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Abstract
Background
Currently, vaccination of livestock with attenuated strains of
Brucella remains an essential measure for controlling brucellosis, although these vaccines
may be dangerous to humans. The aim of this study was to review the risk posed to
humans by occupational exposure to vaccine strains and the measures that should be
implemented to minimize this risk.
Methods
This article reviewed the scientific literature indexed in PubMed up to September
30, 2023, following "the PRISMA guidelines". Special emphasis was placed on the vaccine
strain used and the route of exposure. Non-occupational exposure to vaccine strains,
intentional human inoculation, publications on exposure to wild strains, and secondary
scientific sources were excluded from the study.
Results
Nineteen primary reports were found and classified in three subgroups: safety accidents
in vaccine factories that led to an outbreak (n = 2), survellaince studies on vaccine
manufacturing workers with a serologic diagnosis of
Brucella infection (n = 3), and publications of infection by vaccine strains during their
administration, including case reports, records of occupational accidents and investigations
of outbreaks in vaccination campaigns (n = 14). Although accidental exposure during
vaccine manufacturing were uncommon, they could provoke large outbreaks through airborne
spread with risk of spread to the neighboring population. Besides, despite strict
protection measures, a percentage of vaccine manufacturing workers developed positive
Brucella serology without clinical infection. The most frequent type of exposure with symptomatic
infection was needle injury during vaccine administration. Prolonged contact with
the pathogen, lack of information and a low adherence to personal protective equipment
(PPE) use in the work environment were commonly associated with infection.
Conclusions
Brucella vaccines pose occupational risk of contagion to humans from their production to their
administration to livestock, although morbidity is low and deaths were not reported.
Recommended protective measures and active surveillance of exposed workers appeared
to reduce this risk. It would be advisable to carry out observational studies and/or
systematic registries using solid diagnostic criteria.
Summary
Vaccination of livestock with attenuated strains of
Brucella is an effective measure for controlling brucellosis, and they will continue to apply.
Following "the PRISMA guidelines" we reviewed the risk posed to humans by occupational
exposure to these strains and the measures that should be implemented to minimize
this risk. Nineteen primary reports were included. The most frequent type of exposure
was needle injury during vaccine administration, while safety accidents during vaccine
manufacturing were less frequent but caused large outbreaks. Prolonged contact with
the pathogen, lack of information and a low adherence to personal protective equipment
(PPE) use in the work environment were commonly associated with infection. Despite
strict protection measures, a percentage of vaccine manufacturing workers developed
a positive serology to the vaccine strain without clinical infection. To conclude,
Brucella vaccines pose risk of contagion to humans from their production to their administration
to livestock, but with a low morbi-mortality.
Introduction Systematic reviews and meta-analyses have become increasingly important in health care. Clinicians read them to keep up to date with their field [1],[2], and they are often used as a starting point for developing clinical practice guidelines. Granting agencies may require a systematic review to ensure there is justification for further research [3], and some health care journals are moving in this direction [4]. As with all research, the value of a systematic review depends on what was done, what was found, and the clarity of reporting. As with other publications, the reporting quality of systematic reviews varies, limiting readers' ability to assess the strengths and weaknesses of those reviews. Several early studies evaluated the quality of review reports. In 1987, Mulrow examined 50 review articles published in four leading medical journals in 1985 and 1986 and found that none met all eight explicit scientific criteria, such as a quality assessment of included studies [5]. In 1987, Sacks and colleagues [6] evaluated the adequacy of reporting of 83 meta-analyses on 23 characteristics in six domains. Reporting was generally poor; between one and 14 characteristics were adequately reported (mean = 7.7; standard deviation = 2.7). A 1996 update of this study found little improvement [7]. In 1996, to address the suboptimal reporting of meta-analyses, an international group developed a guidance called the QUOROM Statement (QUality Of Reporting Of Meta-analyses), which focused on the reporting of meta-analyses of randomized controlled trials [8]. In this article, we summarize a revision of these guidelines, renamed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses), which have been updated to address several conceptual and practical advances in the science of systematic reviews (Box 1). Box 1: Conceptual Issues in the Evolution from QUOROM to PRISMA Completing a Systematic Review Is an Iterative Process The conduct of a systematic review depends heavily on the scope and quality of included studies: thus systematic reviewers may need to modify their original review protocol during its conduct. Any systematic review reporting guideline should recommend that such changes can be reported and explained without suggesting that they are inappropriate. The PRISMA Statement (Items 5, 11, 16, and 23) acknowledges this iterative process. Aside from Cochrane reviews, all of which should have a protocol, only about 10% of systematic reviewers report working from a protocol [22]. Without a protocol that is publicly accessible, it is difficult to judge between appropriate and inappropriate modifications. Conduct and Reporting Research Are Distinct Concepts This distinction is, however, less straightforward for systematic reviews than for assessments of the reporting of an individual study, because the reporting and conduct of systematic reviews are, by nature, closely intertwined. For example, the failure of a systematic review to report the assessment of the risk of bias in included studies may be seen as a marker of poor conduct, given the importance of this activity in the systematic review process [37]. Study-Level Versus Outcome-Level Assessment of Risk of Bias For studies included in a systematic review, a thorough assessment of the risk of bias requires both a “study-level” assessment (e.g., adequacy of allocation concealment) and, for some features, a newer approach called “outcome-level” assessment. An outcome-level assessment involves evaluating the reliability