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Diagnostic tools for soil-transmitted helminths control and elimination programs: A pathway for diagnostic product development

Authors:
SYMPOSIUM
Diagnostic tools for soil-transmitted
helminths control and elimination programs:
A pathway for diagnostic product
development
Mark D. Lim
1
*, Simon J. Brooker
1
, Vicente Y. Belizario, Jr.
2
, Franc¸oise Gay-Andrieu
3
,
John Gilleard
4
, Bruno Levecke
5
, Lisette van Lieshout
6
, Graham F. Medley
7
,
Zeleke Mekonnen
8
, Greg Mirams
9
, Sammy M. Njenga
10
, Maurice R. Odiere
11
, James
W. Rudge
7
, Lieven Stuyver
12
, Jozef Vercruysse
5
, Johnny Vlaminck
5
, Judd L. Walson
13,14
,
the Annecy STH diagnostic experts group
1Global Health Division, The Bill & Melinda Gates Foundation, Seattle, United States of America, 2College
of Public Health, University of Philippines, Manila, Philippines, 3bioMe
´rieux, Marcy l’Etoile, France, 4Faculty
of Veterinary Medicine, University of Calgary, Calgary, Canada, 5Faculty of Veterinary Medicine, Gent
University, Merelbeke, Belgium, 6Department of Parasitology, Leiden University Medical Center, Leiden, the
Netherlands, 7Department of Global Health and Development, London School of Hygiene and Tropical
Medicine, London, United Kingdom, 8Jimma University Institute of Health, Jimma, Ethiopia, 9Techion
Group Ltd, Dunedin, New Zealand, 10 Kenya Medical Research Institute, Nairobi, Kenya, 11 Centre for
Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya, 12 Janssen Diagnostics,
Beerse, Belgium, 13 Departments of Global Health, Medicine (Infectious Disease), Pediatrics and
Epidemiology, University of Washington, United States of America, 14 Natural History Museum, London,
United Kingdom
¶ Membership of the Annecy STH diagnostic experts group is listed in the Acknowledgments.
*markdlim@gmail.com
Introduction
The 2020 Roadmap goals endorsed by the World Health Organization (WHO) for soil-trans-
mitted helminths (STHs) (Ascaris lumbricoides,Ancylostoma duodenale,Necator americanus,
Trichuris trichiura) are focused on mass drug administration (MDA) of anthelmintics to con-
trol morbidity associated with moderate- and heavy-intensity infection [1]. As the STH com-
munity approaches the 75% coverage target for preschool- and school-aged children, there is
increasing interest in exploring post-2020 goals that transition from simply monitoring pro-
gram coverage to strengthened monitoring of a program’s impact on transmission of infection
and determining whether enhanced MDA can break STH transmission with minimal risk of
recrudescence [24].
Diagnostics play a critical role in guiding both the deployment of existing STH program
resources and the implementation and evaluation of STH intervention strategies. Currently
used coproscopic methods to detect and quantify STH-specific eggs, such as the Kato-Katz
method, have practical advantages; test kits are inexpensive and relatively easy to perform in
low-resourced field settings. They also have significant disadvantages, including moderate
labor costs, lower than optimal sensitivity, and poor reproducibility in most program settings.
Several academic and small-business efforts continue to develop tools with improved diagnos-
tic performance [57]. However, an objective assessment on the value proposition offered by
these tools has been complicated, as the diagnostic needs of a multiphased STH program have
not been defined [8].
PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0006213 March 1, 2018 1 / 18
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Citation: Lim MD, Brooker SJ, Belizario VY, Jr.,
Gay-Andrieu F, Gilleard J, Levecke B, et al. (2018)
Diagnostic tools for soil-transmitted helminths
control and elimination programs: A pathway for
diagnostic product development. PLoS Negl Trop
Dis 12(3): e0006213. https://doi.org/10.1371/
journal.pntd.0006213
Editor: Haruhiko Maruyama, Miyazaki Daigaku
Igakubu Daigakuin Ikagaku Kangogaku Kenkyuka,
JAPAN
Published: March 1, 2018
Copyright: ©2018 Lim et al. This is an open access
article distributed under the terms of the Creative
Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in
any medium, provided the original author and
source are credited.
Funding: The authors received no specific funding
for this work.
Competing interests: Three of the coauthors are
employed by commercial companies. Franc¸oise
Gay-Andrieu is employed by bioMerieux, Greg
Mirams is employed by Techion Group Ltd, and
Lieven Stuyver is employed by Janssen
Diagnostics. None of these individuals received any
form of compensation contributing to this
manuscript, nor are any products/patents
developed by their affiliated companies described
within the manuscript.
This report shares a user-centered framework developed by a diverse group of key opinion
leaders convened over the past year by the Bill & Melinda Gates Foundation to define circum-
stances in which population-level diagnostic data could guide an STH program manager’s
decision to transition a program to the next phase. The use-cases and companion target prod-
uct profiles (TPPs) are intended to provide the community with a pathway for the research,
development, evaluation, and implementation of diagnostic tools designed for STH programs.
This framework can also be used to prioritize research or product development resources
based on immediate and anticipated program needs.
Current landscape of STH program diagnostics
The number of adult STH worms harbored by an individual determines both their risk of mor-
bidity and contribution to overall transmission [9]. Worm expulsion studies required to quan-
tify worm burden have suboptimal accuracy, are laborious, and are rarely done. Thus, STH
programs employ indirect methods to infer worm burden, such as microscopy-based technol-
ogies for visual identification and quantification of STH-specific eggs from a stool sample.
WHO recommends the use of the Kato-Katz method, a low-cost, simple, and standardized
tool that provides sufficient sensitivity for morbidity control programs aiming to reduce preva-
lence of moderate- and heavy-intensity infections to less than 1% [10]. A key limitation of the
method is its suboptimal sensitivity, particularly in low transmission settings where egg counts
are typically low [11]. Alternatives to Kato-Katz include the Mini-FLOTAC and McMaster
methods, although these tools lack WHO recommendations for programs and thus have been
limited to research use [5,1113]. Recent technology development efforts have also focused on
improved analytical sensitivity, such as molecular assays [6,1417] and enhanced visualization
of helminth eggs [7,18]. Another early area of investigation includes serological and urine-
based measurements [19,20]. However, all these methods potentially incur additional costs-
per-test and resource requirements for STH programs that need to be considered, relative to
the benefits of enhanced efficiency and accuracy [21]. Table 1 highlights other opportunities to
improve coproscopic methods.
Starting from the end: STH diagnostic use-cases and TPPs
Diagnostics are required at different decision points in STH programs, ranging from mapping
endemic geographies to monitoring and evaluation, assessing whether MDA can be stopped,
and post-MDA surveillance [22]. Use-cases depict the link between a specific program deci-
sion to the interpretation of a diagnostic test result, regardless of the technology or method
used to make the measurement [8]. A group of key opinion leaders represented the voice of
the diagnostic user by describing and predicting scenarios faced by STH programs, creating a
Table 1. Limitations and opportunities for improving coproscopy, with the Kato-Katz method as a predicate
technique.
Limitations
• Low sensitivity for very low-intensity infections
• Variable test results impact prevalence
measurements, particularly if eggs are highly clustered
or in low abundance
• Intra-individual variation in egg excretion during
the day and between consecutive days
• Operator-based variability in test results
• Exposure of operator to infectious agents in stool
• Need to process stool samples quickly after
collection, particularly for hookworm analysis
Opportunities for improvement
• Integrated quality control/quality assurance for
preparation (homogenization) and analysis of stool
samples
• Increased throughput
• Electronic connectivity, test results accessible for
remote interpretation
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series of problem statements and decisions that each can be addressed by a hypothetical diag-
nostic. Each solution is further detailed in a TPP as a list of technical characteristics, such as
type of measurement and implementation requirements.
One practical use of a TPP is to provide an objective framework for evaluating existing tech-
nologies and innovations to determine opportunities for product development (Table 2). The
breakdown of an STH program into diagnostic use-cases also ensures that research and prod-
uct development resources are aligned with program time lines by considering global progress
of STH programs and goals (controlling morbidity, interruption of transmission), maturity of
technology landscape, and time lines when technologies will be needed. This framework is not
intended to prevent the development of a single technology that addresses multiple use-cases;
however, a platform must meet the requirements described in each of the various TPPs.
Previous works by Solomon et al. [22] and Hawkins et al. [23] have provided high-level
TPPs. This report builds on these efforts by providing a more comprehensive framework that
links program decision points to detailed use-cases and TPPs. The diagnostic end user is the
STH program manager who requires a population-wide diagnostic assessment to determine
the transition of a program to the next planned phase. This introduces a unique challenge for
developing diagnostic TPPs for population-based intervention programs, as performance
requirements for individual-level assays are in context of decisions informed by population-
level indicators.
