06 Franka 359 370
06 Franka 359 370
06 Franka 359 370
Poxvirus and Rabies Branch, Centers for Disease Control and Prevention, World Organisation for Animal Health
(OIE) Reference Laboratory for Rabies, 1600 Clifton Road NE, MS G47, Atlanta, Georgia, 30329, United States
of America
*Corresponding author: euk5@cdc.gov
The findings and conclusions in this report are those of the authors and do not necessarily represent the official
position of the Centers for Disease Control and Prevention
Summary
Effective real-time surveillance, combined with proficient, decentralised and
validated laboratory diagnostics, is a prerequisite for successful rabies control
and elimination. The selection and prioritisation of surveillance methodologies,
in conjunction with appropriate diagnostic techniques, should reflect the goals
of the disease control and elimination programme (Stage 1: proof of burden;
Stage 2: human rabies prevention; Stage 3: monitoring and assessment of control
measures; Stage 4: verification of rabies elimination; and Stage 5: post elimination).
The development of minimum surveillance requirements, in accordance with
Chapter 1.4 of the World Organisation for Animal Health Terrestrial Animal Health
Code, and routine evaluation of disease elimination indicators are of the utmost
importance if the goal of eliminating dog-mediated human rabies by 2030 is to be
achieved.
Keywords
Laboratory diagnosis – Rabies – Surveillance.
doi: 10.20506/rst.37.2.2807
360 Rev. Sci. Tech. Off. Int. Epiz., 37 (2)
Principles of lyssavirus with OIE Reference Laboratories for Rabies to ensure that
globally acknowledged practices and diagnostic assays are
Case definitions, the standard criteria used to define a Given the diversity of rabies reservoir species and the
disease, are the foundation upon which surveillance systems incidence of rabies during different phases of control and
are built. For the purposes of this paper, the following case elimination efforts, the following stages of rabies control
definitions are recommended: programmes can be defined.
– suspected rabies case (clinical diagnosis)
Stage 1: proof of burden
– probable rabies case (clinical diagnosis)
In many countries, the burden and impact of rabies
– confirmed rabies case (laboratory diagnosis) within animal, and even human, populations is not
– not a rabies case (laboratory diagnosis). known and should be described to advocate for support
for the implementation of control measures. At this stage,
diagnostic capacity is typically limited and public health
Clinical diagnosis recommendations are often not linked to diagnostic
activities.
Suspected rabies case: An animal that presents with
any one of the following signs: hypersalivation, paralysis,
lethargy, unprovoked abnormal aggression (biting two In this situation, surveillance activities should include the
or more people or animals, and/or inanimate objects), targeted sampling of suspected or probable rabid animals
(see case definition above) and laboratory confirmation
abnormal vocalisation, or diurnal activity of a nocturnal
using methods that have acceptable sensitivity and
species.
specificity for lyssaviruses, as defined by the programme.
Serological surveys, which often target healthy (non-rabies-
Probable rabies case: A suspected rabid animal that has suspect) animals, may be applicable in certain settings as
had a known exposure (i.e. bite, scratch, or contact with screening tools for the presence of lyssavirus circulation,
saliva) to a suspected, probable, or confirmed rabid animal, particularly in relation to bat-associated lyssaviruses.
and that is not known to be alive within ten days of the Lyssaviruses should undergo molecular characterisation
observed clinical signs, or a suspected rabid animal that and be described in relation to other epidemiologic findings
dies, is killed, or disappears within ten days of the observed to characterise the reservoir species and transmission
clinical signs. dynamics.
