An effective surveillance system is critical for the elimination of canine rabies in Latin America. Brazil has made substantial progress towards canine rabies elimination, but outbreaks still occurred in the last decade in two states. Brazil uses a health information system (SINAN) to record patients seeking post-exposure prophylaxis (PEP) following contact with an animal suspected of having rabies. This study evaluated: (i) whether SINAN can be reliably used for rabies surveillance; (ii) if patients in Brazil are receiving appropriate PEP and (iii) the benefits of implementing the latest World Health Organization (WHO) recommendations on PEP. Analysing SINAN records from 2008 to 2017 reveals an average of 506,148 bite-injury patients/year [range: 437k-545k] in the country, equivalent to an incidence of 255 bite-injuries/100,000 people/year [range: 231–280]. The number of reports of bites from suspect rabid dogs generally increased over time. In most states, records from SINAN indicating a suspect rabid dog do not correlate with confirmed dog rabies cases reported to the Regional Information System for Epidemiological Surveillance of Rabies (SIRVERA) maintained by the Pan American Health Organization (PAHO). Analyses showed that in 2017, only 45% of patients received appropriate PEP as indicated by the Brazilian Ministry of Health guidance. Implementation of the latest WHO guidance using an abridged intradermal post-exposure vaccination regimen including one precautionary dose for dog bites prior to observation would reduce the volume of vaccine required by up to 64%, with potential for annual savings of over USD 6 million from reduced vaccine use. Our results highlight the need to improve the implementation of SINAN, including training of health workers responsible for delivering PEP using an Integrated Bite Case Management approach so that SINAN can serve as a reliable surveillance tool for canine rabies elimination.
Dog-mediated rabies in humans has been reduced by over 99% in Latin America, but 106 cases in dogs were still reported in 2014 [1]. Dog vaccination and prompt administration of post-exposure prophylaxis (PEP) for bite victims are essential to the successful reduction of human cases of rabies across Latin America [2,3]. However, detecting the final cases of rabies and interrupting transmission is difficult and therefore continued precautionary use of PEP is required for persons bitten by dogs that show signs suspicious of rabies [4]. In Latin America, PEP is broadly available and 0. 2% of people are referred to health services annually after potential exposure to the risk of rabies (mainly because of bites by dogs), with around 25% of patients receiving free PEP [3]. Control of rabies in dogs is expected to reduce bites by rabid dogs but not necessarily bites by healthy dogs for which patients do not require PEP. Unnecessary and indiscriminate use of PEP strains local and national healthcare budgets, and is a missed opportunity for improving the detection of rabies cases [5,6]. Eliminating dog-mediated rabies requires an efficient and sensitive surveillance system that can detect new, but rare, outbreaks of dog rabies. However, outbreaks of dog rabies are difficult to detect without using targeted methods and community surveillance because of the millions of dogs in Latin America and because rabies incidence is low even when endemic (less than 1% of dogs become infected per annum) [7]. Passive surveillance of dog bite victims seeking help within the health care system can support active surveillance in detecting animal rabies cases [8–10]. Dog rabies can be detected by focusing on bite patients and evaluating the dogs responsible for bites, because dog bites are frequent and unprovoked aggression is one the main clinical signs of this disease. Surveillance of bites can also reveal secondary cases caused by a rabid dog and has potential to reduce unnecessary PEP use [5,8, 10,11]. For example, surveillance of dog bites in Haiti identified areas of rabies risk and led to considerable reductions in PEP use [8,11]. Improved surveillance