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Prof. Dr. Sabine Dittrich

Fakultät European Campus Rottal-Inn

Professor:innen

Professorin

AA 239

0991/3615-8875

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Zeitschriftenartikel

  • J. Sapkota
  • R. Hasan
  • R. Onsare
  • S. Arafah
  • S. Kariuki
  • S. Shakoor
  • F. Qamar
  • S. Mundalo
  • F. Njeru
  • R. Too
  • E. Ndegwa
  • J. Andrews
  • Sabine Dittrich

Comparative Analysis of Commercially Available Typhoid Point-of-Care Tests: Results of a Prospective and Hybrid Retrospective Multicenter Diagnostic Accuracy Study in Kenya and Pakistan

In: Journal of Clinical Microbiology vol. 60 pg. e0100022.

  • 30.11.2022 (2022)

DOI: 10.1128/jcm.01000-22

Blood and bone marrow cultures are considered the gold standard for the diagnosis of typhoid, but these methods require infrastructure and skilled staff that are not always available in low- and middle-income countries where typhoid is endemic. The objective of the study is to evaluate the sensitivity and specificity of nine commercially available Salmonella Typhi rapid diagnostic tests (RDTs) using blood culture as a reference standard in a multicenter study. This was a prospective and retrospective multicenter diagnostic accuracy study conducted in two geographically distant areas where typhoid is endemic (Pakistan and Kenya; NCT04801602). Nine RDTs were evaluated, including the Widal test. Point estimates for sensitivity and specificity were calculated using the Wilson method. Latent class analyses were performed using R to address the imperfect gold standard. A total of 531 serum samples were evaluated (264 blood culture positive; 267 blood culture negative). The sensitivity of RDTs varied widely (range, 0 to 78.8%), with the best overall performance shown by Enterocheck WB (72.7% sensitivity, 86.5% specificity). In latent class modeling, CTK IgG was found to have the highest sensitivity (79.1%), while the highest overall accuracy was observed with Enterocheck (73.8% sensitivity, 94.5% specificity). All commercially available Salmonella Typhi RDTs evaluated in the study had sensitivity and specificity values that fell below the required levels to be recommended for an accurate diagnosis. There were minimal differences in RDT performances between regions of endemicity. These findings highlight the clear need for new and more-accurate Salmonella Typhi tests.
  • 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. 7 pg. CD013705.

  • 22.07.2022 (2022)

DOI: 10.1002/14651858.CD013705.pub3

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

  • L. Koeppel
  • Sabine Dittrich
  • S. Brenner Miguel
  • S. Carmona
  • S. Ongarello
  • B. Vetter
  • J. Cohn
  • T. Baernighausen
  • P. Geldsetzer
  • C. Denkinger

Addressing the diagnostic gap in hypertension through possible interventions and scale-up: A microsimulation study

In: PLoS Medicine vol. 19 pg. e1004111.

  • 06.12.2022 (2022)

DOI: 10.1371/journal.pmed.1004111

BACKGROUND Cardiovascular diseases (CVDs) are the leading cause of mortality globally with almost a third of all annual deaths worldwide. Low- and middle-income countries (LMICs) are disproportionately highly affected covering 80% of these deaths. For CVD, hypertension (HTN) is the leading modifiable risk factor. The comparative impact of diagnostic interventions that improve either the accuracy, the reach, or the completion of HTN screening in comparison to the current standard of care has not been estimated. METHODS AND FINDINGS This microsimulation study estimated the impact on HTN-induced morbidity and mortality in LMICs for four different scenarios: (S1) lower HTN diagnostic accuracy; (S2) improved HTN diagnostic accuracy; (S3) better implementation strategies to reach more persons with existing tools; and, lastly, (S4) the wider use of easy-to-use tools, such as validated, automated digital blood pressure measurement devices to enhance screening completion, in comparison to the current standard of care (S0). Our hypothetical population was parametrized using nationally representative, individual-level HPACC data and the global burden of disease data. The prevalence of HTN in the population was 31% out of which 60% remained undiagnosed. We investigated how the alteration of a yearly blood pressure screening event impacts morbidity and mortality in the population over a period of 10 years. The study showed that while improving test accuracy avoids 0.6% of HTN-induced deaths over 10 years (13,856,507 [9,382,742; 17,395,833]), almost 40 million (39,650,363 [31,34,233, 49,298,921], i.e., 12.7% [9.9, 15.8]) of the HTN-induced deaths could be prevented by increasing coverage and completion of a screening event in the same time frame. Doubling the coverage only would still prevent 3,304,212 million ([2,274,664; 4,164,180], 12.1% [8.3, 15.2]) CVD events 10 years after the rollout of the program. Our study is limited by the scarce data available on HTN and CVD from LMICs. We had to pool some parameters across stratification groups, and additional information, such as dietary habits, lifestyle choice, or the blood pressure evolution, could not be considered. Nevertheless, the microsimulation enabled us to include substantial heterogeneity and stochasticity toward the different income groups and personal CVD risk scores in the model. CONCLUSIONS While it is important to consider investing in newer diagnostics for blood pressure testing to continuously improve ease of use and accuracy, more emphasis should be placed on screening completion.
  • Europan Campus Rottal-Inn
  • GESUND
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
  • G. Schierhout
  • B. Tadesse
  • Sabine Dittrich
  • J. Crump
  • J. Kaldor

Differences in diagnosis, management, and outcomes of acute febrile illness by health facility level in southern Ethiopia

In: Scientific Reports (Nature Publishing Group) vol. 12 pg. 19166.

  • 10.11.2022 (2022)

DOI: 10.1038/s41598-022-23641-8

We assessed the diagnosis, management and outcomes of acute febrile illness in a cohort of febrile children aged under 5 years presenting at one urban and two rural health centres and one tertiary hospital between 11 August 2019 and 01 November 2019. Pneumonia was diagnosed in 104 (30.8%) of 338 children at health centres and 128 (65.0%) of 197 at the hospital (p < 0.001). Malaria was detected in 33 (24.3%) of 136 children at the urban health centre, and in 55 (55.6%) of 99 and 7 (7.4%) of 95 children at the rural health centres compared to 11 (11.6%) of 95 at the hospital. Antibacterials were prescribed to 20 (11.5%) of 174 children without guidelines-specified indications (overprescribing) at health centres and in 7 (33.3%) of 21 children at the hospital (p = 0.013). Antimalarials were overprescribed to 13 (7.0%) of 185 children with negative malaria microscopy at the hospital. The fever resolved by day 7 in 326 (99.7%) of 327 children at health centres compared to 177 (93.2%) of 190 at the hospital (p < 0.001). These results suggest that additional guidance to health workers is needed to optimise the use of antimicrobials across all levels of health facilities.
  • 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

  • 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

  • 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. Roberts
  • P. Dahal
  • P. Shrestha
  • W. Schilling
  • R. Shrestha
  • R. Ngu
  • V. Huong
  • H. van Doorn
  • Vilayouth Phimolsarnnousith
  • Thyl Miliya
  • John Crump
  • David Bell
  • Paul Newton
  • Sabine Dittrich
  • Heidi Hopkins
  • Kasia Stepniewska
  • Philippe Guerin
  • Elizabeth Ashley
  • Paul Turner

Antimicrobial resistance patterns in bacteria causing febrile illness in Africa, South Asia, and Southeast Asia: a systematic review of published etiological studies from 1980-2015

In: International Journal of Infectious Diseases vol. 122 pg. 612-621.

  • 09.07.2022 (2022)

DOI: 10.1016/j.ijid.2022.07.018

OBJECTIVE In this study, we aimed to conduct a systematic review to characterize antimicrobial resistance (AMR) patterns for bacterial causes of febrile illness in Africa and Asia. METHODS We included published literature from 1980-2015 based on data extracted from two recent systematic reviews of nonmalarial febrile illness from Africa, South Asia, and Southeast Asia. Selection criteria included articles with full bacterial identification and antimicrobial susceptibility testing (AST) results for key normally sterile site pathogen-drug combinations. Pooled proportions of resistant isolates were combined using random effects meta-analysis. Study data quality was graded using the Microbiology Investigation Criteria for Reporting Objectively (MICRO) framework. RESULTS Of 3475 unique articles included in the previous reviews, 371 included the target pathogen-drug combinations. Salmonella enterica tested against ceftriaxone and ciprofloxacin were the two highest reported combinations (30,509 and 22,056 isolates, respectively). Pooled proportions of resistant isolates were high for third-generation cephalosporins for Klebsiella pneumoniae and Escherichia coli in all regions. The MICRO grading showed an overall lack of standardization. CONCLUSION This review highlights a general increase in AMR reporting and in resistance over time. However, there were substantial problems with diagnostic microbiological data quality. Urgent strengthening of laboratory capacity, standardized testing, and reporting of AST results is required to improve AMR surveillance.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • A. Rao
  • S. Popper
  • S. Gupta
  • V. Davong
  • K. Vaidya
  • A. Chanthongthip
  • Sabine Dittrich
  • et al.

