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A systematic review of indocyanine green lymphography imaging for the diagnosis of primary lymphoedema
research-article
Author(s):
Greta Brezgyte , MSc,
Mike Mills , MSc,
Malou van Zanten , PhD,
Kristiana Gordon , MD,
Peter S Mortimer , MD,
Pia Ostergaard , PhD
Publication date (Electronic):
21 January 2025
Journal:
The British Journal of Radiology
Publisher:
Oxford University Press
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There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
Abstract
Objectives
This systematic review aims to evaluate the use of indocyanine green lymphography (ICGL) for the investigation of the lymphatics in the lower limbs of primary lymphoedema patients.
Methods
MEDLINE and EMBASE articles from January 1, 2000 to September 1, 2023 were searched for. A total of 11 studies were included in the review after a two-stage screening process.
Results
Data on patient demographics, ICG contrast injection technique, imaging protocols, and imaging outcomes were summarized and reviewed in detail. The review highlights the lack of commonality in protocols used. Factors important for good imaging are highly variable, particularly the number of injections, their location, and whether they are delivered intradermally or subcutaneously.
Conclusions
ICGL has strong potential to become a diagnostic tool to diagnose lymphoedema due to its non-ionizing nature and cost-effectiveness. However, due to the lack of thorough phenotyping and genotyping of patients included in the studies, uncertainty still exists as to the value of the described imaging features such as splash, starburst, and diffuse dermal rerouting patterns. Future studies, therefore, should aim to explore the diagnostic utility of ICGL for lymphoedema further through the imaging of primary lymphoedema patients with a confirmed genetic diagnosis and using standardized imaging protocols.
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Most cited references54
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Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement
David Moher, Alessandro Liberati, Jennifer Tetzlaff … (2018)
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.
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A Review of Indocyanine Green Fluorescent Imaging in Surgery
Jarmo Alander, Ilkka Santeri Kaartinen, Aki Laakso … (2012)
The purpose of this paper is to give an overview of the recent surgical intraoperational applications of indocyanine green fluorescence imaging methods, the basics of the technology, and instrumentation used. Well over 200 papers describing this technique in clinical setting are reviewed. In addition to the surgical applications, other recent medical applications of ICG are briefly examined.
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Progress and Impact of 13 Years of the Global Programme to Eliminate Lymphatic Filariasis on Reducing the Burden of Filarial Disease
K. Ramaiah, Eric A. Ottesen (2014)
Introduction Lymphatic filariasis (LF) is a disease of the poor that is prevalent in 73 tropical and sub-tropical countries. LF is caused by three species of filarial worms – Wuchereria bancrofti, Brugia malayi and B. timori – and is transmitted by multiple species of mosquitoes. The disease is expressed in a variety of clinical manifestations, the most common being hydrocele and chronic lymphedema/elephantiasis of the legs or arms. People affected by the disease suffer from disability, stigma and associated social and economic consequences. Marginalized people, particularly those living in areas with poor sanitation and housing conditions are more vulnerable and more affected by the disease. Estimates made in 1996 indicated that 119 million people were infected with LF at that time, 43 million of them having the clinical manifestations (principally lymphedema and hydrocele) of chronic LF disease [1]. Earlier severe resource constraints and lack of operationally feasible strategies in the endemic countries left a significant proportion of the LF endemic population living unprotected and exposed to the risk of LF infection. Despite a long-standing and gloomy outlook for these individuals, the situation turned around dramatically in the 1990s for 2 principal reasons: 1) advances made in point-of-care diagnostics and 2) the finding of the long-term effectiveness of anti-filarial drugs given in single doses that permitted development of the strategy of annual two-drug, single-dose mass drug administration (MDA) to control/eliminate LF [2], [3]. As LF had already been postulated to be an eradicable disease [4] and with the success experienced in LF elimination activities in China [5] and elsewhere, the World Health Assembly (WHA) in May 1997 formulated resolution WHA 50.29 urging all endemic countries to increase their efforts and determination to control and eliminate LF. In response, the WHO was able to launch the Global Programme to Eliminate LF (GPELF) in the year 2000, largely because the manufacturers of albendazole (ALB) and ivermectin, two of the principal drugs used in the GPELF MDAs, donated these drugs for as long as needed to eliminate LF [3]. The principal strategy of the programme has been two-fold: 1) to implement MDA programmes in all endemic areas to achieve total interruption of transmission and (2) to provide effective morbidity management in order to alleviate the suffering in people already affected by filarial disease. The GPELF targets elimination of LF, at least as a public health problem, by the year 2020 [6]. The programme to implement MDAs targeting