Following previous work [22], four broad decision points were used to categorize each use-
case against a hypothetical reduction in population-level infection resulting from program
intervention, as shown in Fig 1. Embedded within this illustration is a spectrum of program
Table 2. Planning processes for product development.
Output Objective Stakeholders responsible for definition
Use-cases • Requires understanding of program workflow; infrastructure; resources to identify needs,
preferences, limitations for implementation
• Define link between phase of program and criteria, with implications of diagnostics-based
decision
• Frame epidemiological/biological characteristics
• Identify stakeholders (data users, test implementers, policy, payors)
• Programs/implementers
• WHO STH program guidelines or
recommendations
With input from:
• Research (laboratory, epidemiology,
field)
TPP • Requires defined use-case
• Define “must-have” criteria for a diagnostic to meet program needs for each use-case
• Assess feasibility of meeting TPP requirements via landscape of existing research/methods/
technologies/available patient specimens
• Define evaluation criteria and methods for assessing new products and regulatory pathway
• Account for cost-effectiveness, scalability, manufacturability
• Programs/implementers
• Research
• Product development
With input from:
• WHO STH program guidelines or
recommendations
• Regulatory
Product development
pathway
• Requires use-case and TPP
• Define regulatory pathway
• Define requirements in accordance with existing or new STH program policies/guidelines/
recommendations
• Define pathway for translating existing reagents/methods into prototype
• Define verification criteria that prototype meets TPP to lock/freeze design
• Define validation criteria to evaluate adherence to TPP in actual operating conditions
• Define product launch plan
• Define payors/donors for program’s diagnostic infrastructure
• Define user-support, quality assurance, monitoring, supply chain requirements
• Define manufacturing and distribution plans
• Research
• Product development
• Regulatory
• WHO STH program guidelines or
recommendations
With input from:
• Country programs
• Representatives from Ministries of
Health
• Program donors
• Implementing nongovernment
organizations
Abbreviations: STH, soil-transmitted helminth; TPP, target product profile.
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decisions to initiate, continue, suspend, or transition to the next planned program phase, in
the context of a program’s goal of morbidity control or elimination of transmission. Those
decisions that are hypothetically guided by diagnostic test results are described in the algo-
rithm shown in Fig 2 and form the basis of the use-case categories:
use-case #1. Determine STH transmission and identify type of MDA,
use-case #2. Assess progress against program goals,
use-case #3. Confirm a decision to stop intervention and transition to surveillance,
use-case #4. Verify sustained break in transmission.
An additional level of detail is provided in the spreadsheet within the supplementary mate-
rials of this article (S1 File).
Several factors were considered in prioritizing a diagnostic that confirms a break in trans-
mission (use-case #3). There is strong interest in leveraging the successes of increased MDA
coverage to further reduce STH transmission beyond the level of morbidity control toward
interruption of transmission [2,3]. Achievement of this goal would allow programs to stop
regular MDA with minimal risk of recrudescence, but there currently lacks a reliable tool to
confirm this end point. However, as discussed later, evidence from research is needed to
develop a rigorous TPP for such a diagnostic. On the shorter term, there may be opportunities
to strengthen STH programs by providing access to technologies that are superior to the Kato-
Katz method (Table 1) for monitoring impact on transmission (use-case #2) [24].
Fig 1. Hypothetical prevalence curve (dots) for a successful STH elimination program, overlaid with program phase (diamond for transition points) and
diagnostic use-cases. MDA, mass drug administration; STH, soil-transmitted helminth.
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The development of a TPP for use-case #4 was felt to be premature and not to be pur-
sued until evidence demonstrates that a strategy for sustained interruption of transmis-
sion is feasible and can be scaled for STH programs. The biomarker landscape that would
meet this context of use is also at its early stages, and resources required to implement the
scale and coverage for this type of surveillance infrastructure need to be further defined
[25].
Across all use-cases is an option to integrate and leverage the resources of other public
health programs. For instance, many STH programs are integrated with schistosomiasis con-
trol efforts due to co-endemicity [8,26], with the Kato-Katz method also able to detect infec-
tion by Schistosoma mansoni and S.japonicum. Non–stool-based biomarkers may provide
opportunities for simultaneous detection of infection by S.haematobium. Post-elimination
surveillance would likely leverage multiple disease surveillance programs through centralized
laboratory analysis.
Use-case #1—Initiate and determine type of MDA
The assay described in this use-case provides results that identify populations that warrant
MDA and determines the frequency of MDA and the frequency of future monitoring. These
decisions are currently based on measurements of two parasitological indicators in school-
aged children: overall prevalence of any STH infection and proportion of individuals harbor-
ing an infection of moderate to heavy intensity [27].
The first indicator relies on aggregated results from individual-level diagnostic tests to
determine whether the prevalence of STH infection is below 20%, exceeds 20%, or is 50%
and above. These thresholds have been defined by WHO and are based on fecal egg counts
(FECs) derived from a Kato-Katz measurement to guide an STH control program in not
providing MDA or providing annual or biannual MDA. Because these programs are cur-
rently focused on controlling morbidity from moderate- to heavy-intensity infection, there
are no recommendations for prevalence less than 20%, nor is the Kato-Katz method suitable
for measuring low FEC. However, a “low transmission” category was included in the popu-
lation stratification (Fig 2) in the hypothetical event that STH elimination programs would
be initiated in lower transmission settings and that a tool that detects lighter infections
would be available.
To meet the needs of the second indicator, a test provides individual-level quantitative
results that are combined to estimate the proportion harboring moderate to heavy intensities
of infection by any STH, thresholds currently based on species-specific FEC (Table 3, [1]).
Fig 2. Diagnostic use-cases, described by program decision algorithm. Dashed box indicates a decision not described under current
WHO guidelines for controlling STH morbidity but that may be important for a program aiming to eliminate transmission of STH. Dx,
diagnostic; KK, Kato-Katz; MDA, mass drug administration; SAC, school-aged children; STH, soil-transmitted helminth.
https://doi.org/10.1371/journal.pntd.0006213.g002
Table 3. Classes of intensity, based on Kato-Katz measurements [1].
STH Individual intensity of infection (in eggs per gram of stool)
Light Moderate Heavy
Ascaris lumbricoides 1–4,999 5,000–49,999 50,000
Trichuris trichiura 1–999 1,000–9,999 10,000
Hookworms 1–1,999 2,000–3,999 4,000
Abbreviation: STH, soil-transmitted helminth.
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These test results also provide a baseline measurement for monitoring the impact of an inter-
vention, as described in latter use-cases.
Use-case #2—Assess progress against program goals
This use-case applies to STH programs that have initiated intervention and seek to evaluate
progress in reducing prevalence and intensity of infection [28]. By comparing population-level
results from previous or baseline measurements, programs that meet their milestones would
continue the intervention strategy as planned. However, an under-performing program would
conduct additional evaluations to determine potential causes, such as assessments of popula-
tion migration, environment, workforce, drug quality, treatment adherence, and anthelmintic
drug resistance.
Decisions made from these quantitative tests are dependent on the type of program and
this use-case was divided into two. Morbidity control programs are initiated in moderate- to
high-prevalence settings and rely on two indicators, overall prevalence of infection by any
STH and the proportion of individuals with moderate and heavy infections (e.g., use-case #2A,
as described in S1 File). An STH program targeting interruption of transmission would initiate
or continue efforts in lower transmission settings and would be focused solely on monitoring
the reduction of overall prevalence (e.g., use-case #2B), because it is unlikely that there will be
any moderately to heavily infected individuals [29].
The Kato-Katz method provides sufficiently reliable analytical data to meet use-case #2A
and is suitable for morbidity control programs focused on moderately to heavily infected indi-
viduals, but improvements to FEC measurements that address reproducibility and throughput
challenges (Table 1) would enhance program efficiency as well as create opportunities for pro-
grams to proceed beyond morbidity control [30,31]. Technologies that meet the needs of use-
case #2B can also be used in moderate and high transmission settings by STH control pro-
grams but offer greater value in lower transmission settings, where the Kato-Katz method fails
to provide reliable data. For practical considerations, a preferred technology would be a plat-
form that addresses multiple use-cases by meeting the requirements described in each of the
associated TPPs.
Use-case #3—Confirm a decision to stop intervention and transition to
post-MDA surveillance
This use-case applies to programs aiming to interrupt transmission of any STH in low- to
very-low- prevalence settings. In this circumstance, program progress and other transmission
measurements would lead a program manager to initiate a test that confirms that a program
can stop MDA and/or other population-directed interventions. Diagnostic results that confirm
a break in transmission with minimal risk of recrudescence would transition program goals
from active intervention to surveillance for recrudescence (use-case #4) or, in the event of dis-
cordant results, would initiate additional assessments.
