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Prof. Dr. Sabine Dittrich

Professor


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Zeitschriftenartikel

  • B. Holloway
  • H. Chandrasekar
  • M. Purohit
  • A. Sharma
  • A. Mathur
  • A. Kc
  • L. Fernandez-Carballo
  • Sabine Dittrich
  • H. Hildenwall
  • A. Bergström

Antibiotic Use before, during, and after Seeking Care for Acute Febrile Illness at a Hospital Outpatient Department: A Cross-Sectional Study from Rural India

In: Antibiotics vol. 11

  • 25.04.2022 (2022)

DOI: 10.3390/antibiotics11050574

Antibiotic resistance is a naturally occurring phenomenon, but the misuse and overuse of antibiotics is accelerating the process. This study aimed to quantify and compare antibiotic use before, during, and after seeking outpatient care for acute febrile illness in Ujjain, India. Data were collected through interviews with patients/patient attendants. The prevalence and choice of antibiotics is described by the WHO AWaRe categories and Anatomical Therapeutic Chemical classes, comparing between age groups. Units of measurement include courses, encounters, and Defined Daily Doses (DDDs). The antibiotic prescription during the outpatient visit was also described in relation to the patients' presumptive diagnosis. Of 1000 included patients, 31.1% (n = 311) received one antibiotic course, 8.1% (n = 81) two, 1.3% (n = 13) three, 0.4% (n = 4) four, 0.1% (n = 1) five, and the remaining 59.0% (n = 590) received no antibiotics. The leading contributors to the total antibiotic volume in the DDDs were macrolides (30.3%), combinations of penicillins, including β-lactamase inhibitors (18.8%), tetracyclines (14.8%), fluoroquinolones (14.6%), and third-generation cephalosporins (13.7%). 'Watch' antibiotics accounted for 72.3%, 52.7%, and 64.0% of encounters before, during, and after the outpatient visit, respectively. Acute viral illness accounted for almost half of the total DDDs at the outpatient visit (642.1/1425.3, 45.1%), for which the macrolide antibiotic azithromycin was the most frequently prescribed antibiotic (261.3/642.1, 40.7%).
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • T. Shimelis
  • S. Vaz Nery
  • B. Tadesse
  • A. Bartlett
  • F. Belay
  • G. Schierhout
  • Sabine Dittrich
  • J. Crump
  • J. Kaldor

Clinical management and outcomes of acute febrile illness in children attending a tertiary hospital in southern Ethiopia

In: BMC Infectious Diseases vol. 22 pg. 434.

  • 04.05.2022 (2022)

DOI: 10.1186/s12879-022-07424-0

BACKGROUND The management of febrile illnesses is challenging in settings where diagnostic laboratory facilities are limited, and there are few published longitudinal data on children presenting with fever in such settings. We have previously conducted the first comprehensive study of infectious aetiologies of febrile children presenting to a tertiary care facility in Ethiopia. We now report on clinicians' prescribing adherence with guidelines and outcomes of management in this cohort. METHODS We consecutively enrolled febrile children aged 2 months and under 13 years, who were then managed by clinicians based on presentation and available laboratory and radiologic findings on day of enrolment. We prospectively collected outcome data on days 7 and 14, and retrospectively evaluated prescribing adherence with national clinical management guidelines. RESULTS Of 433 children enrolled, the most common presenting syndromes were pneumonia and acute diarrhoea, diagnosed in 177 (40.9%) and 82 (18.9%), respectively. Antibacterial agents were prescribed to 360 (84.7%) of 425 children, including 36 (34.0%) of 106 children without an initial indication for antibacterials according to guidelines. Antimalarial drugs were prescribed to 47 (11.1%) of 425 children, including 30 (7.3%) of 411 children with negative malaria microscopy. Fever had resolved in 357 (89.7%) of 398 children assessed at day 7, and in-hospital death within 7 days occurred in 9 (5.9%) of 153 admitted patients. Among children with pneumonia, independent predictors of persisting fever or death by 7 days were young age and underweight for age. Antibacterial prescribing in the absence of a guideline-specified indication (overprescribing) was more likely among infants and those without tachypnea, while overprescribing antimalarials was associated with older age, anaemia, absence of cough, and higher fevers. CONCLUSION Our study underscores the need for improving diagnostic support to properly guide management decisions and enhance adherence by clinicians to treatment guidelines.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • P. Nawtaisong
  • M. Robinson
  • K. Khammavong
  • P. Milavong
  • A. Rachlin
  • Sabine Dittrich
  • A. Dubot-Pérès
  • M. Vongsouvath
  • P. Horwood
  • P. Dussart
  • W. Theppangna
  • B. Douangngeum
  • A. Fine
  • M. Pruvot
  • P. Newton

Zoonotic Pathogens in Wildlife Traded in Markets for Human Consumption, Laos

In: Emerging Infectious Diseases vol. 28 pg. 860-864.

  • (2022)

DOI: 10.3201/eid2804.210249

We tested animals from wildlife trade sites in Laos for the presence of zoonotic pathogens. Leptospira spp. were the most frequently detected infectious agents, found in 20.1% of animals. Rickettsia typhi and R. felis were also detected. These findings suggest a substantial risk for exposure through handling and consumption of wild animal meat.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • H. Slater
  • X. Ding
  • S. Knudson
  • D. Bridges
  • H. Moonga
  • N. Saad
  • M. Smet
  • A. Bennett
  • Sabine Dittrich
  • L. Slutsker
  • G. Domingo

Performance and utility of more highly sensitive malaria rapid diagnostic tests

In: BMC Infectious Diseases vol. 22 pg. 121.

  • 04.02.2022 (2022)

DOI: 10.1186/s12879-021-07023-5

BACKGROUND A new more highly sensitive rapid diagnostic test (HS-RDT) for Plasmodium falciparum malaria (Alere™/Abbott Malaria Ag P.f RDT [05FK140], now called NxTek™ Eliminate Malaria Ag Pf) was launched in 2017. The test has already been used in many research studies in a wide range of geographies and use cases. METHODS In this study, we collate all published and available unpublished studies that use the HS-RDT and assess its performance in (i) prevalence surveys, (ii) clinical diagnosis, (iii) screening pregnant women, and (iv) active case detection. Two individual-level data sets from asymptomatic populations are used to fit logistic regression models to estimate the probability of HS-RDT positivity based on histidine-rich protein 2 (HRP2) concentration and parasite density. The performance of the HS-RDT in prevalence surveys is estimated by calculating the sensitivity and positive proportion in comparison to polymerase chain reaction (PCR) and conventional malaria RDTs. RESULTS We find that across 18 studies, in prevalence surveys, the mean sensitivity of the HS-RDT is estimated to be 56.1% (95% confidence interval [CI] 46.9-65.4%) compared to 44.3% (95% CI 32.6-56.0%) for a conventional RDT (co-RDT) when using nucleic acid amplification techniques as the reference standard. In studies where prevalence was estimated using both the HS-RDT and a co-RDT, we found that prevalence was on average 46% higher using a HS-RDT compared to a co-RDT. For use in clinical diagnosis and screening pregnant women, the HS-RDT was not significantly more sensitive than a co-RDT. CONCLUSIONS Overall, the evidence presented here suggests that the HS-RDT is more sensitive in asymptomatic populations and could provide a marginal improvement in clinical diagnosis and screening pregnant women. Although the HS-RDT has limited temperature stability and shelf-life claims compared to co-RDTs, there is no evidence to suggest, given this test has the same cost as current RDTs, it would have any negative impacts in terms of malaria misdiagnosis if it were widely used in all four population groups explored here.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • A. Chandna
  • R. Mahajan
  • P. Gautam
  • L. Mwandigha
  • K. Gunasekaran
  • D. Bhusan
  • A. Cheung
  • N. Day
  • Sabine Dittrich
  • A. Dondorp
  • T. Geevar
  • S. Ghattamaneni
  • S. Hussain
  • C. Jimenez
  • R. Karthikeyan
  • S. Kumar
  • V. Kumar
  • D. Kundu
  • A. Lakshmanan
  • A. Manesh
  • C. Menggred
  • M. Moorthy
  • J. Osborn
  • M. Richard-Greenblatt
  • S. Sharma
  • V. Singh
  • J. Suri
  • S. Suzuki
  • J. Tubprasert
  • P. Turner
  • A. Villanueva
  • N. Waithira
  • P. Kumar
  • G. Varghese
  • C. Koshiaris
  • Y. Lubell
  • S. Burza

Facilitating safe discharge through predicting disease progression in moderate COVID-19: a prospective cohort study to develop and validate a clinical prediction model in resource-limited settings

In: Clinical Infectious Diseases : an official publication of the Infectious Diseases Society of America

  • 21.03.2022 (2022)

DOI: 10.1093/cid/ciac224

BACKGROUND In locations where few people have received COVID-19 vaccines, health systems remain vulnerable to surges in SARS-CoV-2 infections. Tools to identify patients suitable for community-based management are urgently needed. METHODS We prospectively recruited adults presenting to two hospitals in India with moderate symptoms of laboratory-confirmed COVID-19 in order to develop and validate a clinical prediction model to rule-out progression to supplemental oxygen requirement. The primary outcome was defined as any of the following: SpO2 < 94%; respiratory rate > 30 bpm; SpO2/FiO2 < 400; or death. We specified a priori that each model would contain three clinical parameters (age, sex and SpO2) and one of seven shortlisted biochemical biomarkers measurable using commercially-available rapid tests (CRP, D-dimer, IL-6, NLR, PCT, sTREM-1 or suPAR), to ensure the models would be suitable for resource-limited settings. We evaluated discrimination, calibration and clinical utility of the models in a held-out temporal external validation cohort. RESULTS 426 participants were recruited, of whom 89 (21.0%) met the primary outcome. 257 participants comprised the development cohort and 166 comprised the validation cohort. The three models containing NLR, suPAR or IL-6 demonstrated promising discrimination (c-statistics: 0.72 to 0.74) and calibration (calibration slopes: 1.01 to 1.05) in the validation cohort, and provided greater utility than a model containing the clinical parameters alone. CONCLUSIONS We present three clinical prediction models that could help clinicians identify patients with moderate COVID-19 suitable for community-based management. The models are readily implementable and of particular relevance for locations with limited resources.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • T. Shimelis
  • G. Schierhout
  • B. Tadesse
  • Sabine Dittrich
  • J. Crump
  • J. Kaldor
  • S. Vaz Nery

Timely health care seeking and first source of care for acute febrile illness in children in Hawassa, southern Ethiopia

In: PLoS One vol. 17 pg. e0269725.

  • 09.06.2022 (2022)

DOI: 10.1371/journal.pone.0269725

BACKGROUND Timely health care seeking with access to quality health care are crucial to improve child survival. We conducted a study which aimed to identify factors influencing timely health care seeking and choice of first source of health care in Ethiopia. METHODS A total of 535 caregivers who sought health care for febrile children aged under 5 years at a tertiary hospital, and one urban and two rural health centres in Hawassa, southern Ethiopia were recruited to participate in the study from August to November 2019. Caregivers were interviewed using pretested structured questionnaires on socio-demographic and clinical factors to identify associations with health care seeking practice and first source of care, and reasons for particular practices. Delayed care seeking was defined as seeking care from a health facility after 24 hours of onset of fever. RESULTS Of 535 caregivers who participated, 271 (50.7%) had sought timely health care; 400 (74.8%) utilized a primary health care (PHC) facility as first source; and 282 (52.7%) bypassed the nearest PHC facility. Rural residents (adjusted odds ratio (AOR) 1.85; 95% CI 1.11-3.09), and those who reported cough (AOR 1.87; 95% CI 1.20-2.93) as a reason for consultation were more likely to delay seeking health care. While caregivers were less likely delayed for children aged 24-35 months (AOR 0.50; 95% CI 0.28-0.87) compared to infants. Utilizing higher-level hospitals as the first source of care was less frequent among rural residents (AOR 0.15; 95% CI 0.06-0.39) and in those with no formal education (AOR 0.03; 95% CI 0.01-0.27). Those having a longer travel time to the provider (AOR 2.11; 95% CI 1.09-4.08) more likely utilized higher hospitals. CONCLUSION We identified a need to improve timely health seeking among rural residents, infants, and those presenting with respiratory symptoms. Improvements may be achieved by educating communities on the need of early care seeking, and ensuring the communities members' expectations of services at each level consistent with the services capacity.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • P. van Dorst
  • S. van der Pol
  • O. Salami
  • Sabine Dittrich
  • P. Olliaro
  • M. Postma
  • C. Boersma
  • A. van Asselt

Evaluations of training and education interventions for improved infectious disease management in low-income and middle-income countries: a systematic literature review

In: BMJ Open vol. 12 pg. e053832.