A robust host-response-based signature distinguishes bacterial and viral infections across diverse global populations

In: Cell Reports. Medicine vol. 3 pg. 100842.

  • (2022)

DOI: 10.1016/j.xcrm.2022.100842

Limited sensitivity and specificity of current diagnostics lead to the erroneous prescription of antibiotics. Host-response-based diagnostics could address these challenges. However, using 4,200 samples across 69 blood transcriptome datasets from 20 countries from patients with bacterial or viral infections representing a broad spectrum of biological, clinical, and technical heterogeneity, we show current host-response-based gene signatures have lower accuracy to distinguish intracellular bacterial infections from viral infections than extracellular bacterial infections. Using these 69 datasets, we identify an 8-gene signature to distinguish intracellular or extracellular bacterial infections from viral infections with an area under the receiver operating characteristic curve (AUROC) > 0.91 (85.9% specificity and 90.2% sensitivity). In prospective cohorts from Nepal and Laos, the 8-gene classifier distinguished bacterial infections from viral infections with an AUROC of 0.94 (87.9% specificity and 91% sensitivity). The 8-gene signature meets the target product profile proposed by the World Health Organization and others for distinguishing bacterial and viral infections.
  • 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

  • T. Fox
  • J. Geppert
  • J. Dinnes
  • K. Scandrett
  • J. Bigio
  • G. Sulis
  • D. Hettiarachchi
  • Y. Mathangasinghe
  • P. Weeratunga
  • D. Wickramasinghe
  • H. Berman
  • B. Buckley
  • K. Probyn
  • Y. Sguassero
  • C. Davenport
  • J. Cunningham
  • Sabine Dittrich
  • et al.

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

In: The Cochrane Database of Systematic Reviews vol. 11 pg. CD013652.

  • 17.11.2022 (2022)

DOI: 10.1002/14651858.CD013652.pub2

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.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

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

Mapping the global landscape of chikungunya rapid diagnostic tests: A scoping review

In: PLoS Neglected Tropical Diseases vol. 16 pg. e0010067.

  • 25.07.2022 (2022)

DOI: 10.1371/journal.pntd.0010067

BACKGROUND Chikungunya (CHIKV) is a reemerging arboviral disease and represents a global health threat because of the unprecedented magnitude of its spread. Diagnostics strategies rely heavily on reverse transcriptase-polymerase chain reaction (RT-PCR) and antibody detection by enzyme-linked Immunosorbent assay (ELISA). Rapid diagnostic tests (RDTs) are available and promise to decentralize testing and increase availability at lower healthcare system levels. OBJECTIVES We aim to identify the extent of research on CHIKV RDTs, map the global availability of CHIKV RDTs, and evaluate the accuracy of CHIKV RDTs for the diagnosis of CHIKV. ELIGIBILITY CRITERIA We included studies reporting symptomatic individuals suspected of CHIKV, tested with CHIKV RDTs, against the comparator being a validated laboratory-based RT-PCR or ELISA assay. The primary outcome was the accuracy of the CHIKV RDT when compared with reference assays. SOURCES OF EVIDENCE Medline, EMBASE, and Scopus were searched from inception to 13 October 2021. National regulatory agencies (European Medicines Agency, US Food and Drug Administration, and the Brazilian National Health Surveillance Agency) were also searched for registered CHIKV RDTs. RESULTS Seventeen studies were included and corresponded to 3,222 samples tested with RDTs between 2005 and 2018. The most development stage of CHIKV RDTs studies was Phase I (7/17 studies) and II (7/17 studies). No studies were in Phase IV. The countries that manufacturer the most CHIKV RDTs were Brazil (n = 17), followed by the United States of America (n = 7), and India (n = 6). Neither at EMA nor FDA-registered products were found. Conversely, the ANVISA has approved 23 CHIKV RDTs. Antibody RDTs (n = 43) predominated and demonstrated sensitivity between 20% and 100%. The sensitivity of the antigen RDTs ranged from 33.3% to 100%. CONCLUSIONS The landscape of CHIKV RDTs is fragmented and needs coordinated efforts to ensure that patients in CHIKV-endemic areas have access to appropriate RDTs. Further research is crucial to determine the impact of such tests on integrated fever case management and prescription practices for acute febrile patients.
  • Europan Campus Rottal-Inn
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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
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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
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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

  • 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
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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
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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
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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
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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.
  • Europan Campus Rottal-Inn
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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

  • 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

  • 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.
  • 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

  • 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

  • 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.
  • Europan Campus Rottal-Inn
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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.
  • Europan Campus Rottal-Inn
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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

  • 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.
  • Europan Campus Rottal-Inn
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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.
  • Europan Campus Rottal-Inn
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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.
  • 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

  • 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

  • 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
  • GESUND
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.
  • Europan Campus Rottal-Inn
  • GESUND
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
  • GESUND
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.
  • Europan Campus Rottal-Inn
  • GESUND
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
  • GESUND
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.
  • Europan Campus Rottal-Inn
  • GESUND
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.
  • Europan Campus Rottal-Inn
  • GESUND
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.
  • Europan Campus Rottal-Inn
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Beitrag in Sammelwerk/Tagungsband

  • 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 (Session 131 - Poster Session C: Presentations and Light Lunch)

pg. 482-483.

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

  • W. Phuklia
  • P. Panyanivong
  • D. Sengdetka
  • P. Sonthayanon
  • P. Newton
  • D. Paris
  • N. Day
  • Sabine Dittrich

Novel high-throughput screening method using quantitative PCR to determine the antimicrobial susceptibility of Orientia tsutsugamushi clinical isolates

In: The Journal of Antimicrobial Chemotherapy vol. 74 pg. 74-81.

  • (2019)

DOI: 10.1093/jac/dky402

OBJECTIVES To develop a method to enable the large-scale antimicrobial susceptibility screening of Orientia tsutsugamushi clinical isolates, using one timepoint and one concentration of antibiotics to considerably speed up the time to result. METHODS Growth, harvesting, multiplicity of infection (moi) and the day to determine the MICs were optimized using five O. tsutsugamushi reference strains [susceptible (Karp, Kato and Gilliam) and putatively resistant (AFC-3 and AFSC-4)], one clinical isolate (UT76) and one rodent isolate (TA763). Subsequently, the MICs of azithromycin, chloramphenicol and doxycycline for these strains and 51 clinical isolates including AFSC-7 were determined. An optimal concentration was calculated using the epidemiological cut-off value. RESULTS The conditions for O. tsutsugamushi infection, growth and harvesting were determined to be an moi of 100:1 and trypsinization with the peak growth on day 10. The resulting MICs were in line with previously published susceptibility data for all reference strains, except for Karp and AFSC-4, which showed azithromycin MICs of 0.0156 and 0.0313 mg/L, compared with 0.0078 and 0.0156 mg/L, respectively, in previous reports. The MIC of doxycycline for AFC-3 was 0.125 mg/L compared with >4 mg/L in earlier reports. The final single screening concentrations were identified as: azithromycin, 0.125 mg/L; chloramphenicol, 8 mg/L; and doxycycline, 1 mg/L. CONCLUSIONS This simplified procedure facilitates the simultaneous screening of 48 isolates for actively monitoring potential resistance of this important fever pathogen, with an 8-fold throughput improvement over early methods. The data do not support the existence of doxycycline- and chloramphenicol-resistant scrub typhus.
  • Europan Campus Rottal-Inn
  • GESUND
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.
  • Europan Campus Rottal-Inn
  • GESUND
Beitrag in Sammelwerk/Tagungsband

  • 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

pg. 481.

  • (2019)
  • Europan Campus Rottal-Inn
  • GESUND
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.
  • Europan Campus Rottal-Inn
  • GESUND
Beitrag in Sammelwerk/Tagungsband

  • R. Mather
  • P. Dailey
  • H. Hopkins
  • Sabine Dittrich

Redefining Typhoid Diagnosis: What should a better test look like, and what innovations are available to meet the needs?

pg. 536-537.