The low- to very-low-prevalence threshold that describes the transmission breakpoint is
species specific and has yet to be established, although it can be approximated through mathe-
matical and animal models [32]. Based on studies with A.lumbricoides, worm dynamics
behave differently at low worm burdens compared to high burdens, such that the number of
fertile eggs no longer have a linear relationship to worm burden, making any individual-level
coproscopic measurement unreliable for determining very light intensities of infection rele-
vant to the population-level transmission breakpoint [33]. Nonmicroscopy biomarkers with a
linear relationship to low worm burden, detectable within a dynamic range relevant to the
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transmission breakpoint, are needed. Table 4 provides a high-level overview of desired charac-
teristics for any biomarker meeting this use-case.
Use-case #4—Verify sustained break in transmission
This use-case applies to programs that have successfully interrupted STH transmission (use-
case #3) and seek to verify sustained elimination of transmission [34] or have reason to believe
that there may be a risk of recrudescence. A program would investigate the potential causes of
unexpected results if qualitative test results indicate ongoing transmission. Ideally, the test
detects other diseases under surveillance and requires a specimen that is easier to collect than
stool, such as urine, saliva, or blood, to encourage participation in screening events, with anal-
ysis performed in a centralized laboratory.
The aspirational list of biomarker characteristics described in Table 4 are similar for use-
cases #3 and #4, and stricter definitions warrant further discussion. Similar tests for other dis-
eases have relied on detecting host-response antibodies of infection [35], a class of biomarker
convenient for integrated surveillance. These biomarkers of host response should ideally be
specific for active infection, not exposure. Alternatively, exposure-based biomarkers could be
measured within indicator subpopulations born after transmission has been broken, as these
groups should not have been exposed to STH infection in geographies remaining absent of
transmission [36]. Although species-specific detection is listed in Table 4, it remains unclear if
a pan-STH biomarker would suffice for this use-case.
Use-cases to TPPs
The TPP describes technical performance and implementation requirements for an assay to
meet the decision needs of a program’s specific use-case. Each requirement is defined in a TPP
as minimal or optimal criteria, reflecting a consensus of accepted compromises. To reduce
risks and time lines for developing a product and accelerating adoption, criteria should con-
sider the capacity, resources, and diagnostic workflows of STH programs in the context of
existing research, methodology, and technology landscape.
Requirements for technology performance and implementation are linked and criteria con-
sider trade-offs for supporting a new test within an existing diagnostic system versus costs for
adapting or creating infrastructure. Implementation considerations include: survey design
(population targeted for testing, sampling size), available workforce, workflow (specimen col-
lection and transportation, sample preparation and analysis), throughput and turnaround
time for test results, data requirements, and criteria for reimbursing test costs. Other consider-
ations include external quality assurance requirements and regulatory pathway as well as pro-
gram recommendations, policies, and guidelines.
Table 4. General desired characteristics of use-case #3 and #4 biomarkers.
• Biomarker measurement correlates to active infection by specific species-level STH
• Biomarker clears within 1 year of last prescribed intervention, in absence of reinfection
• Specific for each STH, no cross-reactivity with other pathogens
• Detected in populations residing in geographies with less than 2% prevalence of any STH infection
• Detected in infected individuals who are Kato-Katz negative
• Sufficient abundance in readily accessible body fluid (nonstool)
• Detection maximizes cost-efficiencies (e.g., amenable to pooling, simplified collection and shipment, testing in
young children born after presumed transmission breakage)
• Easily translatable to accessible diagnostic platforms
Abbreviation: STH, soil-transmitted helminth.
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Because diagnostics only approximate a true state of infection, mathematical models can be
used to further inform performance requirements by estimating the impact of different levels
of uncertainty on the accuracy of program decision-making and ultimately on health out-
comes [37]. Models can also provide a health economics framework to justify performance
requirements by weighing the predicted health outcomes against costs incurred by a program
to conduct a survey as well as resources deployed in the event of an incorrect decision [3].
Minimum criteria describe performance characteristics that must be achieved for a test to
be used by most STH programs. Optimal criteria describe attributes that expand the value of
the assay but would not be required by most STH programs. Simply, minimum criteria
describe “must-have” requirements, whereas “nice-to-have” options are listed as optimal,
details that guide product development and evaluation priorities as well as resource allocation.
In addition to setting targets for technology development, these requirements are also criteria
for clinical and field trials and should consider availability and access to patient specimens
from geographies representing the epidemiological and individual context of intended-use
populations. These specimens must naturally represent the diversity and range of biomarkers
to validate the performance claims of a prototype assay, with appropriate analytical and clinical
benchmarks. Excessive technical complexity beyond actual program needs should be avoided,
as each claim needs to be validated with available patient samples.
For example, qualitative yes/no results may be a sufficient level of detail that most programs
require from a test result, such as presence or absence of transmission within a population
(e.g., use-case #3). In this instance, the minimum requirement listed in a TPP would be a quali-
tative test result, for interpretation by a program manager. It is important to differentiate the
presentation of a test result from the method of analysis, as this qualitative output could be
derived from the quantitative analysis of aggregated individual-level data or pooled specimens.
If some programs have the resources and capacity to also act on test results that provide spe-
cies-specific intensities of infection, then quantitation could be listed as optimal criteria. How-
ever, validating that a test reliably provides quantitative test results for each STH species also
requires access to statistically powered quantities of accessible patient specimens that contain
the natural dynamic range of intensities for each STH.
As mentioned earlier, the use-case for monitoring program impact was divided into two
similar use-cases, #2A and #2B, to address programs that intend to reduce transmission
beyond morbidity control (S1 File). However, a TPP for use-case #2B was not developed, as a
lower limit of detection (LOD) would approximate the transmission breakpoint, a species-spe-
cific indicator that requires further definition. At these lower transmission settings, a program
manager might be solely interested in prevalence, unlike morbidity control programs, in
which intensities of infection are an additional program metric.
Two TPPs were developed and finalized by this group of STH stakeholders. Use-cases #1
and #2A were combined because there is little demand for a diagnostic dedicated to use-case
#1, with the current pace of coverage by STH programs (S2 File). Diagnostic tools that address
both use-cases would likely be similar, given the current landscape of coproscopy technologies.
There was agreement on current WHO recommendations for using the Kato-Katz method in
morbidity control programs, but this technique would not meet all requirements described in
this new TPP. With an intent to strengthen a program’s ability to monitor impact, new diag-
nostic products must satisfy all minimum requirements described in this joint TPP.
The second TPP described a tool to confirm a sustained break in transmission, a use-case
that only requires a qualitative test result (S3 File). Conceptually, a platform that meets the
needs of use-case #3 might also satisfy use-case #1–#2 if the test offered quantitative test results
with appropriate upper limits of quantitation, but this warrants further discussion in the
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context of this type of multi-parametric test result. The complete TPPs are available as supple-
mental materials that accompany this article, with key sections for use-case #3 discussed
below.
Discussion on select components of use-case #3 TPP—Confirming break in
transmission
Section 1: Intended use. This diagnostic confirms that transmission of each STH has
been sustainably suppressed below its breakpoint, a qualitative population-level test result pro-
vided by statistical analysis of pooled specimens or data aggregated from multiple individual-
level tests. A negative test result confirms the decision to wind down an active intervention
and transition program goals to surveillance for recrudescence (use-case #4). A positive test
result indicates that transmission has not been broken, requiring the program to investigate
causes of confounding results. An STH program manager would use this test when other met-
rics indicate that the intervention has likely met its end point and seeks confirmation with a
diagnostic survey of a targeted population. These nondiagnostic indicators to initiate testing
have yet to be defined and will be clarified through ongoing research assessing the strategy for
interrupting transmission [38].
The minimum detection requirement is species-level infection by A.lumbricoides,T.tri-
chiura, and hookworms (A.duodenale,N.americanus). Hookworm differentiation is not
required because interventions are the same for the two species. However, some STH pro-
grams or the research community may be interested in differentiation between A.duodenale
and N.americanus or detection of infections by A.ceylanicum and Strongyloides stercoralis,
and these possibilities were listed as optimal criteria. It was noted that neither infections by A.
ceylanicum nor S.stercoralis are treated by MDA-based interventions [39]. In addition to
hookworms, optimal requirements also considered integration of STH programs with those
focused on controlling schistosomiasis (S.mansoni,S.japonicum, and S.haematobium) [1,26].
The intended use of this assay also describes the ideal scenario for implementing a test.
These details are described in Section 4 of the TPP and must be realistic to the workflow and
resources available to an STH program. These considerations also define criteria for additional
methods and accessories required to support the use of the test, such as those for specimen col-
lection and preservation. Health economics and community-acceptability studies that provide
a cost-effectiveness and implementation framework for elimination programs are needed to
determine the ideal diagnostic scenario.