LF (GPELF) completed 13 years of operations in 2012 [7]. With its ambitious goal to eliminate LF by the year 2020, it is essential that progress toward this goal be assessed repeatedly in order to set benchmarks to guide future programmatic planning. How to define and assess this progress remains a challenge, but two strategies have been suggested. The first is to measure reduction in the burden of LF disease (i.e., hydrocele, lymphedema, microfilaraemia and associated subclinical disease) over the past 13 years – i.e., a clinical perspective; the second is to measure reduction in the risk of acquiring infection for populations living in (formerly) endemic areas – i.e., an epidemiologic perspective. In the present report we have pursued the first alternative – to model the decreased burden of LF (defined for the purposes of our calculations as hydrocele, lymphedema, and microfilaraemia) in order to assess the progress towards LF elimination from inception of the MDA programme through 2012 (i.e., during GPELF's first 13 years). In a parallel study, others have recently modeled the programme's progress from the alternative, risk-of-infection viewpoint (Hooper et al., submitted). Methods A simple ‘force-of-treatment’ model was formulated to estimate the impact of MDA on LF infection and disease. Model parameters: Individual countries and regions as the geographic units of assessment The GPELF aims to provide MDA (using ALB+either ivermectin or diethylcarbamazine [DEC]) to entire endemic populations at yearly intervals for 4–6 years. Such a programme, if implemented effectively (i.e. treating at least 65% of the total population during each MDA), is expected to interrupt transmission and eliminate LF [8]. Because the status of MDA activities in all of the 73 endemic countries at the time of this analysis (through 2012) ranged from no MDA at all in some countries to full completion of the MDAs in others, for the present study each country was evaluated separately. First, programme impact was determined for each endemic country; then, the burden of LF remaining in each of the five endemic WHO regions – Southeast Asia (SEAR), Africa (AFR), Western Pacific (WPR), Eastern Mediterranean (EMR) and America (AMR) - was calculated by summing the remaining LF burden for all the endemic countries within each region. Model parameters: Key elements in assessing programme progress Calculating progress of the MDA programme under GPELF – whether by burden or risk estimates – is affected by a number of important specific factors, namely; (1) the number of countries that have successfully completed implementing the MDA programme, (2) the number of countries currently implementing the programme and the geographical coverage or proportion of the endemic population targeted so far in each country, (3) the treatment coverage of the population targeted for MDA in each country, and (4) the duration of the programme (i.e., the number of rounds of MDA implemented) in each country. For the present analysis, all of these data have been sourced from the WHO PC data bank [9]. Model parameters: Calculation of the decrease in LF burden to assess programme progress There are 3 essential steps to assessing the decrease of LF burden since 2000: first, the establishment of the LF base-line burden (in 2000); then, estimation of the MDA impact for countries or IUs where MDAs have taken place during 2000–2012; and, finally, estimation of current burden for countries or IUs where no MDA has taken place. (i) Establishment of base-line data The MDA programme under GPELF was started in the year 2000. To quantify the impact of the MDA programme, first, a base-line disease burden was estimated, considering the year 2000 as the base-line year. After extensive review of the literature in the mid-1990s, Michael et al. (1996) [1] and Michael and Bundy (1997) [10] estimated the LF prevalence and burden for different endemic regions. LF epidemiology is such that, without specific intervention or environment-altering measures, prevalence is unlikely to change over a short period (few years) of time. Hence, for this work the LF prevalence during 1996 to 2000 period is considered to remain unchanged. However, the absolute number of people affected by the disease will have increased because of population growth in the endemic areas. Taking the above factors into account, the base-line LF burden was estimated by extrapolating the prevalence data defined earlier [1] to the population of the endemic countries in the year 2000 (Table 1). As the LF burden estimation for individual countries was not always possible due to paucity and availability of data on prevalence, base-line LF burden estimates were made following the earlier approach of Michael et al. (1996) [1], and utilizing the convention that all the endemic countries for which no specific information was available, within each endemic region, have an approximately similar average prevalence of microfilaraemia and chronic disease. 