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

  • R. Mather
  • H. Hopkins
  • C. Parry
  • Sabine Dittrich

Redefining typhoid diagnosis: what would an improved test need to look like?

In: BMJ Global Health vol. 4 pg. e001831.

  • 31.10.2019 (2019)

DOI: 10.1136/bmjgh-2019-001831

INTRODUCTION Typhoid fever is one of the most common bacterial causes of acute febrile illness in the developing world, with an estimated 10.9 million new cases and 116.8 thousand deaths in 2017. Typhoid point-of-care (POC) diagnostic tests are widely used but have poor sensitivity and specificity, resulting in antibiotic overuse that has led to the emergence and spread of multidrug-resistant strains. With recent advances in typhoid surveillance and detection, this is the ideal time to produce a target product profile (TPP) that guides product development and ensure that a next-generation test meets the needs of users in the resource-limited settings where typhoid is endemic. METHODS A structured literature review was conducted to develop a draft TPP for a next-generation typhoid diagnostic test with minimal and optimal desired characteristics for 36 test parameters. The TPP was refined using feedback collected from a Delphi survey of key stakeholders in clinical medicine, microbiology, diagnostics and public and global health. RESULTS A next-generation typhoid diagnostic test should improve patient management through the diagnosis and treatment of infection with acute Salmonella enterica serovars Typhi or Paratyphi with a sensitivity ≥90% and specificity ≥95%. The test would ideally be used at the lowest level of the healthcare system in settings without a reliable power or water supply and provide results in <15 min at a cost of
  • Europan Campus Rottal-Inn
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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.
  • Europan Campus Rottal-Inn
  • GESUND
Beitrag in Sammelwerk/Tagungsband

  • S. Incardona
  • B. Srivastava
  • S. Sharma
  • S. Ongarello
  • Shenai, S. Loganathan, P.
  • S. Sarin
  • A. Anvikar
  • Sabine Dittrich

Prospective performance evaluation of a combined malaria/CRP rapid diagnostic test in India (Session 81 – Diagnosis of Malaria: Are the Available Tools Sufficient to Eliminate the Disease?)

pg. 380.

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

  • P. Roddy
  • U. Dalrymple
  • T. Jensen
  • Sabine Dittrich
  • V. Rao
  • D. Pfeffer
  • K. Twohig
  • T. Roberts
  • O. Bernal
  • E. Guillen

Quantifying the incidence of severe-febrile-illness hospital admissions in sub-Saharan Africa

In: PLoS One vol. 14 pg. e0220371.

  • 25.07.2019 (2019)

DOI: 10.1371/journal.pone.0220371

Severe-febrile-illness (SFI) is a common cause of morbidity and mortality across sub-Saharan Africa (SSA). The burden of SFI in SSA is currently unknown and its estimation is fraught with challenges. This is due to a lack of diagnostic capacity for SFI in SSA, and thus a dearth of baseline data on the underlying etiology of SFI cases and scant SFI-specific causative-agent prevalence data. To highlight the public health significance of SFI in SSA, we developed a Bayesian model to quantify the incidence of SFI hospital admissions in SSA. Our estimates indicate a mean population-weighted SFI-inpatient-admission incidence rate of 18.4 (6.8-31.1, 68% CrI) per 1000 people for the year 2014, across all ages within areas of SSA with stable Plasmodium falciparum transmission. We further estimated a total of 16,200,337 (5,993,249-27,321,779, 68% CrI) SFI hospital admissions. This analysis reveals the significant burden of SFI in hospitals in SSA, but also highlights the paucity of pathogen-specific prevalence and incidence data for SFI in SSA. Future improvements in pathogen-specific diagnostics for causative agents of SFI will increase the abundance of SFI-specific prevalence and incidence data, aid future estimations of SFI burden, and enable clinicians to identify SFI-specific pathogens, administer appropriate treatment and management, and facilitate appropriate antibiotic use.
  • Europan Campus Rottal-Inn
  • GESUND
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.
  • Europan Campus Rottal-Inn
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Beitrag in Sammelwerk/Tagungsband

  • N. Struck
  • Sabine Dittrich

From Biomarker Discovery to Differential Diagnosis in Malaria Endemic Settings

pg. 261.

  • (2019)
  • Europan Campus Rottal-Inn
  • GESUND
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.
  • 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

  • Europan Campus Rottal-Inn
  • GESUND
Beitrag in Sammelwerk/Tagungsband

  • A. Devine
  • S. Incardona
  • R. Price
  • Sabine Dittrich
  • X. Ding

Treatment algorithms with radical cure of vivax malaria based on sex: a cost-effectiveness analysis to support roll out strategies

pg. 112.

  • (2019)
  • Europan Campus Rottal-Inn
  • GESUND
Beitrag in Sammelwerk/Tagungsband

  • M. Robinson
  • P. Nawtaisong
  • M. Vongsouvath
  • K. Khammavong
  • P. Milavong
  • A. Rachlin
  • Sabine Dittrich
  • A. Dubot-Pérès
  • M. Pruvot
  • P. Newton

Molecular Diagnostics of Potential Pathogens in the Wildlife Trade in Lao PDR

pg. 220.

  • (2018)
  • Europan Campus Rottal-Inn
  • GESUND
Beitrag in Sammelwerk/Tagungsband

  • J. Osborn
  • T. Roberts
  • M. Murtahg
  • C. Kelly-Cirino
  • Sabine Dittrich
  • O. Bernal
  • F. Moussy
  • E. Guillen

Designing a Novel Multiplex Multi-Analyte Diagnostic Platform (MAPDx) to Address Severe Febrile Illness

pg. 383.

  • (2018)
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • Sabine Dittrich
  • L. Boutthasavong
  • D. Keokhamhoung
  • W. Phuklia
  • et al.

A Prospective Hospital Study to Evaluate the Diagnostic Accuracy of Rapid Diagnostic Tests for the Early Detection of Leptospirosis in Laos

In: The American Journal of Tropical Medicine and Hygiene vol. 98 pg. 1056-1060.

  • 22.02.2018 (2018)

DOI: 10.4269/ajtmh.17-0702

Leptospirosis is a globally important cause of acute febrile illness, and a common cause of non-malarial fever in Asia, Africa, and Latin America. Simple rapid diagnostic tests (RDTs) are needed to enable health-care workers, particularly in low resource settings, to diagnose leptospirosis early and give timely targeted treatment. This study compared four commercially available RDTs to detect human IgM against Leptospira spp. in a head-to-head prospective evaluation in Mahosot Hospital, Lao PDR. Patients with an acute febrile illness consistent with leptospirosis (N = 695) were included in the study during the 2014 rainy season. Samples were tested with four RDTs: ("Test-it" [Life Assay, Cape Town, South Africa; N = 418]; "Leptorapide" [Linnodee, Ballyclare, Northern Ireland; N = 492]; "Dual Path Platform" [DPP] [Chembio, Medford, NY; N = 530]; and "SD-IgM" [Standard Diagnostics, Yongin, South Korea; N = 481]). Diagnostic performance characteristics were calculated and compared with a composite reference standard combining polymerase chain reaction (PCR) (rrs), microscopic agglutination tests (MATs), and culture. Of all patients investigated, 39/695 (5.6%) were positive by culture, PCR, or MAT. The sensitivity and specificity of the RDTs ranged greatly from 17.9% to 63.6% and 62.1% to 96.8%, respectively. None of the investigated RDTs reached a sensitivity or specificity of > 90% for detecting Leptospira infections on admission. In conclusion, our investigation highlights the challenges associated with Leptospira diagnostics, particularly in populations with multiple exposures. These findings emphasize the need for extensive prospective evaluations in multiple endemic settings to establish the value of rapid tools for diagnosing fevers to allow targeting of antibiotics.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • A. Fleshman
  • K. Mullins
  • J. Sahl
  • C. Hepp
  • N. Nieto
  • K. Wiggins
  • H. Hornstra
  • D. Kelly
  • T.-C. Chan
  • R. Phetsouvanh
  • Sabine Dittrich
  • et al.