of dog-bite patients can also help to detect the rare but increasing cases in dogs caused by bat rabies in countries such as Brazil [12]. Brazil has one of the largest estimated populations of dogs worldwide and the second largest of the continent after the United States, with around 30–50 million dogs [13,14]. The country has made substantial progress towards the elimination of dog-mediated rabies over the last decades, but cases persist in the state of Maranhão, and a large outbreak recently occurred in Mato Grosso do Sul as a result of incursions from bordering Bolivia [15,16]. Thus, Brazil requires an effective surveillance system to support current dog vaccination campaigns to eliminate rabies from remaining endemic foci. Brazil’s National Health System (SUS) provides universal health coverage to most Brazilians using a decentralized network of public hospitals and health facilities. Since 1998, Brazil has used a national health ‘Information System on Diseases of Compulsory Declaration’ (SINAN) to record all patients seeking medical care in public health facilities following contact with an animal that can transmit rabies. SINAN is a relatively inexpensive tool that records information on patients, the animal contacted and PEP use. The SINAN database records several variables that can be used for rabies surveillance including the severity of the bite, whether the biting animal is suspected for rabies, whether the animal is alive and can be observed for a 10-day period, and the PEP regimen administered to the patient [17,18]. Previous studies have performed descriptive analysis to summarize the SINAN database at national and state level [18–21], but the accuracy of the SINAN database as a tool for the surveillance of rabies and for the appropriate use of PEP has not been evaluated. In Brazil, dog bite incidence was high between 2002 and 2009 with 425 000 bites estimated per year [19,22]. The reduction of canine rabies cases over the last decade in Brazil should cause a concommittant decline in bites from rabid dogs and potential savings in PEP administration, but this has not been realized. Here we examine (i) whether SINAN can be reliably used for rabies surveillance; (ii) if patients in Brazil are receiving appropriate PEP according to Brazilian Ministry of Health (MoH) guidelines and (iii) the benefits of implementing the latest World Health Organization (WHO) recommendations on PEP.
The incidence of patients seeking heath care following a bite (noted here as ‘bite incidence’) in Brazil remained relatively stable from 2008 to 2016, with an average of 257 patients/100 000 population (range: 231–280). Within that range, an increase was observed from 2008 (230 patients/100 000) to 2012 (279 patients/100 000), followed by a decline until 2016 (252 patients/100 000) (Fig 2). Annual bite incidence is, however, very variable per state with a maximum of 544 bites/100 000 population in the state of Roraima and a minimum of 97 bites/100 000 population in Sergipe in 2016 (Fig 2). There was no correlation between bite incidence in a state and either the state’s average income (Spearman’s correlation test, Rho = 0. 20, p-value = 0. 31) in 2016, the state’s number of houses with at least one dog (Spearman’s correlation test, Rho = -0. 18, p-value = 0. 37) in 2013, nor the state’s percentage of houses with at least one (Spearman’s correlation test, Rho = 0. 19, p-value = 0. 33). The percentage of patients bitten by dogs classified as suspect by health workers (including categories ‘rabies suspicious’, ‘rabid’ or ‘dead/disappeared’ in the SINAN form), which are expected to result in the use of PEP, increased from 17% in 2008 to 25% in 2017 (Fig 3A). This increase was mainly due to an increase in the number of dogs that were categorized as ‘non-observable’, which more than doubled (3% to 7%) during this period. Among dog bites, the absolute number and the relative proportion due to suspect rabid dogs varied between states (Fig 3B) and over time from 2008 until 2017 (Fig 3C). For example, the maximum proportion of bites due to suspect dogs was observed in Roraima state (35%) and the minimum proportion in Alagoas (15%). Likewise, the difference in the percentage of bites from suspect dogs between 2008 and 2017 was the highest in Roraima, which increased by 24%, whereas the only reductions were observed in the states of Santa Catarina (-6%) and Mato Grosso do Sul (-0. 