  • 21.02.2022 (2022)

DOI: 10.1136/bmjopen-2021-053832

OBJECTIVES To identify most vital input and outcome parameters required for evaluations of training and education interventions aimed at addressing infectious diseases in low-income and middle-income countries. DESIGN Systematic review. DATA SOURCES PubMed/Medline, Web of Science and Scopus were searched for eligible studies between January 2000 and November 2021. STUDY SELECTION Health economic and health-outcome studies on infectious diseases covering an education or training intervention in low-income and middle-income countries were included. RESULTS A total of 59 eligible studies covering training or education interventions for infectious diseases were found; infectious diseases were categorised as acute febrile infections (AFI), non-AFI and other non-acute infections. With regard to input parameters, the costs (direct and indirect) were most often reported. As outcome parameters, five categories were most often reported including final health outcomes, intermediate health outcomes, cost outcomes, prescription outcomes and health economic outcomes. Studies showed a wide range of per category variables included and a general lack of uniformity across studies. CONCLUSIONS Further standardisation is needed on the relevant input and outcome parameters in this field. A more standardised approach would improve generalisability and comparability of results and allow policy-makers to make better informed decisions on the most effective and cost-effective interventions.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • M. McLaughlin
  • K. Pellé
  • S. Scarpino
  • A. Giwa
  • E. Mount-Finette
  • N. Haidar
  • F. Adamu
  • N. Ravi
  • A. Thompson
  • B. Heath
  • Sabine Dittrich
  • B. Finette

Development and Validation of Manually Modified and Supervised Machine Learning Clinical Assessment Algorithms for Malaria in Nigerian Children

In: Frontiers in Artificial Intelligence vol. 4 pg. 554017.

  • 03.02.2022 (2021)

DOI: 10.3389/frai.2021.554017

It is currently estimated that 67% of malaria deaths occur in children under-five years (WHO, 2020). To improve the identification of children at clinical risk for malaria, the WHO developed community (iCCM) and clinic-based (IMCI) protocols for frontline health workers using paper-based forms or digital mobile health (mHealth) platforms. To investigate improving the accuracy of these point-of-care clinical risk assessment protocols for malaria in febrile children, we embedded a malaria rapid diagnostic test (mRDT) workflow into THINKMD's (IMCI) mHealth clinical risk assessment platform. This allowed us to perform a comparative analysis of THINKMD-generated malaria risk assessments with mRDT truth data to guide modification of THINKMD algorithms, as well as develop new supervised machine learning (ML) malaria risk algorithms. We utilized paired clinical data and malaria risk assessments acquired from over 555 children presenting to five health clinics in Kano, Nigeria to train ML algorithms to identify malaria cases using symptom and location data, as well as confirmatory mRDT results. Supervised ML random forest algorithms were generated using 80% of our field-based data as the ML training set and 20% to test our new ML logic. New ML-based malaria algorithms showed an increased sensitivity and specificity of 60 and 79%, and PPV and NPV of 76 and 65%, respectively over THINKD initial IMCI-based algorithms. These results demonstrate that combining mRDT "truth" data with digital mHealth platform clinical assessments and clinical data can improve identification of children with malaria/non-malaria attributable febrile illnesses.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • J. Verbakel
  • L. Rop
  • I. Stegeman
  • G. Holtman
  • E. Ochodo
  • B. Yang
  • F. Guleid
  • C. Davenport
  • J. Deeks
  • J. Dinnes
  • Sabine Dittrich
  • D. Emperador
  • L. Hooft
  • R. Spijker
  • A. van den Bruel
  • Wang, J.
  • Y. Takwoingi
  • M. Langendam
  • M. Leeflang

Accuracy of routine laboratory tests to predict mortality and deterioration to severe or critical COVID-19 in people with SARS-CoV-2

In: Cochrane Database of Systematic Reviews vol. 2021

  • (2021)

DOI: 10.1002/14651858.cd015050

Objectives This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows: To assess the accuracy of routine blood‐based laboratory tests to predict mortality and deterioration to severe or critical (from mild or moderate) COVID‐19 in people with SARS‐CoV‐2 infection. Secondary objectives Where data are available, we will investigate whether prognostic accuracy varies according to a specific measurement or test, reference standard, timing of outcome verification, sample type, study design, and setting, including prevalence of the target condition (either by stratified analysis or meta‐regression).
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • A. Chandna
  • J. Osborn
  • Q. Bassat
  • D. Bell
  • S. Burza
  • V. DAcremont
  • B. Fernandez-Carballo
  • K. Kain
  • M. Mayxay
  • M. Wiens
  • Sabine Dittrich

Anticipating the future: prognostic tools as a complementary strategy to improve care for patients with febrile illnesses in resource-limited settings

In: BMJ Global Health vol. 6

  • (2021)

DOI: 10.1136/bmjgh-2021-006057

In low-income and middle-income countries, most patients with febrile illnesses present to peripheral levels of the health system where diagnostic capacity is very limited. In these contexts, accurate risk stratification can be particularly impactful, helping to guide allocation of scarce resources to ensure timely and tailored care. However, reporting of prognostic research is often imprecise and few prognostic tests or algorithms are translated into clinical practice.Here, we review the often-conflated concepts of prognosis and diagnosis, with a focus on patients with febrile illnesses. Drawing on a recent global stakeholder consultation, we apply these concepts to propose three use-cases for prognostic tools in the management of febrile illnesses in resource-limited settings: (1) guiding referrals from the community to higher-level care; (2) informing resource allocation for patients admitted to hospital and (3) identifying patients who may benefit from closer follow-up post-hospital discharge. We explore the practical implications for new technologies and reflect on the challenges and knowledge gaps that must be addressed before this approach could be incorporated into routine care settings.Our intention is that these use-cases, alongside other recent initiatives, will help to promote a harmonised yet contextualised approach for prognostic research in febrile illness. We argue that this is especially important given the heterogeneous settings in which care is often provided for patients with febrile illnesses living in low-income and middle-income countries.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • E. Kendall
  • N. Arinaminpathy
  • J. Sacks
  • Y. Manabe
  • Sabine Dittrich
  • S. Schumacher
  • D. Dowdy

Antigen-based Rapid Diagnostic Testing or Alternatives for Diagnosis of Symptomatic COVID-19: A Simulation-based Net Benefit Analysis

In: Epidemiology vol. 32 pg. 811-819.

  • (2021)

DOI: 10.1097/ede.0000000000001400

BACKGROUND SARS-CoV-2 antigen-detection rapid diagnostic tests can diagnose COVID-19 rapidly and at low cost, but lower sensitivity compared with reverse-transcriptase polymerase chain reaction (PCR) has limited clinical adoption. METHODS We compared antigen testing, PCR testing, and clinical judgment alone for diagnosing symptomatic COVID-19 in an outpatient setting (10% COVID-19 prevalence among the patients tested, 3-day PCR turnaround) and a hospital setting (40% prevalence, 24-hour PCR turnaround). We simulated transmission from cases and contacts, and relationships between time, viral burden, transmission, and case detection. We compared diagnostic approaches using a measure of net benefit that incorporated both clinical and public health benefits and harms of the intervention. RESULTS In the outpatient setting, we estimated that using antigen testing instead of PCR to test 200 individuals could be equivalent to preventing all symptomatic transmission from one person with COVID-19 (one "transmission-equivalent"). In a hospital, net benefit analysis favored PCR and testing 25 patients with PCR instead of antigen testing achieved one transmission-equivalent of benefit. In both settings, antigen testing was preferable to PCR if PCR turnaround time exceeded 2 days. Both tests provided greater net benefit than management based on clinical judgment alone unless intervention carried minimal harm and was provided equally regardless of diagnostic approach. CONCLUSIONS For diagnosis of symptomatic COVID-19, we estimated that the speed of diagnosis with antigen testing is likely to outweigh its lower accuracy compared with PCR, wherever PCR turnaround time is 2 days or longer. This advantage may be even greater if antigen tests are also less expensive.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • J. Dinnes
  • J. Deeks
  • S. Berhane
  • M. Taylor
  • A. Adriano
  • C. Davenport
  • Sabine Dittrich
  • D. Emperador
  • Y. Takwoingi
  • J. Cunningham
  • S. Beese
  • J. Domen
  • J. Dretzke
  • L. Di Ferrante Ruffano
  • I. Harris
  • M. Price
  • S. Taylor-Phillips
  • L. Hooft
  • M. Leeflang
  • M. McInnes
  • R. Spijker
  • A. van den Bruel

Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection

In: The Cochrane Database of Systematic Reviews vol. 3 pg. CD013705.

  • 24.03.2021 (2021)

DOI: 10.1002/14651858.cd013705.pub2

BACKGROUND Accurate rapid diagnostic tests for SARS-CoV-2 infection could contribute to clinical and public health strategies to manage the COVID-19 pandemic. Point-of-care antigen and molecular tests to detect current infection could increase access to testing and early confirmation of cases, and expediate clinical and public health management decisions that may reduce transmission. OBJECTIVES To assess the diagnostic accuracy of point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection. We consider accuracy separately in symptomatic and asymptomatic population groups. SEARCH METHODS Electronic searches of the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) were undertaken on 30 Sept 2020. We checked repositories of COVID-19 publications and included independent evaluations from national reference laboratories, the Foundation for Innovative New Diagnostics and the Diagnostics Global Health website to 16 Nov 2020. We did not apply language restrictions. SELECTION CRITERIA We included studies of people with either suspected SARS-CoV-2 infection, known SARS-CoV-2 infection or known absence of infection, or those who were being screened for infection. We included test accuracy studies of any design that evaluated commercially produced, rapid antigen or molecular tests suitable for a point-of-care setting (minimal equipment, sample preparation, and biosafety requirements, with results within two hours of sample collection). We included all reference standards that define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction (RT-PCR) tests and established diagnostic criteria). DATA COLLECTION AND ANALYSIS Studies were screened independently in duplicate with disagreements resolved by discussion with a third author. Study characteristics were extracted by one author and checked by a second; extraction of study results and assessments of risk of bias and applicability (made using the QUADAS-2 tool) were undertaken independently in duplicate. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test and pooled data using the bivariate model separately for antigen and molecular-based tests. We tabulated results by test manufacturer and compliance with manufacturer instructions for use and according to symptom status. MAIN RESULTS Seventy-eight study cohorts were included (described in 64 study reports, including 20 pre-prints), reporting results for 24,087 samples (7,415 with confirmed SARS-CoV-2). Studies were mainly from Europe (n = 39) or North America (n = 20), and evaluated 16 antigen and five molecular assays. We considered risk of bias to be high in 29 (50%) studies because of participant selection; in 66 (85%) because of weaknesses in the reference standard for absence of infection; and in 29 (45%) for participant flow and timing. Studies of antigen tests were of a higher methodological quality compared to studies of molecular tests, particularly regarding the risk of bias for participant selection and the index test. Characteristics of participants in 35 (45%) studies differed from those in whom the test was intended to be used and the delivery of the index test in 39 (50%) studies differed from the way in which the test was intended to be used. Nearly all studies (97%) defined the presence or absence of SARS-CoV-2 based on a single RT-PCR result, and none included participants meeting case definitions for probable COVID-19. Antigen tests Forty-eight studies reported 58 evaluations of antigen tests. Estimates of sensitivity varied considerably between studies. There were differences between symptomatic (72.0%, 95% CI 63.7% to 79.0%; 37 evaluations; 15530 samples, 4410 cases) and asymptomatic participants (58.1%, 95% CI 40.2% to 74.1%; 12 evaluations; 1581 samples, 295 cases). Average sensitivity was higher in the first week after symptom onset (78.3%, 95% CI 71.1% to 84.1%; 26 evaluations; 5769 samples, 2320 cases) than in the second week of symptoms (51.0%, 95% CI 40.8% to 61.0%; 22 evaluations; 935 samples, 692 cases). Sensitivity was high in those with cycle threshold (Ct) values on PCR ≤25 (94.5%, 95% CI 91.0% to 96.7%; 36 evaluations; 2613 cases) compared to those with Ct values >25 (40.7%, 95% CI 31.8% to 50.3%; 36 evaluations; 2632 cases). Sensitivity varied between brands. Using data from instructions for use (IFU) compliant evaluations in symptomatic participants, summary sensitivities ranged from 34.1% (95% CI 29.7% to 38.8%; Coris Bioconcept) to 88.1% (95% CI 84.2% to 91.1%; SD Biosensor STANDARD Q). Average specificities were high in symptomatic and asymptomatic participants, and for most brands (overall summary specificity 99.6%, 95% CI 99.0% to 99.8%). At 5% prevalence using data for the most sensitive assays in symptomatic people (SD Biosensor STANDARD Q and Abbott Panbio), positive predictive values (PPVs) of 84% to 90% mean that between 1 in 10 and 1 in 6 positive results will be a false positive, and between 1 in 4 and 1 in 8 cases will be missed. At 0.5% prevalence applying the same tests in asymptomatic people would result in PPVs of 11% to 28% meaning that between 7 in 10 and 9 in 10 positive results will be false positives, and between 1 in 2 and 1 in 3 cases will be missed. No studies assessed the accuracy of repeated lateral flow testing or self-testing. Rapid molecular assays Thirty studies reported 33 evaluations of five different rapid molecular tests. Sensitivities varied according to test brand. Most of the data relate to the ID NOW and Xpert Xpress assays. Using data from evaluations following the manufacturer's instructions for use, the average sensitivity of ID NOW was 73.0% (95% CI 66.8% to 78.4%) and average specificity 99.7% (95% CI 98.7% to 99.9%; 4 evaluations; 812 samples, 222 cases). For Xpert Xpress, the average sensitivity was 100% (95% CI 88.1% to 100%) and average specificity 97.2% (95% CI 89.4% to 99.3%; 2 evaluations; 100 samples, 29 cases). Insufficient data were available to investigate the effect of symptom status or time after symptom onset. AUTHORS' CONCLUSIONS Antigen tests vary in sensitivity. In people with signs and symptoms of COVID-19, sensitivities are highest in the first week of illness when viral loads are higher. The assays shown to meet appropriate criteria, such as WHO's priority target product profiles for COVID-19 diagnostics ('acceptable' sensitivity ≥ 80% and specificity ≥ 97%), can be considered as a replacement for laboratory-based RT-PCR when immediate decisions about patient care must be made, or where RT-PCR cannot be delivered in a timely manner. Positive predictive values suggest that confirmatory testing of those with positive results may be considered in low prevalence settings. Due to the variable sensitivity of antigen tests, people who test negative may still be infected. Evidence for testing in asymptomatic cohorts was limited. Test accuracy studies cannot adequately assess the ability of antigen tests to differentiate those who are infectious and require isolation from those who pose no risk, as there is no reference standard for infectiousness. A small number of molecular tests showed high accuracy and may be suitable alternatives to RT-PCR. However, further evaluations of the tests in settings as they are intended to be used are required to fully establish performance in practice. Several important studies in asymptomatic individuals have been reported since the close of our search and will be incorporated at the next update of this review. Comparative studies of antigen tests in their intended use settings and according to test operator (including self-testing) are required.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • B. Leticia Fernandez-Carballo
  • C. Escadafal
  • E. MacLean
  • A. Kapasi
  • Sabine Dittrich

Distinguishing bacterial versus non-bacterial causes of febrile illness - A systematic review of host biomarkers

In: The Journal of Infection vol. 82 pg. 1-10.