and validity of the data for each important outcome by determining the methods used to assess them in each individual study [38]. The quality of evidence may differ across outcomes, even within a study, such as between a primary efficacy outcome, which is likely to be very carefully and systematically measured, and the assessment of serious harms [39], which may rely on spontaneous reports by investigators. This information should be reported to allow an explicit assessment of the extent to which an estimate of effect is correct [38]. Importance of Reporting Biases Different types of reporting biases may hamper the conduct and interpretation of systematic reviews. Selective reporting of complete studies (e.g., publication bias) [28] as well as the more recently empirically demonstrated “outcome reporting bias” within individual studies [40],[41] should be considered by authors when conducting a systematic review and reporting its results. Though the implications of these biases on the conduct and reporting of systematic reviews themselves are unclear, some previous research has identified that selective outcome reporting may occur also in the context of systematic reviews [42]. Terminology The terminology used to describe a systematic review and meta-analysis has evolved over time. One reason for changing the name from QUOROM to PRISMA was the desire to encompass both systematic reviews and meta-analyses. We have adopted the definitions used by the Cochrane Collaboration [9]. A systematic review is a review of a clearly formulated question that uses systematic and explicit methods to identify, select, and critically appraise relevant research, and to collect and analyze data from the studies that are included in the review. Statistical methods (meta-analysis) may or may not be used to analyze and summarize the results of the included studies. Meta-analysis refers to the use of statistical techniques in a systematic review to integrate the results of included studies. Developing the PRISMA Statement A three-day meeting was held in Ottawa, Canada, in June 2005 with 29 participants, including review authors, methodologists, clinicians, medical editors, and a consumer. The objective of the Ottawa meeting was to revise and expand the QUOROM checklist and flow diagram, as needed. The executive committee completed the following tasks, prior to the meeting: a systematic review of studies examining the quality of reporting of systematic reviews, and a comprehensive literature search to identify methodological and other articles that might inform the meeting, especially in relation to modifying checklist items. An international survey of review authors, consumers, and groups commissioning or using systematic reviews and meta-analyses was completed, including the International Network of Agencies for Health Technology Assessment (INAHTA) and the Guidelines International Network (GIN). The survey aimed to ascertain views of QUOROM, including the merits of the existing checklist items. The results of these activities were presented during the meeting and are summarized on the PRISMA Web site (http://www.prisma-statement.org/). Only items deemed essential were retained or added to the checklist. Some additional items are nevertheless desirable, and review authors should include these, if relevant [10]. For example, it is useful to indicate whether the systematic review is an update [11] of a previous review, and to describe any changes in procedures from those described in the original protocol. Shortly after the meeting a draft of the PRISMA checklist was circulated to the group, including those invited to the meeting but unable to attend. A disposition file was created containing comments and revisions from each respondent, and the checklist was subsequently revised 11 times. The group approved the checklist, flow diagram, and this summary paper. Although no direct evidence was found to support retaining or adding some items, evidence from other domains was believed to be relevant. For example, Item 5 asks authors to provide registration information about the systematic review, including a registration number, if available. Although systematic review registration is not yet widely available [12],[13], the participating journals of the International Committee of Medical Journal Editors (ICMJE) [14] now require all clinical trials to be registered in an effort to increase transparency and accountability [15]. Those aspects are also likely to benefit systematic reviewers, possibly reducing the risk of an excessive number of reviews addressing the same question [16],[17] and providing greater transparency when updating systematic reviews. The PRISMA Statement The PRISMA Statement consists of a 27-item checklist (Table 1; see also Text S1 for a downloadable Word template for researchers to re-use) and a four-phase flow diagram (Figure 1; see also Figure S1 for a downloadable Word template for researchers to re-use). The aim of the PRISMA Statement is to help authors improve the reporting of systematic reviews and meta-analyses. We have focused on randomized trials, but PRISMA can also be used as a basis for reporting systematic reviews of other types of research, particularly evaluations of interventions. PRISMA may also be useful for critical appraisal of published systematic reviews. However, the PRISMA checklist is not a quality assessment instrument to gauge the quality of a systematic review. 10.1371/journal.pmed.1000097.g001 Figure 1 Flow of information through the different phases of a systematic review. 10.1371/journal.pmed.1000097.t001 Table 1 Checklist of items to include when reporting a systematic review or meta-analysis. Section/Topic # Checklist Item Reported on Page # TITLE Title 1 Identify the report as a systematic review, meta-analysis, or both. ABSTRACT Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). METHODS Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis. Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified. RESULTS Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome-level assessment (see Item 12). Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group and (b) effect estimates and confidence intervals, ideally with a forest plot. Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). DISCUSSION Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., health care providers, users, and policy makers). Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review level (e.g., incomplete retrieval of identified research, reporting bias). Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. From QUOROM to PRISMA The new PRISMA checklist differs in several respects from the QUOROM checklist, and the substantive specific changes are highlighted in Table 2. Generally, the PRISMA checklist “decouples” several items present in the QUOROM checklist and, where applicable, several checklist items are linked to improve consistency across the systematic review report. 