Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Exposure history, post-exposure prophylaxis use, and clinical characteristics of human rabies cases in China, 2006–2012

Abstract

Rabies is still a public health threat in China. Evaluating the exposure history, clinical characteristics, and post-exposure prophylaxis (PEP) of the cases could help in identifying approaches to reducing the number of these preventable deaths. We analysed data collected from 10,971 case-investigations conducted in China from 2006 to 2012. Most cases (n = 7,947; 92.0%) were caused by animal bites; 5,800 (55.8%) and 2,974 (28.6%) exposures were from domestic and free-roaming dogs, respectively. Only 278 (4.8%) of these domestic dogs had previously received rabies vaccination. Among all cases, 5,927 (59.7%) cases had category III wounds, 1,187 (11.7%) cases initiated the rabies PEP vaccination and 234 (3.9%) cases with category III wounds received rabies immunoglobulin. In our adjusted logistic regression model, male cases (adjusted odds ratio [aOR] = 1.25, 95% confidence interval [CI]: 1.09–1.44) and farmers (aOR = 1.39, 95% CI: 1.10–1.77) and person older than 55 years (aOR = 1.48, 95% CI: 1.01–2.17) were less likely than females and persons in other occupations or younger than 15 years to initiate PEP vaccination. The median incubation period was 66 days (interquartile range (IQR): 33–167 days). To reduce the number of human deaths due to rabies, rabies prevention campaigns targeting males and farmers and older people should be conducted. Increasing routine rabies vaccination among domestic dogs will be essential in the long term.

Introduction

Rabies is an acute and fatal zoonotic disease commonly transmitted to humans through a bite or scratch from an infected animal1. Outbreaks of rabies, which can result from uncontrolled populations of rabid animals, represent a health security threat. Globally, rabies causes approximately 59,000 human deaths every year, 95% of which occur in Asia and Africa2,3. Progression to infection after exposure to rabies can be prevented with post-exposure prophylaxis (PEP), comprising of appropriate wound treatment, followed by completion of the rabies PEP vaccination series and the administration of rabies immunoglobulin (RIG) when warranted4. Despite these effective treatments, between 1960 and 2014, there have been an average of 2,198 rabies-related deaths each year in China, and so rabies remains a considerable public health threat5.

Rabies has been a notifiable disease in China since 19555, with case reporting and investigation implemented in 2005. Medical institutions must report all clinically diagnosed and laboratory-confirmed rabies cases to the National Notifiable Infectious Disease Reporting Information System (NIDRIS), after which, county-level Centers for Disease Control and Prevention (CDC) initiate case investigations. China’s national policy requires wound treatment and PEP vaccination for category II and category III exposures, as well as RIG administration for category III exposure6. The PEP vaccination series can be administered as either Zagreb 2–1–1, in which two doses of vaccine are injected intramuscularly on day 0 (one into each of the two deltoid or thigh sites) followed by a single dose on days 7 and 21, or the five-dose Essen regimen, in which one dose is administered intramuscularly on days 0, 3, 7, 14, and 28, based on the World Health Organization (WHO) Expert Consultation on Rabies (2013 version)4. All patients with exposure categories II or III should initiate either series as soon as possible following possible rabies exposure4. At present, human rabies immune globulin (HRIG) and equine rabies antiserum (ERA) are approved for use in China, however, patients typically pay for the PEP vaccination series and RIG as ‘out-of-pocket’ expenses.

Rabies vaccination coverage for dogs remains low in China7. Although there are numerous free-roaming dogs in China, no national programme exists for mandatory rabies vaccination. As a result, the prevention of human rabies relies on community rabies awareness, as well as access to health care for appropriate administration of PEP vaccinations and RIG as recommended by national policy. In this project, we analysed information from human rabies case investigations, conducted between 2006 and 2012, in order to describe exposure history, clinical characteristics and PEP practices of rabies cases in China. Our findings can help to target future interventions, and to improve community awareness and clinical practice involving rabies exposures.

