count. New clinical decision rules were developed to distinguish bacterial from viral meningitis and those of alternative aetiology.ResultsThe cohort included 3,002 children (median age 2·4 months); 1,101/3,002 (36·7%) had meningitis, including 180 bacterial, 423 viral and 280 with no pathogen identified. Enterovirus was the most common pathogen in those aged ConclusionsBacterial meningitis comprised 6% of children with suspected meningitis/encephalitis. Our clinical decision rules provide potential novel approaches to assist with identifying children with bacterial meningitis.FundingThis study was funded by the Meningitis Research Foundation, Pfizer and the NIHR Programme Grants for Applied Research.
Development of an enhanced scoring system to predict ICU readmission or in-hospital death within 24 hours using routine patient data from two NHS Foundation Trusts
RationaleIntensive care units (ICUs) admit the most severely ill patients. Once these patients are discharged from the ICU to a step-down ward, they continue to have their vital signs monitored by nursing staff, with Early Warning Score (EWS) systems being used to identify those at risk of deterioration.ObjectivesWe report the development and validation of an enhanced continuous scoring system for predicting adverse events, which combines vital signs measured routinely on acute care wards (as used by most EWS systems) with a risk score of a future adverse event calculated on discharge from the ICU.DesignA modified Delphi process identified candidate variables commonly available in electronic records as the basis for a ‘static’ score of the patient’s condition immediately after discharge from the ICU. L1-regularised logistic regression was used to estimate the in-hospital risk of future adverse event. We then constructed a model of physiological normality using vital sign data from the day of hospital discharge. This is combined with the static score and used continuously to quantify and update the patient’s risk of deterioration throughout their hospital stay.SettingData from two National Health Service Foundation Trusts (UK) were used to develop and (externally) validate the model.ParticipantsA total of 12 394 vital sign measurements were acquired from 273 patients after ICU discharge for the development set, and 4831 from 136 patients in the validation cohort.ResultsOutcome validation of our model yielded an area under the receiver operating characteristic curve of 0.724 for predicting ICU readmission or in-hospital death within 24 hours. It showed an improved performance with respect to other competitive risk scoring systems, including the National EWS (0.653).ConclusionsWe showed that a scoring system incorporating data from a patient’s stay in the ICU has better performance than commonly used EWS systems based on vital signs alone.Trial registration numberISRCTN32008295.
Impact of a package of diagnostic tools, clinical algorithm, and training and communication on outpatient acute fever case management in low- and middle-income countries: protocol for a randomized controlled trial
Abstract Background The management of acute febrile illnesses places a heavy burden on clinical services in many low- and middle-income countries (LMICs). Bacterial and viral aetiologies of acute fevers are often clinically indistinguishable and, in the absence of diagnostic tests, the ‘just-in-case’ use of antibiotics by many health workers has become common practice, which has an impact on drug-resistant infections. Our study aims to answer the following question: in patients with undifferentiated febrile illness presenting to outpatient clinics/peripheral health centres in LMICs, can we demonstrate an improvement in clinical outcomes and reduce unnecessary antibiotic prescription over current practice by using a combination of simple, accurate diagnostic tests, clinical algorithms, and training and communication (intervention package)? Methods We designed a randomized, controlled clinical trial to evaluate the impact of our intervention package on clinical outcomes and antibiotic prescription rates in acute febrile illnesses. Available, point-of-care, pathogen-specific and non-pathogen specific (host markers), rapid diagnostic tests (RDTs) included in the intervention package were selected based on pre-defined criteria. Nine clinical study sites in six countries (Burkina Faso, Ghana, India, Myanmar, Nepal and Uganda), which represent heterogeneous outpatient care settings, were selected. We considered the expected seasonal variations in the incidence of acute febrile illnesses across all the sites by ensuring a recruitment period of 12 months. A master protocol was developed and adapted for country-specific ethical submissions. Diagnostic algorithms and choice of RDTs acknowledged current data on aetiologies of acute febrile illnesses in each country. We included a qualitative evaluation of drivers and/or deterrents of uptake of new diagnostics and antibiotic use for acute febrile illnesses. Sample size estimations were based on historical site data of antibiotic prescription practices for malarial and non-malarial acute fevers. Overall, 9 semi-independent studies will enrol a minimum of 21,876 patients and an aggregate data meta-analysis will be conducted on completion. Discussion This study is expected to generate vital evidence needed to inform policy decisions on the role of rapid diagnostic tests in the clinical management of acute febrile illnesses, with a view to controlling the rise of antimicrobial resistance in LMICs. Trial registration Clinicaltrials.gov NCT04081051. Registered on 6 September 2019. Protocol version 1.4 dated 20 December 2019
C-Reactive Protein for the Early Assessment of Non-Malarial Febrile Patients: A Retrospective Diagnostic Study.