10.1371/journal.pmed.1000097.t002 Table 2 Substantive specific changes between the QUOROM checklist and the PRISMA checklist (a tick indicates the presence of the topic in QUOROM or PRISMA). Section/Topic Item QUOROM PRISMA Comment Abstract √ √ QUOROM and PRISMA ask authors to report an abstract. However, PRISMA is not specific about format. Introduction Objective √ This new item (4) addresses the explicit question the review addresses using the PICO reporting system (which describes the participants, interventions, comparisons, and outcome(s) of the systematic review), together with the specification of the type of study design (PICOS); the item is linked to Items 6, 11, and 18 of the checklist. Methods Protocol √ This new item (5) asks authors to report whether the review has a protocol and if so how it can be accessed. Methods Search √ √ Although reporting the search is present in both QUOROM and PRISMA checklists, PRISMA asks authors to provide a full description of at least one electronic search strategy (Item 8). Without such information it is impossible to repeat the authors' search. Methods Assessment of risk of bias in included studies √ √ Renamed from “quality assessment” in QUOROM. This item (12) is linked with reporting this information in the results (Item 19). The new concept of “outcome-level” assessment has been introduced. Methods Assessment of risk of bias across studies √ This new item (15) asks authors to describe any assessments of risk of bias in the review, such as selective reporting within the included studies. This item is linked with reporting this information in the results (Item 22). Discussion √ √ Although both QUOROM and PRISMA checklists address the discussion section, PRISMA devotes three items (24–26) to the discussion. In PRISMA the main types of limitations are explicitly stated and their discussion required. Funding √ This new item (27) asks authors to provide information on any sources of funding for the systematic review. The flow diagram has also been modified. Before including studies and providing reasons for excluding others, the review team must first search the literature. This search results in records. Once these records have been screened and eligibility criteria applied, a smaller number of articles will remain. The number of included articles might be smaller (or larger) than the number of studies, because articles may report on multiple studies and results from a particular study may be published in several articles. To capture this information, the PRISMA flow diagram now requests information on these phases of the review process. Endorsement The PRISMA Statement should replace the QUOROM Statement for those journals that have endorsed QUOROM. We hope that other journals will support PRISMA; they can do so by registering on the PRISMA Web site. To underscore to authors, and others, the importance of transparent reporting of systematic reviews, we encourage supporting journals to reference the PRISMA Statement and include the PRISMA Web address in their Instructions to Authors. We also invite editorial organizations to consider endorsing PRISMA and encourage authors to adhere to its principles. The PRISMA Explanation and Elaboration Paper In addition to the PRISMA Statement, a supporting Explanation and Elaboration document has been produced [18] following the style used for other reporting guidelines [19]–[21]. The process of completing this document included developing a large database of exemplars to highlight how best to report each checklist item, and identifying a comprehensive evidence base to support the inclusion of each checklist item. The Explanation and Elaboration document was completed after several face to face meetings and numerous iterations among several meeting participants, after which it was shared with the whole group for additional revisions and final approval. Finally, the group formed a dissemination subcommittee to help disseminate and implement PRISMA. Discussion The quality of reporting of systematic reviews is still not optimal [22]–[27]. In a recent review of 300 systematic reviews, few authors reported assessing possible publication bias [22], even though there is overwhelming evidence both for its existence [28] and its impact on the results of systematic reviews [29]. Even when the possibility of publication bias is assessed, there is no guarantee that systematic reviewers have assessed or interpreted it appropriately [30]. Although the absence of reporting such an assessment does not necessarily indicate that it was not done, reporting an assessment of possible publication bias is likely to be a marker of the thoroughness of the conduct of the systematic review. Several approaches have been developed to conduct systematic reviews on a broader array of questions. For example, systematic reviews are now conducted to investigate cost-effectiveness [31], diagnostic [32] or prognostic questions [33], genetic associations [34], and policy making [35]. The general concepts and topics covered by PRISMA are all relevant to any systematic review, not just those whose objective is to summarize the benefits and harms of a health care intervention. However, some modifications of the checklist items or flow diagram will be necessary in particular circumstances. For example, assessing the risk of bias is a key concept, but the items used to assess this in a diagnostic review are likely to focus on issues such as the spectrum of patients and the verification of disease status, which differ from reviews of interventions. The flow diagram will also need adjustments when reporting individual patient data meta-analysis [36]. We have developed an explanatory document [18] to increase the usefulness of PRISMA. For each checklist item, this document contains an example of good reporting, a rationale for its inclusion, and supporting evidence, including references, whenever possible. We believe this document will also serve as a useful resource for those teaching systematic review methodology. We encourage journals to include reference to the explanatory document in their Instructions to Authors. Like any evidence-based endeavor, PRISMA is a living document. To this end we invite readers to comment on the revised version, particularly the new checklist and flow diagram, through the PRISMA Web site. We will use such information to inform PRISMA's continued development. Supporting Information Figure S1 Flow of information through the different phases of a systematic review (downloadable template document for researchers to re-use). (0.08 MB DOC) Click here for additional data file. Text S1 Checklist of items to include when reporting a systematic review or meta-analysis (downloadable template document for researchers to re-use). (0.04 MB DOC) Click here for additional data file.