10.1371/journal.pntd.0003319.t001 Table 1 Burden of LF in 1996 and 2000 considered as base-line to understand the impact of MDA (2000–2012) under GPELF. LF burden 1996 LF burden 2000 WHO Region Total Population endemic countries Mf carriers Lymphoedema cases Hydrocele cases Total infected Total Population endemic countries Mf carriers Lymphoedema cases Hydrocele cases Total infected SEAR 1335 41.91 9.49 14.53 61.86 1506 47.40 10.74 16.47 70.00 AFR 474 25.78 4.31 9.43 37.06 568 30.91 5.17 11.31 44.44 WPR 1113 11.14 1.52 1.87 13.32 1261 12.62 1.72 2.12 15.10 EMR 100 0.0598 0.0100 0.0199 0.0897 116 0.0700 0.0117 0.0233 0.1050 AMR 179 0.1252 0.0179 0.0179 0.1610 199 0.1397 0.0200 0.0200 0.1796 Total 3200 79.01 15.35 25.87 112.50 3650 91.14 17.66 29.94 129.82 All figures in millions. The 1996 estimates were based on the work done by Michael et al. (1996). The 1996 data were extrapolated to the populations of each endemic country in 2000 to derive the baseline estimated for GPELF. (ii) Estimation of MDA impact on LF burden for all countries or IUs with MDA in place Since the decrease in LF burden is a direct result of the treatment provided to populations during the MDA, the model to estimate this burden decrease can be described as a ‘force-of-treatment’ model (see below). To quantify this force-of-treatment, a ‘treatment index’ (TI) was constructed. The TI is defined as the average number of treatments taken by persons in areas included in MDA. It takes into account three key parameters – the size of the population targeted, the treatment coverage and the number of rounds of MDA implemented. These data can be sourced from the WHO PC data bank [9]. The TI is calculated as the total number of treatments consumed divided by the size of the population of IUs included in MDA. How to interpret what the TI implies about the effect of the programme's MDAs on LF burden can be determined from considering the empiric observations reported in earlier studies of endemic populations treated with the same treatment regimens as those used in the current MDAs; these were reviewed and are summarized below and in Figures 1 and 2. 10.1371/journal.pntd.0003319.g001 Figure 1 Empiric observations defining the relationship between number of treatments per person and % reduction in Mf prevalence 1 year later. 10.1371/journal.pntd.0003319.g002 Figure 2 Empiric observations defining the relationship between number of treatments and % reduction in hydrocele prevalence 1 year later. For microfilaraemia, two of the principal anti-filaria drugs used in MDA campaigns – DEC and ivermectin – have been recognized to exhibit remarkable, rapid effects on decreasing microfilaraemia. The anti-microfilarial effect of both drugs is further fortified when they are administered in combination with ALB, a broad spectrum anti- helminth drug that affects both adult worm viability and production of microfilariae [11]. The impact of treatment on microfilaraemia is evident from the first round of MDA and increases with each round of treatment year after year. While one round of mass treatment has been reported to reduce the Mf prevalence (assessed ∼1 yr post treatment) by 26% to 41%, 5–6 rounds led to 88%–90% reduction [12]–[21]. A review by de Kraker et al. (2006) [22] highlighted that both the drug combinations used in GPELF – ALB+DEC and ALB+ivermectin – strongly reduce the LF infection levels, but even 4–6 rounds of single-dose DEC alone can cause reduction of mf prevalence by as much as 86% [13], [23]. Hence, in the present effort to establish the relationship between the number of treatments and the % reduction in microfilaraemia prevalence, results were included from all the community level studies that administered annual single dose treatment (Figure 1), regardless of the specific MDA regimen employed. This empirically derived relationship between the number of treatments given and the decrease in microfilaraemia prevalence (Figure 1), in fact, defines the relationship between the TI and mf prevalence, since the TI is the population-level equivalent of the number of treatments administered at the individual-level. For microfilaraemia, there is a steady increase in reduction of prevalence as the treatment index increases, such that the reduction was close to 95% at a treatment index of about 6.0. For hydrocele, a similar review was undertaken of available information on the effect that treatment with anti-filarial drugs has on hydrocele prevalence [13], [24]–[29]. Treatment with DEC single dose was common to all of the studies providing results that were used in the analyses. Only one study each evaluated single dose of DEC+ivermectin [13] and ivermectin alone [29] and in both the studies the impact of these drugs was similar to that of DEC. The number of treatments given in these studies ranged from 2 to 12 and in most of the studies treatments were given at yearly or half-yearly interval. A model fitting the non-linear relationship (Fig. 2) was used to define the relationship between the number of treatments and % reduction in prevalence of hydrocele - again, defining the TI for the effect of MDA on hydrocele prevalence (Figure 2). This reduction increased progressively up to 4 treatments, but beyond that the treatment appears to have little additional impact; also, the maximum reduction seen with repeated treatments was approximately 60% (Figure 2). For lymphedema, different from microfilaraemia and hydrocele, information is scanty on the impact of annual MDA on lymphedema. Studies in Indonesia [30], [31], China [32], and Polynesia [24], all showed reduction in lymphedema prevalence, but all used more prolonged courses or different treatment regimens from those used in the GPELF MDAs. Post-GPELF, three studies evaluated the impact of MDA on lymphedema. In Ghana, one round of MDA with ivermectin and ALB showed no impact on lymphedema [33]. Administration of annual, single-dose DEC for 4 years in Papua New Guinea reduced the lymphedema prevalence by 20% [13]. Seven years of treatment in India showed 14% reduction in lymphedema prevalence in communities treated with annual DEC and 15% reduction in communities treated with ivermectin [29]. In light of these outcomes, a cautious and conservative approach was adopted for