4%). The total number of dogs reported as ‘laboratory confirmed rabies’ in SINAN was much higher (2482 dogs) than in the SIRVERA database (269 dogs) for the period of 2008–2017. More than 2000 reports in the SINAN data could therefore be considered as ‘false positives’, assuming these were not verified for inclusion in SIRVERA. Out of the 27 states in Brazil, 26 reported at least one lab-positive rabid dog in SINAN whereas over the same period only 14 states reported confirmed rabid dogs in SIRVERA (Fig 4A and 4B). States reporting the most positive rabid dogs also differed between SINAN and SIRVERA. In SINAN, larger more populous states such as Sao Paulo and Minas Gerais reported the most positive dogs with 481 and 296 respectively (Fig 4A), while from SIRVERA the states of Maranhão and Mato Grosso do Sul reported the most positive dogs with 116 and 83 respectively (Fig 4B). On a monthly basis, trends in rabies-positive dogs were similar in SINAN and SIRVERA for states with known foci of rabies transmission, such as Maranhão (2011–2014) and Mato Grosso do Sul (2015) (Fig 4C). However, in states with very few or no rabies cases identified in SIRVERA, such as Bahia, Minas Gerais, Sao Paulo and Rio Grande do Sul, monthly data on positive dogs from SINAN showed very different temporal trends, with peaks in cases that were not evident in SIRVERA (Fig 4C). Based on SINAN, there was an increase in the percentage of patients requiring PEP (either vaccines or vaccine and serum) from 2008 (67%) to 2015 (77%). In the last two years, however, there has been a reduction with 59% of patients receiving PEP in 2017, which coincides with a vaccination shortage experienced by Brazil in 2015 (Fig 5A). This reduction was observed in 19 out of 27 states. Based on the PEP guidelines from the Ministry of Health used from 2008–2017, we estimated the percentage of patients that received appropriate PEP. The percentage of patients receiving appropriate PEP remained relatively stable at approximately 56% from 2008 (56%) to 2015 (54%). However, appropriate PEP administration declined in the last two years to 45% in 2017 (Fig 5A). Most of the incorrect PEP use in 2017 was due to either an under-use of vaccines or serum in high-risk bites that required PEP (37% of total PEP) or an unnecessary use of vaccines and serum in low-risk bites that did not require PEP (8% of total PEP). Under-use following a national vaccine shortage in 2015 increased from 25% to 37% (2017) of total PEP. We used patient presentations in 2017 as a baseline from which to estimate vaccine requirements under different hypothetical PEP regimens. We estimated that 1,152,057 doses of vaccines were needed for appropriate PEP administration using the 5 dose IM Essen regimen that was recommended up to 2017 across Brazil. In comparison, we estimated that 1,040,444 doses would be needed under the 4 dose IM updated Essen regimen recommended in the updated MoH guidelines in 2017 and the WHO (Fig 5C). If Brazil implemented the latest WHO recommendations (e. g. 3 ID doses for complete prophylaxis), the number of required doses without vial sharing would be reduced to 631,835 (39% reduction from the 4 dose IM regime), and with vial sharing to 379,101 (64% reduction). Considering a price of 10 USD for each 0. 5 mL vaccine vial, the WHO recommendations without vial sharing (6. 31M USD) would save 4. 08 M USD in vaccine costs compared to the current 4 IM guidelines (10. 40M USD). Under the hypothetical scenario with complete vial sharing (3. 79M USD), savings of up to 6. 61M USD in vaccine costs could be made. In practice considerable vial sharing would be expected, especially in urban clinics with high throughput of patients, and so savings of between 4. 08 M USD and 6. 61M USD would be expected.