  • 19.02.2021 (2021)

DOI: 10.1016/j.jinf.2021.01.028

BACKGROUND Acute febrile illnesses (AFIs) represent a major disease burden globally; however, the paucity of reliable, rapid point-of-care testing makes their diagnosis difficult. A simple tool for distinguishing bacterial versus non-bacterial infections would radically improve patient management and reduce indiscriminate antibiotic use. Diagnostic tests based on host biomarkers can play an important role here, and a target product profile (TPP) was developed to guide development. OBJECTIVES To qualitatively evaluate host biomarkers that can distinguish bacterial from non-bacterial causes of AFI. DATA SOURCES The PubMed database was systematically searched for relevant studies published between 2015 and 2019. STUDY ELIGIBILITY CRITERIA Studies comparing diagnostic performances of host biomarkers in patients with bacterial versus non-bacterial infections were included. PARTICIPANTS Studies involving human participants and/or human samples were included. METHODS We collected information following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A risk of bias assessment was performed, based on a modified QUADAS-2 (Quality Assessment of Diagnostic Accuracy Score 2). RESULTS We identified 1107 publications. Following screening, 55 publications were included, with 265 biomarker entries. Entries mostly comprised protein biomarkers (58.9%), followed by haematological, RNA, and metabolite biomarkers (15.5%, 8.7%, 12.5%). Sensitivity/specificity was reported for 45.7% of biomarker entries. We assessed a high overall risk of bias for most entries (75.8%). In studies with low/medium risk of bias, four biomarker entries tested in blood samples had sensitivity/specificity of more than 0.90/0.80. Only 12 additional biomarker entries were identified with sensitivity/specificity of more than 0.65/0.65. CONCLUSIONS Most recently assessed biomarkers represent well-known biomarkers, e.g. C-reactive protein and procalcitonin. Some protein biomarkers with the highest reported performances include a combined biomarker signature (CRP, IP-10, and TRAIL) and human neutrophil lipocalin (HNL). Few new biomarkers are in the pipeline; however, some RNA signatures show promise. Further high-quality studies are needed to confirm these findings.
  • Europan Campus Rottal-Inn
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Zeitschriftenartikel

  • C. Escadafal
  • S. Incardona
  • B. Fernandez-Carballo
  • Sabine Dittrich

The good and the bad: using C reactive protein to distinguish bacterial from non-bacterial infection among febrile patients in low-resource settings

In: BMJ Global Health vol. 5

  • (2020)

DOI: 10.1136/bmjgh-2020-002396

C reactive protein (CRP), a marker for the presence of an inflammatory process, is the most extensively studied marker for distinguishing bacterial from non-bacterial infections in febrile patients. A point-of-care test for bacterial infections would be of particular use in low-resource settings where other laboratory diagnostics are not always available, antimicrobial resistance rates are high and bacterial infections such as pneumonia are a leading cause of death. This document summarises evidence on CRP testing for bacterial infections in low-income and middle-income countries (LMICs). With a push for universal health coverage and prevention of antimicrobial resistance, it is important to understand if CRP might be able to do the job. The use of CRP polarised the global health community and the aim of this document is to summarise the 'good and the bad' of CRP in multiple settings in LMICs. In brief, the literature that was reviewed suggests that CRP testing may be beneficial in low-resource settings to improve rational antibiotic use for febrile patients, but the positive predictive value is insufficient to allow it to be used alone as a single tool. CRP testing may be best used as part of a panel of diagnostic tests and algorithms. Further studies in low-resource settings, particularly with regard to impact on antibiotic prescribing and cost-effectiveness of CRP testing, are warranted.
  • Europan Campus Rottal-Inn
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Zeitschriftenartikel

  • Sabine Dittrich
  • M. Lamy
  • S. Acharya
  • H. Thu
  • R. Datta
  • S. Blacksell
  • P. Hein
  • C. Mercado
  • X. Ding
  • A. Chebbi

Diagnosing malaria and other febrile illnesses during the COVID-19 pandemic

In: The Lancet Global Health vol. 8 pg. e879-e880.

  • (2020)

DOI: 10.1016/s2214-109x(20)30210-2

As the global malaria community observes World Malaria Day on April 25, 2020, we have plenty to celebrate. Yet this year, the coronavirus disease 2019 (COVID-19) outbreak is greatly dampening the spirits. While the Asia-Pacific region has made substantial progress against malaria, with a 42% reduction in confirmed cases between 2010 and 2018,1 the emergence of COVID-19 could undermine elimination efforts. Like malaria, one of the most common symptoms of COVID-19 is fever.2 Diagnosis of fever in the Asia-Pacific region has always been a challenge due to the large number of febrile diseases prevalent in the region, including malaria, dengue fever, scrub typhus, typhoid fever, and leptospirosis, among others, and to health systems' insufficient capacity to cope with them.3 With COVID-19 added to the mix, differentiation between these diseases becomes even more difficult. Furthermore, due to physical distancing measures and personal protective equipment (PPE) requirements, COVID-19 is limiting access to health care. To ensure that health emergencies such as COVID-19 do not impede progress towards elimination of malaria, health-care workers at the frontline must be better equipped to tackle such threats.
  • Europan Campus Rottal-Inn
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Zeitschriftenartikel

  • T. Althaus
  • J. Thaipadungpanit
  • R. Greer
  • M. Swe
  • Sabine Dittrich
  • P. Peerawaranun
  • P. Smit
  • T. Wangrangsimakul
  • S. Blacksell
  • J. Winchell
  • M. Diaz
  • N. Day
  • F. Smithuis
  • P. Turner
  • Y. Lubell

Causes of fever in primary care in Southeast Asia and the performance of C-reactive protein in discriminating bacterial from viral pathogens

In: International Journal of Infectious Diseases vol. 96 pg. 334-342.

  • 11.05.2020 (2020)

DOI: 10.1016/j.ijid.2020.05.016

OBJECTIVES This study investigated causes of fever in the primary levels of care in Southeast Asia, and evaluated whether C-reactive protein (CRP) could distinguish bacterial from viral pathogens. METHODS Blood and nasopharyngeal swab specimens were taken from children and adults with fever (>37.5 °C) or history of fever (<14 days) in Thailand and Myanmar. RESULTS Of 773 patients with at least one blood or nasopharyngeal swab specimen collected, 227 (29.4%) had a target organism detected. Influenza virus type A was detected in 85/227 cases (37.5%), followed by dengue virus (30 cases, 13.2%), respiratory syncytial virus (24 cases, 10.6%) and Leptospira spp. (nine cases, 4.0%). Clinical outcomes were similar between patients with a bacterial or a viral organism, regardless of antibiotic prescription. CRP was higher among patients with a bacterial organism compared with those with a viral organism (median 18 mg/L, interquartile range [10-49] versus 10 mg/L [≤8-22], p = 0.003), with an area under the curve of 0.65 (95% CI 0.55-0.75). CONCLUSIONS Serious bacterial infections requiring antibiotics are an exception rather than the rule in the first line of care. CRP testing could assist in ruling out such cases in settings where diagnostic uncertainty is high and routine antibiotic prescription is common. The original CRP randomised controlled trial was registered with ClinicalTrials.gov, number NCT02758821.
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Zeitschriftenartikel

  • N. Thi Thuy Do
  • R. Greer
  • Y. Lubell
  • Sabine Dittrich
  • M. Vandendorpe
  • A. van Nguyen
  • P. Ngoc Thach
  • T. Thi Dieu Ngan
  • N. van Kinh
  • C. Hung Thai
  • T. Le Dung
  • T. Nguyen Thi Cam
  • T. Nguyen
  • B. Nadjm
  • H. van Doorn
  • S. Lewycka

Implementation of C-reactive protein point of care testing to improve antibiotic targeting in respiratory illness in Vietnamese primary care (ICAT): a study protocol for a cluster randomised controlled trial

In: BMJ Open vol. 10 pg. e040977.

  • 23.12.2020 (2020)

DOI: 10.1136/bmjopen-2020-040977

INTRODUCTION C-reactive protein (CRP), a biomarker of infection, has been used widely in high-income settings to guide antibiotic treatment in patients presenting with respiratory illnesses in primary care. Recent trials in low- and middle-income countries showed that CRP testing could safely reduce antibiotic use in patients with non-severe acute respiratory infections (ARIs) and fever in primary care. The studies, however, were conducted in a research-oriented context, with research staff closely monitoring healthcare behaviour thus potentially influencing healthcare workers' prescribing practices. For policy-makers to consider wide-scale roll-out, a pragmatic implementation study of the impact of CRP point of care (POC) testing in routine care is needed. METHODS AND ANALYSIS A pragmatic, cluster-randomised controlled trial, with two study arms, consisting of 24 commune health centres (CHC) in the intervention arm (provision of CRP tests with additional healthcare worker guidance) and 24 facilities acting as controls (routine care). Comparison between the treatment arms will be through logistic regression, with the treatment assignment as a fixed effect, and the CHC as a random effect. With 48 clusters, an average of 10 consultations per facility per week will result in approximately 520 over 1 year, and 24 960 in total (12 480 per arm). We will be able to detect a reduction of 12% to 23% or more in immediate antibiotic prescription as a result of the CRP POC intervention. The primary endpoint is the proportion of patient consultations for ARI resulting in immediate antibiotic prescription. Secondary endpoints include the proportion of all patients receiving an antibiotic prescription regardless of ARI diagnosis, frequency of re-consultation, subsequent antibiotic use when antibiotics are not prescribed, referral and hospitalisation. ETHICS AND DISSEMINATION The study protocol was approved by the Oxford University Tropical Research Ethics Committee (OxTREC, Reference: 53-18), and the ethical committee of the National Hospital for Tropical Diseases in Vietnam (Reference:07/HDDD-NDTW/2019). Results from this study will be disseminated via meetings with stakeholders, conferences and publications in peer-reviewed journals. Authorship and reporting of this work will follow international guidelines. TRIAL REGISTRATION DETAILS NCT03855215; Pre-results.
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Zeitschriftenartikel

  • A. Devine
  • R. Howes
  • D. Price
  • K. Moore
  • B. Ley
  • J. Simpson
  • Sabine Dittrich
  • R. Price

Cost-Effectiveness Analysis of Sex-Stratified Plasmodium vivax Treatment Strategies Using Available G6PD Diagnostics to Accelerate Access to Radical Cure

In: The American Journal of Tropical Medicine and Hygiene vol. 103 pg. 394-403.

  • 30.04.2020 (2020)

DOI: 10.4269/ajtmh.19-0943

Tafenoquine has been licensed for the single-dose radical cure of Plasmodium vivax in adults; however, it is only recommended in patients with > 70% of normal glucose-6-phosphate dehydrogenase (G6PD) activity. Because this may hinder widespread use, we investigated sex-based treatment strategies in which all adult patients are tested with a qualitative G6PD rapid diagnostic test (RDT). Glucose-6-phosphate dehydrogenase normal males are prescribed tafenoquine in all three strategies, whereas G6PD normal females are prescribed either a low-dose 14-day primaquine regimen (PQ14, total dose 3.5 mg/kg) or a high-dose 7-day primaquine regimen (PQ7, total dose 7 mg/kg), or referred to a healthcare facility for quantitative G6PD testing before prescribing tafenoquine. Patients testing G6PD deficient are prescribed a weekly course of primaquine for 8 weeks. We compared the cost-effectiveness of these three strategies to usual care in four countries using a decision tree model. Usual care in Ethiopia does not include radical cure, whereas Afghanistan, Indonesia, and Vietnam prescribe PQ14 without G6PD screening. The cost per disability-adjusted life-year (DALY) averted was expressed through incremental cost-effectiveness ratios (ICERs). Compared with usual care, the ICERs for a sex-based treatment strategy with PQ7 for females from a healthcare provider perspective were $127 per DALY averted in Vietnam, $466 in Ethiopia, $1,089 in Afghanistan, and $4,443 in Indonesia. The PQ14 and referral options cost more while averting fewer DALYs than PQ7. This study provides an alternative cost-effective mode of rolling out tafenoquine in areas where initial testing with only a G6PD RDT is feasible.
  • Europan Campus Rottal-Inn
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Zeitschriftenartikel

  • J. Schneider
  • C. Boehme
  • B. Borisch
  • Sabine Dittrich

Application of a simple point-of-care test to reduce UK healthcare costs and adverse events in outpatient acute respiratory infections

In: Journal of Medical Economics vol. 23 pg. 673-682.