estimating the impact of MDA; it is postulated that for a TI of ≥3 (equivalent to nearly 4 rounds of MDA) lymphedema prevalence will be reduced by not more than 14%, the least reduction observed with annual MDA [29]. A TI 1.9 billion treatments were delivered, prevented 7.4 million cases of hydrocele and 4.3 million cases of lymphedema. While these estimates on the number of hydrocele cases prevented are similar to the estimates in the present study, there is less agreement on the number of lymphedema cases prevented. The estimated 5.49 million lymphedema cases prevented in this study, after 13 years of MDA and delivery of 6.37 billion treatments, was lower, likely because of both the different strategies for calculating the effects and the conservative approach adopted in assessing the impact of MDA on lymphedema. The estimated 5.49 million lymphedema cases prevented in this study was a minimum number, and the actual reduction may be much higher. Of the various factors influencing the outcome of MDA programmes, treatment coverage is particularly important [8]. In this study, the impact of MDA was assessed using the reported treatment coverage – i.e. the treatment coverage reported by the country level programme managers and compiled in WHO's PC data bank [9]. There are, however, a number of reports suggesting that the programme-reported treatment coverage in the South-east Asia region, particularly in India, may be higher than the actual treatment coverage in the communities. For example, while programme-reported treatment coverage in India was generally in the range of 58% to 90%, various independent studies showed treatment coverage that varied widely and ranged from 90% in different parts of the country [58]–[74]. The data from these published studies give rise to an average ‘evaluated’ treatment coverage rate of 51.0%, less than the 71.33% average reported national coverage [9]. Since the TI used to calculate programme impact in our model incorporates programme coverage, it is necessary to understand the effect of this difference between reported and evaluated coverage. For India, the TI based on reported coverage was 5.27, but only 4.21 when based on ‘evaluated’ coverage – a difference of 20%. Interestingly, however, when those different TI's were applied to the model (Figs. 1 & 2), the effect was minimal, because for TI's >4, little or no additional benefit was achieved on the 3 parameters measured (microfilaraemia, hydrocele, lymphedema/elephantiasis). In other words, the initial rounds of MDA will exert greater impact on these manifestations compared to later rounds, a finding already reported empirically and shown in various studies [12], [13], [15], [17]–[20]. However, if the treatment coverage rate is high, a higher TI can be achieved in the early rounds of the programme, and fewer rounds of MDA may be required to maximize both impact and cost-effectiveness. It is possible that preventive chemotherapy as well as other interventions implemented against other vector-borne diseases have added to the impact of LF MDA and caused further reduction in LF burden in some countries. Principal among these other interventions are the ivemectin distribution under the African Programme for Onchocrciasis Control (APOC) and the malaria control measures of insecticide treated nets (ITN) and indoor residual spraying (IRS). Currently, ivermectin is distributedfor onchocerciasis control in as many as 26 countries in Africa, covering nearly 130 million population [75]. Most of the 26 countries are co-endemic for LF also and while less than half of this LF-endemic population is under specific treatment as part of the GPELF, many are likely receiving benefit from the ivermectin being used for onchocerciasis control, as has been demonstrated specifically in a number of countries in West Africa [76]–[80]. Similarly, the malaria control measures have been shown to reduce LF transmission considerably and remain promising adjuncts to the MDA of the GPELF activities [81]–[83]. While these coincident intervention measures have, and will continue to have, positive impact on the LF elimination efforts, quantification of their impact remains a daunting challenge. The reduction in LF burden achieved during the GPELF's first 13 years is almost certainly higher than shown through our analyses both because of the additional, on-going intervention measures and because of our conservative approach to estimating the impact on chronic disease. Though, there can be little question that impressive gains in decreasing LF burden have been achieved as a result of 13 years of MDA in the GPELF, still, however, a considerable burden of LF remains – estimated at 36.45 million Mf cases, 16.68 million cases of lymphedema and 19.43 million cases of hydrocele (Table 4). Extension of MDA to all at-risk countries and to all regions within those countries where MDA has not yet started is absolutely necessary to reduce the number of microfilaraemia cases and transmission. Such an extension of MDA will also reduce a proportion of hydrocele and lymphedema cases, but the burden of LF disease needs also to be approached directly. Techniques for effective morbidity management – both medical and surgical – are available but not nearly so widely implemented as they could or should be. The present model's calculations take into consideration only those burden-reducing benefits coming pari passu with MDA implementation. When appropriate morbidity management strategies are finally introduced and accelerated, the burden of LF disease will fall even more dramatically (and the model can be adapted accordingly).