An effective national surveillance system is essential to detect remaining cases of dog-mediated rabies and to ensure that patients bitten by dogs that pose a risk of rabies transmission are given appropriate PEP. Control programmes in Brazil have substantially reduced dog-mediated rabies transmission and human cases of dog-mediated rabies in the last decade. Despite this reduction in dog rabies, our results show that the number of patients presenting to health facilities due to bites by dogs have remained relatively constant in the country over the last decade. However, the number of bites by high-risk ‘suspect’ dogs indicating the need PEP have increased. This mismatch between rabies cases and suspicion of a rabid dog suggests a ‘fear’ of rabies by health workers that has contributed to a risk averse increase in PEP use over the last decade, with only half of patients being administered PEP appropriately. Following the human rabies vaccine shortage experienced in 2015, the percentage of patients receiving appropriate PEP declined. We do not know of any human rabies deaths from dog-mediated rabies as a result of this apparent misuse of PEP and suggest that more judicious use of PEP could be safely undertaken if health workers are appropriately trained in risk assessments of bitten patients and use available epidemiological data to evaluate the risk of dog rabies in their area. Our analysis also showed that switching to ID administration of rabies vaccines according to the latest WHO position could save millions of dollars to the Brazilian health system related to vaccine volume, although the implementation of such a switch requires further investigation. The overall incidence of patients in Brazil seeking care due to dog bites (255 bites/ 100,000 people) was similar to estimates from Kenya (289 bites) [32] but higher than incidence in patients reported in Tanzania (12–120) [33], Uganda (40) [34,35] and Switzerland (180) [36]. Community-based surveys focusing on dog bites, not on patients seeking care, show a much larger bite incidence in India (1700–2500) [37] and the USA (300–1000) [38]. Although bite incidence has remained relatively stable over the last decade in Brazil, bite incidence varies more than 6-fold between states, resulting in an uneven burden to state health centers that assess and treat patients. There was also a small increase up to 2012 followed by a decrease. Although the causes of this temporal variation remain unknown, changing dog populations, dog ownership patterns and access to health care could all have contributed to the observed decline after 2012. For example, large densely populated states such as São Paulo have a relatively low bite incidence but a high absolute number of patient presentations compared to less populous states such as Roraima that have a much higher incidence of bite patients. Because most of these bites come from healthy dogs, investigation of the factors underpinning these differences is warranted. In our study, we did not find any correlation between bite incidence and each state’s average income nor the number (or percentage of houses) with at least one dog, suggesting that bite incidence was not necessarily explained by socio-economic status nor the overall dog population. A more detailed analysis at the municipality level could reveal local drivers associated with bite incidence such as the dog population (and human: dog ratio), the percentage of free-roaming dogs or people’s attitudes to dogs and their care. For example, some states might have a disproportionately higher population of free-roaming dogs or dog breeds that are more prone to bite as well as a higher proportion of at-risk populations (e. g. young males under 20 years old [26,39]. A particularly high bite incidence was observed in the state of Roraima, which neighbours with Venezuela. Attention should be given to improve measures in this state, since bites pose a considerable public health burden even in the absence of rabies and information on rabies in Venezuela is currently limited. In Roraima, no rabies cases have been reported to SIRVERA in the last decade but there is little active surveillance, which could contribute to a slow public health response if rabies were to emerge. Despite a substantial reduction in dog-positive cases in the last decade, our analysis shows that the percentage of bites from dogs that are considered ‘suspect’ for rabies (i. e. showing symptoms, death or disappear) has increased. Most of the increase is due to dogs that were reported to not be observable. This increase is also very variable across states, with some states such as Roraima showing an increase of over 30%. An increase in the percentage of non-observable dogs could arise from an increase in bites from free-roaming dogs or a decreased in bites from owned (observable) dogs due to more responsible pet ownership. Alternatively, this could be due to increased unwillingness of health workers to perform dog follow up and the recommended 10-day observation and to directly prescribe PEP to avoid risks related to PEP underuse. Current data cannot resolve either of these hypotheses which requires further research. Similarly, about a third of reports from suspect dogs do not have data entered on whether the dog is observable or not, which highlights the need for better training of health workers in this crucial step that should determine PEP administration. If dogs are not properly observed and assessed following a bite, this will increase the chance that genuinely rabid dogs will not be identified, which could result in further dog-to-dog transmission, or even failure to detect bat-to-dog transmission without any emergency response or prevention