  • 07.04.2020 (2020)

DOI: 10.1080/13696998.2020.1736872

Background: Acute respiratory infection (ARI) accounts for over two-thirds of total antibiotic prescriptions although most are caused by viruses that do not benefit from antibiotics. Most antibiotics are prescribed in the outpatients setting. Antibiotic overuse leads to antibiotic-related adverse events (AEs), inclusive of secondary infections, resistance, and increased costs. Point-of-care tests (POCT) may reduce unnecessary antibiotics. A cost analysis was performed to assess diagnostic POCT options to identify patients with an ARI that may benefit from antibiotics in a United Kingdom (UK) outpatient setting.Methods: Healthcare savings were estimated using a budget impact analysis based on UK National Institute for Health and Care Excellence (NICE) data and direct costs (antibiotics, AEs, POCTs) derived from published literature. Otitis media, sinusitis, pharyngitis and bronchitis were considered the most common ARIs. Antibiotic-related AE costs were calculated using re-consultation costs for anaphylaxis, Stevens-Johnson syndrome, allergies/diarrhea/nausea, C. difficile infection (CDI). Potential cost-savings from POCTs was assessed by evaluating NICE guideline-referenced POCTs (CRP, FebriDx, Sarasota, FL) as well as a target product profile (TPP).Results: Fifty-percent (7,718,283) of ARI consultations resulted in antibiotics while guideline-based prescribing suggest appropriate antibiotic prescriptions are warranted 9% (1,444,877) of ARI consultations. Direct antibiotic costs for actual ARI consultations associated with antibiotics was £24,003,866 vs. £4,493,568 for guideline-based, "appropriate" antibiotic prescriptions. Antibiotic-related AEs and re-consultations for actual vs. appropriate prescribing totaled £302,496,486 vs. £63,854,269. ARI prescribing plus AE costs totaled £326,729,943 annually without the use of delayed prescribing practices or POCT while the addition of delayed prescribing plus POCT totaled £60,114,564-£78,148,933 depending on the POCT.Conclusions: Adding POCT to outpatient triage of ARI can reduce unnecessary antibiotics and antibiotic-related AEs, resulting in substantial cost savings. Further, near patient diagnostic testing can benefit health systems and patients by avoiding exposure to unnecessary drugs, side effects and antibiotic resistant pathogens.Key points for decision makersMany patients are unnecessarily treated with antibiotics for respiratory infections.Antibiotic misuse leads to unnecessary adverse events, secondary infections, re-consultations, antimicrobial resistance and increased costs.Point-of-care diagnostic tests used to guide antibiotic prescriptions will avoid unnecessary adverse health effects and expenses.
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Zeitschriftenartikel

  • J. Osborn
  • T. Roberts
  • E. Guillen
  • O. Bernal
  • P. Roddy
  • S. Ongarello
  • A. Sprecher
  • A.-L. Page
  • I. Ribeiro
  • E. Piriou
  • A. Tamrat
  • R. La Tour
  • V. Rao
  • L. Flevaud
  • T. Jensen
  • L. McIver
  • C. Kelly
  • Sabine Dittrich

Prioritising pathogens for the management of severe febrile patients to improve clinical care in low- and middle-income countries

In: BMC Infectious Diseases vol. 20 pg. 117.

  • 10.02.2020 (2020)

DOI: 10.1186/s12879-020-4834-1

BACKGROUND Severe febrile illness without a known source (SFWS) is a challenge for clinicians when deciding how to manage a patient, particularly given the wide spectrum of potential aetiologies that contribute to fever. These infections are difficult to distinguish clinically, and accurate diagnosis requires a plethora of diagnostics including blood cultures, imaging techniques, molecular or serological tests, and more. When laboratory services are available, a limited test menu hinders clinical decision-making and antimicrobial stewardship, leading to empiric treatment and suboptimal patient outcomes. To specifically address SFWS, this work aimed to identify priority pathogens for a globally applicable panel for fever causing pathogens. METHOD A pragmatic two-pronged approach combining currently available scientific data in an analytical hierarchy process and systematically gathered expert input, was designed to address the lack of comprehensive global aetiology data. The expert re-ranked list was then further adapted for a specific use case to focus on community acquired infections in whole blood specimens. The resulting list was further analysed to address different geographical regions (Asia, Africa, and Latin America), and Cohen kappa scores of agreement were calculated. RESULTS The expert ranked prioritized pathogen list generated as part of this two-pronged approach included typhoidal Salmonella, Plasmodium species and Mycobacterium tuberculosis as the top 3 pathogens. This pathogen list was then further adapted for the SFWS use case to develop a final pathogen list to inform product development. Subsequent analysis comparing the relevance of the SFWS pathogen list to multiple populations and geographical regions showed that the SFWS prioritized list had considerable utility across Africa and Asia, but less so for Latin America. In addition, the list showed high levels of agreement across different patient sub-populations, but lower relevance for neonates and symptomatic HIV patients. CONCLUSION This work highlighted once again the challenges of prioritising in global health, but it also shows that taking a two-pronged approach, combining available prevalence data with expert input, can result in a broadly applicable priority list. This comprehensive utility is particularly important in the context of product development, where a sufficient market size is essential to achieve a sustainable commercialized diagnostic product to address SFWS.
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Zeitschriftenartikel

  • J. Moreira
  • J. Barros
  • O. Lapouble
  • M. Lacerda
  • I. Felger
  • P. Brasil
  • Sabine Dittrich
  • A. Siqueira

When fever is not malaria in Latin America: a systematic review

In: BMC Medicine vol. 18 pg. 294.

  • 21.09.2020 (2020)

DOI: 10.1186/s12916-020-01746-z

BACKGROUND In malaria-endemic countries, febrile episodes caused by diseases other than malaria are a growing concern. However, limited knowledge of the prevalent etiologic agents and their geographic distributions restrict the ability of health services to address non-malarial morbidity and mortality through effective case management. Here, we review the etiology of fever in Latin America (LA) between 1980 and 2015 and map significant pathogens commonly implicated in febrile infectious diseases. METHODS A literature search was conducted, without language restrictions, in three distinct databases in order to identify fever etiology studies that report laboratory-confirmed fever-causing pathogens that were isolated from usually sterile body sites. Data analyses and mapping was conducted with Tableau Desktop (version 2018.2.3). RESULTS Inclusion criteria were met by 625 publications corresponding to data relative to 34 countries. Studies using serology (n = 339) predominated for viral infections, culture (n = 131) for bacteria, and microscopy (n = 62) for fungi and parasites. The pathogen groups most frequently reported were viral infections (n = 277), bacterial infections (n = 265), parasitic infections (n = 59), fungal infections (n = 47), and more than one pathogen group (n = 24). The most frequently reported virus was dengue virus (n = 171), followed by other arboviruses (n = 55), and hantavirus (n = 18). For bacteria, Staphylococcus spp. (n = 82), Rickettsia spp. (n = 70), and Leptospira spp. (n = 55) were frequently reported. Areas with biggest gaps on etiology of fever were apparent. CONCLUSIONS This review provides a landscape of pathogens causing febrile illness other than malaria in LA for over 30 years. Our findings highlight the need to standardize protocols and report guidelines for fever etiology studies for better comparability of results and improved interpretation. Lastly, we should improve existing national laboratory surveillance systems, especially from low- to middle-income countries, to inform global fever policy priorities and timely identify emerging infections threats. STUDY REGISTRATION PROSPERO systematic review registration number: CRD42016049281.
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Zeitschriftenartikel

  • J. Moreira
  • C. Escadafal
  • Sabine Dittrich
  • P. Brasil
  • A. Siqueira

Antibiotic prescription and antipyretic use in febrile patients attending emergency departments in Rio de Janeiro, Brazil: A cross-sectional study

In: International Journal of Infectious Diseases vol. 101 pg. 410-411.

  • (2020)

DOI: 10.1016/j.ijid.2020.09.1077

Background: Fever is a leading cause of a visit to Emergency Departments (ED), and few studies described the antibiotic prescription in this setting across Latin America. Antipyretics are commonly used home medications that result in a lowering of temperature when a patient comes seeking care. We aim to evaluate antibiotic prescription and antipyretic use at home among patients presenting to ED with a complaint of fever in Rio de Janeiro, Brazil. Methods & Materials: We did a cross-sectional study of patients who presented with fever to two urban ED between October 25, 2018, and March 29, 2019. Eligible subjects had a history of fever ≤7 days or had a measured temperature ≥37.5°C at the ED. Consented participants were interviewed and medical records were reviewed to extract information related to diagnosis and prescribed antibiotics. Results: Of 1551 triaged patients, 374 (24.1%) presented with fever. Among those, 248 (66.3%) had a temperature ≥37.5°C at arrival at the ED. The mean age was 30.6 [0–84] years, adults (82.5%) and females (54.8%) predominated. Suspicion of infection was attributed in 198/374 (53%), and upper respiratory tract infection 84/198 (42.4%) was the primary source of infection. Antibiotic was prescribed to 131/374 (35%) and varied accordingly to the foci of infection and the temperature recorded. Patients who had temperature ≥37.5°C at presentation were more likely to be diagnosed with an infection [OR: 2.2 (95% 1.4–3.5)] and were prescribed antibiotics most frequently [OR: 2 (95% 1.1–3.5)] compared to those with temperature <37.5°C. The antibiotic class most frequently prescribed was beta-lactam (57%), quinolone (17.5%), and macrolide (16.7%). A total of 249/374 (66.6%) received antipyretic at home and dipyrone (72.2%) was the antipyretic of choice. Conclusion: Antibiotic prescription in febrile patients presenting to the surveyed ED is common and respiratory infections accounted for the main indication for a prescription. These data highlight the need for more concerted interventions targeting the rational use of antibiotics. Antipyretics use is ubiquitous, and their use might influence clinical decisions in febrile patients.
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Zeitschriftenartikel

  • S. Incardona
  • D. Bell
  • A. Campillo
  • J. Cunningham
  • F. Ariey
  • T. Fandeur
  • J. Luchavez
  • C. Luna
  • D. Ménard
  • S. Nhem
  • J. Sornillo
  • B. Witkowski
  • Z. Katz
  • Sabine Dittrich
  • X. Ding

Keep the quality high: the benefits of lot testing for the quality control of malaria rapid diagnostic tests

In: Malaria Journal vol. 19 pg. 247.

  • 13.07.2020 (2020)

DOI: 10.1186/s12936-020-03324-3

BACKGROUND The production and use of malaria rapid diagnostic tests (RDTs) has risen dramatically over the past 20 years. In view of weak or non-existing in vitro diagnostics (IVD) regulations and post-marketing surveillance (PMS) systems in malaria endemic countries, the World Health Organization, later joined by the Foundation for Innovative New Diagnostics, established an independent, centralized performance evaluation and Lot Testing (LT) programme to safeguard against poor quality of RDTs being distributed through the public health sector of malaria endemic countries. RDT performances and manufacturer quality management systems have evolved over the past decade raising questions about the future need for a centralized LT programme. RESULTS Between 2007 and 2017, 6056 lots have been evaluated, representing approximately 1.6 Billion RDTs. A total of 69 lots (1.1%) failed the quality control. Of these failures, 26 were detected at receipt of the RDT lot in the LT laboratory, representing an estimated 7.9 million poor quality RDTs, and LT requesters were advised that RDTs were not of sufficient quality for use in patient management. Forty-three were detected after long-term storage in the laboratory, of which 24 (56%) were found to be due to a major issue with insufficient buffer volume in single use buffer vials, others predominantly showing loss of sensitivity. The annual cost of running the programme, based on expenses recorded in years 2014-2016, an estimated volume of 700 lots per year and including replenishment of quality control samples, was estimated at US$ 178,500 ($US 255 per lot tested). CONCLUSIONS Despite the clear benefits of the centralized LT programme and its low cost compared with the potential costs of each country establishing its own PMS system for RDTs, funding concerns have made its future beyond 2020 uncertain. In order to manage the risks of misdiagnosis due to low quality RDTs, and to ensure the continued safety and reliability of malaria case management, there is a need to ensure that an effective and implementable approach to RDT quality control continues to be available to programmes in endemic countries.
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Zeitschriftenartikel

  • J. Deeks
  • J. Dinnes
  • Y. Takwoingi
  • C. Davenport
  • R. Spijker
  • S. Taylor-Phillips
  • A. Adriano
  • S. Beese
  • J. Dretzke
  • L. Di Ferrante Ruffano
  • I. Harris
  • M. Price
  • Sabine Dittrich
  • D. Emperador
  • L. Hooft
  • M. Leeflang
  • A. van den Bruel

Antibody tests for identification of current and past infection with SARS-CoV-2

In: The Cochrane Database of Systematic Reviews vol. 6 pg. CD013652.