Results

Characteristics of cases and rabies exposures

We obtained data from 11,902 case investigations, performed between January 1 2006 and December 31 2012, from 30 of the 31 provinces in China (no rabies case were reported from Tibet during the project period8). We then cross-referenced these case investigations with the 16,628 rabies cases reported to NIDRIS for the same period. Of the case investigations, 10,971 were successfully matched to NIDRIS. Unmatched case investigations included 931 suspected rabies cases (did not conform to the clinically diagnosed or laboratory-confirmed case definitions), which are not reportable to NIDRIS. Since investigation of human rabies cases (data included in this analysis) is not mandatory but only encouraged, we did not receive data for the remaining 5,657 (34%) clinically diagnosed or laboratory-confirmed cases reported to NIDRIS.

Of the 10,971 successfully matched cases, 10,818 (98.6%) were diagnosed clinically and 153 (1.4%) were diagnosed by laboratory testing. Most rabies cases were male (n = 7,615; 69.4%), farmers (n = 7,624; 71.8%), and lived in rural areas (n = 7,443; 76.4%). Cases were primarily aged 55–64 years (n = 2,290; 20.9%) followed by those ≥65 years (n = 2,062; 18.8%) and <15 years (n = 1,980; 18.0%).

The majority (n = 7,947; 92.0%) of human rabies cases were associated with an animal bite (Table 1). Exposures were most frequently caused by the case’s own domesticated dog (n = 3,875; 37.3%), a free-roaming dog (n = 2,974; 28.6%), or a neighbor’s domesticated dog (n = 1,925; 18.5%). Wounds from domesticated animals (dogs and cats) were responsible for more than half (n = 6,143; 59.1%) of the investigated rabies cases. Of these domesticated animals, only 292 (4.8%) were vaccinated against rabies (278 dogs and 14 cats). One suspected person-to-person transmission was reported, in which a 54-year-old mother was infected with rabies after being bitten by her infected son. Due to the lack of laboratory testing, however, this person-to-person transmission could not be confirmed.

Table 1 Characteristics of exposure history and post-exposure prophylaxis, according to data from human rabies case investigations, China, 2006–2012.

Case investigation data indicated that 1,281 (12.9%) of the total 10,971 cases experienced category I wounds. After confirming exposure routes, 727 cases were bitten or scratched by animal. However, further details regarding the wounds were lacking, and a definitive exposure category could not be confirmed, therefore, 727 cases were reclassified as having category “II or III” wounds. The remaining 554 cases could not be assigned an exposure category due to missing data or unknown exposure route, and they were defined as having an “unknown” wound. The majority of rabies-related wounds were classified as “category II” (n = 2,725; 27.4%), “category III” (n = 5,927; 59.7%), “category II or III” (n = 727; 7.3%) or “unknown” (n = 554; 5.6%). A large percentage of rabies cases (n = 4337; 40.5%) suffered bites on the head, face, neck, or hand; which are highly innervated parts of the body.

Wound treatment, PEP vaccination, and RIG

Following rabies exposure, 1,095 (10.0%) cases sought wound treatment at a medical facility and 577 (5.3%) cases received appropriate wound treatment, including flushing and disinfection of the wound site at the medical facility. Of all cases, 1,187 (11.7%) began a rabies PEP vaccination schedule. Of these cases, the majority (n = 847; 71.4%) began the five-dose Essen regimen, 15 cases (1.3%) began the 2–1–1 Zagreb regimen, and the remaining cases vaccination schedules were missing (n = 325; 27.4%). 280 cases received RIG, more than half of whom received HRIG (n = 195; 69.6%), while 36 (12.9%) cases received ERA, data on RIG type was missing for 49 (17.5%) cases.

In bivariate analysis, sex (p < 0.01), occupation (p-values = 0.01), and age group occupation (p < 0.01) were each statistically associated with failure to begin a PEP vaccination series. There was no statistically significant difference between rural and urban cases in terms of failure to begin PEP vaccination (p = 0.36).

In the multivariable model, sex (male; adjusted odds ratios [aOR] = 1.25, 95% confidence interval [CI]: 1.09–1.44), occupation (farmer aOR = 1.39, 95% CI: 1.10–1.77) and age group (“≥55” aOR = 1.48, 95% CI: 1.01–2.17) remained statistically associated with a failure to begin PEP vaccination (Table 2).

Table 2 Risk factors associated with failure to begin PEP vaccination, according to data obtained from human rabies case investigations, China, 2006–2012.