Rev. Sci. Tech. Off. Int. Epiz., 37 (2) 361
the possible reintroduction of the disease, as well as for of adequate reporting of positive and negative rabies cases
the presence of other rabies virus variants and non-rabies- from Member Countries.
virus lyssaviruses. Appropriate border and trade security
policies should be implemented. Given the large degree The World Health Organization’s Rabies Bulletin Europe
of international trade and travel, most countries should (www.who-rabies-bulletin.org/site-page/what-rabies),
consider the continuation of their PPHSSs and active which serves as a surveillance database for 44 European
surveillance activities, albeit at a reduced intensity. Only countries (including the Russian Federation), is currently
primary rabies diagnostic assays should be considered, the most effective database, providing both numerator
and all detected lyssaviruses should undergo molecular (positive cases) and denominator (the number of tested
characterisation to determine the likely origin of the animals) data (18). To assess and address the ‘disconnect’
infection. or gap between estimated, reported, and true rabies
data in Africa, the Pan-African Rabies Control Network
(PARACON) is currently developing and implementing a
Characteristics of effective regional rabies-specific disease surveillance bulletin, based
on the District Health Information System 2 platform (19).
surveillance systems This surveillance bulletin aims to store data and facilitate
automatic data analyses and output reporting for selected
Key components for effective and useful surveillance indicators, but also to enhance the sharing of submitted
systems are: data with approved international authorities, reducing
redundancy and reporting fatigue.
a) adequate and clear reporting regulations (policies and
laws for notification)
In addition to paper-based reporting, alternative approaches,
b) a decentralised laboratory diagnostic system and such as using mobile phones as surveillance tools (20, 21,
infrastructure 22) or as dog vaccination and monitoring tools (23), are
c) an integrated surveillance system, paper-based or being implemented to improve real-time monitoring and
electronic, with clear case definitions, standardised surveillance.
indicators, zero reporting (i.e. reporting all tested animals
even if there were no positive results) and minimum Sample sizes
requirements
One of the contested factors of adequate rabies surveillance is
d) resources the minimum sample size for reporting (including reporting
e) a regional approach to surveillance (in addition to all tested samples, even if no positive results were detected,
national or within-country approaches). i.e. zero reporting). In the past, target values for the number
of samples to be tested for animal rabies surveillance were
The departmental and legal separation of the human and recommended by the international regulatory bodies of
animal health sectors, as well as an absence of requirements the OIE, WHO, and European Union (EU) (24). It is now
for disease notification and reportability (or lack of generally accepted that defining a sample size for rabies
enforcement) in many countries in which rabies is endemic, surveillance in animals is problematic, prompting countries
creates a barrier to effective rabies surveillance and response that experience difficulties in meeting such requirements to
activities. Rabies control programmes should consider resort to sampling healthy animals (25).
integrating veterinary and human health detection and
response practices. Given that rabies is not present in the brain until shortly
before the onset of symptoms, testing healthy animals is
rarely recommended and this sampling strategy should not
Reporting and disseminating results
be used as proof of freedom from the disease. In situations
Over the years, many international reporting systems where adequate numbers of clinically ill animals cannot
have been implemented, with varying degrees of be identified and tested, the results of animals placed in
success. The World Health Organization’s (WHO’s) Rabnet observation/quarantine for suspected rabies, due to bites or
platform (no longer in use) (13) and the OIE’s World other suspicious behaviour, should supplement diagnostic
Animal Health Information Database (WAHID) interface results. It was estimated that detection probabilities of
(www.oie.int/wahis_2/public/wahid.php/Wahidhome/ <0.1 are broadly typical of rabies surveillance systems in
Home) (14, 15), as well as the Pan American Health rabies-endemic countries and areas without a history of
Organization’s (PAHO’s) epidemiologic surveillance system rabies (26). It is vital that zero reporting and minimum
(Sistema de Información Epidemiológica or SIEPI) in Latin sample sizes, and sampling based on the definitions of
America (16, 17), have all experienced challenges in terms suspect and probable cases, are agreed upon and enforced.
