febrile illness evaluation in a broad range of endemicities fiebre protocol for CORD-Papers-2022-06-02 (Version 1)

Title: Febrile Illness Evaluation in a Broad Range of Endemicities (FIEBRE): protocol for a multisite prospective observational study of the causes of fever in Africa and Asia
Abstract: INTRODUCTION: Fever commonly leads to healthcare seeking and hospital admission in sub-Saharan Africa and Asia. There is only limited guidance for clinicians managing non-malarial fevers which often results in inappropriate treatment for patients. Furthermore there is little evidence for estimates of disease burden or to guide empirical therapy control measures resource allocation prioritisation of clinical diagnostics or antimicrobial stewardship. The Febrile Illness Evaluation in a Broad Range of Endemicities (FIEBRE) study seeks to address these information gaps. METHODS AND ANALYSIS: FIEBRE investigates febrile illness in paediatric and adult outpatients and inpatients using standardised clinical laboratory and social science protocols over a minimum 12-month period at five sites in sub-Saharan Africa and Southeastern and Southern Asia. Patients presenting with fever are enrolled and provide clinical data pharyngeal swabs and a venous blood sample; selected participants also provide a urine sample. Laboratory assessments target infections that are treatable and/or preventable. Selected point-of-care tests as well as blood and urine cultures and antimicrobial susceptibility testing are performed on site. On day 28 patients provide a second venous blood sample for serology and information on clinical outcome. Further diagnostic assays are performed at international reference laboratories. Blood and pharyngeal samples from matched community controls enable calculation of AFs and surveys of treatment seeking allow estimation of the incidence of common infections. Additional assays detect markers that may differentiate bacterial from non-bacterial causes of illness and/or prognosticate illness severity. Social science research on antimicrobial use will inform future recommendations for fever case management. Residual samples from participants are stored for future use. ETHICS AND DISSEMINATION: Ethics approval was obtained from all relevant institutional and national committees; written informed consent is obtained from all participants or parents/guardians. Final results will be shared with participating communities and in open-access journals and other scientific fora. Study documents are available online (https://doi.org/10.17037/PUBS.04652739).
Published: 2020-07-21
Journal: BMJ Open
DOI: 10.1136/bmjopen-2019-035632
DOI_URL: http://doi.org/10.1136/bmjopen-2019-035632
Author Name: Hopkins Heidi
Author link: https://covid19-data.nist.gov/pid/rest/local/author/hopkins_heidi
Author Name: Bassat Quique
Author link: https://covid19-data.nist.gov/pid/rest/local/author/bassat_quique
Author Name: Chandler Clare IR
Author link: https://covid19-data.nist.gov/pid/rest/local/author/chandler_clare_ir
Author Name: Crump John A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/crump_john_a
Author Name: Feasey Nicholas A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/feasey_nicholas_a
Author Name: Ferrand Rashida A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/ferrand_rashida_a
Author Name: Kranzer Katharina
Author link: https://covid19-data.nist.gov/pid/rest/local/author/kranzer_katharina
Author Name: Lalloo David G
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lalloo_david_g
Author Name: Mayxay Mayfong
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mayxay_mayfong
Author Name: Newton Paul N
Author link: https://covid19-data.nist.gov/pid/rest/local/author/newton_paul_n
Author Name: Mabey David
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mabey_david
Author Name: Blacksell, Stuart D
Author link: https://covid19-data.nist.gov/pid/rest/local/author/blacksell_stuart_d
Author Name: Chansamouth, Vilada
Author link: https://covid19-data.nist.gov/pid/rest/local/author/chansamouth_vilada
Author Name: Craig, Scott B
Author link: https://covid19-data.nist.gov/pid/rest/local/author/craig_scott_b
Author Name: Dauya, Ethel
Author link: https://covid19-data.nist.gov/pid/rest/local/author/dauya_ethel
Author Name: De Lamballerie, Xavier
Author link: https://covid19-data.nist.gov/pid/rest/local/author/de_lamballerie_xavier
Author Name: Dubot-Peres, Audrey
Author link: https://covid19-data.nist.gov/pid/rest/local/author/dubot_peres_audrey
Author Name: Durkin, Michelle M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/durkin_michelle_m
Author Name: Fink, Colin
Author link: https://covid19-data.nist.gov/pid/rest/local/author/fink_colin
Author Name: Fitzgerald, Felicity C
Author link: https://covid19-data.nist.gov/pid/rest/local/author/fitzgerald_felicity_c
Author Name: Graves, Stephen R
Author link: https://covid19-data.nist.gov/pid/rest/local/author/graves_stephen_r
Author Name: Jones, Jayne
Author link: https://covid19-data.nist.gov/pid/rest/local/author/jones_jayne
Author Name: Kain, Kevin C
Author link: https://covid19-data.nist.gov/pid/rest/local/author/kain_kevin_c
Author Name: Lubell, Yoel
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lubell_yoel
Author Name: Maurer, Florian P
Author link: https://covid19-data.nist.gov/pid/rest/local/author/maurer_florian_p
Author Name: Valente, Marta
Author link: https://covid19-data.nist.gov/pid/rest/local/author/valente_marta
Author Name: Wheat, Joseph
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wheat_joseph
sha: eb89ba38df11b4bf3e03027ebf0ed1a23cbed561
license: cc-by-nc
license_url: https://creativecommons.org/licenses/by-nc/4.0/
source_x: PMC
source_x_url: https://www.ncbi.nlm.nih.gov/pubmed/
pubmed_id: 32699131
pubmed_id_url: https://www.ncbi.nlm.nih.gov/pubmed/32699131