Section 2: Population needs and performance characteristics. The results from a test
meeting the needs of use-case #3 provide an indicator of worm and population dynamics to
determine if an intervention has reduced parasite reproduction to a point at which local
extinction is highly probable (i.e., transmission breakpoint) [40]. In this use-case, criteria for
clinical sensitivity is based on an individual’s intensity of infection in relation to this transition
point in transmission dynamics, with a true positive test result identifying an individual who is
transmitting any STH infection [41]. Phenotypic characteristics related to the number of worms
harbored by an individual who would be classified as positive under this use-case remain unde-
fined, as individuals classified as test negative may still be infected with STH but not contribut-
ing to transmission. Early-stage research is aimed at developing biomarkers that are fit for this
context of use and can be measured in non–stool-based specimens. As with any biomarker-
based measurement, it is important to assess the reliability of results by addressing potential
sources of interindividual variability, including age, nutritional status, and social dynamics.
These variables might be approximated by mathematical and animal modeling to guide bio-
marker and epidemiological research [40]. The early-stage nature of these investigations is
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reflected in this version of the TPP and is subject to updates, as additional evidence justifies a
rigorous performance requirement.
Analytical sensitivity describes technical performance of the assay (e.g., with spiked sam-
ples) and defines the required minimum concentrations of a target analyte that must be mea-
sured reliably (95% confidence). Only the lower LOD needs to be defined for a qualitative test
and set below the confidence intervals for a diagnostic cutoff. Since this cutoff cannot yet be
defined, key opinion leaders agreed that a test must have superior analytical sensitivity com-
pared to current FEC methods. Given the current lack of validated analytical comparators in
this range of light infection, in the interim, the LOD was defined as less than 1 egg per 41.7 mg
of homogenized stool (equivalent to 24 eggs per gram). This section will be updated in future
TPPs as evidence becomes available to justify an appropriate unit of measurement related to
clinically relevant diagnostic cutoffs for this use-case, with validated analytical benchmarks
that are not egg-based measurements or limited to stool samples.
Quality control requirements address confidence in test results and consider costs for inte-
grating controls within an individual assay as well as costs and resources for external assess-
ments. For stool-based specimens, there was consensus that individual assays require internal
controls as a pre-analytical assurance that stool samples were uniformly homogenized and pre-
pared, addressing some of the challenges described in Table 1. There was also agreement that
external quality assessment programs would be needed to ensure that STH testing locations
that likely vary in infrastructure and workforce are providing consistent results [42,43].
Section 3: Regulatory and statutory needs. The regulatory pathway for global health
diagnostics was not defined when the Kato-Katz method was recommended by WHO in 1985
for schistosomiasis control programs [44]. This method would likely not have passed current
regulatory requirements if introduced today, given the risk of variable test results and lack of
quality control. There was consensus that quality results and reproducibility will be required
for any new tests and that these products must be developed using design-control processes
[45] and standards defined by ISO13485 [46]. The latter is an internationally recognized stan-
dard for developing medical devices through documented processes that ensure consistent
attention to quality considerations, from design and development to manufacture and
delivery.
In addition to adherence to International Organization for Standardization (ISO) processes,
the product-development process will also be defined by the regulatory labeling of the tool for
research use only (RUO), investigational use only (IUO), or as an in vitro diagnostic (IVD).
Beyond ISO and design control requirements, the regulatory pathway for this assay is currently
not known and will be updated in future TPPs.
Tests that guide individual-level treatment decisions are typically classified as IVDs and
may also require WHO’s prequalification (PQ) for use in global health settings, in addition to
clearance by stringent national regulatory authorities, before they can be procured and used
within a program [47]. Unlike traditional IVDs, STH programs do not make individual-level
treatment decisions but instead focus on MDA with albendazole or mebendazole. The assay
described in use-cases #1 and #3 guide treatment decisions that have population health impli-
cations for correct and incorrect results; premature cessation of population-based treatment
could result in recrudescence [48]. An alternative consequence is overtreatment and wasted
program resources. These types of assays would likely be developed following a regulatory
pathway for an IVD, whereas RUO may be suitable for use-cases #2 and #4.
Future discussions are needed to determine the regulatory pathway of tests described in all
four use-cases. One important consideration is the implication of a decision based on an incor-
rect test result and steps to mitigate unintended health outcomes. For use-case #3, an increased
risk of recrudescence due to premature wind-down of a program might be mitigated if tests
PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0006213 March 1, 2018 11 / 18
described in use-case #4 are in place and populations remain under surveillance. Likewise, an
increased risk of overtreatment due to late wind-down of a program might be mitigated if
monitoring tests described in use-case #3 are in place. For use-cases #2 and #4, if the intended
purpose of monitoring and surveillance tests is to trigger confirmatory testing or initiate test-
ing to investigate inconsistent results, then these assays would only guide program testing, not
treatment decisions. These hypothetical scenarios exemplify the intertwining nature of pro-
gram guidelines with the regulatory pathway for developing an assay.
Section 4: Healthcare/program system needs. This section includes requirements for the
successful implementation of a diagnostic. Because targeted population-level data are required
for the program decision, minimum data requirements also include geospatial information.
There was no advantage for receiving the test result at the point of contact (e.g., rapid diagnos-
tic test) because population-level data is required for program decisions, with acceptable turn-
around time for results being over a period of weeks and months.
For the testing environment, key opinion leaders agreed that the testing site should be in
proximity to a community or school, preferably at a district-level health center or through a
mobile van campaign, to increase community participation and adherence in MDA events.
This was based on reports of community involvement in improving the health outcome
provided by MDA, particularly because STH infection is predominantly driven by an indi-
vidual’s interaction with their local environment, including access to clean water and sanita-
tion [49,50]. The global neglected tropical disease (NTD) agenda is also aligned with aims
to strengthen general healthcare services within impoverished communities, increasing
opportunities for developing an STH diagnostic on platforms that address other community
health needs [51].
District-level settings often have sufficient resources to perform simple diagnostic tests,
such as microscopy or rapid diagnostic tests, with access to running water and sufficient elec-
tricity during test operation and at least one individual who can be trained to perform a simple
test. These settings rarely have sterile work stations and minimal biosafety resources; thus,
TPP requirements address the safety of the test operator and local environment by reducing
exposure to biospecimens and reagents through design (e.g., self-containment and safety lock)
as well as simple disposal processes. Optimal requirements would be met if the test did not
require consistent electricity to operate, such as through a battery, and thus were operational
in less-resourced settings.
Conclusion
The success of the current WHO STH control strategy has catalyzed interest in moving beyond
coverage estimates and morbidity control to improving program efficiency and exploring the
prospect of breaking the transmission of STHs to reduce resources required for sustaining ver-
tical STH programs. These aspirations require surveys of the targeted populations, and the aim
of the hypothetical use-cases was to simulate STH program decisions requiring diagnostic
information. The context within these use-cases frame performance and implementation
requirements for the design and evaluation of existing and new tools. This approach ensures
that user needs are the destination of a research and product development road map, instead
of forcing the adoption of an imperfect technology. In the best-case scenario, one technology
is able meet the requirements of multiple TPPs.
The current TPP for use-case #1 and #2A addresses the needs of morbidity control pro-
grams but does not address the needs of elimination programs that would initiate or continue
in lower transmission settings (e.g., <20% apparent prevalence). The Kato-Katz method meets
most, but not all, of the minimum criteria in this TPP, as it offers sufficient analytical and
PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0006213 March 1, 2018 12 / 18
clinical sensitivity but does not meet precision and reproducibility criteria (§2.5 and 2.6), nor
does it meet regulatory requirements (§3.1). New tools that meet all requirements described in
this TPP are needed as one step towards strengthening STH program efficiency. Opportunities
for improvement are also highlighted in Table 1, and as with any new tool, it is important to
consider manufacturability, use, and cost-effectiveness from the program perspective.
STH programs that aim to move beyond morbidity control towards interruption of trans-
mission are described in use-cases #2B, #3, and #4. Tests for use-case #2B will require a lower
LOD than use-case #2A, but there is insufficient information to provide definitive criteria, as
this approximates the transmission breakpoint. There is a need to define the epidemiological
characteristics of a transmission breakpoint to understand the risk criteria of an individual’s
contribution to STH transmission within a given population. This is challenging given the
wide range of contextual factors that define population heterogeneity, such as seasonality, indi-
vidual health/nutritional status, environmental exposure, and/or social behaviors. These fac-
tors may influence STH transmission and thus, also, breakpoints [52]. Mathematical modeling
and animal studies can approximate the extent of these potential contributions to guide defini-
tions of phenotypic characteristics (§2.1), information necessary for defining clinical utility
requirements of biomarkers. A TPP for use-case #2B and #3 diagnostics also requires proof of
concept that programs can interrupt transmission in a scalable and cost-effective manner, with
a strategy that verifies decision points requiring diagnostic surveys and test implementation
scenarios (timing, sampling size, etc.).