Rev. Sci. Tech. Off. Int. Epiz., 37 (2) 363
To ensure that the surveillance system detects the majority With progress in science and technology, novel diagnostic
of cases, it is critical that case-based surveillance (in which techniques for rabies are being developed. RT–PCR
all suspected or probable cases are reported and investigated techniques are frequently used in routine diagnostics
immediately) is implemented and maintained. If no positive (32, 33), and others, such as isothermal recombinase
cases are detected, zero reporting (reporting the number of polymerase amplification (RPA), are actively being explored
tested or assessed animals) is paramount. It is of the utmost (34) (Table I).
importance, especially for activities directed towards
eliminating rabies (Stages 3 and 4), in areas with a low Besides DFA, DRIT and pan-lyssavirus RT–PCR assays,
incidence of rabies cases, to define an indicator containing novel, field-ready, rapid diagnostic techniques have been
information about the proportion of laboratory-confirmed undergoing development and standardisation in recent
positive rabies cases from all tested or assessed animals. A years (64). Such techniques are vital for any decentralised
requirement for the minimum number of suspect animals laboratory-based surveillance system. Lateral flow devices
to be tested or assessed for rabies must be included (27). (LFDs), based on immunochromatographic reaction, have
been extensively assessed at multiple locations to detect
To ensure effective surveillance, it is also crucial that WHO rabies virus antigen in the field (65). Although LFDs
and OIE recommendations, as well as case definitions, seem very promising, evaluations have shown a high
indicators, and minimum requirements, are routinely number of false-negative results and significant batch-to-
revisited and assessed by independent experts (2, 18, 25). batch variability, making these tests incompatible with
surveillance programmes that affect human treatment
decisions or are attempting to confirm rabies-free status.
Table I
Comparison of rabies assays and their use under different animal rabies surveillance programmes (35)
Stage 3: Stage 4:
Stage 1: Stage 2: Stage 5:
monitoring verification Sample
Assay (References) proof of human rabies post-
of control of rabies required
burden prevention elimination
measures elimination
Reverse–transcription polymerase chain reaction +++ +++ +++ +++ +++ Brain
Molecular
Direct fluorescent antigen (DFA) test (29, 46, 47) +++ +++ +++ +++ +++ Brain
Direct rapid immunohistochemical test (DRIT) (30, +++ +++ +++ +++ +++ Brain
31, 48, 49, 50)
Antigen
incidence setting, i.e. the elimination phase (Stages 4 and 5; integrated surveillance systems, such as the European Food
active plus passive surveillance; RT–PCR screening). Safety Authority (EFSA), which monitors Campylobacter,
Listeria, verotoxigenic Escherichia coli (VTEC), Yersinia spp.,
Brucella, Mycobacterium bovis, Trichinella and Echinoccoccus,
The future of integrated as well as rabies and food-borne outbreaks, are built in
parallel to existing disease-specific systems (70).
surveillance approaches Where integrated national surveillance systems neglect to
include rabies surveillance (or its reservoir component),
Many of the efforts for integrated approaches towards
independent human and/or animal rabies (and animal-bite)
prevention and preparedness that address all three aspects
surveillance systems are often developed and implemented
of the human–animal–vector triad currently focus on pilot
locally, depending on the specific conditions and needs in
testing programmes and the implementation of a targeted,
that particular area.
risk-based strategy. The goal is to detect disease spread
early and to implement intervention strategies before the
agent reaches humans (68, 69). Often, however, such In Haiti, an independent, laboratory-based surveillance
efforts fall short, resulting in the establishment of very system, composed of active, community animal-bite
specific programmes aimed predominantly at one particular investigation and PPHS animal rabies investigation, has
pathogen, without any integration or multi-use options for proven successful in real-time monitoring and assessment
other pathogens. As a result, the quality of pan-disease data of the rabies burden (27). In certain instances, where
collection systems is less than ideal. the emphasis is only on human rabies prevention and
control, and where the surveillance of domestic animals or
Neglect is most severe in the integrated surveillance of wildlife exceeds public health surveillance needs, targeted
diseases in both domestic and wild animals. In other cases, surveillance platforms are being developed in parallel.