Biomarkers, especially CRP, have demonstrated their relevance to differentiate viral from bacterial infection, even though a reliable threshold is far to being found. In low- and middle-income countries, affordable and user-friendly rapid diagnostic tests based on biomarkers can be widely adopted to help health workers in the management of non-malarial fever. The primary objective of this study is to assess the best CRP cut-off to distinguish viral from bacterial infections. Other biomarkers were evaluated for the same purpose, alone or in combination with CRP. We retrospectively collected data from two referral hospital departments for infectious and tropical diseases in Italy. Areas under the ROC curve (AUC) were calculated and then compared using the DeLong test. Overall, we included 1193 febrile cases (viral 20.74% vs. bacterial 79.25%). We also collected malaria (n = 202) and intestinal parasite (n = 186) cases to establish their impact on biomarkers. CRP had the best accuracy in differentiating viral from bacterial infections. The best performance of CRP was a cut-off of 11 mg/L. All other biomarkers studied had significantly lower accuracy. Median CRP values were within the normal ranges in parasitic infections, while they were higher in malaria. None of the combinations of CRP with other biomarkers significantly increased the accuracy of CRP alone.
Scaling up COVID-19 rapid antigen tests: promises and challenges.
WHO recommends a minimum of 80% sensitivity and 97% specificity for antigen-detection rapid diagnostic tests (Ag-RDTs), which can be used for patients with symptoms consistent with COVID-19. However, after the acute phase when viral load decreases, use of Ag-RDTs might lead to high rates of false negatives, suggesting that the tests should be replaced by a combination of molecular and serological tests. When the likelihood of having COVID-19 is low, such as for asymptomatic individuals in low prevalence settings, for travel, return to schools, workplaces, and mass gatherings, Ag-RDTs with high negative predictive values can be used with confidence to rule out infection. For those who test positive in low prevalence settings, the high false positive rate means that mitigation strategies, such as molecular testing to confirm positive results, are needed. Ag-RDTs, when used appropriately, are promising tools for scaling up testing and ensuring that patient management and public health measures can be implemented without delay.
Egg excretion indicators for the measurement of soil-transmitted helminth response to treatment.
BackgroundPeriodic administration of anthelmintic drugs is a cost-effective intervention for morbidity control of soil-transmitted helminth (STH) infections. However, with programs expanding, drug pressure potentially selecting for drug-resistant parasites increases. While monitoring anthelmintic drug efficacy is crucial to inform country control program strategies, different factors must be taken into consideration that influence drug efficacy and make it difficult to standardize treatment outcome measures. We aimed to identify suitable approaches to assess and compare the efficacy of different anthelmintic treatments.MethodologyWe built an individual participant-level database from 11 randomized controlled trials and two observational studies in which subjects received single-agent or combination therapy, or placebo. Eggs per gram of stool were calculated from egg counts at baseline and post-treatment. Egg reduction rates (ERR; based on mean group egg counts) and individual-patient ERR (iERR) were utilized to express drug efficacy and analyzed after log-transformation with a linear mixed effect model. The analyses were separated by follow-up duration (14-21 and 22-45 days) after drug administration.Principal findingsThe 13 studies enrolled 5,759 STH stool-positive individuals; 5,688 received active medication or placebo contributing a total of 11,103 STH infections (65% had two or three concurrent infections), of whom 3,904 (8,503 infections) and 1,784 (2,550 infections) had efficacy assessed at 14-21 days and 22-45 days post-treatment, respectively. Neither the number of helminth co-infections nor duration of follow-up affected ERR for any helminth species. The number of participants treated with single-dose albendazole was 689 (18%), with single-dose mebendazole 658 (17%), and with albendazole-based co-administrations 775 (23%). The overall mean ERR assessed by day 14-21 for albendazole and mebendazole was 94.5% and 87.4%, respectively on Ascaris lumbricoides, 86.8% and 40.8% on hookworm, and 44.9% and 23.8% on Trichuris trichiura. The World Health Organization (WHO) recommended criteria for efficacy were met in 50%, 62%, and 33% studies of albendazole for A. lumbricoides, T. trichiura, and hookworm, respectively and 25% of mebendazole studies. iERR analyses showed similar results, with cure achieved in 92% of A. lumbricoides-infected subjects treated with albendazole and 93% with mebendazole; corresponding figures for hookworm were 70% and 17%, and for T. trichiura 22% and 20%.Conclusions/significanceCombining the traditional efficacy assessment using group averages with individual responses provides a more complete picture of how anthelmintic treatments perform. Most treatments analyzed fail to meet the WHO minimal criteria for efficacy based on group means. Drug combinations (i.e., albendazole-ivermectin and albendazole-oxantel pamoate) are promising treatments for STH infections.
Response to Visceral Leishmaniasis Cases through Active Case Detection and Vector Control in Low-Endemic Hilly Districts of Nepal.