Comparative pan-genomic analyses of Orientia tsutsugamushi reveal an exceptional model of bacterial evolution driving genomic diversity

In: Microbial Genomics vol. 4

  • 23.07.2018 (2018)

DOI: 10.1099/mgen.0.000199

Orientia tsutsugamushi, formerly Rickettsia tsutsugamushi, is an obligate intracellular pathogen that causes scrub typhus, an underdiagnosed acute febrile disease with high morbidity. Scrub typhus is transmitted by the larval stage (chigger) of Leptotrombidium mites and is irregularly distributed across endemic regions of Asia, Australia and islands of the western Pacific Ocean. Previous work to understand population genetics in O. tsutsugamushi has been based on sub-genomic sampling methods and whole-genome characterization of two genomes. In this study, we compared 40 genomes from geographically dispersed areas and confirmed patterns of extensive homologous recombination likely driven by transposons, conjugative elements and repetitive sequences. High rates of lateral gene transfer (LGT) among O. tsutsugamushi genomes appear to have effectively eliminated a detectable clonal frame, but not our ability to infer evolutionary relationships and phylogeographical clustering. Pan-genomic comparisons using 31 082 high-quality bacterial genomes from 253 species suggests that genomic duplication in O. tsutsugamushi is almost unparalleled. Unlike other highly recombinant species where the uptake of exogenous DNA largely drives genomic diversity, the pan-genome of O. tsutsugamushi is driven by duplication and divergence. Extensive gene innovation by duplication is most commonly attributed to plants and animals and, in contrast with LGT, is thought to be only a minor evolutionary mechanism for bacteria. The near unprecedented evolutionary characteristics of O. tsutsugamushi, coupled with extensive intra-specific LGT, expand our present understanding of rapid bacterial evolutionary adaptive mechanisms.
  • Europan Campus Rottal-Inn
  • GESUND
Beitrag in Sammelwerk/Tagungsband

  • C. Escadafal
  • S. Geis
  • J. Malava
  • L. Banda
  • H. Mvula
  • J. Saul
  • A. Mace
  • V. Harris
  • Sabine Dittrich

Preliminary Data from a Biomarker Evaluation Trial among Non-Severe Febrile Patients in a Malaria Endemic Setting in Malawi

pg. 427.

  • (2018)
  • Europan Campus Rottal-Inn
  • GESUND
Beitrag in Sammelwerk/Tagungsband

  • J. Barber
  • J. Osborn
  • O. Bernal
  • E. Guillen
  • C. Kelly-Cirino
  • Sabine Dittrich

Febrile Patient Management Worldwide: Analysis of Existing Guidelines and Algorithms to Inform Novel Diagnostic and Algorithmic Solutions . Barber J., Osborn J., Bernal O., Guillen E., Kelly-Cirino C., Dittrich S.

pg. 604-605.

  • (2018)
  • Europan Campus Rottal-Inn
  • GESUND
Beitrag in Sammelwerk/Tagungsband

  • S. Incardona
  • K. Torres
  • W. Oyibo
  • S. Ongarello
  • A. Mace
  • F. Alava
  • Sabine Dittrich
  • et al.

Performance of a New Multiplex Fever Pathogen Rapid Test to Detect Malaria When Used by Health Workers in Peru and Nigeria

pg. 539-540.

  • (2018)
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • K. Woods
  • C. Nic-Fhogartaigh
  • C. Arnold
  • L. Boutthasavong
  • W. Phuklia
  • C. Lim
  • A. Chanthongthip
  • S. Tulsiani
  • S. Craig
  • M-A Burns
  • S. Weier
  • V. Davong
  • S. Sihalath
  • D. Limmathurotsakul
  • D. Dance
  • N. Shetty
  • M. Zambon
  • P. Newton
  • Sabine Dittrich

A comparison of two molecular methods for diagnosing leptospirosis from three different sample types in patients presenting with fever in Laos

In: Clinical Microbiology and Infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases vol. 24 pg. 1017.e1-1017.e7.

  • 26.10.2017 (2018)

DOI: 10.1016/j.cmi.2017.10.017

OBJECTIVES To compare two molecular assays (rrs quantitative PCR (qPCR) versus a combined 16SrRNA and LipL32 qPCR) on different sample types for diagnosing leptospirosis in febrile patients presenting to Mahosot Hospital, Vientiane, Laos. METHODS Serum, buffy coat and urine samples were collected on admission, and follow-up serum ∼10 days later. Leptospira spp. culture and microscopic agglutination tests (MAT) were performed as reference standards. Bayesian latent class modelling was performed to estimate sensitivity and specificity of each diagnostic test. RESULTS In all, 787 patients were included in the analysis: 4/787 (0.5%) were Leptospira culture positive, 30/787 (3.8%) were MAT positive, 76/787 (9.7%) were rrs qPCR positive and 20/787 (2.5%) were 16SrRNA/LipL32 qPCR positive for pathogenic Leptospira spp. in at least one sample. Estimated sensitivity and specificity (with 95% CI) of 16SrRNA/LipL32 qPCR on serum (53.9% (33.3%-81.8%); 99.6% (99.2%-100%)), buffy coat (58.8% (34.4%-90.9%); 99.9% (99.6%-100%)) and urine samples (45.0% (27.0%-66.7%); 99.6% (99.3%-100%)) were comparable with those of rrs qPCR, except specificity of 16SrRNA/LipL32 qPCR on urine samples was significantly higher (99.6% (99.3%-100%) vs. 92.5% (92.3%-92.8%), p <0.001). Sensitivities of MAT (16% (95% CI 6.3%-29.4%)) and culture (25% (95% CI 13.3%-44.4%)) were low. Mean positive Cq values showed that buffy coat samples were more frequently inhibitory to qPCR than either serum or urine (p <0.001). CONCLUSIONS Serum and urine are better samples for qPCR than buffy coat, and 16SrRNA/LipL32 qPCR performs better than rrs qPCR on urine. Quantitative PCR on admission is a reliable rapid diagnostic tool, performing better than MAT or culture, with significant implications for clinical and epidemiological investigations of this global neglected disease.
  • Europan Campus Rottal-Inn
  • GESUND
Beitrag in Sammelwerk/Tagungsband

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

Prioritizing Pathogens to Support Diagnostic Product Development for Febrile Illness Management: A Novel Yet Pragmatic Approach

pg. 386.

  • (2018)
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • D.A.B. Dance
  • M. Knappik
  • Sabine Dittrich
  • V. Davong
  • J. Silisouk
  • M. Vongsouvath
  • S. Rattanavong
  • A. Pierret
  • P. Newton
  • et al.

Evaluation of consensus method for the culture of Burkholderia pseudomallei in soil samples from Laos

In: Wellcome Open Research vol. 3 pg. 132.

  • (2018)

DOI: 10.12688/wellcomeopenres.14851.1

  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • C. Escadafal
  • C. Nsanzabana
  • J. Archer
  • V. Chihota
  • W. Rodriguez
  • Sabine Dittrich

New Biomarkers and Diagnostic Tools for the Management of Fever in Low- and Middle-Income Countries: An Overview of the Challenges

In: Diagnostics (Basel, Switzerland) vol. 7 pg. 44.

  • 21.07.2017 (2017)

DOI: 10.3390/diagnostics7030044

A lack of simple, inexpensive, and rapid diagnostic tests for febrile illnesses other than malaria leads to overtreatment with antibiotics for those who test negative for malaria, and contributes to the global rise in antimicrobial resistance. New tests for the detection of host biomarkers provide promising tools to differentiate bacterial from non-bacterial infections in febrile patients. However, most available biomarker tests are not currently used in resource-limited settings, and very few evaluations have been performed in low- and middle-income country populations with non-severe febrile illness. As a result, our knowledge of the performance of these tests in settings with high prevalence of infectious and poverty-related diseases such as malaria, HIV, malnutrition and intestinal parasites is poor. This paper describes challenges faced during the process of getting to an approved test, including difficulties in selecting the most appropriate fever biomarkers; suitable study designs and sites for test evaluations; lack of available reference tests to evaluate the performance of new tests; and lack of clear regulatory pathways to introduce such tests. As many new biomarker assays are in development, understanding these challenges will better enable those working in this area to address them during product development.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • B. Tadesse
  • E. Ashley
  • S. Ongarello
  • J. Havumaki
  • M. Wijegoonewardena
  • I. González
  • Sabine Dittrich

Antimicrobial resistance in Africa: a systematic review

In: BMC Infectious Diseases vol. 17 pg. 616.