measures. In states with endemic transmission of rabies in the last five years, such as Maranhão and Mato Grosso do Sul, data from SINAN matches reasonably well with the positive cases reported to SIRVERA, suggesting that SINAN could be used effectively to enhance rabies surveillance. However, hundreds of ‘false positives’ were observed in other states such as São Paulo, Bahia or Minas Gerais. ‘False positives’ could arise if health workers accidentally mis-record data on SINAN forms and this data is not further checked. Alternatively, mistakes could be made to justify the use of PEP if health workers are not confident in recommending appropriate PEP. Discriminating between these hypotheses will require further work on the factors contributing to the recording of the SINAN data by health workers. We hypothesize that in states with endemic rabies healthcare workers may be more aware of risks because they have received specific and recent training on rabies by the Ministry of Health and PANAFTOSA following outbreaks and thus take more care to record data. In contrast, in states where rabies has been absent for many years health care workers may become lax in recording because the repercussions of over- or under-prescription may not have immediately apparent ramifications. States such as São Paulo or Minas Gerais have also the largest human populations of Brazil and thus, even if the percentage of mistakes on recording SINAN data is the same as in other smaller states, it results in a larger number of ‘false positives’. However, maintaining vigilance in rabies-free states is important when the risk of importation from endemic areas remains. Overall, these results highlight the need to both improve and update health care worker’s knowledge on the signs of rabies in dogs by strengthening a ‘one health’ link with veterinarians. For example, a user-friendly mobile app could i) put in contact state’s health workers with veterinarians to improve dog assessments, ii) improve dog follow ups, and (iii) rapidly detect a ‘false positive’ or priority areas for educational campaigns on dog rabies and vaccination. ‘One health’ workshops performed annually in each state could also help in updating knowledge of health and veterinarian professionals on the current rabies situation, dog assessment, and best surveillance practices. Inadequate training of health workers may also limit the appropriate administration of PEP according to the guidelines of the Brazilian MoH. We estimated that PEP use increased over the last decade to almost 80% of patients seeking healthcare in 2015, although only around 58% of patients were administered PEP appropriately according to guidelines. Despite an increase in overall PEP use until 2015, the main cause of inappropriate PEP was ‘under-use’ of vaccines or serum when required for high-risk bites. The vaccine shortage experienced in 2015 reduced PEP use for the following two years, but also reduced the appropriate administration to 45% in 2017, and ‘under-use’ increased by 12% from 2015 to 2017. This suggests that vaccine shortages resulted in inappropriate PEP use rather than a more rationalized use. Given that no human rabies cases of dog-mediated rabies were observed as a result of inappropriate PEP use as defined by current guidelines, this indicates that further improvements can be made in identifying the risk that a biting animal does have rabies. Updating health workers knowledge on both national and state guidelines for PEP administration is urgently required, particularly in northern states such as Roraima, where the turnover of health professionals is high. One approach to reduce PEP costs in Brazil would be adoption of the latest WHO recommendations [29]. We estimate that in 2017, the use of the 1-week abridged ID regimen could have saved at least 4. 08 M USD only on vaccine volume. This reduction is much higher than changing to the 4 dose IM regimen recommended by the Brazilian MoH and the WHO. Reductions in vaccine volume related to adopting WHO recommendations will come with a cost of training health workers to use this technique and replace the current vial/transport system of PEP. Cost reduction of vaccines could outweigh possible obstacles associated with changing to ID, but a cost-benefit analysis should evaluate whether cost reductions could outweigh costs associated with training. Several countries (Philippines, Sri Lanka, Bhutan, several states in India, Bangladesh, and Madagascar) with a high number of people attending health care after a bite have successfully switched from IM to ID vaccination [40]. Furthermore, ID vaccination is already undertaken in several Brazilian states as pre-exposure prophylaxis of professionals working in at-risk laboratories or activities. Many health workers therefore already have experience of ID vaccination with the BCG vaccine for tuberculosis disease and more recently with fractionated dosing of yellow fever vaccine. A more detailed analysis of SINAN data at the municipality level could provide evidence of which health centers would have the highest levels of dose sharing based on patient throughput and identify small health centers where vial sharing is not possible due to a low number of patients seeking health care each day. The economic savings associated with a change in PEP administration could be used, for example, to improve activities of rabies surveillance and prophylaxis in a large population of Brazil, including people exposed to vampire bat bites. Our analysis of the SINAN data allows several conclusions to be drawn about potential for improvements to surveillance and PEP administration at the state and national level, however we acknowledge several