Introduction Brucellosis is one of the most common zoonotic infections globally [1], transmitted to humans through consumption of unpasteurised dairy products or through direct contact with infected animals, placentas or aborted foetuses. This bacterial disease causes a severely debilitating and disabling illness, with fever, sweating, fatigue, weight loss, headache, and joint pain persisting for weeks to months. Neurological complications, endocarditis and testicular or bone abscess formation can also occur [2]. Additionally, brucellosis has major economic ramifications due to time lost by patients from normal daily activities [2] and losses in animal production [3]. In a review of 76 diseases and syndromes of animals, brucellosis lies within the top 10 in terms of impact on impoverished people [4]. In 1992, the World Bank commissioned the original Global Burden of Disease (GBD) study, providing a comprehensive assessment of 107 diseases and injuries and 10 risk factors in eight major regions [5]. This review did not include any neglected tropical zoonoses. Such diseases often do not attract the interest of health researchers or sufficient resources for adequate control, yet they continue to impact significantly on human health and wellbeing, livestock productivity and local and national economies. There is a need for more accurate data relating to the burden of neglected zoonoses to facilitate more effective implementation of disease control interventions. In 2009, the Foodborne Disease Burden Epidemiology Reference Group (FERG) of the World Health Organization (WHO) commissioned a series of systematic reviews on the burden of neglected zoonotic diseases, with the aim of incorporating the findings into the overall global burden of disease assessments. This report presents a systematic review of scientific literature published between 1990–June 2010 relating to the frequency of human brucellosis. The objectives of this review were to identify high quality disease incidence data to complement existing knowledge [6] of the global disease burden and, ultimately, to contribute towards the calculation of a Disability-Adjusted Life Years (DALY) estimate for brucellosis. A systematic review of scientific literature investigating the clinical manifestations of brucellosis is the subject of a companion paper. Methods Searching Thirty three databases were searched for relevant articles using the search strings of both (brucellosis OR malta fever) and (brucellosis OR malta fever OR brucella melitensis OR brucella abortus) AND (symptom* OR sequelae* OR morbidity OR mortality OR transmission mode OR foodborne), with a publication limitation of 1990–30 June, 2010. The search term was adapted to the predominate language of the database. If a database did not allow the combining of Boolean operators, (18 of 33 databases), ‘brucellosis’ was used as the sole term. Reference Manager bibliographic software was used to manage citations. Duplicate entries were identified by considering the author, the year of publication, the title of the article, and the volume, issue and page numbers of the source. In questionable cases, the abstract texts were compared. Selection The articles were sorted by a team of four reviewers with a combined fluency in English, German, French, and Spanish. Articles in other languages were noted for future translation, pending resources. All reports were classified into one of two categories, based on the abstracts: Category 1: Relevant - articles related to human brucellosis infection in populations (i.e. disease frequency) or cases of human brucellosis (i.e. disease morbidity); Category 2: Irrelevant - articles related to non-human brucellosis; articles addressing topics not related to the current review, such as genetics, laboratory diagnostic tests, experimental laboratory animal studies The abstracts of studies belonging to Category 1 and meeting the following criteria for disease frequency were retained: published between 1990 and 30 June 2010, at least 100 study subjects drawn from the general population, prevalence or incidence data included and some information relating to diagnostic tests provided. The abstracts of studies meeting the following criteria for disease morbidity were also retained: published between 1990 and 30 June 2010, at least 10 study subjects, clinical symptoms/syndromes described and some information relating to diagnostic tests provided. The assessment and classification of morbidity articles will be the subject of a companion paper and will not be considered further here. Articles for which the necessary data for classification could not be obtained were identified for possible future assessment, according to availability of resources. In general, non peer-reviewed or review articles, conference proceedings and book chapters were excluded. Validity Assessment After applying the aforementioned screening steps, the full text of each selected article was retrieved for detailed analysis. Each article was reviewed by two or three reviewers, and classification discrepancies were resolved by discussion. Frequency studies were classified as prevalence studies if they stated a specified study population and area and an outcome expressed as the proportion of the study population identified as brucellosis seropositive (%); or as incidence studies if they presented the time period of observation, information about