  • 11.09.2017 (2017)

DOI: 10.1186/s12879-017-2713-1

BACKGROUND Antimicrobial resistance (AMR) is widely acknowledged as a global problem, yet in many parts of the world its magnitude is still not well understood. This review, using a public health focused approach, aimed to understand and describe the current status of AMR in Africa in relation to common causes of infections and drugs recommended in WHO treatment guidelines. METHODS PubMed, EMBASE and other relevant databases were searched for recent articles (2013-2016) in accordance with the PRISMA guidelines. Article retrieval and screening were done using a structured search string and strict inclusion/exclusion criteria. Median and interquartile ranges of percent resistance were calculated for each antibiotic-bacterium combination. RESULTS AMR data was not available for 42.6% of the countries in the African continent. A total of 144 articles were included in the final analysis. 13 Gram negative and 5 Gram positive bacteria were tested against 37 different antibiotics. Penicillin resistance in Streptococcus pneumoniae was reported in 14/144studies (median resistance (MR): 26.7%). Further 18/53 (34.0%) of Haemophilus influenza isolates were resistant to amoxicillin. MR of Escherichia coli to amoxicillin, trimethoprim and gentamicin was 88.1%, 80.7% and 29.8% respectively. Ciprofloxacin resistance in Salmonella Typhi was rare. No documented ceftriaxone resistance in Neisseria gonorrhoeae was reported, while the MR for quinolone was 37.5%. Carbapenem resistance was common in Acinetobacter spp. and Pseudomonas aeruginosa but uncommon in Enterobacteriaceae. CONCLUSION Our review highlights three important findings. First, recent AMR data is not available for more than 40% of the countries. Second, the level of resistance to commonly prescribed antibiotics was significant. Third, the quality of microbiological data is of serious concern. Our findings underline that to conserve our current arsenal of antibiotics it is imperative to address the gaps in AMR diagnostic standardization and reporting and use available information to optimize treatment guidelines.
  • Europan Campus Rottal-Inn
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Beitrag in Sammelwerk/Tagungsband

  • C. Escadafal
  • C. Nzansabana
  • J. Archer
  • V. Chihota
  • W. Rodriguez
  • Sabine Dittrich

From New Biomarkers to Diagnostic Tools for the Management of Fever in Low- and Middle-Income Countries: An Overview of the Challenges

pg. 286.

  • (2017)
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • A. Kapasi
  • Sabine Dittrich
  • I. González
  • T. Rodwell

Host Biomarkers for Distinguishing Bacterial from Non-Bacterial Causes of Acute Febrile Illness: A Comprehensive Review

In: PLoS One vol. 11 pg. e0160278.

  • 03.08.2016 (2016)

DOI: 10.1371/journal.pone.0160278

BACKGROUND In resource limited settings acute febrile illnesses are often treated empirically due to a lack of reliable, rapid point-of-care diagnostics. This contributes to the indiscriminate use of antimicrobial drugs and poor treatment outcomes. The aim of this comprehensive review was to summarize the diagnostic performance of host biomarkers capable of differentiating bacterial from non-bacterial infections to guide the use of antibiotics. METHODS Online databases of published literature were searched from January 2010 through April 2015. English language studies that evaluated the performance of one or more host biomarker in differentiating bacterial from non-bacterial infection in patients were included. Key information extracted included author information, study methods, population, pathogens, clinical information, and biomarker performance data. Study quality was assessed using a combination of validated criteria from the QUADAS and Lijmer checklists. Biomarkers were categorized as hematologic factors, inflammatory molecules, cytokines, cell surface or metabolic markers, other host biomarkers, host transcripts, clinical biometrics, and combinations of markers. FINDINGS Of the 193 citations identified, 59 studies that evaluated over 112 host biomarkers were selected. Most studies involved patient populations from high-income countries, while 19% involved populations from low- and middle-income countries. The most frequently evaluated host biomarkers were C-reactive protein (61%), white blood cell count (44%) and procalcitonin (34%). Study quality scores ranged from 23.1% to 92.3%. There were 9 high performance host biomarkers or combinations, with sensitivity and specificity of ≥85% or either sensitivity or specificity was reported to be 100%. Five host biomarkers were considered weak markers as they lacked statistically significant performance in discriminating between bacterial and non-bacterial infections. DISCUSSION This manuscript provides a summary of host biomarkers to differentiate bacterial from non-bacterial infections in patients with acute febrile illness. Findings provide a basis for prioritizing efforts for further research, assay development and eventual commercialization of rapid point-of-care tests to guide use of antimicrobials. This review also highlights gaps in current knowledge that should be addressed to further improve management of febrile patients.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • A. Rachlin
  • Sabine Dittrich
  • K. Phommasone
  • A. Douangnouvong
  • R. Phetsouvanh
  • P. Newton
  • D. Dance

Investigation of Recurrent Melioidosis in Lao People's Democratic Republic by Multilocus Sequence Typing

In: The American Journal of Tropical Medicine and Hygiene vol. 94 pg. 1208-1211.

  • 21.03.2016 (2016)

DOI: 10.4269/ajtmh.15-0909

Melioidosis is an infectious disease caused by the saprophytic bacterium Burkholderia pseudomallei In northeast Thailand and northern Australia, where the disease is highly endemic, a range of molecular tools have been used to study its epidemiology and pathogenesis. In the Lao People's Democratic Republic (Laos) where melioidosis has been recognized as endemic since 1999, no such studies have been undertaken. We used a multilocus sequence typing scheme specific for B. pseudomallei to investigate nine cases of culture-positive recurrence occurring in 514 patients with melioidosis between 2010 and 2015: four were suspected to be relapses while the other five represented reinfections. In addition, two novel sequence types of the bacterium were identified. The low overall recurrence rates (2.4%) and proportions of relapse and reinfection in the Laos are consistent with those described in the recent literature, reflecting the effective use of appropriate antimicrobial therapy.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • Sabine Dittrich
  • Elizabeth Card
  • Weerawat Phuklia
  • Williams Rudgard
  • Joy Silousok
  • Phonelavanh Phoumin
  • Latsaniphone Bouthasavong
  • Sarah Azarian
  • Viengmon Davong
  • David Dance
  • Manivanh Vongsouvath
  • Rattanaphone Phetsouvanh
  • Paul Newton

Survival and Growth of Orientia tsutsugamushi in Conventional Hemocultures

In: Emerging Infectious Diseases vol. 22 pg. 1460-3.

  • (2016)

DOI: 10.3201/eid2208.151259

Orientia tsutsugamushi, which requires specialized facilities for culture, is a substantial cause of disease in Asia. We demonstrate that O. tsutsugamushi numbers increased for up to 5 days in conventional hemocultures. Performing such a culture step before molecular testing could increase the sensitivity of O. tsutsugamushi molecular diagnosis.
  • Europan Campus Rottal-Inn
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Zeitschriftenartikel

  • Sabrina Weiss
  • Angela Menezes
  • Kate Woods
  • Anisone Chanthongthip
  • Sabine Dittrich
  • Agatha Opoku-Boateng
  • Maimuna Kimuli
  • Victoria Chalker

An Extended Multilocus Sequence Typing (MLST) Scheme for Rapid Direct Typing of Leptospira from Clinical Samples

In: PLoS Neglected Tropical Diseases vol. 10 pg. e0004996.

  • 21.09.2016 (2016)

DOI: 10.1371/journal.pntd.0004996

BACKGROUND Rapid typing of Leptospira is currently impaired by requiring time consuming culture of leptospires. The objective of this study was to develop an assay that provides multilocus sequence typing (MLST) data direct from patient specimens while minimising costs for subsequent sequencing. METHODOLOGY AND FINDINGS An existing PCR based MLST scheme was modified by designing nested primers including anchors for facilitated subsequent sequencing. The assay was applied to various specimen types from patients diagnosed with leptospirosis between 2014 and 2015 in the United Kingdom (UK) and the Lao Peoples Democratic Republic (Lao PDR). Of 44 clinical samples (23 serum, 6 whole blood, 3 buffy coat, 12 urine) PCR positive for pathogenic Leptospira spp. at least one allele was amplified in 22 samples (50%) and used for phylogenetic inference. Full allelic profiles were obtained from ten specimens, representing all sample types (23%). No nonspecific amplicons were observed in any of the samples. Of twelve PCR positive urine specimens three gave full allelic profiles (25%) and two a partial profile. Phylogenetic analysis allowed for species assignment. The predominant species detected was L. interrogans (10/14 and 7/8 from UK and Lao PDR, respectively). All other species were detected in samples from only one country (Lao PDR: L. borgpetersenii [1/8]; UK: L. kirschneri [1/14], L. santarosai [1/14], L. weilii [2/14]). CONCLUSION Typing information of pathogenic Leptospira spp. was obtained directly from a variety of clinical samples using a modified MLST assay. This assay negates the need for time-consuming culture of Leptospira prior to typing and will be of use both in surveillance, as single alleles enable species determination, and outbreaks for the rapid identification of clusters.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • Thomas Weitzel
  • Sabine Dittrich
  • Javier López
  • Weerawat Phuklia
  • Constanza Martinez-Valdebenito
  • Katia Velásquez
  • Stuart Blacksell
  • Daniel Paris
  • Katia Abarca

Endemic Scrub Typhus in South America

In: The New England Journal of Medicine vol. 375 pg. 954-61.