limitations. First, the SINAN dataset includes a small but unknown number of ‘duplicate’ records, corresponding to patients accessing more than one health centre and generating more than one SINAN form. We expect this percentage to be low and not to bias results at the state level. Second, errors on data recording, which are likely generating many of the rabies-positive dogs in the database, can mislead the assessment of whether PEP was appropriately administered. For example, health workers can mis-record the ‘rabid dog’ field in the form manually or when transcribing data from handwriting to digital format. These errors, adding ‘false positives’ to the dataset, will prevail if not checked by local or national authorities responsible for SINAN. In our analysis, although we reported and excluded missing data and attempted to minimize the influence of data inconsistencies, inaccuracies will undoubtedly still be present. Third, SINAN does not capture patients that seek private health care following a dog bite or patients who are bitten that do not seek health care. Therefore, our estimates of bite incidence, although high, are likely an underestimate of the true burden of dog bites, although more than 70% of patients seek emergency healthcare within the public SUS system [41,42]. Fourth, reports of rabid dogs to SIRVERA likely underestimated the actual number of rabid dogs in Brazil. This is mainly due to a non-automatic transmission of SINAN data to SIRVERA and a lack of data uploading from states or national levels. We stress the need to improve partnerships between national and regional authorities for a more coordinated effort to eliminate canine rabies in the continent. However, if rabies is circulating in dogs within a state, we expect that at least occasionally cases will be reported to SIRVERA because canine rabies is a mandatory notifiable disease in Brazil, dog rabies cases are routinely monitored and other species infected with rabies (e. g. bats) are detected through passive surveillance [1,43,44]. Detection capacity will ultimately depend on laboratory capacity, which remains variable between states and countries of Latin America [1]. Fifth, we did not obtain data from the last three months of 2017 from all states because the data, requested in 2018, was not yet entered to the national database. This shows that months of delays can limit timely control measures based on data from SINAN. Finally, data on the number of doses administered, although in the SINAN form, is not filled electronically to the main national system, which reduces our ability to estimate both appropriate PEP and potential for cost savings. Previous studies at the state level in Brazil have shown that 8–55% of patients do not complete the PEP prescribed and 70% of PEP courses are interrupted due to withdrawal of patients [45,46]. Overall, these limitations reinforce the need for improving the accuracy of SINAN so that it can be used as an efficient passive surveillance tool for dog rabies. In summary, this study demonstrated an increasing and uneven burden related to the prevention of dog-mediated rabies to the Brazilian health care system, despite a major reduction in disease transmission throughout the country. Our results highlight that improving the training of health workers, automating the data recording system to identify and require correction of errors, and changing PEP administration protocols could substantially reduce healthcare costs. Focusing on Brazil as an example, this study calls for improving passive surveillance and strengthening ‘One health’ links between health workers and veterinarians in order to move forward towards the elimination of dog-mediated rabies across Latin America. Better use of PEP and enhanced surveillance could enable more efficient and effective allocation of resources towards other emerging public health problems such as PrEP and PEP for vampire bat rabies prevention.
Dog-mediated rabies has declined to only a few cases in Latin America over the last decade. Brazil has the largest human and dog population of Latin America. Despite the decline of canine rabies, the country’s public health system still spends millions of dollars annually on half a million patients seeking health care for dog bites. In this study, we analysed a decade of national surveillance data on dog bites. These data suggest that health workers report dog rabies in many states where the disease is likely to be absent, with false positive cases frequently reported into the surveillance system. In addition, only half of patients appear to receive the appropriate rabies post-exposure prophylaxis as recommended by the Ministry of Health. We estimated that Brazil could save up to USD 6 million per annum on vaccine by reducing the number of doses administered during prophylaxis and adopting the intradermal vaccine delivery technique following the latest WHO recommendations. Our study highlights an urgent need for updating health care workers on canine rabies knowledge, prophylaxis and assessment of dog bites to improve prophylaxis provision and surveillance of dog rabies.
medicine and health sciences
post-exposure prophylaxis
immunology
tropical diseases
geographical locations
vertebrates
dogs
animals
mammals
vaccines
preventive medicine
rabies
neglected tropical diseases
infectious disease control
vaccination and immunization
public and occupational health
infectious diseases
zoonoses
south america
epidemiology
brazil
people and places
infectious disease surveillance
eukaryota
prophylaxis
disease surveillance
biology and life sciences
viral diseases
amniotes
organisms
An evaluation of Brazil’s surveillance and prophylaxis of canine rabies between 2008 and 2017