pmcid: PMC7375419
pmcid_url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375419
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375419/
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Keywords Extracted from Text Content: Lao People's Democratic Republic venous blood  CRP urine left micro-organisms employees participants EDTA blood samples serum buffy coat pharyngeal HBP convalescent sera minors blood immune ≥15 myeloid cells GENBANK pharyngeal samples serum cryptococcal antigen F o r p e e r r e Patients convalescent venous blood stratum Venous blood ≥600 Southeast Asia arboviruses plasma 43,44 heparin binding protein Laos Naso-and/or oropharyngeal swabs suprapubic tenderness 5 myeloid cells urine cultures Nigeria 12 APC children people patient specimens serum CrAg Harmonised protocol sTREM-1 inpatients urinary tract patients Blood endothelial RSV costovertebral angle urinary lipoarabinomannan angiopoietin 2
Extracted Text Content in Record: First 5000 Characters:on behalf of the FIEBRE Consortium** Key words: fever, fever aetiology, fever diagnosis, non-malaria febrile illness, fever case management, diagnosis, antibiotic, antimicrobial Word count (not including Abstract): 4,000 I, the Submitting Author has the right to grant and does grant on behalf of all authors of the Work (as defined in the below author licence), an exclusive licence and/or a non-exclusive licence for contributions from authors who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY licence shall apply, and/or iii) in accordance with the terms applicable for US Federal Government officers or employees acting as part of their official duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd ("BMJ") its licensees and where the relevant Journal is co-owned by BMJ to the co-owners of the Journal, to publish the Work in this journal and any other BMJ products and to exploit all rights, as set out in our licence. The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to the Submitting Author unless you are acting as an employee on behalf of your employer or a postgraduate student of an affiliated institution which is paying any applicable article publishing charge ("APC") for Open Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative Commons licence -details of these licences and which Creative Commons licence will apply to this Work are set out in our licence referred to above. Other than as permitted in any relevant BMJ Author's Self Archiving Policies, I confirm this Work has not been accepted for publication elsewhere, is not being considered for publication elsewhere and does not duplicate material already published. I confirm all authors consent to publication of this Work and authorise the granting of this licence. Fever commonly leads to health care seeking and hospital admission in sub-Saharan Africa and Asia. There is only limited guidance for clinicians managing non-malarial fevers, which often results in inappropriate treatment for patients. Furthermore, there is little evidence for estimates of disease burden, or to guide empirical therapy, control measures, resource allocation, prioritization of clinical diagnostics, or antimicrobial stewardship. The Febrile Illness Evaluation in a Broad Range of Endemicities (FIEBRE) study seeks to address these information gaps. FIEBRE investigates febrile illness in paediatric and adult outpatients and inpatients, using standardised clinical, laboratory, and social science protocols, over a minimum 12-month period at four sites in sub-Saharan Africa and Southeast Asia. Patients presenting with fever are enrolled, and provide clinical data, pharyngeal swabs, and a venous blood sample; selected participants also provide a urine sample. Laboratory assessments target infections that are treatable and/or preventable. Selected point-of-care tests, and blood and urine cultures and antimicrobial susceptibility testing, are performed on site. On day 28, patients provide a second venous blood sample for serology, and information on clinical outcome. Further diagnostic assays are performed at international reference laboratories. Blood and pharyngeal samples from matched community controls enable calculation of attributable fractions; and surveys of treatment seeking allow estimation of the incidence of common infections. Additional assays detect markers that may differentiate bacterial from non-bacterial causes of illness, and/or prognosticate illness severity. Qualitative research on antimicrobial use will inform future recommendations for fever case management. Residual samples from participants are stored for future use. Ethics approval was obtained from all relevant institutional and national committees; written informed consent is obtained from all participants or parents/guardians. Final results will be shared Harmonised protocol at multiple sites to allow comparison of results across diverse epidemiological, geographic, and cultural settings  Collection of data from inpatients, outpatients, and community controls of all ages ≥2 months, at multiple sites across Africa and Asia, over the course of >12 months at each site to capture seasonal variation Fever is one of the most common symptoms leading to health care seeking and hospital admission in sub-Saharan Africa and Asia. 1 2 Current age-specific WHO algorithms for the primary care level provide only limited guidance to clinicians for the management of non-malarial fevers. If the malaria test is negative, the patient is classified as "Fever: no malaria" in the Integrated Management of Childhood Illness (IMCI) guidelines 3 or in the Integrated Management of Adolescent and Adult Illness (IMAI) guidelines 4 and advice is given to "treat according to the ap