the study population size and area, and an outcome expressed as the number of new brucellosis cases per population at risk per time period. Articles were coded based on the following parameters: Study design. Longitudinal - clear start/end date with a study period of several months to years Cross-sectional - a short study period of several weeks or, occasionally, several months Routine data – data officially reported by health services or routine data recorded by a health facility or local authority Sampling methods. The sampling approaches were defined in order of decreasing quality as: cluster sampling proportional to size, simple random cluster sampling, simple random sampling without clustering or non-random sampling. The method of case acquisition (active, passive) was also evaluated. Studies not meeting any of these classifications were coded as “other”. Study level. The study area was categorised in decreasing order of quality as: national, provincial, district or sub-district level. Studies not meeting any of these classifications were coded as “other”. Diagnostic methods. Tests were categorised in decreasing order of quality as: ELISA +/− Rose Bengal Test (RBT) or lateral flow assay only RBT only One of the following tests: microscopic agglutination test (MAT), complement fixation test (CFT), 2-Mercaptoethylamine test (2ME), standard tube agglutination test (STAT) of 1∶160 or greater dilution, Wright agglutination test (WAT) or Huddleson test. Studies diagnosing seropositives based on a STAT result of a dilution of less than 1∶160 were excluded. Study quality. Studies were given an overall quality grade of 1, 2, or 3, as shown in Table 1. Quality 1 studies had well described study design and methods. Their sampling approaches and study level were highly ranked, e.g. active sampling by cluster sampling proportional to size or simple random cluster sampling approaches at the national or provincial level. The diagnostic methods were also highly ranked, such as ELISA, lateral flow assay or RBT. Quality 2 studies contained some weaknesses in their sampling approach and/or diagnostic methods. Although data were extracted from Quality 3 studies, they were not included in the final analysis, due to either a lack of information about the methods and approaches preventing adequate assessment of the quality of the study or obvious biases in study design and implementation. 10.1371/journal.pntd.0001865.t001 Table 1 Grading of study quality based on study methodology criteria. Methodological Criteria Overall Study Quality Quality 1 Quality 2 Quality 3 Sampling approach Cluster sampling proportional to size ✓ ✓ Simple random cluster sampling ✓ ✓ ✓ Simple random sampling without clustering ✓ ✓ Non-random sampling ✓ Case acquisition Active ✓ ✓ Passive ✓ Study level National ✓ ✓ Provincial ✓ ✓ ✓ District ✓ ✓ ✓ Sub-district ✓ ✓ Diagnostic methods ELISA with/without additional method ✓ ✓ Lateral flow assay with/without additional method ✓ ✓ RBT with additional method ✓ ✓ ✓ RBT only ✓ ✓ MAT, CFT, STAT, WAT, 2ME, Huddleson alone or in combination ✓ ✓ Data Extraction The following information was extracted from each article, and they were grouped according to geographic region, as identified by the GBD consortium: Seroprevalence studies: study period, size of study population, seroprevalence as a percentage Incidence studies: study period, size of reference population, number of cases, incidence rate Data Analysis Seroprevalence data were multiplied by the duration of seropositivity, assumed to be 10.9 years [7], to determine the proportion of the general population seroconverting each year due to brucellosis exposure. Using a conservative estimate of 10% of seroconversions representing true clinical cases, these proportions were multiplied by 0.1 and converted to rates per 100,000 person-years for the general population. Additional Targeted Searching Given that high quality data were also likely to be available through routine reporting systems in developed countries with strong public health systems, additional data sources were identified through a non-systematic, targeted search. Results Searching Table 2 lists the databases searched and the number of articles identified for each. A total of 28,824 articles were identified, of which 59% were duplicates, leaving 11,000 original reports. 10.1371/journal.pntd.0001865.t002 Table 2 Databases searched and number of hits. Database Website No. hits Global databases Medline http://www.ncbi.nlm.nih.gov/sites/pubmed 6176 ISI Web of Science http://isiwebofknowledge.com 3458 EMBASE http://www.embase.com 4980 Popline http://www.popline.org 55 CAB http://www.cabdirect.org 3424 ProMed http://www.promedmail.org 666 The Cochrane Library http://www.thecochranelibrary.com 100 BIOLINE http://www.bioline.org.br 37 WHOLIS http://www.bireme.br 76 Regional WHO databases African Index Medicus http://indexmedicus.afro.who.int 14 Index Medicus for the Eastern Mediterranean Region http://www.emro.who.int/whalecom0/Library/Databases/wxis.exe/Library/Databases/iah/ 526 Western Pacific Region Index Medicus http://www.wprim.org/ 96 Index Medicus for the South-East Asia Region http://imsear.hellis.org/ 247 Afro Library http://afrolib.afro.who.int/ 2 Other regional databases Health Information Locator http://www.bireme.br 7 Institute of Tropical Medicine, Antwerp, Belgium http://lib.itg.be:8000/webspirs/start.ws 122 King's Fund