Among cases with category II or above exposures who began PEP vaccination (n = 1,127), 224 (19.9%) cases completed the entirety of the vaccination series according to the recommended schedule (4 for the 2–1–1 Zagreb regimen and 220 for the five-dose Essen regimen) (Table 3). Of the 5,927 cases with category III exposures, 234 cases (3.9%) received RIG, but only 42 cases (0.7%) received both a complete PEP vaccination series and RIG as recommended. Of the 632 cases beginning but not completing a PEP vaccination series, 440 cases (69.6%) developed symptoms of rabies during the PEP vaccination schedule. Furthermore, 47 cases (7.4%) did not believe that finishing the series was necessary, 11 cases (1.7%) were unable to afford the remaining PEP vaccinations, 10 cases (1.6%) cases developed adverse vaccine reaction, and in one case (0.2%), the doctor did not think the case needed to complete the series. Reasons for incomplete vaccine series for the remaining 123 cases (19.5%) were missing.

Table 3 Completion of post-exposure prophylaxis by wound exposure category, according to data obtained from human rabies case investigations, China, 2006–2012.

Of the 440 cases who developed symptoms of rabies before completing the vaccination schedule, 209 cases (47.5%) did not receive recommended wound treatment (wound flushing and disinfection) at a medical facility, and 116 cases (26.4%) with category III exposure or bites at rich innervation areas (head, face, neck, hand) did not receive RIG. Of these 440 cases, 173 (39.3%) received wound flushing and disinfection at a medical facility within one day of exposure and 283 (64.3%) began PEP vaccination within one day of exposure. With regard to RIG, only 89 (20.2%) cases received RIG within one day of exposure.

The majority of cases with exposure classified as category II or above received wound treatment (n = 726; 90.6%), PEP vaccination (n = 649; 76.6%), and RIG (n = 171; 79.2%) at a medical facility on the same day as exposure (Table 4). 31 cases who were clinically diagnosed with rabies received the complete PEP vaccination series and RIG, along with integrated wound treatment in the medical facility, regardless of exposure category, but still died as a result of rabies (see Supplementary Table S2). Of these 31 cases, 30 (96.8%) initiated PEP vaccination within one day of exposure (see Supplementary Table S2).

Table 4 Time interval from rabies exposure to post-exposure prophylaxis by exposure category, according to data obtained from human rabies case investigations, China, 2006–2012.

Clinical characteristics of the rabies cases

We received information on the clinical characteristics of 10,670 rabies cases. Of these cases, almost all cases (n = 10,579; 99.2%) developed furious manifestations including hydrophobia (n = 9,158; 85.8%), aerophobia (n = 9,045; 84.8%), agitation (n = 8,074; 75.7%), photophobia (n = 6,160; 57.7%), convulsions (n = 4,718; 44.2%) and mental disorders (n = 2,428; 22.8%) (Table 5). Clinically diagnosed cases and laboratory-confirmed cases had similar manifestations.

Table 5 Clinical manifestations of human rabies cases by diagnosis type, China, 2006–2012.

The median incubation period (time from exposure to the development of symptoms) was 66 days (interquartile range [IQR] 33–167), although this median varied by exposure category and age group. The median incubation period was 80 days (IQR 37–222) for category II and 61 days (IQR 31–138) for category III (p < 0.01) (see Supplementary Tables S3 and S4). Cases with bites on the head, face, neck, or hand had shorter incubation periods (58 days [IQR 30–115]) than cases with other wounds (76 days [IQR 37–218]) (p < 0.01). Children younger than 15 years of age had the shortest incubation period (52 days [IQR 25–127]) among all age groups, regardless of exposure category (p < 0.01) (see Supplementary Tables S3 and S4). The median clinical course duration (from symptom onset to death) was 3 days (IQR 2–5) for all cases.

Discussion

This national level analysis of human rabies case investigations provides important information on exposure history, PEP use, and clinical characteristics of human rabies cases in China9,10,11,12. Overall, most persons with rabies, including those with category III exposure, did not seek health care for wound treatment or PEP vaccination, with this trend particularly prominent for males, farmers and older people. Among those who began the PEP vaccination series, less than half received all the required PEP vaccination doses. Of cases that required RIG, only a low percentage of category III patients received appropriate RIG treatments. Although clinically diagnosed and laboratory-confirmed cases presented with similar symptoms, increased laboratory testing would likely avoid possible misdiagnoses13.