Keywords Extracted from PMC Text: patient Nigeria12 Leishmania Venous blood ≥15 Blood myeloid cells suprapubic tenderness FIEBRE left Lao People's Democratic Republic recently.2 EDTA serum urinary tract Study18 endothelial Patients blood participants stratum retailers convalescent sera illness,10 mid-2020 blood samples pharyngeal minors serum CrAg urine inpatients CIs ≥600 children 's Laos GENBANK AFs pharyngeal swabs buffy coat people plasma people's LMICs Asia.1 2 arboviruses guidelines3 pharyngeal samples resistance.47 Bangladesh −80°C urine cultures Asia.13 venous blood patient's clean-catch angiopoietin 2,43 44 patients serum cryptococcal antigen costovertebral angle bloodstream immune Nasopharyngeal member.24 specimens ±1.7 elsewhere.39 urinary lipoarabinomannan ShareAlike oropharyngeal swabs Score29 Mozambique
Extracted PMC Text Content in Record: First 5000 Characters:Fever is one of the most common symptoms leading to healthcare seeking and hospital admission in sub-Saharan Africa and Asia.1 2 Current age-specific WHO algorithms for the primary care level provide only limited guidance to clinicians for the management of non-malarial fevers. If the malaria test is negative, the patient is classified as 'fever: no malaria' in the Integrated Management of Childhood Illness guidelines3 or in the Integrated Management of Adolescent and Adult Illness guidelines,4 and advice is given to 'treat according to the apparent cause of fever.' Many febrile illnesses present with non-specific symptoms and signs, and the current recommendations often result in treatable diseases being left untreated or treated with inappropriate antimicrobials on the one hand and overtreatment of self-limiting conditions with antimicrobials on the other, with important implications for the development of antimicrobial resistance.5 6 Little is currently known about the causes of fever in many low-income and middle-income countries (LMICs),7–9 so there is sparse evidence on which to base empirical treatment guidelines for febrile patients, especially in more remote areas. Some studies provide an indication of the clinical spectrum of febrile illness,10 11 but these studies were often disease specific, for example, focussing on urinary tract infections in Nigeria12 or arboviruses in Asia.13 A few studies designed to look at aetiologies of fever in given locations have been published recently.2 14–17 While the results are useful within the specific study areas, the epidemiology of infections varies in place and time, so the generalisability of single-site studies is uncertain. Furthermore, the study approaches were heterogeneous—with differences in patient age, type of health facility, seasons covered, inclusion criteria, study design, sampling techniques and pathology tests employed—making it difficult to compare findings across sites and to produce a clear picture of the most common causes of fever in each geographical setting, age group and at each level of care. In addition, there is disabling heterogeneity in eligibility criteria, case definitions, use of diagnostic tests that are not sufficiently validated or standardised and lack of control groups, preventing calculation of attributable fractions (AFs). Recently, two multisite, prospective, case–control studies demonstrated the potential of using harmonised research protocols with standardised diagnostic methods to investigate the causes of clinical syndromes with high morbidity and mortality in resource-limited settings: the Global Enteric Multicenter Study18 and the Pneumonia Aetiology Research for Child Health study19 determined the predominant infectious causes of diarrhoea and pneumonia, respectively, among children in multiple African and Asian countries. Improved diagnosis and treatment of febrile illness matter both for the care of individual patients and for public health goals. Besides data gaps on prevalence of specific infections in febrile patients, there is very little information on incidence for many of the infections thought to be clinically important in Africa and Asia. Consequently, there is little information on which to base estimates of burden of disease or to guide empirical therapy, control measures and resource allocation.20 In addition, the ability to differentiate between bacterial and viral infections and between broad groups of bacterial pathogens based on antimicrobial susceptibility, could have a major global impact on antimicrobial resistance by limiting the unnecessary use of antimicrobials. However, there are limited data on antimicrobial usage and how and why the frequency and appropriateness of usage vary across LMICs. There is increasing emphasis on identification and incorporation into point-of-care diagnostic tests of markers of immune and endothelial activation (hereafter 'biomarkers') that can distinguish between bacterial causes of fever requiring antimicrobial treatment and viral or self-limiting infections,21 or that can identify current or incipient severe illness.22 23 The Febrile Illness Evaluation in a Broad Range of Endemicities (FIEBRE) study has been designed to help address these information gaps. FIEBRE is a multisite investigation in paediatric and adult outpatients and inpatients, using standardised clinical, reference laboratory and social science protocols, in low-resource regions from which few or no data are available. FIEBRE is being conducted at five sites in sub-Saharan Africa and Southeastern and Southern Asia, and the full protocol, data collection forms, standard operating procedures and other supplementary information are freely available to researchers who may wish to conduct harmonised work at other sites (accessible on the FIEBRE study website (https://doi.org/10.17037/PUBS.04652739) or from coinvestigators). This paper describes the clinical, epidemiological and laboratory activi
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