Information & Library Service http://www.kingsfund.org.uk/library/ 0 African Journals Online http://ajol.info/ 71 LILACS http://www.bireme.br 538 MedCarib http://www.bireme.br 9 REPIDISCA http://www.bireme.br 29 PAHO http://www.bireme.br 157 IBECS http://www.bireme.br 148 CUIDEN http://www.index-f.com/ 17 Indian Medlars Center IndMed http://indmed.nic.in/ 84 KoreaMed http://www.koreamed.org/SearchBasic.php 89 Japan Science and Technology Information Aggregator http://www.jstage.jst.go.jp/search/?typej=on&typep=on&typer=on&search=1 137 Health Research and Development Information Network http://www.herdin.ph/ 0 Panteleimon http://www.panteleimon.org/maine.php3 6 l'Ecole Nationale de la Santé Publique http://test.bdsp.ehesp.fr/Base/ 191 La Bibliotàgue de Santé Tropicale http://www.santetropicale.com/resume/catalogue.asp 0 System for Information on Grey Literature in Europe http://opensigle.inist.fr 474 Swiss Tropical and Public Health Institute, Human and Animal Health Unit, electronic departmental reference library 6906 Flow of Selected Studies Figure 1 shows a detailed flow diagram of the selection of articles included in the systematic review. In total, 275 frequency and morbidity studies were selected, for which full text was available for 153. However, 14 of these were in languages in which the team was not competent (Croatian (6), Turkish (4), Korean (2), Persian (1), Mandarin(1)), leaving 61 frequency studies for quality assessment. Three were classified as Quality 1 and 26 as Quality 2. Thirty-two were excluded from further analysis as Quality 3, due to either a strong possibility of bias, a study population not representative of the general population, or a lack of adequate information to allow a proper assessment of study quality. Except for two articles in Spanish, all Quality 1 and Quality 2 studies were in English. 10.1371/journal.pntd.0001865.g001 Figure 1 Flow of selected studies. *Some frequency studies were also classified as morbidity studies. Study Characteristics Fifteen articles presented incidence data. Six of these were longitudinal prospective studies [8]–[13], with the remainder retrospectively reviewing data collected mainly in health centres [14]–[21]. Three incidence studies did not describe the diagnostic tests used but were included because they filled gaps in available data and had otherwise well-documented methods and results [15], [17], [20]. Seroprevalence data were presented in fourteen articles, from surveys conducted in communities [22]–[28] or from blood donor screening [29]–[32]. Due to a lack of data, several studies focusing on specific sub-groups of the general population where also included: two studies of nomadic communities [33], [34] and one of school children [35]. Studies of Quality 1 and 2 were only available for 15 countries from the following GBD geographic regions: Northern African and Middle East (17 studies) [8]–[11], [14], [16], [18], [19], [22], [25]–[27], [30], [32], [34]–[36], Western Europe (8 studies) [12],[13],[17],[20],[21],[23],[24],[28], South and Central America (2 studies) [29],[31], Sub-Saharan Africa (1 study) [33] and North America (1 study) [15], as shown in Figure 2. One additional Quality 1 seroprevalence study from Central Asia [7] was identified through targeted non-systematic searching which, although not fulfilling the publication date criteria of the systematic review, was included in data analysis because it provided otherwise missing data. 10.1371/journal.pntd.0001865.g002 Figure 2 Geographical distribution of selected studies. Study characteristics of Quality 1 and 2 seroprevalence and incidence articles are provided as Supplementary Information (Tables S1 and S2), grouped by GBD geographic region. Confidence intervals for seroprevalence estimates were only provided in four articles [7],[22],[25],[33]. The normal approximation to the binomial was used to calculate confidence intervals for the prevalence estimates of the remaining articles. Although some studies used a cluster-based sampling approach, they did not present adequate information for the calculation of adjusted confidence intervals. Data Analysis Table 3 shows the incidence of brucellosis in the general population per 100,000 person-years by country, including rates directly reported as well as those calculated from seroprevalences. The studies are classified as containing data from the national and/or sub-national level. Where incidence rates were reported for several years, only the most recent data are provided. 10.1371/journal.pntd.0001865.t003 Table 3 Brucellosis incidence by country (cases per 100,000 person-years). Country Study level Incidence per 100,000 per year North Africa and Middle East Egypt Sub-national 0.28–70.00 Iraq Sub-national 52.29–268.81 Iran Sub-national○ 0.73–141.60 Jordan National 25.70–130.00 Oman Sub-national* 11.01 Palestine Sub-national 8.00 Saudi Arabia National 137.61 Sub-national 6.00–149.54 Turkey Sub-national 11.93–49.54 Sub-Saharan Africa Chad Sub-national+ 34.86 Western Europe Germany National 0.03 Greece Sub-national 4.00–32.49 Italy National 1.40 Central Asia Kyrgyzstan National 88.00 Central and Southern Latin America Argentina Sub-national 12.84 Mexico Sub-national 25.69 North America USA Sub-national 0.02–0.09 ○ includes one study of a nomadic community. * children only. + nomadic community. A wide variation in reported brucellosis incidence is evident