Diagnostic needs will adjust over time as emerging research continues to evolve program
strategies. These TPPs and use-cases are living documents that capture the current trajectory
of STH programs to identify gaps that can be addressed through research and product
development.
Key learning points
The soil-transmitted helminth (STH) community has started exploring opportunities
to strengthen a control program’s ability to monitor changes in prevalence of infec-
tion, potentially to a reduction that is sustained below transmission breakpoints.
Current global strategies have been successful with existing diagnostics, and more
ambitious program end points would likely require different tools to evaluate the
impact of population-directed interventions.
Newly created target product profiles (TPPs) described in this article aim to direct the
development and evaluation of diagnostic tools that improve the efficiency of control
and elimination programs.
The STH community lacks a tool to confirm a break in transmission, and based on the
new TPP, critical evidence to inform the development of this diagnostic is currently
unavailable. Additional research is needed to define species-specific transmission
breakpoints and guide the translation of individual-level test results to population-
level transmission indicators.
PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0006213 March 1, 2018 13 / 18
Supporting information
S1 File. Overview of diagnostics use-cases for STH control and elimination programs.
STH, soil-transmitted helminth.
(PDF)
S2 File. Target product profile for STH use-case #1 and #2A diagnostic (mapping, moni-
toring population-level intervention). STH, soil-transmitted helminth.
(PDF)
S3 File. Target product profile for STH use-case #3 diagnostic (confirming decision to stop
population-level intervention). STH, soil-transmitted helminth.
(PDF)
Acknowledgments
Members of Annecy STH diagnostic experts group, Fondation Me
´rieux Les Pensières Center
for Global Health, Annecy, France, are:
Hafid Abaibou, bioMe
´rieux, France,
Vicente Belizario, University of Philippines, Manila, Philippines,
Mark Bradley, GlaxoSmithKline, UK,
Simon Brooker, Bill & Melinda Gates Foundation, USA,
Donald Bundy, Bill & Melinda Gates Foundation, USA,
Dan Campbell, Dan Campbell Consulting, USA,
William Colon, Janssen Diagnostics, Belgium,
Lauren Cutright, Bill & Melinda Gates Foundation, USA,
Marc Engelen, Janssen Diagnostics, Belgium,
Franc¸oise Gay-Andrieu, bioMe
´rieux, France,
Cristina Giachetti, Bill & Melinda Gates Foundation, USA,
John Gilleard, University of Calgary, Canada,
Jiagang Guo, NTD Department, World Health Organization, Switzerland,
John Hawdon, George Washington University, USA,
Deirdre Hollingsworth, University of Warwick, UK,
Sunny Jiang, University of California, Irvine, USA,
Peter Jourdan, Natural History Museum, UK,
Karine Kaiser, bioMe
´rieux, France,
Stella Kepha, London School of Hygiene and Tropical Medicine/Kenya Medical Research
Institute, Kenya,
Marianna Kim, BioFire Defense, USA,
Alejandro Krolewiecki, Universidad Nacional de Salta/Fundacion Mundo Sano, Argentina,
Zeleke Mekonnen, Jimma University, Ethiopia,
Bruno Levecke, Ghent University, Belgium,
Mark D. Lim, Bill & Melinda Gates Foundation, USA,
James McCarthy, QIMR Berghofer Medical Research, Australia,
Graham Medley, London School of Hygiene and Tropical Medicine, UK,
Rojelio Mejia, Baylor College of Medicine, USA,
Greg Mirams, Techion Group Limited, New Zealand,
Antonio Montresor, NTD Department, World Health Organization, Switzerland,
Molly Mort, Bill & Melinda Gates Foundation, USA,
PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0006213 March 1, 2018 14 / 18
Sammy Njenga, Kenya Medical Research Institute, Kenya,
Maurice Odiere, Kenya Medical Research Institute, Kenya,
Kendra Palmer, Bill & Melinda Gates Foundation, USA,
Laura Rinaldi, University of Napoli Federico II, Italy,
Christine Rozand, bioMe
´rieux, France,
James Rudge, London School of Hygiene and Tropical Medicine, UK,
Steven Silber, Johnson & Johnson, Global Public Health, USA,
Erin Stuckey, Bill & Melinda Gates Foundation, USA,
Lieven Stuyver, Janssen Diagnostics, Belgium,
Rebecca Traub, The University of Melbourne, Australia,
Jurg Utzinger, Swiss Tropical and Public Health Institute, Switzerland,
Lisette van Lieshout, Leiden University Medical Center, the Netherlands,
Jozef Vercruysse, Ghent University, Belgium,
Johnny Vlaminck, Ghent University, Belgium,
Judd Walson, University of Washington, USA, and Natural History Museum, London, UK,
Joanne Webster, Royal Veterinary College, University of London, UK,
Steven Williams, Smith College and University of Massachusetts, USA.
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... But transmission could rebound from residual hotspots if interventions are halted without a thorough epidemiological evaluation [6]. Hence, firstly, sensitive and specific diagnostic methods to low intensity infections are essential [7,8]. WHO guidelines recommend detecting and measuring infection with Kato-Katz technique based on a single stool sample per child [3,9]. ...
... WHO guidelines recommend detecting and measuring infection with Kato-Katz technique based on a single stool sample per child [3,9]. If this technique is suitable for low intensity settings is questionable [8]. Secondly, robust survey methods to identify ongoing transmission hotspots are also crucial [7,10]. ...
... It also had the highest sensitivity using a composite reference standard; microscopy techniques showed limited sensitivity. This is in accordance with other studies, which expose that microscopy sensitivity is reduced in low intensity infections [8,[35][36][37][38][39]. ...
Article
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World Health Organization goals against soil-transmitted helminthiases (STH) are pointing towards seeking their elimination as a public health problem: reducing to less than 2% the proportion of moderate and heavy infections. Some regions are reaching WHO goals, but transmission could rebound if strategies are discontinued without an epidemiological evaluation. For that, sensitive diagnostic methods to detect low intensity infections and localization of ongoing transmission are crucial. In this work, we estimated and compared the STH infection as obtained by different diagnostic methods in a low intensity setting. We conducted a cross-sectional study enrolling 792 participants from a district in Mozambique. Two stool samples from two consecutive days were collected from each participant. Samples were analysed by Telemann, Kato-Katz and qPCR for STH detection. We evaluated diagnostic sensitivity using a composite reference standard. By geostatistical methods, we estimated neighbourhood prevalence of at least one STH infection for each diagnostic method. We used environmental, demographical and socioeconomical indicators to account for any existing spatial heterogeneity in infection. qPCR was the most sensitive technique compared to composite reference standard: 92% (CI: 83%– 97%) for A . lumbricoides , 95% (CI: 88%– 98%) for T . trichiura and 95% (CI: 91%– 97%) for hookworm. qPCR also estimated the highest neighbourhood prevalences for at least one STH infection in a low intensity setting. While 10% of the neighbourhoods showed a prevalence above 20% when estimating with single Kato-Katz from one stool and Telemann from one stool, 86% of the neighbourhoods had a prevalence above 20% when estimating with qPCR. In low intensity settings, STH estimated prevalence of infection may be underestimated if based on Kato-Katz. qPCR diagnosis outperformed the microscopy methods. Thus, implementation of qPCR based predictive maps at STH control and elimination programmes would disclose hidden transmission and facilitate targeted interventions for transmission interruption.
... PCR-based molecular approaches, and especially quantitative PCR (qPCR)-based diagnosis, are relatively inexpensive, can be performed at higher throughput, and can be highly sensitive and species-specific, offering the prospect of diagnosing even very low level helminth infections (Pilotte et al., 2016;Easton et al., 2017;Grant et al., 2019). These benefits emphasise their suitability toward supporting the World Health Organisation (WHO) roadmaps to achieve elimination of helminth infections of public health concern (Lim et al., 2018;Gass, 2020;Papaiakovou et al., 2021). However, PCR-based approaches have their own caveats (Papaiakovou et al., 2019a); given that PCR-based diagnostics typically rely on targeting conserved genes or repetitive regions of helminth genomes of specific species and are often tested only on a few, geographically restricted samples, they run the risk of being unable to detect and measure (and may in fact be confounded by) within-and between-species genetic variation. ...