  • (2016)

DOI: 10.1056/nejmoa1603657

Scrub typhus is a life-threatening zoonosis caused by Orientia tsutsugamushi organisms that are transmitted by the larvae of trombiculid mites. Endemic scrub typhus was originally thought to be confined to the so called "tsutsugamushi triangle" within the Asia-Pacific region. In 2006, however, two individual cases were detected in the Middle East and South America, which suggested that the pathogen was present farther afield. Here, we report three autochthonous cases of scrub typhus caused by O. tsutsugamushi acquired on Chiloé Island in southern Chile, which suggests the existence of an endemic focus in South America. (Funded by the Chilean Comisión Nacional de Investigación Científica y Tecnológica and the Wellcome Trust.).
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • Sabine Dittrich
  • William Rudgard
  • Kate Woods
  • Joy Silisouk
  • Weerawat Phuklia
  • Viengmon Davong
  • Manivanh Vongsouvath
  • Koukeo Phommasone
  • Sayaphet Rattanavong
  • Michael Knappik
  • Scott Craig
  • Steven Weier
  • Suhella Tulsiani
  • David Dance
  • Paul Newton

The Utility of Blood Culture Fluid for the Molecular Diagnosis of Leptospira: A Prospective Evaluation

In: The American Journal of Tropical Medicine and Hygiene vol. 94 pg. 736-740.

  • 15.02.2016 (2016)

DOI: 10.4269/ajtmh.15-0674

Leptospirosis is an important zoonosis worldwide, with infections occurring after exposure to contaminated water. Despite being a global problem, laboratory diagnosis remains difficult with culture results taking up to 3 months, serology being retrospective by nature, and polymerase chain reaction showing limited sensitivity. Leptospira have been shown to survive and multiply in blood culture media, and we hypothesized that extracting DNA from incubated blood culture fluid (BCF), followed by quantitative real-time polymerase chain reaction (qPCR) could improve the accuracy and speed of leptospira diagnosis. We assessed this retrospectively, using preincubated BCF of Leptospira spp. positive (N= 109) and negative (N= 63) febrile patients in Vientiane, Lao PDR. The final method showed promising sensitivities of 66% (95% confidence interval [CI]: 55-76) and 59% (95% CI: 49-68) compared with direct or direct and indirect testing combined, as the respective reference standards (specificities > 95%). Despite these promising diagnostic parameters, a subsequent prospective evaluation in a Lao hospital population (N= 352) showed that the sensitivity was very low (∼30%) compared with qPCR on venous blood samples. The disappointingly low sensitivity does suggest that venous blood samples are preferable for the clinical microbiology laboratory, although BCF might be an alternative if leptospirosis is only suspected postadmission after antibiotics have been used.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • Patpong Rongkard
  • Viriya Hantrakun
  • Sabine Dittrich
  • Prapaporn Srilohasin
  • Premjit Amornchai
  • Sayan Langla
  • Cherry Lim
  • Nicholas Day
  • David AuCoin
  • Vanaporn Wuthiekanun
  • Direk Limmathurotsakul

Utility of a Lateral Flow Immunoassay (LFI) to Detect Burkholderia pseudomallei in Soil Samples

In: PLoS Neglected Tropical Diseases vol. 10 pg. e0005204.

  • 14.12.2016 (2016)

DOI: 10.1371/journal.pntd.0005204

BACKGROUND Culture is the gold standard for the detection of environmental B. pseudomallei. In general, soil specimens are cultured in enrichment broth for 2 days, and then the culture broth is streaked on an agar plate and incubated further for 7 days. However, identifying B. pseudomallei on the agar plates among other soil microbes requires expertise and experience. Here, we evaluate a lateral flow immunoassay (LFI) developed to detect B. pseudomallei capsular polysaccharide (CPS) in clinical samples as a tool to detect B. pseudomallei in environmental samples. METHODOLOGY/PRINCIPAL FINDINGS First, we determined the limit of detection (LOD) of LFI for enrichment broth of the soil specimens. Soil specimens (10 grams/specimen) culture negative for B. pseudomallei were spiked with B. pseudomallei ranging from 10 to 105 CFU, and incubated in 10 ml of enrichment broth in air at 40°C. Then, on day 2, 4 and 7 of incubation, 50 μL of the upper layer of the broth were tested on the LFI, and colony counts to determine quantity of B. pseudomallei in the broth were performed. We found that all five soil specimens inoculated at 10 CFU were negative by LFI on day 2, but four of those five specimens were LFI positive on day 7. The LOD of the LFI was estimated to be roughly 3.8x106 CFU/ml, and culture broth on day 7 was selected as the optimal sample for LFI testing. Second, we evaluated the utility of the LFI by testing 105 soil samples from Northeast Thailand. All samples were also tested by standard culture and quantitative PCR (qPCR) targeting orf2. Of 105 soil samples, 35 (33%) were LFI positive, 25 (24%) were culture positive for B. pseudomallei, and 79 (75%) were qPCR positive. Of 11 LFI positive but standard culture negative specimens, six were confirmed by having the enrichment broth on day 7 culture positive for B. pseudomallei, and an additional three by qPCR. The LFI had 97% (30/31) sensitivity to detect soil specimens culture positive for B. pseudomallei. CONCLUSIONS/SIGNIFICANCE The LFI can be used to detect B. pseudomallei in soil samples, and to select which samples should be sent to reference laboratories or proceed further for bacterial isolation and confirmation. This could considerably decrease laboratory workload and assist the development of a risk map for melioidosis in resource-limited settings.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • A. Taylor
  • K. Vongphayloth
  • M. Vongsouvath
  • M. Grandadam
  • P. Brey
  • P. Newton
  • I. Sutherland
  • Sabine Dittrich

Large-Scale Survey for Tickborne Bacteria, Khammouan Province, Laos

In: Emerging Infectious Diseases vol. 22 pg. 1635-9.

  • (2016)

DOI: 10.3201/eid2209.151969

We screened 768 tick pools containing 6,962 ticks from Khammouan Province, Laos, by using quantitative real-time PCR and identified Rickettsia spp., Ehrlichia spp., and Borrelia spp. Sequencing of Rickettsia spp.-positive and Borrelia spp.-positive pools provided evidence for distinct genotypes. Our results identified bacteria with human disease potential in ticks in Laos.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • Olivier Ribolzi
  • Emma Rochelle-Newall
  • Sabine Dittrich
  • Yves Auda
  • Paul Newton
  • Sayaphet Rattanavong
  • Michael Knappik
  • Bounsamai Soulileuth
  • Oloth Sengtaheuanghoung
  • David Dance
  • Alain Pierret

Land use and soil type determine the presence of the pathogen Burkholderia pseudomallei in tropical rivers

In: Environmental science and pollution research international vol. 23 pg. 7828-39.

  • 13.01.2016 (2016)

DOI: 10.1007/s11356-015-5943-z

Burkholderia pseudomallei is the bacterium that causes melioidosis in humans. While B. pseudomallei is known to be endemic in South East Asia (SEA), the occurrence of the disease in other parts of the tropics points towards a potentially large global distribution. We investigated the environmental factors that influence the presence (and absence) of B. pseudomallei in a tropical watershed in SEA. Our main objective was to determine whether there is a link between the presence of the organism in the hydrographic network and the upstream soil and land-use type. The presence of B. pseudomallei was determined using a specific quantitative real-time PCR assay following enrichment culture. Land use, soil, geomorphology, and environmental data were then analyzed using partial least squares discriminant analysis (PLSDA) to compare the B. pseudomallei positive and negative sites. Soil type in the surrounding catchment and turbidity had a strong positive influence on the presence (acrisols and luvisols) or absence (ferralsols) of B. pseudomallei. Given the strong apparent links between soil characteristics, water turbidity, and the presence/absence of B. pseudomallei, actions to raise public awareness about factors increasing the risk of exposure should be undertaken in order to reduce the incidence of melioidosis in regions of endemicity.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • Sabine Dittrich
  • Birkneh Tadesse
  • Francis Moussy
  • Arlene Chua
  • Anna Zorzet
  • Thomas Tängdén
  • David Dolinger
  • Anne-Laure Page
  • John Crump
  • Valerie DAcremont
  • Quique Bassat
  • Yoel Lubell
  • Paul Newton
  • Norbert Heinrich
  • Timothy Rodwell
  • Iveth González

Target Product Profile for a Diagnostic Assay to Differentiate between Bacterial and Non-Bacterial Infections and Reduce Antimicrobial Overuse in Resource-Limited Settings: An Expert Consensus

In: PLoS One vol. 11 pg. e0161721.