  • 25.06.2020 (2020)

DOI: 10.1002/14651858.cd013652

BACKGROUND The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and resulting COVID-19 pandemic present important diagnostic challenges. Several diagnostic strategies are available to identify current infection, rule out infection, identify people in need of care escalation, or to test for past infection and immune response. Serology tests to detect the presence of antibodies to SARS-CoV-2 aim to identify previous SARS-CoV-2 infection, and may help to confirm the presence of current infection. OBJECTIVES To assess the diagnostic accuracy of antibody tests to determine if a person presenting in the community or in primary or secondary care has SARS-CoV-2 infection, or has previously had SARS-CoV-2 infection, and the accuracy of antibody tests for use in seroprevalence surveys. SEARCH METHODS We undertook electronic searches in the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions. We conducted searches for this review iteration up to 27 April 2020. SELECTION CRITERIA We included test accuracy studies of any design that evaluated antibody tests (including enzyme-linked immunosorbent assays, chemiluminescence immunoassays, and lateral flow assays) in people suspected of current or previous SARS-CoV-2 infection, or where tests were used to screen for infection. We also included studies of people either known to have, or not to have SARS-CoV-2 infection. We included all reference standards to define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction tests (RT-PCR) and clinical diagnostic criteria). DATA COLLECTION AND ANALYSIS We assessed possible bias and applicability of the studies using the QUADAS-2 tool. We extracted 2x2 contingency table data and present sensitivity and specificity for each antibody (or combination of antibodies) using paired forest plots. We pooled data using random-effects logistic regression where appropriate, stratifying by time since post-symptom onset. We tabulated available data by test manufacturer. We have presented uncertainty in estimates of sensitivity and specificity using 95% confidence intervals (CIs). MAIN RESULTS We included 57 publications reporting on a total of 54 study cohorts with 15,976 samples, of which 8526 were from cases of SARS-CoV-2 infection. Studies were conducted in Asia (n = 38), Europe (n = 15), and the USA and China (n = 1). We identified data from 25 commercial tests and numerous in-house assays, a small fraction of the 279 antibody assays listed by the Foundation for Innovative Diagnostics. More than half (n = 28) of the studies included were only available as preprints. We had concerns about risk of bias and applicability. Common issues were use of multi-group designs (n = 29), inclusion of only COVID-19 cases (n = 19), lack of blinding of the index test (n = 49) and reference standard (n = 29), differential verification (n = 22), and the lack of clarity about participant numbers, characteristics and study exclusions (n = 47). Most studies (n = 44) only included people hospitalised due to suspected or confirmed COVID-19 infection. There were no studies exclusively in asymptomatic participants. Two-thirds of the studies (n = 33) defined COVID-19 cases based on RT-PCR results alone, ignoring the potential for false-negative RT-PCR results. We observed evidence of selective publication of study findings through omission of the identity of tests (n = 5). We observed substantial heterogeneity in sensitivities of IgA, IgM and IgG antibodies, or combinations thereof, for results aggregated across different time periods post-symptom onset (range 0% to 100% for all target antibodies). We thus based the main results of the review on the 38 studies that stratified results by time since symptom onset. The numbers of individuals contributing data within each study each week are small and are usually not based on tracking the same groups of patients over time. Pooled results for IgG, IgM, IgA, total antibodies and IgG/IgM all showed low sensitivity during the first week since onset of symptoms (all less than 30.1%), rising in the second week and reaching their highest values in the third week. The combination of IgG/IgM had a sensitivity of 30.1% (95% CI 21.4 to 40.7) for 1 to 7 days, 72.2% (95% CI 63.5 to 79.5) for 8 to 14 days, 91.4% (95% CI 87.0 to 94.4) for 15 to 21 days. Estimates of accuracy beyond three weeks are based on smaller sample sizes and fewer studies. For 21 to 35 days, pooled sensitivities for IgG/IgM were 96.0% (95% CI 90.6 to 98.3). There are insufficient studies to estimate sensitivity of tests beyond 35 days post-symptom onset. Summary specificities (provided in 35 studies) exceeded 98% for all target antibodies with confidence intervals no more than 2 percentage points wide. False-positive results were more common where COVID-19 had been suspected and ruled out, but numbers were small and the difference was within the range expected by chance. Assuming a prevalence of 50%, a value considered possible in healthcare workers who have suffered respiratory symptoms, we would anticipate that 43 (28 to 65) would be missed and 7 (3 to 14) would be falsely positive in 1000 people undergoing IgG/IgM testing at days 15 to 21 post-symptom onset. At a prevalence of 20%, a likely value in surveys in high-risk settings, 17 (11 to 26) would be missed per 1000 people tested and 10 (5 to 22) would be falsely positive. At a lower prevalence of 5%, a likely value in national surveys, 4 (3 to 7) would be missed per 1000 tested, and 12 (6 to 27) would be falsely positive. Analyses showed small differences in sensitivity between assay type, but methodological concerns and sparse data prevent comparisons between test brands. AUTHORS' CONCLUSIONS The sensitivity of antibody tests is too low in the first week since symptom onset to have a primary role for the diagnosis of COVID-19, but they may still have a role complementing other testing in individuals presenting later, when RT-PCR tests are negative, or are not done. Antibody tests are likely to have a useful role for detecting previous SARS-CoV-2 infection if used 15 or more days after the onset of symptoms. However, the duration of antibody rises is currently unknown, and we found very little data beyond 35 days post-symptom onset. We are therefore uncertain about the utility of these tests for seroprevalence surveys for public health management purposes. Concerns about high risk of bias and applicability make it likely that the accuracy of tests when used in clinical care will be lower than reported in the included studies. Sensitivity has mainly been evaluated in hospitalised patients, so it is unclear whether the tests are able to detect lower antibody levels likely seen with milder and asymptomatic COVID-19 disease. The design, execution and reporting of studies of the accuracy of COVID-19 tests requires considerable improvement. Studies must report data on sensitivity disaggregated by time since onset of symptoms. COVID-19-positive cases who are RT-PCR-negative should be included as well as those confirmed RT-PCR, in accordance with the World Health Organization (WHO) and China National Health Commission of the People's Republic of China (CDC) case definitions. We were only able to obtain data from a small proportion of available tests, and action is needed to ensure that all results of test evaluations are available in the public domain to prevent selective reporting. This is a fast-moving field and we plan ongoing updates of this living systematic review.
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Zeitschriftenartikel

  • S. Pokharel
  • L. White
  • R. Aguas
  • O. Celhay
  • K. Pellé
  • Sabine Dittrich

Algorithm in the Diagnosis of Febrile Illness Using Pathogen-specific Rapid Diagnostic Tests

In: Clinical Infectious Diseases : an official publication of the Infectious Diseases Society of America vol. 70 pg. 2262-2269.

  • (2020)

DOI: 10.1093/cid/ciz665

BACKGROUND In the absence of proper guidelines and algorithms, available rapid diagnostic tests (RDTs) for common acute undifferentiated febrile illnesses are often used inappropriately. METHODS Using prevalence data of 5 common febrile illnesses from India and Cambodia, and performance characteristics (sensitivity and specificity) of relevant pathogen-specific RDTs, we used a mathematical model to predict the probability of correct identification of each disease when diagnostic testing occurs either simultaneously or sequentially in various algorithms. We developed a web-based application of the model so as to visualize and compare output diagnostic algorithms when different disease prevalence and test performance characteristics are introduced. RESULTS Diagnostic algorithms with appropriate sequential testing predicted correct identification of etiology in 74% and 89% of patients in India and Cambodia, respectively, compared with 46% and 49% with simultaneous testing. The optimally performing sequential diagnostic algorithms differed in India and Cambodia due to varying disease prevalence. CONCLUSIONS Simultaneous testing is not appropriate for the diagnosis of acute undifferentiated febrile illnesses with presently available tests, which should deter the unsupervised use of multiplex diagnostic tests. The implementation of adaptive algorithms can predict better diagnosis and add value to the available RDTs. The web application of the model can serve as a tool to identify the optimal diagnostic algorithm in different epidemiological settings, while taking into account the local epidemiological variables and accuracy of available tests.
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Zeitschriftenartikel

  • C. Escadafal
  • S. Geis
  • A. Siqueira
  • S. Agnandji
  • T. Shimelis
  • B. Tadesse
  • M. Massinga Loembé
  • V. Harris
  • B. Fernandez-Carballo
  • A. Macé
  • S. Ongarello
  • W. Rodriguez
  • Sabine Dittrich

Bacterial versus non-bacterial infections: a methodology to support use-case-driven product development of diagnostics

In: BMJ Global Health vol. 5

  • (2020)

DOI: 10.1136/bmjgh-2020-003141

Acute febrile illness (AFI) is one of the most common reasons for seeking medical care in low-income and middle-income countries. Bacterial infections account for a relatively small proportion of AFIs; however, in the absence of a simple diagnostic test to guide clinical decisions, healthcare professionals often presume that a non-malarial febrile illness is bacterial in origin, potentially resulting in inappropriate antibiotic use. An accurate differential diagnostic tool for AFIs is thus essential, to both limit antibiotic use to bacterial infections and address the antimicrobial resistance crisis that is emerging globally, without resorting to multiple or complex pathogen-specific assays. The Biomarker for Fever-Diagnostic (BFF-Dx) study is one of the largest fever biomarker studies ever undertaken. We collected samples and classified disease aetiology in more than 1900 individuals, distributed among enrolment centres in three countries on two continents. Identical protocols were followed at each study site, and the same analyses were conducted in each setting, enabling like-with-like comparisons to be made among the large sample set generated. The BFF-Dx methodology can act as a model for other researchers, facilitating wider utility of the work in the future. The established sample collection is now accessible to researchers and companies and will facilitate the development of future fever-related diagnostic tests. Here, we outline the methodology used to determine the sample populations and to differentiate bacterial versus non-bacterial AFIs. Future publications will set out in more detail the study's demographics, the causes of fever identified and the performance of selected biomarkers.
  • Europan Campus Rottal-Inn
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Zeitschriftenartikel

  • I. Stegeman
  • E. Ochodo
  • F. Guleid
  • G. Holtman
  • B. Yang
  • C. Davenport
  • J. Deeks
  • J. Dinnes
  • Sabine Dittrich
  • D. Emperador
  • L. Hooft
  • R. Spijker
  • Y. Takwoingi
  • A. van den Bruel
  • Wang, J.
  • M. Langendam
  • J. Verbakel
  • M. Leeflang

Routine laboratory testing to determine if a patient has COVID-19

In: The Cochrane Database of Systematic Reviews vol. 11 pg. CD013787.

  • 19.11.2020 (2020)

DOI: 10.1002/14651858.cd013787

BACKGROUND Specific diagnostic tests to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and resulting COVID-19 disease are not always available and take time to obtain results. Routine laboratory markers such as white blood cell count, measures of anticoagulation, C-reactive protein (CRP) and procalcitonin, are used to assess the clinical status of a patient. These laboratory tests may be useful for the triage of people with potential COVID-19 to prioritize them for different levels of treatment, especially in situations where time and resources are limited. OBJECTIVES To assess the diagnostic accuracy of routine laboratory testing as a triage test to determine if a person has COVID-19. SEARCH METHODS On 4 May 2020 we undertook electronic searches in the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions. SELECTION CRITERIA We included both case-control designs and consecutive series of patients that assessed the diagnostic accuracy of routine laboratory testing as a triage test to determine if a person has COVID-19. The reference standard could be reverse transcriptase polymerase chain reaction (RT-PCR) alone; RT-PCR plus clinical expertise or and imaging; repeated RT-PCR several days apart or from different samples; WHO and other case definitions; and any other reference standard used by the study authors. DATA COLLECTION AND ANALYSIS Two review authors independently extracted data from each included study. They also assessed the methodological quality of the studies, using QUADAS-2. We used the 'NLMIXED' procedure in SAS 9.4 for the hierarchical summary receiver operating characteristic (HSROC) meta-analyses of tests for which we included four or more studies. To facilitate interpretation of results, for each meta-analysis we estimated summary sensitivity at the points on the SROC curve that corresponded to the median and interquartile range boundaries of specificities in the included studies. MAIN RESULTS We included 21 studies in this review, including 14,126 COVID-19 patients and 56,585 non-COVID-19 patients in total. Studies evaluated a total of 67 different laboratory tests. Although we were interested in the diagnotic accuracy of routine tests for COVID-19, the included studies used detection of SARS-CoV-2 infection through RT-PCR as reference standard. There was considerable heterogeneity between tests, threshold values and the settings in which they were applied. For some tests a positive result was defined as a decrease compared to normal vaues, for other tests a positive result was defined as an increase, and for some tests both increase and decrease may have indicated test positivity. None of the studies had either low risk of bias on all domains or low concerns for applicability for all domains. Only three of the tests evaluated had a summary sensitivity and specificity over 50%. These were: increase in interleukin-6, increase in C-reactive protein and lymphocyte count decrease. Blood count Eleven studies evaluated a decrease in white blood cell count, with a median specificity of 93% and a summary sensitivity of 25% (95% CI 8.0% to 27%; very low-certainty evidence). The 15 studies that evaluated an increase in white blood cell count had a lower median specificity and a lower corresponding sensitivity. Four studies evaluated a decrease in neutrophil count. Their median specificity was 93%, corresponding to a summary sensitivity of 10% (95% CI 1.0% to 56%; low-certainty evidence). The 11 studies that evaluated an increase in neutrophil count had a lower median specificity and a lower corresponding sensitivity. The summary sensitivity of an increase in neutrophil percentage (4 studies) was 59% (95% CI 1.0% to 100%) at median specificity (38%; very low-certainty evidence). The summary sensitivity of an increase in monocyte count (4 studies) was 13% (95% CI 6.0% to 26%) at median specificity (73%; very low-certainty evidence). The summary sensitivity of a decrease in lymphocyte count (13 studies) was 64% (95% CI 28% to 89%) at median specificity (53%; low-certainty evidence). Four studies that evaluated a decrease in lymphocyte percentage showed a lower median specificity and lower corresponding sensitivity. The summary sensitivity of a decrease in platelets (4 studies) was 19% (95% CI 10% to 32%) at median specificity (88%; low-certainty evidence). Liver function tests The summary sensitivity of an increase in alanine aminotransferase (9 studies) was 12% (95% CI 3% to 34%) at median specificity (92%; low-certainty evidence). The summary sensitivity of an increase in aspartate aminotransferase (7 studies) was 29% (95% CI 17% to 45%) at median specificity (81%) (low-certainty evidence). The summary sensitivity of a decrease in albumin (4 studies) was 21% (95% CI 3% to 67%) at median specificity (66%; low-certainty evidence). The summary sensitivity of an increase in total bilirubin (4 studies) was 12% (95% CI 3.0% to 34%) at median specificity (92%; very low-certainty evidence). Markers of inflammation The summary sensitivity of an increase in CRP (14 studies) was 66% (95% CI 55% to 75%) at median specificity (44%; very low-certainty evidence). The summary sensitivity of an increase in procalcitonin (6 studies) was 3% (95% CI 1% to 19%) at median specificity (86%; very low-certainty evidence). The summary sensitivity of an increase in IL-6 (four studies) was 73% (95% CI 36% to 93%) at median specificity (58%) (very low-certainty evidence). Other biomarkers The summary sensitivity of an increase in creatine kinase (5 studies) was 11% (95% CI 6% to 19%) at median specificity (94%) (low-certainty evidence). The summary sensitivity of an increase in serum creatinine (four studies) was 7% (95% CI 1% to 37%) at median specificity (91%; low-certainty evidence). The summary sensitivity of an increase in lactate dehydrogenase (4 studies) was 25% (95% CI 15% to 38%) at median specificity (72%; very low-certainty evidence). AUTHORS' CONCLUSIONS Although these tests give an indication about the general health status of patients and some tests may be specific indicators for inflammatory processes, none of the tests we investigated are useful for accurately ruling in or ruling out COVID-19 on their own. Studies were done in specific hospitalized populations, and future studies should consider non-hospital settings to evaluate how these tests would perform in people with milder symptoms.
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Zeitschriftenartikel