Article
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The identification of gastrointestinal helminth infections of humans and livestock almost exclusively relies on the detection of eggs or larvae in faeces, followed by manual counting and morphological characterisation to differentiate species using microscopy-based techniques. However, molecular approaches based on the detection and quantification of parasite DNA are becoming more prevalent, increasing the sensitivity, specificity and throughput of diagnostic assays. High-throughput sequencing, from single PCR targets through to the analysis of whole genomes, offers significant promise towards providing information-rich data that may add value beyond traditional and conventional molecular approaches; however, thus far, its utility has not been fully explored to detect helminths in faecal samples. In this study, low-depth whole genome sequencing, i.e. genome skimming, has been applied to detect and characterise helminth diversity in a set of helminth-infected human and livestock faecal material. The strengths and limitations of this approach are evaluated using three methods to characterise and differentiate metagenomic sequencing data based on (i) mapping to whole mitochondrial genomes, (ii) whole genome assemblies, and (iii) a comprehensive internal transcribed spacer 2 (ITS2) database, together with validation using quantitative PCR (qPCR). Our analyses suggest that genome skimming can successfully identify most single and multi-species infections reported by qPCR and can provide sufficient coverage within some samples to resolve consensus mitochondrial genomes, thus facilitating phylogenetic analyses of selected genera, e.g. Ascaris spp. Key to this approach is both the availability and integrity of helminth reference genomes, some of which are currently contaminated with bacterial and host sequences. The success of genome skimming of faecal DNA is dependent on the availability of vouchered sequences of helminths spanning both taxonomic and geographic diversity, together with methods to detect or amplify minute quantities of parasite nucleic acids in mixed samples.
... Therefore, the currently used tests are prone to human-error, have a relatively low throughput rate and also impede an integrated M&E of multiple NTDs programs [3,4]. As a response to this gap in the diagnostic armamentarium, the WHO has recently established the Diagnostic Technical Advisory Group (WHO-DTAG) with the purpose to identify the diagnostic needs for NTDs and to define the minimal and ideal characteristics for new diagnostics that intent to guide NTD programs-the so-called target product profiles (TPPs) [5][6][7][8]. Currently, TPPs have been developed for four NTDs that are emendable through large-scale deworming programs, including lymphatic filariasis [9], onchocerciasis [10], schistosomiasis [11] and soil-transmitted helminthiasis [12]. ...
Article
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Background WHO recommends periodical assessment of the prevalence of any soil-transmitted helminth (STH) infections to adapt the frequency of mass drug administration targeting STHs. Today, detection of eggs in stool smears (Kato-Katz thick smear) remains the diagnostic standard. However, stool examination (coprology) has important operational drawbacks and impedes integrated surveys of multiple neglected tropical diseases. Therefore, the aim of the present study was to assess the potential of applying serology instead of coprology in STH control program decision-making. Methodology An antibody-ELISA based on extract of Ascaris lung stage larvae (AsLungL3-ELISA) was applied in ongoing monitoring activities of the Ethiopian national control program against schistosomiasis and soil-transmitted helminthiasis. Blood and stool samples were collected from over 6,700 students (median age: 11) from 63 schools in 33 woredas (districts) across the country. Stool samples of two consecutive days were analyzed applying duplicate Kato-Katz thick smear. Principal findings On woreda level, qualitative (seroprevalence) and quantitative (mean optical density ratio) serology results were highly correlated, and hence seroprevalence was chosen as parameter. For 85% of the woredas, prevalence based on serology was higher than those based on coprology. The results suggested cross-reactivity of the AsLungL3-ELISA with Trichuris . When extrapolating the WHO coproprevalence thresholds, there was a moderate agreement (weighted κ = 0.43) in program decision-making. Using the same threshold values would predominantly lead to a higher frequency of drug administration. Significance This is the first time that serology for soil-transmitted helminthiasis is applied on such large scale, thereby embedded in a control program context. The results underscore that serology holds promise as a tool to monitor STH control programs. Further research should focus on the optimization of the diagnostic assay and the refinement of serology-specific program decision-making thresholds.
... Although these methods are effortless to perform and are relatively cheap, they may fail to detect helminth infections of lower intensity (Khurana and Sethi. 2017;Lim et al., 2018). In this study, we tried to evaluate the diagnostic performance of multiple stool samples versus a single stool sample in detecting STH by K-K and DSM. ...
Article
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Soil-transmitted helminths (STHs) are widely distributed globally and India is a significant contributor to the overall global burden of the disease. Microscopic methods like Kato-Katz (K-K) thick smear and direct smear microscopy by wet mount (DSM) are widely used for STH diagnosis due to their ease in performance. Still, low sensitivity proves to be a significant limitation of these methods. This study explores the diagnostic performance of two and three consecutive-day stool samples compared to the common practice of single stool sample examination. We observed that the three consecutive-day stool examination technique increased overall helminth positivity from 12% to 16.3% in K-K and 11.5-15.9% in DSM, indicating that multiple sampling can diagnose intestinal helminthiasis more accurately. A significant increase in the intensities of hookworms (by 37.5%; p value: 0.001) and Trichuris trichiura (by 47.8%; p value: 0.037) (measured in terms of fecal egg count) was also observed. The methods undertaken in the current study are comparable in detecting the helminths as the marginal increase in positivity by K-K (16.32% vs. 15.86%) was statistically insignificant.
... Existing limitations in diagnostic methodologies for the detection of STH in general and in particular for S. stercoralis, pose a significant challenge towards determining the efficacy of treatment in the context of a randomized clinical trial. In this context, a more precise assessment is required to identify meaningful significant differences between treatment arms, and are affected by sensitivity, specificity, reproducibility and operator dependency, the later emphasized in multicentric trials 41 . The contribution of qPCR into solving these weaknesses will be explored in our trial and will add to efforts initiated by other groups to evaluate molecular biology tools as a potential improvement in the assessment of key outcomes in randomized clinical trials of anthelmintic drugs 42 . ...
Article
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Background: Soil-transmitted helminths (STH) are targeted for control through mass drug-administration campaigns to prevent morbidity affecting at-risk groups in endemic regions. Although broadly successful, the use of albendazole and mebendazole achieved variable progress, with deficiencies against Trichuris trichiura and a predictable low efficacy against Strongyloides stercoralis . Novel drug combinations offer a potential solution, providing they can be delivered safely and maintain efficacy against all STH species. Here we present the protocol of a clinical trial to evaluate a fixed-dose combination (FDC) tablet containing albendazole and ivermectin that will be compared against albendazole against STH . Methods: An adaptive phase II/III randomized controlled trial will be undertaken in STH endemic sites in Ethiopia, Kenya and Mozambique to evaluate an oral FDC of 400 mg albendazole and either 9- or 18 mg ivermectin. FDC will be administered as a single dose or single doses over three-consecutive days and assessed against a single dose of 400 mg albendazole. In the phase II trial, 126 T. trichiura -infected children weighting 15 to 45 kg will be treated in a dose-escalation manner to determine safety objectives. In the phase III trial, 1097 participants aged 5 to 18 years old infected with T. trichiura, hookworm and S. stercoralis will be recruited to determine safety and efficacy. The trial will be open-label with blinded outcome assessors. Cure rate measured 21-days after-treatment in duplicate Kato-Katz is the primary efficacy outcome. Secondary objectives include efficacy evaluation by quantitative polymerase chain reaction (PCR) as an outcome measurement, description of pharmacokinetic parameters, palatability and acceptability evaluations, and monitoring of anthelmintic resistance. Conclusions: This trial with registrational goals seeks to evaluate an innovative fixed-dose combination of albendazole and ivermectin co-formulated tablets, with the goal of providing an anthelmintic regimen with improved efficacy and spectrum of coverage against STH. ClinicalTrials.gov registration: NCT05124691 (18/11/2021).
... The World Health Organisation (WHO) revised the neglected tropical disease (NTD) roadmap (2021-2030) [40], which sets out a strategic vision to control and 'eliminate' 20 NTDs afflicting humans, including STHs. As the control of STHs relies heavily on MDA, consideration must be given to which strategy is best suited to achieving a substantial, measurable and sustained reduction or elimination of transmission, and how novel diagnostics approaches can support sound surveillance strategies [34,41]. ...
Article
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Gastrointestinal (GI) helminth infections cause significant morbidity in both humans and animals worldwide. Specific and sensitive diagnosis is central to the surveillance of such infections and to determine the effectiveness of treatment strategies used to control them. In this article, we: (i) assess the strengths and limitations of existing methods applied to the diagnosis of GI helminth infections of humans and livestock; (ii) examine high-throughput sequencing approaches, such as targeted molecular barcoding and shotgun sequencing, as tools to define the taxonomic composition of helminth infections; and (iii) discuss the current understanding of the interactions between helminths and microbiota in the host gut. Stool-based diagnostics are likely to serve as an important tool well into the future; improved diagnostics of helminths and their environment in the gut may assist the identification of biomarkers with the potential to define the health/disease status of individuals and populations, and to identify existing or emerging anthelmintic resistance. Graphical Abstract
... When the economy is good, then it will build a better house, a healthier latrine, send the children to school to know more about health problems, buy radio and television so you can hear broadcasts about health education, so that it can change behavior towards clean and healthy lifestyle. [4] Helminth control begins by reducing the prevalence worm infection by killing the helminth through medication to reduce the intensity of infection (the number of helminth per person), so that can improve health status. But infection treatment must be accompanied by efforts to have a clean and healthy lifestyle, sanitation environment and intake of nutritious food. ...