In China, the rate of pre-exposure prophylaxis vaccination for rabies is extremely low among the general population14. Therefore, rabies prevention largely relies on PEP following potential rabies exposure. Appropriate and timely wound treatment can reduce rabies viral loads and risk of secondary bacterial infections within bite or scratch sites. However, our study indicated that a relatively low percentage of exposed individuals sought appropriate wound treatment at medical facilities. The low proportion of patients beginning and subsequently completing the entire PEP vaccination series was a major factor in the onset of rabies in our analysis. This is due to the mechanism of protection offered by PEP. PEP vaccination stimulates the immune system to generate antibodies to protect the body from imminent infection. Therefore, completing the entire PEP vaccination schedule is crucial to ensure sufficient antibody titers are attaining to neutralize rabies virus, and prevent the onset of active rabies infections in exposed individuals. As such, those not completing full PEP schedules would be less likely to generate protective titers of antibody to prevent infection.

For cases with category III exposure, RIG is also recommended in addition to wound treatment and PEP vaccination. Following the primary dose of vaccination, it takes approximately 7 days to generate sufficient antibodies titers (above 0.5 IU/mL) to neutralise rabies virus15. During this period, infiltration of RIG locally within the wound site provides additional protection by blocking the systemic spread of rabies virus. However, the percentage of patients receiving RIG among those with category III exposure was small in our analysis, indicating that the lack of administration of RIG is another important risk factor for the onset of rabies.

The small percentage of cases beginning the PEP series in our study is similar to the percentages reported in other countries. For example, in India, 20.9% and 1.3% of rabies patients initiated PEP vaccination and RIG, respectively16. In the Philippines, only 1.7% of rabies cases received PEP17. In China, the percentage of patients beginning and completing PEP as recommended could be limited by three factors: the high out-of-pocket cost of rabies vaccines and RIG, access to appropriate rabies outpatient care, and community levels of knowledge regarding rabies prevention.

According to the National Bureau of Statistics of China, the average annual income for residents of rural areas was approximately 5,490 RMB (822 US dollar) between 2006 and 2012. The average total of a complete PEP vaccination (5 doses) and RIG were more than 300 RMB (45 US dollars) and 1,000 RMB (150 US dollars), respectively. As theses cost are only partially subsidised by the national health insurance system, PEP and RIG can be prohibitively expensive for many Chinese residents, especially for farmers who were indicated in this study as high-risk individuals for rabies.

However, not all PEP vaccination schedules pose similar upfront on consequential costs. For example, compared with the five-dose Essen regimen, the Zagreb regimen with 4 vaccine doses and 3 clinic-visits can reduce direct out-of-pocket vaccination and travel expenses, and minimize lost working time, which may effectively promote PEP vaccination compliance18,19. Furthermore, the 3-clinic-visit intradermal PEP schedule recommended by the WHO in 2018 is even more economical than the Essen or Zagreb regimens20. Therefore, we advise expanding the use of the currently used Zagreb regimen in China, and additionally exploring the feasibility of alternative intradermal 3 clinic-visit vaccination schedules for rabies PEP in China.

Similarly to previous studies of human rabies in China, we found that rabies disproportionately affects those in rural areas5. These epidemiological trends likely reflect the unequal distribution of medical resources in China, and the logistical challenges of long distances and limited transportation to medical facilities for rural and remote mountainous communities21,22. Access to rabies clinics on a national scale has never been assessed, and an accurate understanding of the situation would provide evidence for a rational approach for the distribution of PEP clinics in the future. In addition, health education, bite prevention and rabies awareness is insufficient in rural areas and remote mountainous communities23, which may lead to reduced healthcare seeking behavior for PEP treatment due to lack of perceived risk or lack of knowledge regarding rabies prevention. The results of this study suggest that males, farmers and older age groups are at highest risk for rabies infection, and as such, should be prioritized for rabies awareness, bite reduction and infection prevention education.

Our analysis also indicated inappropriate PEP practice conducted within medical facilities. Standard wound treatment regimen includes wound flushing and disinfection, as well as surgical procedures if necessary4,6. Flushing and disinfection are essential steps to reduce rabies viral load and the risk of secondary bacterial infection within the wound site. However, only 52.7% of the cases treated at medical facilities received appropriate wound care including flushing and disinfection.