regionally, as well as within countries. In the North Africa and Middle East region, for example, incidences calculated from a seroprevalence study in Iraq ranged from 52.3 cases per 100,000 person-years in a rural area to 268.8 cases per 100,000 person-years in a semi-rural area [25]. In Egypt, two prospective incidence studies incorporating a surveillance system for acute febrile illness in different rural areas provided rates of 18 [8] and 70 [9] cases per 1000,000 person-years. Only 5.7% of these cases were detected through passive hospital-based surveillance [9]. Incidence rates in Western Europe and North America were generally much lower than in other regions, although some within-country variation was still evident. In Greece, for example, respective rates of 4 [20] and 32 cases [13] per 100,000 person-years were reported in western and central areas. The study in western Greece also identified that one quarter of these cases, although diagnosed in health facilities, were not officially reported to the provincial public health department. Although rates in the USA were very low, counties within 100 km of the Mexican border had a higher disease incidence (0.18 compared to 0.02) than those in non-border states [15]. Additional Targeted Searching Surveillance data from the European Food Safety Authority were obtained, giving an overall incidence for the European Union of 0.08 cases per 100,000 person-years, three quarters of which were reported by Greece, Spain, and Portugal [37]. Global data obtained non-systematically from various sources including health ministries, international organisations and scientific articles has been previously summarised according to continent and country by Pappas, and a global map was produced [6]. Discussion The epidemiology of human brucellosis evolved over the previous 15 years, as a result of socioeconomic factors, improved surveillance systems, animal-based control programs and international tourism [6]. Additionally, political changes have influenced disease epidemiology, with brucellosis emerging as a major human health problem in countries of the former Soviet Union following its dissolution in 1991 [3]. The current review complements previous assessments of brucellosis disease burden [6] by presenting epidemiological data from scientific studies published between 1990–June 2010 which have been quality screened according to strict criteria. There is an obvious lack of high quality scientific data relating to brucellosis incidence globally, with the majority of data coming from the North Africa and Middle East region. Major gaps exist for Eastern Europe and the Asia-Pacific, both of which had no available data, as well as for Central and South America (only two studies) and Africa (excluding Egypt, only one study). One of the major factors limiting the usefulness of the identified studies was the lack of clearly described methods, particularly in relation to sampling approaches and case definitions. For many studies, it was not possible to assess whether the study had been conducted in such a way to minimise the risk of bias, resulting in the exclusion of data that may have been of acceptable quality. Brucellosis incidence varies widely not only between countries but also within countries. Although it is not possible to rule out study biases as potential causes of these differences, rates differing by five times in one study in Iraq [25] or by four times in similarly designed studies in Egypt [8],[9] suggest that demographic, occupational, and socioeconomic factors may play a role. Aggregated data at national or regional levels cannot capture these complexities of disease dynamics and, consequently, at-risk populations or areas may be overlooked. A lower disease incidence is seen in developed countries when compared to low and middle income countries. However, brucellosis still targets specific sub-groups of these populations, such as Turkish immigrants in Germany [21] or Hispanic communities of low socioeconomic status in the USA [15]. Brucellosis clearly remains a disease of public health importance even in developed countries. Although grey literature can provide high quality data, data from well designed scientific studies are preferred. Passively acquired national data in many brucellosis-endemic countries are likely to underestimate the true disease burden. In an Egyptian study incorporating an active acute febrile illness surveillance system to identify and confirm suspected cases, brucellosis incidence in the study area was 70 cases per 100,000 person-years. Only 5.7% of these cases were identified through hospital-based surveillance, from which the incidence rate would be calculated as 3.8 cases per 100,000 person-years using a case definition based on laboratory confirmation or 6 cases per 100,000 person-years using a clinical definition. Reliance on routine hospital-based incidence data would have, therefore, underestimated incidence by 12–18 times [9]. Official data from the Ministry of Health provided an incidence rate of only 0.3 cases per 100,000 person-years [6]. Such underestimations of disease incidence could relate to barriers to accessing health care or to case mismanagement and misdiagnosis. A retrospective review of hospital records in western Greece identified an additional source of error in official passively acquired data, with a brucellosis under-reporting rate from hospitals