Author and article information
Contributors
Greta Brezgyte
Mike Mills:
ORCID: https://orcid.org/0000-0001-6316-4561
Malou van Zanten:
ORCID: https://orcid.org/0000-0001-9620-075X
Kristiana Gordon:
ORCID: https://orcid.org/0000-0002-7840-5644
Peter S Mortimer:
ORCID: https://orcid.org/0000-0003-1901-6849
Pia Ostergaard:
ORCID: https://orcid.org/0000-0002-2190-1356
Journal
Journal ID (nlm-ta): Br J Radiol
Journal ID (iso-abbrev): Br J Radiol
Journal ID (publisher-id): bjr
Title:
The British Journal of Radiology
Publisher:
Oxford University Press
ISSN
(Print):
0007-1285
ISSN
(Electronic):
1748-880X
Publication date Collection:
April
2025
Publication date
(Electronic):
21
January
2025
Publication date PMC-release: 21
January
2025
Volume: 98
Issue: 1168
Pages: 517-526
Affiliations
School of Health & Medical Sciences, City St George’s, University of London , Cranmer Terrace, London SW17 0RE, United Kingdom
School of Health & Medical Sciences, City St George’s, University of London , Cranmer Terrace, London SW17 0RE, United Kingdom
School of Health & Medical Sciences, City St George’s, University of London , Cranmer Terrace, London SW17 0RE, United Kingdom
School of Health & Medical Sciences, City St George’s, University of London , Cranmer Terrace, London SW17 0RE, United Kingdom
Lymphovascular Medicine, Dermatology Department , St George's University Hospitals NHS Foundation Trust, London SW17 0QT, United Kingdom
School of Health & Medical Sciences, City St George’s, University of London , Cranmer Terrace, London SW17 0RE, United Kingdom
Author notes
Corresponding author: Pia Ostergaard, PhD, School of Health & Medical Sciences, City
St George’s, University of London, London SW17 0RE, United Kingdom (
posterga@
123456sgul.ac.uk
)
Author information
Mike Mills
https://orcid.org/0000-0001-6316-4561
Malou van Zanten
https://orcid.org/0000-0001-9620-075X
Kristiana Gordon
https://orcid.org/0000-0002-7840-5644
Peter S Mortimer
https://orcid.org/0000-0003-1901-6849
Pia Ostergaard
https://orcid.org/0000-0002-2190-1356
Article
Publisher ID: tqaf006DOI: 10.1093/bjr/tqaf006
PMC ID: 11919075
PubMed ID: 39836641
SO-VID: c4916f0e-0959-4095-bf3a-ecdfc6f1989f
Copyright © © The Author(s) 2025. Published by Oxford University Press on behalf of the British
Institute of Radiology.
License:
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
History
Date
received
: 24
July
2024
Date
revision received
: 18
December
2024
Date
accepted
: 04
January
2025
Date: 12
February
2025
Page count
Pages: 11
Funding
Funded by:
Medical Research Council, DOI 10.13039/501100000265;
Funded by:
British Heart Foundation, DOI 10.13039/501100000274;
Award ID: MR/P011543/1
Award ID: RG/17/7/33217
Categories
Subject:
Systematic Review
Subject:
Bjr/Musc
Subject:
AcademicSubjects/MED00870
ScienceOpen disciplines: Radiology & Imaging
Data availability:
ScienceOpen disciplines: Radiology & Imaging
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