The visceral leishmaniasis (VL) elimination program in Nepal has largely completed the attack phase and is moving toward consolidation and maintenance phases. New VL foci are, however, appearing in Nepal, and therefore new innovative community-centered strategies need to be developed and tested. We conducted early case detection by an index case-based approach and assessed the feasibility, efficacy, and cost of an intervention for sandfly control through indoor residual spraying (IRS) or insecticidal wall painting (IWP) in new and low-endemic districts Palpa and Surkhet. IRS was performed in 236 households and IWP in 178 households. We screened 1,239 and 596 persons in Palpa and Surkhet, respectively, resulting in the detection of one VL case in Palpa. Both IWP and IRS were well accepted, and the percentage reductions in sandfly density after 1, 9, and 12 months of intervention were 90%, 81%, and 75%, respectively, for IWP and 81%, 59%, and 63% respectively for IRS. The cost per household protected per year was USD 10.3 for IRS and 32.8 for IWP, although over a 2-year period, IWP was more cost-effective than IRS. Active case detection combined with sandfly control through IWP or IRS can support to VL elimination in the consolidation and maintenance phase.
A Qualitative Assessment of a Training and Communication Intervention on Antibiotic Prescription Practices Among Health Workers and Outpatients at Public Health Facilities in Uganda.
BackgroundAntibiotic prescribing practices are 1 of the contributing causes of antimicrobial resistance (AMR). The study explored the key drivers and barriers to adherence to prescribing instructions among healthcare workers and outpatient attendees with the aim of developing a training and communication intervention to improve adherence to prescription.MethodsPrior to randomized trials at 3 health centers in Uganda (Aduku, Kihihi, and Nagongera), a pre-intervention qualitative assessment was conducted to explore behavioral drivers for adherence to prescriptions and the communication of adherence messages. Based on the findings, a training and communication package was developed for healthcare workers and patients at Day 0 of the trial. During the trial's Day 7 patient follow-up, in-depth interviews were conducted to further investigate adherence behaviors.ResultsFive main themes were identified that acted as drivers or barriers to prescription adherence. Key drivers included: drug availability at health facility, health worker knowledge, and communication to patients. Barriers included: care-seeker use of treatment resorts and an inability by care-seeker to buy drugs.ConclusionsThe T&C appeared to influence both health workers' and patients' behavior and improve adherence to prescription.The adapted T&C should be considered a toolkit to improve antibiotic use across health facilities accompanied with appropriate guidelines to mitigate AMR.
Breakthrough treatments for Ebola virus disease, but no access-what went wrong, and how can we do better?
Three years since proving effective for Ebola virus disease in a clinical trial, two breakthrough treatments are registered and stockpiled in the USA but still not registered and generally available in the countries most affected by this deadly infection of epidemic potential. Analysing the reasons for this, we see a fragmentation of the research and development value chain, with different stakeholders taking on different steps of the research and development process, without the public health-focused leadership needed to ensure the end goal of equitable access in countries where Ebola virus disease is prevalent. Current financial incentives for companies to overcome market failures and engage in epidemic-prone diseases are geared towards registration and stockpiling in the USA, without responsibility to provide access where and when needed. Ebola virus disease is the case in point, but not unique-a situation seen again for mpox and likely to occur again for other epidemics primarily affecting disempowered communities. Stronger leadership in African countries will help drive drug development efforts for diseases that primarily affect their communities, and ensure all partners align with and commit to an end-to-end approach to pharmaceutical development and manufacturing that puts equitable access when and where needed at its core.
Target product profile for a dengue pre-vaccination screening test.
With increasing geographic spread, frequency, and magnitude of outbreaks, dengue continues to pose a major public health threat worldwide. Dengvaxia, a dengue live-attenuated tetravalent vaccine, was licensed in 2015, but post hoc analyses of long-term data showed serostatus-dependent vaccine performance with an excess risk of hospitalized and severe dengue in seronegative vaccine recipients. The World Health Organization (WHO) recommended that only persons with evidence of past dengue infection should receive the vaccine. A test for pre-vaccination screening for dengue serostatus is needed. To develop the target product profile (TPP) for a dengue pre-vaccination screening test, face-to-face consultative meetings were organized with follow-up regional consultations. A technical working group was formed to develop consensus on a reference test against which candidate pre-vaccination screening tests could be compared. The group also reviewed current diagnostic landscape and the need to accelerate the evaluation, regulatory approval, and policy development of tests that can identify seropositive individuals and maximize public health impact of vaccination while avoiding the risk of hospitalization in dengue-naive individuals. Pre-vaccination screening strategies will benefit from rapid diagnostic tests (RDTs) that are affordable, sensitive, and specific and can be used at the point of care (POC). The TPP described the minimum and ideal characteristics of a dengue pre-vaccination screening RDT with an emphasis on high specificity. The group also made suggestions for accelerating access to these RDTs through streamlining regulatory approval and policy development. Risk and benefit based on what can be achieved with RDTs meeting minimal and optimal characteristics in the TPP across a range of seroprevalences were defined. The final choice of RDTs in each country will depend on the performance of the RDT, dengue seroprevalence in the target population, tolerance of risk, and cost-effectiveness.