  • L. Porte
  • P. Legarraga
  • V. Vollrath
  • X. Aguilera
  • J. Munita
  • R. Araos
  • G. Pizarro
  • P. Vial
  • M. Iruretagoyena
  • Sabine Dittrich
  • T. Weitzel

Evaluation of a novel antigen-based rapid detection test for the diagnosis of SARS-CoV-2 in respiratory samples

In: International Journal of Infectious Diseases vol. 99 pg. 328-333.

  • 01.06.2020 (2020)

DOI: 10.1016/j.ijid.2020.05.098

OBJECTIVES In the context of the coronavirus disease 2019 (COVID-19) pandemic, the development and validation of rapid and easy-to-perform diagnostic methods are of high priority. This study was performed to evaluate a novel rapid antigen detection test (RDT) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory samples. METHODS The fluorescence immunochromatographic SARS-CoV-2 antigen test (Bioeasy Biotechnology Co., Shenzhen, China) was evaluated using universal transport medium with nasopharyngeal (NP) and oropharyngeal (OP) swabs from suspected COVID-19 cases. Diagnostic accuracy was determined in comparison to SARS-CoV-2 real-time (RT)-PCR. RESULTS A total of 127 samples were included; 82 were RT-PCR-positive. The median patient age was 38 years, 53.5% were male, and 93.7% were from the first week after symptom onset. Overall sensitivity and specificity were 93.9% (95% confidence interval 86.5-97.4%) and 100% (95% confidence interval 92.1-100%), respectively, with a diagnostic accuracy of 96.1% and Kappa coefficient of 0.9. Sensitivity was significantly higher in samples with high viral loads. CONCLUSIONS The RDT evaluated in this study showed a high sensitivity and specificity in samples mainly obtained during the first week of symptoms and with high viral loads, despite the use of a non-validated sample material. The assay has the potential to become an important tool for early diagnosis of SARS-CoV-2, particularly in situations with limited access to molecular methods.
  • Europan Campus Rottal-Inn
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Zeitschriftenartikel

  • T. Shimelis
  • B. Tadesse
  • F. W/Gebriel
  • J. Crump
  • G. Schierhout
  • Sabine Dittrich
  • J. Kaldor
  • S. Vaz Nery

Aetiology of acute febrile illness among children attending a tertiary hospital in southern Ethiopia

In: BMC Infectious Diseases vol. 20 pg. 903.

  • 30.11.2020 (2020)

DOI: 10.1186/s12879-020-05635-x

BACKGROUND The diagnosis of non-malarial aetiologies, which now represent the majority of febrile illnesses, has remained problematic in settings with limited laboratory capacity. We aimed to describe common aetiologies of acute febrile illness among children in a setting where malaria transmission has declined. METHODS A prospective cross-sectional study was conducted among children aged at least 2 months and under 13 years presenting with fever (temperature of ≥37.5 °C or a history of fever in the past 48 h) to Hawassa Comprehensive Specialized Hospital, southern Ethiopia, from May 2018 through February 2019. Clinical and demographic data were gathered for consecutive participants, and malaria microscopy, HIV testing, and blood and urine cultures were performed regardless of clinical presentation. Additionally, stool analyses (culture and rotavirus/adenovirus RDT) and throat swab for group A Streptococcus (GAS) and urine Streptococcus pneumoniae were performed by RDTs for children with specific conditions. The antimicrobial susceptibility of bacterial isolates was determined using disc diffusion method. RESULTS During the study period 433 children were recruited, median age 20 months (range, 2 months - 12 years) and 178 (41.1%) female. Malaria was diagnosed in 14 (3.2%) of 431 children, and 3 (0.7%) had HIV infection. Bacteraemia or fungaemia was detected in 27 (6.4%) of 421 blood cultures, with Staphylococcus aureus isolated in 16 (3.8%). Urinary tract infections (UTIs) were detected in 74 (18.4%) of 402, with Escherichia coli isolated in 37 (9.2%). Among 56 children whose stool specimens were tested, 14 (25%) were positive for rotavirus, 1 (1.8%) for Salmonella Paratyphi A, and 1 (1.8%) for Shigella dysenteriae. Among those with respiratory symptoms, a throat swab test for GAS and urine test for S. pneumoniae were positive in 28 (15.8%) of 177 and 31 (17.0%) of 182, respectively. No test was positive for a pathogen in 266 (61.4%) of 433 participants. Bacterial isolates were frequently resistant to ampicillin, trimethoprim-sulfamethoxazole, tetracycline, and amoxicillin and clavulanic acid. CONCLUSION Our results showed low proportions of malaria and bacteraemia among febrile children. In contrast, the frequent detection of UTI emphasize the need to support enhanced diagnostic capacity to ensure appropriate antimicrobial intervention.
  • Europan Campus Rottal-Inn
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Zeitschriftenartikel

  • J. Deeks
  • J. Dinnes
  • Y. Takwoingi
  • C. Davenport
  • M. Leeflang
  • R. Spijker
  • L. Hooft
  • A. van den Bruel
  • D. Emperador
  • Sabine Dittrich

Diagnosis of SARS-CoV-2 infection and COVID-19: accuracy of signs and symptoms; molecular, antigen, and antibody tests; and routine laboratory markers

In: Cochrane Database of Systematic Reviews

  • (2020)

DOI: 10.1002/14651858.CD013596

Objectives This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows: To assess the diagnostic accuracy of laboratory real‐time polymerase chain reaction (RT‐PCR) and other laboratory molecular tests to determine if a person presenting in the community or in secondary care has SARS‐CoV‐2 infection. To assess the diagnostic accuracy of each rapid PCR and antigen test to determine if a person presenting in the community or in secondary care has SARS‐CoV‐2 infection. To assess the diagnostic accuracy of each antibody test to determine if a person presenting in the community or in secondary care has SARS‐CoV‐2 infection, or has previously had SARS‐CoV‐2 infection. To assess the diagnostic accuracy of signs and symptoms to determine if a person presenting in the community, general practice, or at the emergency department has SARS‐CoV‐2 infection, COVID‐19 pneumonia, or severe COVID‐19 pneumonia/ARDS requiring hospital admission. To assess the diagnostic accuracy of routine laboratory testing to determine if a person has COVID‐19 pneumonia or SARS‐CoV‐2 infection. Secondary objectives Where data are available, for reviews #1 to #5, we will investigate the accuracy (either by stratified analysis or meta‐regression) according to: laboratory method, days of symptoms, severity of symptoms, reference standard, sample type, study design, setting; test brand and version, days of symptoms, severity of symptoms, reference standard, sample type, study design, setting; current infection or past infection, test brand and version, days of symptoms or days since symptoms resolved, reference standard, study design, setting; days of symptoms, reference standard, study design, setting; specific measurement or biomarker, days of symptoms, severity of symptoms, reference standard, sample type, study design, setting.
  • Europan Campus Rottal-Inn
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Zeitschriftenartikel

  • M. Cheng
  • J. Papenburg
  • M. Desjardins
  • S. Kanjilal
  • C. Quach
  • M. Libman
  • Sabine Dittrich
  • C. Yansouni

Diagnostic Testing for Severe Acute Respiratory Syndrome-Related Coronavirus 2: A Narrative Review

In: Annals of Internal Medicine vol. 172 pg. 726-734.

  • 13.04.2020 (2020)

DOI: 10.7326/m20-1301

Diagnostic testing to identify persons infected with severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection is central to control the global pandemic of COVID-19 that began in late 2019. In a few countries, the use of diagnostic testing on a massive scale has been a cornerstone of successful containment strategies. In contrast, the United States, hampered by limited testing capacity, has prioritized testing for specific groups of persons. Real-time reverse transcriptase polymerase chain reaction-based assays performed in a laboratory on respiratory specimens are the reference standard for COVID-19 diagnostics. However, point-of-care technologies and serologic immunoassays are rapidly emerging. Although excellent tools exist for the diagnosis of symptomatic patients in well-equipped laboratories, important gaps remain in screening asymptomatic persons in the incubation phase, as well as in the accurate determination of live viral shedding during convalescence to inform decisions to end isolation. Many affluent countries have encountered challenges in test delivery and specimen collection that have inhibited rapid increases in testing capacity. These challenges may be even greater in low-resource settings. Urgent clinical and public health needs currently drive an unprecedented global effort to increase testing capacity for SARS-CoV-2 infection. Here, the authors review the current array of tests for SARS-CoV-2, highlight gaps in current diagnostic capacity, and propose potential solutions.
  • Europan Campus Rottal-Inn
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Zeitschriftenartikel

  • R Kadam
  • W. White
  • N. Banks
  • Z. Katz
  • Sabine Dittrich
  • C. Kelly-Cirino

Target Product Profile for a mobile app to read rapid diagnostic tests to strengthen infectious disease surveillance

In: PLoS One vol. 15 pg. e0228311.

  • 29.01.2020 (2020)

DOI: 10.1371/journal.pone.0228311

The essential role of rapid diagnostic tests (RDTs) in disease control is compromised every time a test is not performed correctly or its result is not reported accurately and promptly. A mobile app that utilizes the camera and connectivity of a common smartphone can fill this role of supporting the test's proper execution and the automatic transmission of results. In a consensus process with 51 expert participants representing the needs of clinical users, healthcare programs, health information systems, surveillance systems, and global public health stakeholders, we developed a Target Product Profile describing the minimal and optimal characteristics of such an app. We collected feedback over two rounds and refined the characteristics to arrive at a preferred agreement level of greater than 75%, with an average of 92% agreement (range: 79-100%). As per this feedback, such an app should be compatible with many RDTs and mobile devices without needing accessories. The app should assist the user with RDT-specific instructions, include checks to facilitate quality control of the testing process and suggest results with ≥ 95% accuracy across common lighting conditions while allowing the user to determine the final result. Data from the app must be under the control of the health program that operates it, and the app should support at least one of the common data exchange formats HL7, FHIR, ASTM or JSON. The Target Product Profile also lays out the minimum data security and privacy requirements for the app.
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Zeitschriftenartikel

  • J. Wongsantichon
  • Y. Jaiyen
  • Sabine Dittrich
  • J. Salje

Orientia tsutsugamushi

In: Trends in Microbiology vol. 28 pg. 780-781.