to the public health department of 26% [20]. Consequently, one quarter of cases diagnosed through the hospital system were not included in the official government data. Indeed, incidence rates identified in studies conducted between 1999–2005 in different regions of Greece ranged from 4–32.5 cases per 100,000 person-years, whereas aggregated data published by the European Food Safety provided a national incidence of just 0.9 cases per 100,000 person-years in 2009 [37]. Research Agenda Strengthening public health systems would improve the quality of data captured through routine reporting. In many brucellosis endemic countries, however, health systems are weak and high quality research is needed. Brucellosis incidence and prevalence studies are notably lacking from Eastern Europe, the Asia-Pacific, Central and South America and Sub-Saharan Africa. Researchers must have an adequate foundation in the principles of epidemiology and biostatistics to ensure that their studies are designed, implemented, and analysed in a manner which minimises bias and maximises the usefulness of the data. An integrated approach to disease surveillance involving both human health and veterinary services would allow a better understanding of disease dynamics at the animal-human interface, as well as a more cost-effective utilisation of resources [38],[39]. A checklist of requirements for representative seroprevalence and incidence studies is given in Table 4. 10.1371/journal.pntd.0001865.t004 Table 4 Key considerations for representative brucellosis seroprevalence and incidence studies. Seroprevalence Incidence Study population Defined study zone, geographically or in terms of an administrative unit ✓ ✓ Clear inclusion and exclusion criteria ✓ ✓ Study population representative of general population, not high risk groups alone ✓ ✓ Ongoing community education campaigns to raise disease awareness ✓ ✓ Sampling Sample size based on appropriate calculation, ideally including clustering of individuals ✓ Random sampling strategy, ideally using probability proportional to size ✓ Active surveillance system in health centres and/or in communities at household level ✓ Multidisciplinary study team to investigate disease dynamics at animal-human interface ✓ ✓ Diagnostic testing Clearly described testing methods, including details of manufacturer or developer ✓ ✓ Concise serological and clinical case definitions ✓ ✓ ELISA, lateral flow or RBT preferred testing methods ✓ ✓ Reporting STROBE checklist followed [40] ✓ ✓ Consideration of test performance in the analysis of results ✓ ✓ Consideration of sensitivity of the surveillance system in the analysis of results ✓ Limitations Although test performance was considered in the initial ranking of each article and, thus, influenced study inclusion in the review, the individual results of each study were not adjusted for test performance. This is because test performance can vary significantly according to test manufacturer or laboratory protocol, and such detailed information was not available. The calculation of incidence rates from seroprevalence studies is based on two assumptions. The assumed duration of seropositivity of 10.9 years has been determined mathematically using Vensim software [7]. The assumption that 10% seroconversions represent true clinical cases is conservative and is likely to underestimate the true burden of disease. Studies for which a title or abstract was not published in a language using the Latin alphabet, such as those published only in Chinese characters or Arabic script, may not have been identified during the original database search. Of the foreign language studies that were identified, those published in languages in which the team was not competent were excluded from the analysis. It is possible that some of these studies contained data that could have contributed to this global assessment of brucellosis frequency. Additionally, although studies in English were independently reviewed by three team members, this was not always possible for studies reviewed in other languages (German, French, Spanish). Conclusion This systematic review adds to the understanding of the global burden of brucellosis by identifying high quality data from scientific studies according to strict screening criteria. Disease incidence varied significantly within regions and within countries. Aggregated data do not capture the complexities of disease dynamics and at-risk populations may be overlooked. As many brucellosis-endemic countries do not have strong health systems, passively acquired official data likely underestimate the true burden. The brucellosis research agenda should focus on designing and implementing high quality studies to investigate disease seroprevalence and/or incidence, particularly in Eastern Europe, the Asia-Pacific, Central and South America and Africa. Supporting Information Table S1 Selected brucellosis seroprevalence studies by region. (DOC) Click here for additional data file. Table S2 Selected brucellosis incidence studies by region. (DOC) Click here for additional data file. Checklist S1 PRISMA checklist. (DOC) Click here for additional data file.
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History
Date
received
: 22
June
2023
Date
accepted
: 27
December
2023
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Tables: 1,
Pages: 12
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