  • 25.08.2016 (2016)

DOI: 10.1371/journal.pone.0161721

Acute fever is one of the most common presenting symptoms globally. In order to reduce the empiric use of antimicrobial drugs and improve outcomes, it is essential to improve diagnostic capabilities. In the absence of microbiology facilities in low-income settings, an assay to distinguish bacterial from non-bacterial causes would be a critical first step. To ensure that patient and market needs are met, the requirements of such a test should be specified in a target product profile (TPP). To identify minimal/optimal characteristics for a bacterial vs. non-bacterial fever test, experts from academia and international organizations with expertise in infectious diseases, diagnostic test development, laboratory medicine, global health, and health economics were convened. Proposed TPPs were reviewed by this working group, and consensus characteristics were defined. The working group defined non-severely ill, non-malaria infected children as the target population for the desired assay. To provide access to the most patients, the test should be deployable to community health centers and informal health settings, and staff should require <2 days of training to perform the assay. Further, given that the aim is to reduce inappropriate antimicrobial use as well as to deliver appropriate treatment for patients with bacterial infections, the group agreed on minimal diagnostic performance requirements of >90% and >80% for sensitivity and specificity, respectively. Other key characteristics, to account for the challenging environment at which the test is targeted, included: i) time-to-result <10 min (but maximally <2 hrs); ii) storage conditions at 0-40°C, ≤90% non-condensing humidity with a minimal shelf life of 12 months; iii) operational conditions of 5-40°C, ≤90% non-condensing humidity; and iv) minimal sample collection needs (50-100μL, capillary blood). This expert approach to define assay requirements for a bacterial vs. non-bacterial assay should guide product development, and enable targeted and timely efforts by industry partners and academic institutions.
  • Europan Campus Rottal-Inn
  • GESUND
Beitrag in Sammelwerk/Tagungsband

  • Sabine Dittrich
  • P. Panyanivong
  • S. Thongpaseuth
  • D. Paris
  • S. Blacksell
  • R. Phetsouvanh
  • P. Newton

How to Optimally Diagnose Orientia Tsutsugamushi or Rickettsia Typhi Infections in Patients With Central Nervous System Disease?

pg. 162-163.

  • (2015)
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • M. Knappik
  • D. Dance
  • S. Rattanavong
  • A. Pierret
  • O. Ribolzi
  • V. Davong
  • J. Silisouk
  • M. Vongsouvath
  • P. Newton
  • Sabine Dittrich

Evaluation of Molecular Methods To Improve the Detection of Burkholderia pseudomallei in Soil and Water Samples from Laos

In: Applied and Environmental Microbiology vol. 81 pg. 3722-7.

  • 27.03.2015 (2015)

DOI: 10.1128/aem.04204-14

Burkholderia pseudomallei is the cause of melioidosis, a severe and potentially fatal disease of humans and animals. It is endemic in northern Australia and Southeast Asia and is found in soil and surface water. The environmental distribution of B. pseudomallei worldwide and within countries where it is endemic, such as the Lao People's Democratic Republic (Laos), remains unclear. However, this knowledge is important to our understanding of the ecology and epidemiology of B. pseudomallei and to facilitate public health interventions. Sensitive and specific methods to detect B. pseudomallei in environmental samples are therefore needed. The aim of this study was to compare molecular and culture-based methods for the detection of B. pseudomallei in soil and surface water in order to identify the optimal approach for future environmental studies in Laos. Molecular detection by quantitative real-time PCR (qPCR) was attempted after DNA extraction directly from soil or water samples or after an overnight enrichment step. The positivity rates obtained by qPCR were compared to those obtained by different culture techniques. The rate of detection from soil samples by qPCR following culture enrichment was significantly higher (84/100) than that by individual culture methods and all culture methods combined (44/100; P < 0.001). Similarly, qPCR following enrichment was the most sensitive method for filtered river water compared with the sensitivity of the individual methods and all individual methods combined. In conclusion, molecular detection following an enrichment step has proven to be a sensitive and reliable approach for B. pseudomallei detection in Lao environmental samples and is recommended as the preferred method for future surveys.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • Sabine Dittrich
  • W. Phuklia
  • G. Turner
  • S. Rattanavong
  • V.ilada Chansamouth
  • et al.

Neorickettsia sennetsu as a Neglected Cause of Fever in South-East Asia

In: PLoS Neglected Tropical Diseases vol. 9 pg. e0003908.

  • 09.07.2015 (2015)

DOI: 10.1371/journal.pntd.0003908

Neorickettsia sennetsu infection is rarely recognized, with less than 100 globally reported patients over the last 50 years. The disease is thought to be contracted by eating raw fish, a staple of many South-East Asian cuisines. In 2009, the first patient with sennetsu was identified in the Lao PDR (Laos), raising the question as to how common this organism and related species are in patients presenting with fever. We investigated the frequency of N. sennetsu infection at hospitals in diverse areas of Laos. Consenting febrile hospital inpatients from central (Vientiane: n = 1,013), northern (Luang Namtha: n = 453) and southern (Salavan: n = 171) Laos were screened by PCR for N. sennetsu, if no previous positive direct diagnostic test was available. A PCR-restriction fragment length polymorphism assay was developed to differentiate between N. sennetsu, Ehrlichia chaffeensis and Anaplasma phagocytophilum. To allow more detailed studies of N. sennetsu, culture was successfully established using a reference strain (ATCC VR-367), identifying a canine-macrophage cell line (DH82) to be most suitable to visually identify infection. After screening, N. sennetsu was identified and sequence confirmed in four (4/1,637; 0.2%) Lao patients. Despite the previously identified high seroprevalence of N. sennetsu antibodies in the Lao population (~17%), acute N. sennetsu infection with sufficient clinical signs to prompt hospitalization appears to be rare. The reservoir, zoonotic cycle and pathogenicity of N. sennetsu remain unclear and require further investigations.
  • Europan Campus Rottal-Inn
  • GESUND
Beitrag in Sammelwerk/Tagungsband

  • M. Mayxay
  • O. Sengvilaipaseuth
  • A. Chanthongthip
  • A. Dubot-Pérès
  • J.-M. Rolain
  • P. Parola
  • S. Craig
  • S. Tulsiani
  • M.-A. Burns
  • M. Khanthavong
  • S. Keola
  • T. Pongvongsa
  • D. Raoult
  • Sabine Dittrich
  • P. Newton

Causes of Fever in Rural Southern Laos

pg. 517-520.

  • (2015)
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • I. Vongphoumy
  • D. Dance
  • Sabine Dittrich
  • J. Logan
  • V. Davong
  • S. Rattanavong
  • J. Blessmann

Case report: Actinomycetoma caused by Nocardia aobensis from Lao PDR with favourable outcome after short-term antibiotic treatment

In: PLoS Neglected Tropical Diseases vol. 9 pg. e0003729.