  • 23.03.2020 (2020)

DOI: 10.1016/j.tim.2020.02.014

Orientia tsutsugamushi is an obligate intracellular bacterial pathogen that causes the mite-borne human disease scrub typhus, one of the most widespread and severe rickettsial infections. Symptoms typically begin 7–14 days after inoculation and include headache, fever, rash, myalgia, and a painless eschar at the site of the mite’s bite. Untreated, the disease can escalate to cause multiple organ failure and death. Major challenges to disease control include slow and inaccurate diagnostic tests and low awareness amongst clinicians. O. tsutsugamushi infects a range of host cell types including endothelial cells, monocytes/macrophages, and dendritic cells, and it replicates directly in the host cell cytoplasm. Aspects of its infection cycle and biology differentiate it from other genera in the family Rickettsiaceae; these include a microtubule-driven mode of motility, a budding mechanism of host cell exit, a minimal peptidoglycan-like cell wall, and a highly repetitive genome.
  • Europan Campus Rottal-Inn
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Zeitschriftenartikel

  • M. Cheng
  • C. Yansouni
  • N. Basta
  • M. Desjardins
  • S. Kanjilal
  • K. Paquette
  • C. Caya
  • M. Semret
  • C. Quach
  • M. Libman
  • L. Mazzola
  • J. Sacks
  • Sabine Dittrich
  • J. Papenburg

Serodiagnostics for Severe Acute Respiratory Syndrome-Related Coronavirus 2 : A Narrative Review

In: Annals of Internal Medicine vol. 173 pg. 450-460.

  • 04.06.2020 (2020)

DOI: 10.7326/m20-2854

Accurate serologic tests to detect host antibodies to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) will be critical for the public health response to the coronavirus disease 2019 pandemic. Many use cases are envisaged, including complementing molecular methods for diagnosis of active disease and estimating immunity for individuals. At the population level, carefully designed seroepidemiologic studies will aid in the characterization of transmission dynamics and refinement of disease burden estimates and will provide insight into the kinetics of humoral immunity. Yet, despite an explosion in the number and availability of serologic assays to test for antibodies against SARS-CoV-2, most have undergone minimal external validation to date. This hinders assay selection and implementation, as well as interpretation of study results. In addition, critical knowledge gaps remain regarding serologic correlates of protection from infection or disease, and the degree to which these assays cross-react with antibodies against related coronaviruses. This article discusses key use cases for SARS-CoV-2 antibody detection tests and their application to serologic studies, reviews currently available assays, highlights key areas of ongoing research, and proposes potential strategies for test implementation.
  • Europan Campus Rottal-Inn
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Zeitschriftenartikel

  • K. Phakhounthong
  • M. Mukaka
  • Sabine Dittrich
  • A. Tanganuchitcharnchai
  • N. Day
  • L. White
  • P. Newton
  • S. Blacksell

The temporal dynamics of humoral immunity to Rickettsia typhi infection in murine typhus patients

In: Clinical Microbiology and Infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases vol. 26 pg. 781.e9-781.e16.

  • 31.10.2019 (2020)

DOI: 10.1016/j.cmi.2019.10.022

OBJECTIVES This study examined individuals with Rickettsia typhi infection in the Lao People's Democratic Republic (Lao PDR) to (a) investigate humoral immune dynamics; (b) determine the differences in reference diagnostic results and recommend appropriate cut-offs; (c) determine differences in immune response after different antibiotic treatments; and (d) determine appropriate diagnostic cut-off parameters for indirect immunofluorescence assay (IFA). METHODS Sequential serum samples from 90 non-pregnant, adults were collected at seven time-points (days 0, 7, 14, 28, 90, 180 and 365) as part of a clinical antibiotic treatment trial. Samples were tested using IFA to determine IgM and IgG antibody reciprocal end-point titres against R. typhi and PCR. RESULTS For all 90 individuals, reciprocal R. typhi IgM and IgG antibody titres ranged from <400 to ≥3200. The median half-life of R. typhi IgM was 126 days (interquartile range 36-204 days) and IgG was 177 days (interquartile range 134-355 days). Overall median patient titres for R. typhi IgM and IgG were significantly different (p < 0.0001) and at each temporal sample collection point (range p < 0.0001 to p 0.0411). Using Bayesian latent class model analysis, the optimal diagnostic cut-off reciprocal IFA titer on patient admission for IgM was 800 (78.6%, 95% CI 71.6%-85.2% sensitivity; 89.9%, 95% CI 62.5%-100% specificity), and for IFA IgG 1600 (77.3%; 95% CI 68.2%-87.6% sensitivity; 99%, 95% CI 95%-100% specificity). CONCLUSIONS This study suggests suitable diagnostic cut-offs for local diagnostic laboratories and other endemic settings and highlights antibody persistence following acute infection. Further studies are required to validate and define cut-offs in other geographically diverse locations.
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Zeitschriftenartikel

  • T. Struyf
  • J. Deeks
  • J. Dinnes
  • Y. Takwoingi
  • C. Davenport
  • M. Leeflang
  • R. Spijker
  • L. Hooft
  • D. Emperador
  • Sabine Dittrich
  • J. Domen
  • S. Horn
  • A. van den Bruel

Signs and symptoms to determine if a patient presenting in primary care or hospital outpatient settings has COVID-19 disease

In: The Cochrane Database of Systematic Reviews vol. 7 pg. CD013665.

  • 07.07.2020 (2020)

DOI: 10.1002/14651858.cd013665

BACKGROUND Some people with SARS-CoV-2 infection remain asymptomatic, whilst in others the infection can cause mild to moderate COVID-19 disease and COVID-19 pneumonia, leading some patients to require intensive care support and, in some cases, to death, especially in older adults. Symptoms such as fever or cough, and signs such as oxygen saturation or lung auscultation findings, are the first and most readily available diagnostic information. Such information could be used to either rule out COVID-19 disease, or select patients for further diagnostic testing. OBJECTIVES To assess the diagnostic accuracy of signs and symptoms to determine if a person presenting in primary care or to hospital outpatient settings, such as the emergency department or dedicated COVID-19 clinics, has COVID-19 disease or COVID-19 pneumonia. SEARCH METHODS On 27 April 2020, we undertook electronic searches in the Cochrane COVID-19 Study Register and the University of Bern living search database, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions. SELECTION CRITERIA Studies were eligible if they included patients with suspected COVID-19 disease, or if they recruited known cases with COVID-19 disease and controls without COVID-19. Studies were eligible when they recruited patients presenting to primary care or hospital outpatient settings. Studies including patients who contracted SARS-CoV-2 infection while admitted to hospital were not eligible. The minimum eligible sample size of studies was 10 participants. All signs and symptoms were eligible for this review, including individual signs and symptoms or combinations. We accepted a range of reference standards including reverse transcription polymerase chain reaction (RT-PCR), clinical expertise, imaging, serology tests and World Health Organization (WHO) or other definitions of COVID-19. DATA COLLECTION AND ANALYSIS Pairs of review authors independently selected all studies, at both title and abstract stage and full-text stage. They resolved any disagreements by discussion with a third review author. Two review authors independently extracted data and resolved disagreements by discussion with a third review author. Two review authors independently assessed risk of bias using the QUADAS-2 checklist. Analyses were descriptive, presenting sensitivity and specificity in paired forest plots, in ROC (receiver operating characteristic) space and in dumbbell plots. We did not attempt meta-analysis due to the small number of studies, heterogeneity across studies and the high risk of bias. MAIN RESULTS We identified 16 studies including 7706 participants in total. Prevalence of COVID-19 disease varied from 5% to 38% with a median of 17%. There were no studies from primary care settings, although we did find seven studies in outpatient clinics (2172 participants), and four studies in the emergency department (1401 participants). We found data on 27 signs and symptoms, which fall into four different categories: systemic, respiratory, gastrointestinal and cardiovascular. No studies assessed combinations of different signs and symptoms and results were highly variable across studies. Most had very low sensitivity and high specificity; only six symptoms had a sensitivity of at least 50% in at least one study: cough, sore throat, fever, myalgia or arthralgia, fatigue, and headache. Of these, fever, myalgia or arthralgia, fatigue, and headache could be considered red flags (defined as having a positive likelihood ratio of at least 5) for COVID-19 as their specificity was above 90%, meaning that they substantially increase the likelihood of COVID-19 disease when present. Seven studies carried a high risk of bias for selection of participants because inclusion in the studies depended on the applicable testing and referral protocols, which included many of the signs and symptoms under study in this review. Five studies only included participants with pneumonia on imaging, suggesting that this is a highly selected population. In an additional four studies, we were unable to assess the risk for selection bias. These factors make it very difficult to determine the diagnostic properties of these signs and symptoms from the included studies. We also had concerns about the applicability of these results, since most studies included participants who were already admitted to hospital or presenting to hospital settings. This makes these findings less applicable to people presenting to primary care, who may have less severe illness and a lower prevalence of COVID-19 disease. None of the studies included any data on children, and only one focused specifically on older adults. We hope that future updates of this review will be able to provide more information about the diagnostic properties of signs and symptoms in different settings and age groups. AUTHORS' CONCLUSIONS The individual signs and symptoms included in this review appear to have very poor diagnostic properties, although this should be interpreted in the context of selection bias and heterogeneity between studies. Based on currently available data, neither absence nor presence of signs or symptoms are accurate enough to rule in or rule out disease. Prospective studies in an unselected population presenting to primary care or hospital outpatient settings, examining combinations of signs and symptoms to evaluate the syndromic presentation of COVID-19 disease, are urgently needed. Results from such studies could inform subsequent management decisions such as self-isolation or selecting patients for further diagnostic testing. We also need data on potentially more specific symptoms such as loss of sense of smell. Studies in older adults are especially important.
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Zeitschriftenartikel

  • K. Pellé
  • C. Rambaud-Althaus
  • V. DAcremont
  • G. Moran
  • R. Sampath
  • Z. Katz
  • F. Moussy
  • G. Mehl
  • Sabine Dittrich

Electronic clinical decision support algorithms incorporating point-of-care diagnostic tests in low-resource settings: a target product profile

In: BMJ Global Health vol. 5 pg. e002067.

  • 28.02.2020 (2020)

DOI: 10.1136/bmjgh-2019-002067

Health workers in low-resource settings often lack the support and tools to follow evidence-based clinical recommendations for diagnosing, treating and managing sick patients. Digital technologies, by combining patient health information and point-of-care diagnostics with evidence-based clinical protocols, can help improve the quality of care and the rational use of resources, and save patient lives. A growing number of electronic clinical decision support algorithms (CDSAs) on mobile devices are being developed and piloted without evidence of safety or impact. Here, we present a target product profile (TPP) for CDSAs aimed at guiding preventive or curative consultations in low-resource settings. This document will help align developer and implementer processes and product specifications with the needs of end users, in terms of quality, safety, performance and operational functionality. To identify the characteristics of CDSAs, a multidisciplinary group of experts (academia, industry and policy makers) with expertise in diagnostic and CDSA development and implementation in low-income and middle-income countries were convened to discuss a draft TPP. The TPP was finalised through a Delphi process to facilitate consensus building. An agreement greater than 75% was reached for all 40 TPP characteristics. In general, experts were in overwhelming agreement that, given that CDSAs provide patient management recommendations, the underlying clinical algorithms should be human-interpretable and evidence-based. Whenever possible, the algorithm's patient management output should take into account pretest disease probabilities and likelihood ratios of clinical and diagnostic predictors. In addition, validation processes should at a minimum show that CDSAs are implementing faithfully the evidence they are based on, and ideally the impact on patient health outcomes. In terms of operational needs, CDSAs should be designed to fit within clinic workflows and function in connectivity-challenged and high-volume settings. Data collected through the tool should conform to local patient privacy regulations and international data standards.
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Zeitschriftenartikel

  • Y. Lubell
  • A. Chandna
  • F. Smithuis
  • L. White
  • H. Wertheim
  • M. Redard-Jacot
  • Z. Katz
  • A. Dondorp
  • N. Day
  • N. White
  • Sabine Dittrich

Economic considerations support C-reactive protein testing alongside malaria rapid diagnostic tests to guide antimicrobial therapy for patients with febrile illness in settings with low malaria endemicity

In: Malaria Journal vol. 18 pg. 442.