Article
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Indonesia still has health problem, especially soil transmitted helminth. These helminths can cause deteriorate health, nutrition, intelligence and productivity of patients so causes a lot of losses economically. The aim of this article is to review the rational treatment of helminth infection. Albendazole, mebendazole, and pyrantel pamoate are the drugs recommended by the WHO. However, the uses of the three are different, especially for mass treatment or selective medicine. This review conclude that the three drugs are used according to the target patient's age with dosages and preparations that must be adjusted.
Article
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Background We previously demonstrated that serology holds promise as an alternative diagnostic tool to copromicroscopy to monitor and evaluate deworming programs targeting soil-transmitted helminths (STHs). Here we explored the dynamics of anti- Ascaris antibodies (Ab) and evaluated the Ab-isotype of choice to assess the longitudinal exposure to Ascaris in Ethiopian school children. Methodology Between October 2018 and February 2020, stool and blood samples were collected every four months from school children (4 to 6 years of age). Stool samples were analyzed by duplicate Kato-Katz to assess the presence and intensity of any STH infection. Plasma Ab-responses against the total extract of Ascaris suum lung third stage larvae were measured through in-house Ab-ELISA’s for seven different Ab-isotypes. Principal findings At baseline, 42.4% of the 66 children were excreting eggs of any STH, Trichuris (37.9%) being the most prevalent. The cumulative prevalence (proportion of children tested that positive at least once over the entire study period) was 56.1% for Trichuris and 31.8% for Ascaris . For Ascaris , re-infections were frequently observed, whereas for Trichuris , children often remained excreting eggs following drug administration. When measuring anti- Ascaris Ab-levels, the cumulative seroprevalence was generally higher (IgG4: 60.6%; IgG1: 50.0%; IgE: 36.4%). The individual anti- Ascaris IgG4 levels at baseline were positively associated with the fecal egg counts averaged over the study period, the rate of egg-appearance and the number of positive test results. There was no apparent cross-reactivity between the anti- Ascaris IgG4 Ab-ELISA and Trichuris . Conclusions/Significance We demonstrate that the children are exposed to STH before the age of four and that both the exposure to Ascaris , highlighting that the exposure to disease is underestimated when measured with copromicroscopy. Compared to other Ab-isotypes, IgG4 is the Ab-isotype of choice to measure Ascaris exposure in STH endemic settings. Finally, the results also highlight that measuring anti- Ascaris IgG4 levels holds promise as a tool to identify individuals at higher risk for continued exposure to this STH.
Article
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Recently, the World Health Organization established the Diagnostic Technical Advisory Group to identify and prioritize diagnostic needs for neglected tropical diseases, and to ultimately describe the minimal and ideal characteristics for new diagnostic tests (the so-called target product profiles (TPPs)). We developed two generic frameworks: one to explore and determine the required sensitivity (probability to correctly detect diseased persons) and specificity (probability to correctly detect persons free of disease), and another one to determine the corresponding samples sizes and the decision rules based on a multi-category lot quality assurance sampling (MC-LQAS) approach that accounts for imperfect tests. We applied both frameworks for monitoring and evaluation of soil-transmitted helminthiasis control programs. Our study indicates that specificity rather than sensitivity will become more important when the program approaches the endgame of elimination and that the requirements for both parameters are inversely correlated, resulting in multiple combinations of sensitivity and specificity that allow for reliable decision making. The MC-LQAS framework highlighted that improving diagnostic performance results in a smaller sample size for the same level of program decision making. In other words, the additional costs per diagnostic tests with improved diagnostic performance may be compensated by lower operational costs in the field. Based on our results we proposed the required minimal and ideal diagnostic sensitivity and specificity for diagnostic tests applied in monitoring and evaluating of soil-transmitted helminthiasis control programs.
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Worms infection is still common in Indonesia with a prevalence that varies around 40% -60% at all ages. This disease can be caused by infection of Soil-Transmitted Helminths (STH) that require soil media to infect humans. The many plantation lands in Jember are a suitable environment for the development of STH and STH identification in soil can be done by flotation method using MgSO4 solution or sucrose. The comparison of the effectiveness of the MgSO4 solution with the sucrose solution has not been widely studied. Therefore, the aim of this study was to compare the efficacy of using saturated MgSO4 solution with saturated sucrose to identify eggs and larvae of STH in Sumber Wadung plantation soil, Hargomulyo Village, Silo District, Jember Regency using the flotation method. Soil samples were taken as many as 35 samples in the garden area, 35 samples around the river, and 35 samples in residential areas,. The results of identification of STH eggs and larvae obtained Ascarid eggs (1.9%) and Hookworm larvae (0.01%). The number of positive soil samples containing STH eggs and larvae using different solutions is the same as three samples (0.02%).The Wilcoxon test results showed that there was no difference in the results of using the MgSO4 solution with the sucrose solution in the flotation method (p> 0.05) so that the MgSO4 solution and sucrose solution could be used to detect eggs and larvae of STH worms and had the same effectiveness. Keyword: Soil-transmitted helminths, saturated MgSO4, saturated sucrose, flotation
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Background There is an increased focus on whether mass drug administration (MDA) programmes alone can interrupt the transmission of soil-transmitted helminths (STH). Mathematical models can be used to model these interventions and are increasingly being implemented to inform investigators about expected trial outcome and the choice of optimum study design. One key factor is the choice of threshold for detecting elimination. However, there are currently no thresholds defined for STH regarding breaking transmission. Methods We develop a simulation of an elimination study, based on the DeWorm3 project, using an individual-based stochastic disease transmission model in conjunction with models of MDA, sampling, diagnostics and the construction of study clusters. The simulation is then used to analyse the relationship between the study end-point elimination threshold and whether elimination is achieved in the long term within the model. We analyse the quality of a range of statistics in terms of the positive predictive values (PPV) and how they depend on a range of covariates, including threshold values, baseline prevalence, measurement time point and how clusters are constructed. Results End-point infection prevalence performs well in discriminating between villages that achieve interruption of transmission and those that do not, although the quality of the threshold is sensitive to baseline prevalence and threshold value. Optimal post-treatment prevalence threshold value for determining elimination is in the range 2% or less when the baseline prevalence range is broad. For multiple clusters of communities, both the probability of elimination and the ability of thresholds to detect it are strongly dependent on the size of the cluster and the size distribution of the constituent communities. Number of communities in a cluster is a key indicator of probability of elimination and PPV. Extending the time, post-study endpoint, at which the threshold statistic is measured improves PPV value in discriminating between eliminating clusters and those that bounce back. Conclusions The probability of elimination and PPV are very sensitive to baseline prevalence for individual communities. However, most studies and programmes are constructed on the basis of clusters. Since elimination occurs within smaller population sub-units, the construction of clusters introduces new sensitivities for elimination threshold values to cluster size and the underlying population structure. Study simulation offers an opportunity to investigate key sources of sensitivity for elimination studies and programme designs in advance and to tailor interventions to prevailing local or national conditions.
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The Sustainable Development Goals (SDGs) call for an integrated response, the kind that has defined Neglected Tropical Diseases (NTDs) efforts in the past decade. NTD interventions have the greatest relevance for SDG3, the health goal, where the focus on equity, and its commitment to reaching people in need of health services, wherever they may live and whatever their circumstances, is fundamentally aligned with the target of Universal Health Coverage. NTD interventions, however, also affect and are affected by many of the other development areas covered under the 2030 Agenda. Strategies such as mass drug administration or the programmatic integration of NTD and WASH activities (SDG6) are driven by effective global partnerships (SDG17). Intervention against the NTDs can also have an impact on poverty (SDG1) and hunger (SDG2), can improve education (SDG4), work and economic growth (SDG8), thereby reducing inequalities (SDG10). The community-led distribution of donated medicines to more than 1 billion people reinforces women's empowerment (SDG5), logistics infrastructure (SDG9) and non-discrimination against disability (SDG16). Interventions to curb mosquito-borne NTDs contribute to the goals of urban sustainability (SDG11) and resilience to climate change (SDG13), while the safe use of insecticides supports the goal of sustainable ecosystems (SDG15). Although indirectly, interventions to control water- and animal-related NTDs can facilitate the goals of small-scale fishing (SDG14) and sustainable hydroelectricity and biofuels (SDG7). NTDs proliferate in less developed areas in countries across the income spectrum, areas where large numbers of people have little or no access to adequate health care, clean water, sanitation, housing, education, transport and information. This scoping review assesses how in this context, ending the epidemic of the NTDs can impact and improve our prospects of attaining the SDGs.