  • 16.04.2015 (2015)

DOI: 10.1371/journal.pntd.0003729

BACKGROUND Mycetoma is a neglected, chronic, localized, progressively destructive, granulomatous infection caused either by fungi (eumycetoma) or by aerobic actinomycetes (actinomycetoma). It is characterized by a triad of painless subcutaneous mass, multiple sinuses and discharge containing grains. Mycetoma commonly affects young men aged between 20 and 40 years with low socioeconomic status, particularly farmers and herdsmen. METHODOLOGY/PRINCIPAL FINDINGS A 30 year-old male farmer from an ethnic minority in Phin District, Savannakhet Province, Lao PDR (Laos) developed a painless swelling with multiple draining sinuses of his right foot over a period of approximately 3 years. X-ray of the right foot showed osteolysis of tarsals and metatarsals. Aerobic culture of sinus discharge yielded large numbers of Staphylococcus aureus and a slow growing Gram-positive rod. The organism was subsequently identified as Nocardia aobensis by 16S ribosomal RNA gene sequencing. The patient received antimicrobial treatment with amikacin and trimethoprim-sulfamethoxazole according to consensus treatment guidelines. Although slight improvement was noted the patient left the hospital after 14 days and did not take any more antibiotics. Over the following 22 weeks the swelling of his foot subsequently diminished together with healing of discharging sinuses. CONCLUSION This is the first published case of Actinomycetoma caused by Nocardia aobensis and the second case of Actinomycetoma from Laos. A treatment course of only 14 days with amikacin and trimethoprim-sulfamethoxazole was apparently sufficient to cure the infection, although long-term treatment up to one year is currently recommended. Treatment trials or prospective descriptions of outcome for actinomycetoma should investigate treatment efficacy for the different members of Actinomycetales, particularly Nocardia spp., with short-term and long-term treatment courses.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • Günther Slesak
  • Saythong Inthalath
  • Sabine Dittrich
  • Daniel Paris
  • Paul Newton

Leeches as further potential vectors for rickettsial infections

In: Proceedings of the National Academy of Sciences of the United States of America vol. 112 pg. E6593-4.

  • 23.11.2015 (2015)

DOI: 10.1073/pnas.1515229112

We were very interested in the discovery and comprehensive investigation by Dieme et al. (1) of mosquitos as potential vectors for Rickettisa felis. We would like to draw attention to another ectoparasite that we encountered as a possibly overlooked potential vector for rickettsial infections: the leech. In 2008, a 39-y-old diabetic woman was admitted to a hospital in Northern Laos with a 7-d history of fever, headaches, limb pains, chills, and 2 d of nausea and vomiting. She had a typical eschar on her right anteromedial thigh (7 × 4 mm) (Fig. 1). She remembered being bitten by a terrestrial leech (Haemadipsida spp.), while working in a rice field, exactly at the eschar site 5 d before onset of fever. No tick or other ectoparasite was observed at this site until eschar manifestation. Molecular characterization of eschar biopsy revealed amplicons of 100% identity to the Rickettsia felis-URRWXCal2 strain (2). The patient responded promptly to treatment with oral doxycycline.
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • C. Nic Fhogartaigh
  • D. Dance
  • V. Davong
  • P. Tann
  • R. Phetsouvanh
  • P. Turner
  • Sabine Dittrich
  • P. Newton

A novel technique for detecting antibiotic-resistant typhoid from rapid diagnostic tests

In: Journal of Clinical Microbiology vol. 53 pg. 1758-60.

  • 11.03.2015 (2015)

DOI: 10.1128/jcm.00531-15

Fluoroquinolone-resistant typhoid is increasing. An antigen-detecting rapid diagnostic test (RDT) can rapidly diagnose typhoid from blood cultures. A simple, inexpensive molecular technique performed with DNA from positive RDTs accurately identified gyrA mutations consistent with phenotypic susceptibility testing results. Field diagnosis combined with centralized molecular resistance testing could improve typhoid management and surveillance in low-resource settings.
  • Europan Campus Rottal-Inn
  • GESUND
Beitrag in Sammelwerk/Tagungsband

  • Sabine Dittrich
  • P. Sunyakumthorn
  • S. Rattanavong
  • R. Phetsouvanh
  • P. Panyanivong
  • A. Sengduangphachanh
  • P. Phouminh
  • T. Anantatat
  • A. Chanthongthip
  • S. Lee
  • A. Dubot-Pérès
  • N. Day
  • et al.

Blood–Brain Barrier Function and Biomarkers of Central Nervous System Injury in Rickettsial Versus Other Neurological Infections in Laos

pg. 232-237.

  • (2015)
  • Europan Campus Rottal-Inn
  • GESUND
Zeitschriftenartikel

  • Sabine Dittrich
  • Sayaphet Rattanavong
  • Sue Lee
  • Phonepasith Panyanivong
  • Scott Craig
  • Suhella Tulsiani
  • Stuart Blacksell
  • David Dance
  • Audrey Dubot-Pérès
  • Amphone Sengduangphachanh
  • Phonelavanh Phoumin
  • Daniel Paris
  • Paul Newton

Orientia, rickettsia, and leptospira pathogens as causes of CNS infections in Laos: a prospective study

In: The Lancet Global Health vol. 3 pg. e104-12.

  • (2015)

DOI: 10.1016/s2214-109x(14)70289-x

BACKGROUND Scrub typhus (caused by Orientia tsutsugamushi), murine typhus (caused by Rickettsia typhi), and leptospirosis are common causes of febrile illness in Asia; meningitis and meningoencephalitis are severe complications. However, scarce data exist for the burden of these pathogens in patients with CNS disease in endemic countries. Laos is representative of vast economically poor rural areas in Asia with little medical information to guide public health policy. We assessed whether these pathogens are important causes of CNS infections in Laos. METHODS Between Jan 10, 2003, and Nov 25, 2011, we enrolled 1112 consecutive patients of all ages admitted with CNS symptoms or signs requiring a lumbar puncture at Mahosot Hospital, Vientiane, Laos. Microbiological examinations (culture, PCR, and serology) targeted so-called conventional bacterial infections (Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, S suis) and O tsutsugamushi, Rickettsia typhi/Rickettsia spp, and Leptospira spp infections in blood or cerebrospinal fluid (CSF). We analysed and compared causes and clinical and CSF characteristics between patient groups. FINDINGS 1051 (95%) of 1112 patients who presented had CSF available for analysis, of whom 254 (24%) had a CNS infection attributable to a bacterial or fungal pathogen. 90 (35%) of these 254 infections were caused by O tsutsugamushi, R typhi/Rickettsia spp, or Leptospira spp. These pathogens were significantly more frequent than conventional bacterial infections (90/1051 [9%] vs 42/1051 [4%]; p<0·0001) by use of conservative diagnostic definitions. CNS infections had a high mortality (236/876 [27%]), with 18% (13/71) for R typhi/Rickettsia spp, O tsutsugamushi, and Leptospira spp combined, and 33% (13/39) for conventional bacterial infections (p=0·076). INTERPRETATION Our data suggest that R typhi/Rickettsia spp, O tsutsugamushi, and Leptospira spp infections are important causes of CNS infections in Laos. Antibiotics, such as tetracyclines, needed for the treatment of murine typhus and scrub typhus, are not routinely advised for empirical treatment of CNS infections. These severely neglected infections represent a potentially large proportion of treatable CNS disease burden across vast endemic areas and need more attention. FUNDING Wellcome Trust UK.
  • Europan Campus Rottal-Inn
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Zeitschriftenartikel

  • A. Bonačić Marinović
  • M. Koopmans
  • Sabine Dittrich
  • P. Teunis
  • C. Swaan
  • J. van Steenbergen
  • M. Kretzschmar

Speed versus coverage trade off in targeted interventions during an outbreak

In: Epidemics vol. 8 pg. 28-40.

  • 15.08.2014 (2014)

DOI: 10.1016/j.epidem.2014.05.003

Which case-based intervention measures should be applied during an epidemic outbreak depends on how timely they can be applied and how effective they are. During the course of each individual's infection, the earlier control measures are applied on him/her the more effectively further disease spread can be prevented. However, quick implementation can lead to loss of efficacy or coverage, e.g., when individuals are targeted based on rapid but poorly sensitive diagnostic tests in place of slower but accurate PCR tests. To analyse this trade off between speed and coverage we used stochastic models considering how the individual reproduction density is modified by interventions. We took as example the case-based intervention strategy employed in the Netherlands during the beginning of the H1N1 pandemic. Suspected cases were isolated and samples were collected for PCR diagnosis. In case of positive diagnosis, antiviral drugs were provided to contacts as post-exposure prophylaxis. At the time there were also rapid influenza diagnostic tests (RIDTs) available which provided results within an hour after sample collection compared to a median of 2.7 days for PCR tests, but they were less sensitive. We studied how interventions based on RIDTs with various sensitivities affect the outbreak size and how these compare to PCR diagnosis based interventions. Using an intervention based on a bedside RIDT with 60% detection ratio or a laboratory RIDT with 70% detection ratio is as effective as the most effective PCR-diagnosis based intervention. Relative performances of interventions are not dependent on the basic reproduction number R0 but only on distributions of individual reproduction density and of delay periods. The individual reproduction density combines R0 and infection time distribution, both crucial in determining the impact of case-based interventions during epidemic outbreaks.
  • Europan Campus Rottal-Inn
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