  • 26.12.2019 (2019)

DOI: 10.1186/s12936-019-3059-5

Malaria is no longer a common cause of febrile illness in many regions of the tropics. In part, this success is a result of improved access to accurate diagnosis and effective anti-malarial treatment, including in many hard-to-reach rural areas. However, in these settings, management of other causes of febrile illness remains challenging. Health systems are often weak and other than malaria rapid tests no other diagnostics are available. With millions of deaths occurring annually due to treatable bacterial infections and the ever increasing spread of antimicrobial resistance, improvement in the management of febrile illness is a global public health priority. Whilst numerous promising point-of-care diagnostics are in the pipeline, substantial progress can be made in the interim with existing tools: C-reactive protein (CRP) is a highly sensitive and moderately specific biomarker of bacterial infection and has been in clinical use for these purposes for decades, with dozens of low-cost devices commercially available. This paper takes a health-economics approach to consider the possible advantages of CRP point-of-care tests alongside rapid diagnostic tests for malaria, potentially in a single multiplex device, to guide antimicrobial therapy for patients with febrile illness. Three rudimentary assessments of the costs and benefits of this approach all indicate that this is likely to be cost-effective when considering the incremental costs of the CRP tests as compared with either (i) the improved health outcomes for patients with bacterial illnesses; (ii) the costs of antimicrobial resistance averted; or (iii) the economic benefits of better management of remaining malaria cases and shorter malaria elimination campaigns in areas of low transmission. While CRP-guided antibiotic therapy alone cannot resolve all challenges associated with management of febrile illness in remote tropical settings, in the short-term a multiplexed CRP and malaria RDT could be highly cost-effective and utilize the well-established funding and distribution systems already in place for malaria RDTs. These findings should spark further interest amongst industry, academics and policy-makers in the development and deployment of such diagnostics, and discussion on their geographically appropriate use.
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Bericht/Report

  • S. Arafah
  • S. Blacksell
  • M. Mayo
  • B. Currie
  • A. Macé
  • S. Ongarello
  • A. Gunasekera
  • J. Esfandiari
  • Sabine Dittrich

Performance Evaluation of a Novel Multiplexed Lateral Flow Assay to Identify Common Causes of Fever in Asia and Inform Treatment Decisions

University of Oxford/Nuffield Department of Medicine - Centre for Tropical Medicine and Global Health

  • 2019 (2019)
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Zeitschriftenartikel

  • P. Dailey
  • J. Osborn
  • E. Ashley
  • E. Baron
  • D. Dance
  • D. Fusco
  • C. Fanello
  • Y. Manabe
  • M. Mokomane
  • P. Newton
  • B. Tessema
  • C. Isaacs
  • Sabine Dittrich

Defining System Requirements for Simplified Blood Culture to Enable Widespread Use in Resource-Limited Settings

In: Diagnostics (Basel, Switzerland) vol. 9

  • 11.01.2019 (2019)

DOI: 10.3390/diagnostics9010010

Bacterial blood stream infections (BSI) are a common cause of mortality and morbidity globally. As the causative agents and the resulting treatment decisions vary, near-patient testing and surveillance tools are necessary to monitor bacterial causes and resistance to antimicrobial agents. The gold standard to identify BSIs is blood culture (BC), a methodology not widely available in resource-limited settings. The aim of the study was to map out a target product profile of a simplified BC system (SBCS) to inform product development efforts. To identify the desired characteristics of a SBCS, we enlisted a small group of specialists working in Africa and Asia. Questions were used to understand challenges and how these constraints inform system requirements. The specialists were infectious disease physicians, public health/clinical microbiologists, clinical researchers, and technology experts with different geographical backgrounds. All suggested that BC should ideally be available at the district hospital level. Many of the same operational challenges, such as limited availability of culture bottles, electricity and internet connectivity, profuse dust, the lack of ambient temperature control, and human capacity constraints were identified across the different regions. BCs, although the accepted gold standard for diagnosis of BSIs, are not widely available outside of reference/research centers in Africa and Asia. To extend the reach of this important tool, it is crucial to engage product developers and academic research partners to develop accessible alternatives.
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Zeitschriftenartikel

  • A. Dubot-Pérès
  • M. Mayxay
  • R. Phetsouvanh
  • Sue Lee
  • S. Rattanavong
  • M. Vongsouvath
  • V. Davong
  • V. C.hansamouth
  • Koukeo Phommasone
  • C. Moore
  • Sabine Dittrich
  • O. Lattana
  • J. Sirisouk
  • P. Phoumin
  • P. Panyanivong
  • A. Sengduangphachanh
  • B. Sibounheuang
  • A. Chanthongthip
  • M. Simmalavong
  • D. Sengdatka
  • A. Seubsanith
  • V. Keoluangkot
  • P. Phimmasone
  • K. Sisout
  • K. Detleuxay
  • K. Luangxay
  • I. Phouangsouvanh
  • S. Craig
  • S. Tulsiani
  • M.-A. Burns
  • D. Dance
  • S. Blacksell
  • X. Lamballerie
  • P. Newton

Management of Central Nervous System Infections, Vientiane, Laos, 2003-2011

In: Emerging Infectious Diseases vol. 25 pg. 898-910.

  • (2019)

DOI: 10.3201/eid2505.180914

During 2003-2011, we recruited 1,065 patients of all ages admitted to Mahosot Hospital (Vientiane, Laos) with suspected central nervous system (CNS) infection. Etiologies were laboratory confirmed for 42.3% of patients, who mostly had infections with emerging pathogens: viruses in 16.2% (mainly Japanese encephalitis virus [8.8%]); bacteria in 16.4% (including Orientia tsutsugamushi [2.9%], Leptospira spp. [2.3%], and Rickettsia spp. [2.3%]); and Cryptococcus spp. fungi in 6.6%. We observed no significant differences in distribution of clinical encephalitis and meningitis by bacterial or viral etiology. However, patients with bacterial CNS infection were more likely to have a history of diabetes than others. Death (26.3%) was associated with low Glasgow Coma Scale score, and the mortality rate was higher for patients with bacterial than viral infections. No clinical or laboratory variables could guide antibiotic selection. We conclude that high-dependency units and first-line treatment with ceftriaxone and doxycycline for suspected CNS infections could improve patient survival in Laos.
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Zeitschriftenartikel

  • K. Pelle
  • M. McLaughlin
  • A. Giwa
  • E. Mount-Finette
  • S. Scarpino
  • N. Haidar
  • F. Adamu
  • T. Adeyoju
  • N. Ravi
  • A. Thompson
  • B. Finette
  • Sabine Dittrich

A Report on the Integration of a Malaria Rapid Diagnostic Test in a Point of Care Clinical Decision Support Platform, MEDSCINC, for Use in Primary Healthcare Settings in Kano State, Nigeria

In: American Journal of Tropical Medicine and Hygiene pg. 481-481.

  • 2019 (2019)
  • Europan Campus Rottal-Inn
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Zeitschriftenartikel

  • T. Althaus
  • R. Greer
  • M. Swe
  • J. Cohen
  • N. Tun
  • J. Heaton
  • S. Nedsuwan
  • D. Intralawan
  • N. Sumpradit
  • Sabine Dittrich
  • Z. Doran
  • N. Waithira
  • H. Thu
  • H. Win
  • J. Thaipadungpanit
  • P. Srilohasin
  • M. Mukaka
  • P. Smit
  • E. Charoenboon
  • M. Haenssgen
  • T. Wangrangsimakul
  • S. Blacksell
  • D. Limmathurotsakul
  • N. Day
  • F. Smithuis
  • Y. Lubell

Effect of point-of-care C-reactive protein testing on antibiotic prescription in febrile patients attending primary care in Thailand and Myanmar: an open-label, randomised, controlled trial

In: The Lancet Global Health vol. 7 pg. e119-e131.

  • (2019)

DOI: 10.1016/s2214-109x(18)30444-3

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Zeitschriftenartikel

  • D. Bhaskaran
  • S. Chadha
  • S. Sarin
  • R. Sen
  • S. Arafah
  • Sabine Dittrich

Diagnostic tools used in the evaluation of acute febrile illness in South India: a scoping review

In: BMC Infectious Diseases vol. 19 pg. 970.

  • 13.11.2019 (2019)

DOI: 10.1186/s12879-019-4589-8

BACKGROUND Acute febrile illness (AFI) is characterized by malaise, myalgia and a raised temperature that is a nonspecific manifestation of infectious diseases in the tropics. The lack of appropriate diagnostics for the evaluation of AFI leads to increased morbidity and mortality in resource-limited settings, specifically low-income countries like India. The review aimed to identify the number, type and quality of diagnostics used for AFI evaluation during passive case detection at health care centres in South India. METHODS A scoping review of peer-reviewed English language original research articles published between 1946-July 2018 from four databases was undertaken to assess the type and number of diagnostics used in AFI evaluation in South India. Results were stratified according to types of pathogen-specific tests used in AFI management. RESULTS The review included a total of 40 studies, all conducted in tertiary care centres (80% in private settings). The studies demonstrated the use of 5-22 tests per patient for the evaluation of AFI. Among 25 studies evaluating possible causes of AFI, 96% tested for malaria followed by 80% for dengue, 72% for scrub typhus, 68% for typhoid and 60% for leptospirosis identifying these as commonly suspected causes of AFI. 54% studies diagnosed malaria with smear microscopy while others diagnosed dengue, scrub typhus, typhoid and leptospirosis using antibody or antigen detection assays. 39% studies used the Weil-Felix test (WFT) for scrub typhus diagnosis and 82% studies used the Widal test for diagnosing typhoid. CONCLUSIONS The review demonstrated the use of five or more pathogen-specific tests in evaluating AFI as well as described the widespread use of suboptimal tests like the WFT and Widal in fever evaluation. It identified the need for the development of better-quality tests for aetiological diagnosis and improved standardised testing guidelines for AFI.
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Zeitschriftenartikel

  • N. Struck
  • Sabine Dittrich

From Biomarker Discovery to Differential Diagnosis in Malaria Endemic Settings

In: American Journal of Tropical Medicine and Hygiene pg. 261.

  • 2019 (2019)
  • Europan Campus Rottal-Inn
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Zeitschriftenartikel

  • P. Newton
  • V. Keolouangkhot
  • S. Lee
  • K. Choumlivong
  • S. Sisouphone
  • M. Vongsouvath
  • M. Mayxay
  • V. Chansamouth
  • V. Davong
  • K. Phommasone
  • J. Sirisouk
  • S. Blacksell
  • P. Nawtaisong
  • C. Moore
  • J. Castonguay-Vanier
  • Sabine Dittrich
  • S. Rattanavong
  • K. Chang
  • C. Darasavath
  • O. Rattanavong
  • D. Paris
  • R. Phetsouvanh

A Prospective, Open-label, Randomized Trial of Doxycycline Versus Azithromycin for the Treatment of Uncomplicated Murine Typhus

In: Clinical Infectious Diseases : an official publication of the Infectious Diseases Society of America vol. 68 pg. 738-747.

  • (2019)

DOI: 10.1093/cid/ciy563

BACKGROUND Murine typhus, or infection with Rickettsia typhi, is a global but neglected disease without randomized clinical trials to guide antibiotic therapy. METHODS A prospective, open, randomized trial was conducted in nonpregnant, consenting inpatient adults with rapid diagnostic test evidence of uncomplicated murine typhus at 2 hospitals in Vientiane, Laos. Patients were randomized to 7 days (D7) or 3 days (D3) of oral doxycycline or 3 days of oral azithromycin (A3). Primary outcome measures were fever clearance time and frequencies of treatment failure and relapse. RESULTS Between 2004 and 2009, the study enrolled 216 patients (72 per arm); 158 (73.2%) had serology/polymerase chain reaction (PCR)-confirmed murine typhus, and 52 (24.1%) were R. typhi PCR positive. The risk of treatment failure was greater for regimen A3 (22.5%; 16 of 71 patients) than for D3 (4.2%; 3 of 71) or D7 (1.4%; 1 of 71) (P < .001). Among R. typhi PCR-positive patients, the area under the time-temperature curve and the fever clearance time were significantly higher for A3 than for D3 (1.8- and 1.9-fold higher, respectively; P = .005) and D7 (1.5- and 1.6-fold higher; P = .02). No patients returned with PCR-confirmed R. typhi relapse. CONCLUSION In Lao adults, azithromycin is inferior to doxycycline as oral therapy for uncomplicated murine typhus. For doxycycline, 3- and 7-day regimens have similar efficacy. Azithromycin use in murine typhus should be reconsidered. Investigation of genomic and phenotypic markers of R. typhi azithromycin resistance is needed. CLINICAL TRIAL REGISTRATION ISRCTN47812566.
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Zeitschriftenartikel

  • G. Bancone
  • D. Menard
  • N. Khim
  • S. Kim
  • L. Canier
  • C. Nguong
  • K. Phommasone
  • M. Mayxay
  • Sabine Dittrich
  • M. Vongsouvath
  • N. Fievet
  • J.-Y. Le Hesran
  • V. Briand
  • S. Keomany
  • P. Newton
  • G. Gorsawun
  • K. Tardy
  • C. Chu
  • O. Rattanapalroj
  • T. Le Dong
  • H. Quang
  • N. Tam-Uyen
  • N. Thuy-Nhien
  • T. Hien
  • M. Kalnoky
  • F. Nosten

Molecular characterization and mapping of glucose-6-phosphate dehydrogenase (G6PD) mutations in the Greater Mekong Subregion

In: Malaria Journal vol. 18 pg. 20.

  • 23.01.2019 (2019)

DOI: 10.1186/s12936-019-2652-y

BACKGROUND Plasmodium vivax malaria elimination can only be achieved by the deployment of 8-aminoquinolines (primaquine and tafenoquine) in combination with ACT to kill both blood and liver-stage parasites. However, primaquine and the other 8-aminoquinolines cause dose-dependent haemolysis in subjects with G6PD deficiency, an X-linked disorder of red blood cells that is very common in populations living in tropical and subtropical areas. In order to inform safer use of 8-aminoquinolines in the Greater Mekong Subregion, a multi-centre study was carried out to assess the prevalence of G6PD deficiency and to identify the main G6PD variants in samples collected in Cambodia, Lao PDR, Myanmar, Thailand and Vietnam. METHODS Blood samples were collected in the five countries during National Malaria Surveys or during Population Surveys. During Population Surveys samples were characterized for G6PD phenotype using the Fluorescent Spot Test. Samples were then genotyped for a panel of G6PD mutations. RESULTS G6PD deficiency was found to be common in the region with an overall mean prevalence of deficient or mutated hemizygous males of 14.0%, ranging from a mean 7.3% in Thailand, 8.1% in Lao PDR, 8.9% in Vietnam, 15.8% in Myanmar and 18.8% in Cambodia. Mahidol and Viangchan mutations were the most common and widespread variants found among the nine investigated. CONCLUSIONS Owing to the high prevalence of G6PD deficiency in the Greater Mekong Subregion, strategies for vivax malaria elimination should include point-of-care G6PD testing (both qualitative and quantitative) to allow safe and wide treatment with 8-aminoquinolines.
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