Rev. Sci. Tech. Off. Int. Epiz., 37 (2) 365
In Canada, RageDB is a spatio-temporal, Web-based pathogens (73, 74), as well as those gained from successful
database application that focuses on the storage, analysis rabies control and elimination efforts implemented in
and communication of surveillance data on raccoon-rabies certain regions in past decades (75). The establishment of a
variants, in collaboration with public health, agriculture and formal and standardised process by which rabies elimination
wildlife agencies (71). In the United States, a geographic is certified at national and regional levels by independent
information system- (GIS-) based, centralised, rabies experts (and international agencies and partners) is of
surveillance database and Internet mapping application urgent importance if the goal of eliminating dog-mediated
were developed and piloted in eight states as a new tool for human rabies by 2030 is to be reached. Now is the time
the rapid real-time mapping and dissemination of data on to form an independent, international oversight board,
animal rabies cases, in relation to unaffected areas, rabies- which will regularly convene to review predetermined sets
enzootic areas, and baited areas where interventions are of criteria (minimum surveillance requirements, agreed-
currently in progress (72). The integration of surveillance upon indicators, zero reporting) for each country involved
systems and the human–animal–vector approach should be in rabies elimination; to determine the status of elimination
emphasised, sought and planned for, in preference to the efforts; to provide recommendations; and to coordinate
development and dissemination of incompatible, temporary, global investment, based on collaborative prioritisation.
or individual disease/species surveillance systems.
Conclusions
If elimination efforts are successful, rabies will be the first
zoonotic disease ever to be eliminated worldwide, with
millions of lives and billions of dollars saved. For this to
happen, however, it is vital to apply the lessons learned
from successful programmes to control and eliminate other
Résumé
Une surveillance efficace en temps réel soutenue par des tests diagnostiques
performants et validés réalisés par des laboratoires décentralisés est une condition
préalable pour que les efforts de contrôle et d’élimination de la rage soient
couronnés de succès. Le choix et la priorisation des méthodes de surveillance et
des techniques diagnostiques qui leur sont associées doivent tenir compte des
objectifs du programme de lutte et d’élimination de la rage (phase 1 : détermination
de la charge induite par la maladie ; phase 2 : prévention de la rage humaine ;
phase 3 : suivi et évaluation des mesures de lutte ; phase 4 : vérification de
l’absence de rage ; phase 5 : post-élimination). Il est essentiel d’élaborer des
mesures minimales de surveillance en conformité avec les dispositions du
chapitre 1.4. du Code sanitaire pour les animaux terrestres de l’Organisation
mondiale de la santé animale et de procéder à une évaluation systématique
des indicateurs de l’élimination de la maladie si l’on veut atteindre l’objectif de
l’élimination de la rage humaine transmise par les chiens d’ici 2030.
Mots-clés
Diagnostic de laboratoire – Rage – Surveillance.
366 Rev. Sci. Tech. Off. Int. Epiz., 37 (2)
Resumen
Para que las actividades de control y eliminación de la rabia culminen con éxito es
requisito previo e indispensable una vigilancia eficaz en tiempo real, combinada
con una labor competente y descentralizada de diagnósticos de laboratorio
validados. La selección y jerarquización de los métodos de vigilancia, junto con
el uso de técnicas apropiadas de diagnóstico, deben responder a los objetivos
marcados en el programa de control y eliminación de la enfermedad (fase 1: datos
demostrativos de la carga de enfermedad; fase 2: prevención de la rabia humana;
fase 3: seguimiento y evaluación de las medidas de control; fase 4: verificación
de la eliminación de la rabia; y fase 5: periodo posterior a la eliminación).
La definición de requisitos mínimos de vigilancia, de conformidad con el
capítulo 1.4. del Código Sanitario para los Animales Terrestres de la Organización
Mundial de Sanidad Animal (OIE), así como la evaluación sistemática de
indicadores relativos a la eliminación de la enfermedad, revisten la mayor
importancia para que se cumpla el objetivo de haber eliminado la rabia transmitida
por perros para 2030.
Palabras clave
Diagnóstico de laboratorio – Rabia – Vigilancia.
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