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Background: A method is outlined for the use of an individual-based stochastic model of parasite transmission dynamics to assess different designs for a cluster randomized trial in which mass drug administration (MDA) is employed in attempts to eliminate the transmission of soil-transmitted helminths (STH) in defined geographic locations. The hypothesis to be tested is: Can MDA alone interrupt the transmission of STH species in defined settings? Clustering is at a village level and the choice of clusters of villages is stratified by transmission intensity (low, medium and high) and parasite species mix (either Ascaris, Trichuris or hookworm dominant). Results: The methodological approach first uses an age-structured deterministic model to predict the MDA coverage required for treating pre-school aged children (Pre-SAC), school aged children (SAC) and adults (Adults) to eliminate transmission (crossing the breakpoint in transmission created by sexual mating in dioecious helminths) with 3 rounds of annual MDA. Stochastic individual-based models are then used to calculate the positive and negative predictive values (PPV and NPV, respectively, for observing elimination or the bounce back of infection) for a defined prevalence of infection 2 years post the cessation of MDA. For the arm only involving the treatment of Pre-SAC and SAC, the failure rate is predicted to be very high (particularly for hookworm-infected villages) unless transmission intensity is very low (R0, or the effective reproductive number R, just above unity in value). Conclusions: The calculations are designed to consider various trial arms and stratifications; namely, community-based treatment and Pre-SAC and SAC only treatment (the two arms of the trial), different STH transmission settings of low, medium and high, and different STH species mixes. Results are considered in the light of the complications introduced by the choice of statistic to define success or failure, varying adherence to treatment, migration and parameter uncertainty.
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Introduction Health laboratory services are a critical component of national health systems but face major operational challenges in resource-limited (RL) settings. New funding for health systems strengthening in RL countries has increased the demand for diagnostics and provided opportunities to address these constraints. An approach to sustainably strengthen national laboratory systems in sub-Saharan African countries is the Strengthening Laboratory Management Toward Accreditation (SLMTA) programme. External Quality Assessment (EQA) is a requirement for laboratory accreditation. EQA comprises proficiency testing (PT), rechecking of samples and on-site evaluation. Materials and methods A systematic literature search was conducted to identify studies addressing laboratory EQA and quality monitoring in RL countries. Unpublished reports were also sought from national laboratory authorities and personnel. Results PT schemes in RL countries are provided by commercial companies, institutions in developed countries and national programmes. Most government-supported PT schemes address single diseases using a vertical approach. Regional approaches to delivering PT have also been implemented across RL countries. Rechecking schemes address mainly tuberculosis (TB), malaria and human immunodeficiency virus (HIV); integrated rechecking programmes have been piloted. Constraints include sample transportation, communication of results, unknown proficiency of referee staff and limited resources for corrective action. Global competency assessment standards for malaria microscopists have been established. Conclusions EQA is vital for monitoring laboratory performance and maintaining quality of laboratory services, and is a valuable tool for identifying and assessing technology in use, identifying gaps in laboratory performance and targeting training needs. Accreditation of PT providers and competency of EQA personnel must be ensured.
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Trends The Kato-Katz technique is a widespread tool in intestinal helminth epidemiological surveys. It is used in monitoring and evaluation programmes to investigate the prevalence and geographical distribution of soil-transmitted helminth and Schistosoma mansoni infections – determining the WHO treatment strategy to be used. While the need for more sensitive diagnostic methods for these intestinal parasites has been identified, the cost of developing and employing new and potentially more rapid tests is considered relatively expensive, particularly compared to the Kato-Katz technique (which is often referred to as cheap). Consequently, this area has suffered from a lack of investment. The actual cost of using the Kato-Katz technique is higher and more variable than is often being assumed, and it is difficult to implement at a large scale.
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Quality by design is a comprehensive program that begins with understanding user needs and continues through (but does not end with) monitoring customer acceptance. Management tools and processes such as ISO 9000 standards and the Food and Drug Administration Quality System Regulations exist to guide medical device manufacturers in quality practices. The goal is to deliver products acceptable for their intended use. Quality control begins with defining attributes ranging from color to accuracy and precision. Failure mode and effects analysis and risk analysis consider both probability and severity of potential malfunctions and their effects on patients or operators. Tools used to implement design and production practices include Program Evaluation and Review Technique (PERT) charts and industry-conceived concepts, such as Six Sigma techniques. Their use varies with manufacturer, depending on product and customer needs and the manufacturer’s specific quality practices. Verification confirms that input goals are met. Then, validation assures that intended clinical needs are continually satisfied by establishing adequate production specifications. Conformance is monitored to verify that stable, consistent processes are in place, and precise user instructions enable the device to satisfy its intended use. Finally, complaint tracking can help assess whether needs have been met. Modifications in service, hardware, or instructions (including quality control) might be required. Therefore, both manufacturers and users work in partnership for continual improvement. The manufacturer’s knowledge of design, production, and service needs of its devices enable it to recommend appropriate quality-control protocols for clinical testing.
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This protocol is an extension to: Nat. Protoc. 5, 503–515 (2010); doi: 10.1038/nprot.2009.235; published online 25 February 2010 The FLOTAC is a sensitive, accurate, and precise technique for the diagnosis of protozoan and helminth infections in humans and animals. However, it requires centrifugation, and hence might be out of reach in resource-constrained settings. As an extension of the original FLOTAC protocol, this protocol describes the Mini-FLOTAC technique, a logical evolution of FLOTAC conceived to perform multivalent, qualitative, and quantitative diagnosis of helminth and protozoan infections in human and animal feces, and urine. This has been found to be of most use in the processing of large numbers of samples with rapid laboratory workup, and for veterinary applications directly on-farm. In addition to the Mini-FLOTAC apparatus, we describe the use of the Fill-FLOTAC, a closed system used to facilitate the performance of the first four consecutive steps of the Mini-FLOTAC technique: fecal sample collection and weighing, homogenization, filtration, and filling of the Mini-FLOTAC chambers. Processing of an individual sample using this protocol requires ∼12 min.
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Epidemics, such as HIV in the early 1980s and Ebola in 2014, inspire decisive government investment and action, and individual and societal concern, sometimes bordering on panic. By contrast, endemic diseases, such as HIV in 2017 and tuberculosis, struggle to maintain the same attention. For many, the paradox is that endemic disease, in its totality, continues to impose a far higher public health burden than epidemic disease. Overall, the swift political response to epidemics has resulted in success. It has proven possible to eradicate epidemic diseases, often without the availability of vaccines and other biomedical technologies. In recent times, only HIV has made the transition from epidemic to endemic, but diseases that have existed for centuries continue to cause most of the infectious disease burden.
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Emerging infectious diseases (EIDs) threaten the health of people, animals, and crops globally, but our ability to predict their occurrence is limited. Current public health capacity and ability to detect and respond to EIDs is typically weakest in low- and middle-income countries (LMICs). Many known drivers of EID emergence also converge in LMICs. Strengthening capacity for surveillance of diseases of relevance to local populations can provide a mechanism for building the cross-cutting and flexible capacities needed to tackle both the burden of existing diseases and EID threats. A focus on locally relevant diseases in LMICs and the economic, social, and cultural contexts of surveillance can help address existing inequalities in health systems, improve the capacity to detect and contain EIDs, and contribute to broader global goals for development.
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Purpose of review: Soil-transmitted helminths (STH) are endemic in 120 countries and are associated with substantial morbidity and loss of economic productivity. Although current WHO guidelines focus on morbidity control through mass drug administration (MDA), there is global interest in whether a strategy targeting disease elimination might be feasible in some settings. This review summarizes the prospects for switching from control to an elimination strategy. Recent findings: STH control efforts have reduced the intensity of infections in targeted populations with associated reductions in morbidity. However, adults are not frequently targeted and remain important reservoirs for reinfection of treated children. Recent modeling suggests that transmission interruption may be possible through expanded community-wide delivery of MDA, the feasibility of which has been demonstrated by other programs. However, these models suggest that high levels of coverage and compliance must be achieved. Potential challenges include the risk of prematurely dismantling STH programs and the potential increased risk of antihelminthic resistance. Summary: Elimination of STH may offer an opportunity to eliminate substantial STH-related morbidity while reducing resource needs of neglected tropical disease programs. Evidence from large community trials is needed to determine the feasibility of interrupting the transmission of STH in some geographic settings.