Additionally, according to the position of WHO and national guidelines in China, category I exposures do not lead to active rabies infection15,20. Our original dataset contained 1,281 cases initially classified as having category I exposure by healthcare workers. Based on the exposure routes of these wounds and our standardized classification system of rabies exposure, 727 (56.7%) of these cases should have been classified as having category II or III exposure. Because our study is retrospective in nature, we cannot confirm the exposure categories of the other 554 rabies cases (1.3% laboratory-confirmed and 98.7% clinically diagnosed) whose exposure routes were missing, these 554 cases’ exposure categories were unknown. These wounds might be very small and ignored in clinical practice, then lead to the misclassification of exposure category. However, clinicians can distinguish these small wounds by scrubbing exposed patient’s skin with alcohol wipes in clinics15. Therefore, the improvement of clinical practice in rabies PEP clinics is needed, especially, the classification of rabies exposure, which should be addressed in rabies intervention programmes.

The low percentage of cases with category III wounds receiving appropriate RIG in our study is also of concern, and underlying issues of appropriate care needs to be addressed. Therefore, we suggest that medical facilities require an audit of rabies PEP practices and procedures, to identify opportunities to improve healthcare worker training and awareness in order to support future rabies intervention programmes.

However, even when appropriate and timely treatment was administered regardless of exposure category, including wound flushing and disinfection, completion of a PEP vaccination series, and RIG, 31 cases in our study developed active rabies infections. Even though all 31 cases were clinically diagnosed, definitions of clinical diagnosis are strict with regards to clinical manifestation, and our analysis showed 99% cases developed symptoms of furious rabies. We believe that the most likely cause of death was rabies, although we cannot exclude the possibility that a minority of them died of other causes. These deaths could also be due to PEP failure due to non-standard practice, insufficient RIG dosing, ineffective vaccine or immunocompromised patients. To identify specific causes for PEP failure is beyond the scope of our study, but further work is required to identify potential areas for improving PEP success rates. Investigations could include the effects of source and cold-chain maintenance on vaccine efficacy, determining best-practices for identifying and appropriately monitoring antibody responses in immune deficient patients, and as previously mentioned, compliance with recommended RIG dosing in current medical facilities. We suggest assessing antibody levels after PEP vaccination for patients with documented immunodeficiency, and a booster should be administered if antibody levels drop below 0.5 IU /mL4.

For cases included in this study, the incubation period ranged from 1 month to 5 months after exposure, which is considerably longer than indicated in other studies, with ranges from 1 month to 2 months, and from 3 weeks to 3 months6,13,24. Incubation periods varied according to exposure category, wound type and age group. Category III exposures indicates that the wound is large and deep, resulting in a high viral inoculation loads and subsequently shorter incubation periods6. As the rabies virus is neurotropic, bites in the highly enervated areas of the head, face, neck or hands leads to shorter incubation periods6,13. Children younger than 15 years of age had shorter incubation periods than all other age groups. This could be due to their close interactions with pets (e.g., dogs and cats) while playing with, petting or kissing the animal, leading to higher rates of bites on the head, face, neck, or hand.

Previous studies have suggested that easily clinically distinguishable furious rabies accounts for 66% of all classic rabies cases in general. However, the remaining 33% of cases present as paralytic rabies, whose clinical manifestations are easily misdiagnosed as other diseases, in the absence of laboratory confirmation24. In our study, nearly all of included cases (99%) manifested as furious rabies. Because paralytic rabies has similar manifestations with myelitis and Guillain-Barre syndrome (GBS), and laboratory confirmation rates for rabies is low, patients presenting with paralytic rabies might not be correctly diagnosed by clinicians in China25,26,27. Likely misdiagnosis can lead to an underestimation of the disease burden of rabies in China. Therefore, awareness of symptomology of rabies in clinicians should be improved, so that in the case of a patient presenting with myelitis and/or GBS, clinicians will consider an alternative diagnosis of rabies. In such cases, clinicians should investigate the patient history for the possibility of exposure to a rabid animal bite or scratch, including the often overlooked exposure to bats28.

During the study period, dogs were the main source of human rabies in China, with more than half of cases resulting from bites from domesticated dogs. This reflects similar findings in other countries, including India16 and Indonesia29, where, like China, universal dog rabies vaccination programmes are not in affect. Currently in China, dogs are required to be registered and receive an annual examination, which could cost between 500RMB and 1,000 RMB (75–150 US dollars) in Beijing30. Although dog rabies vaccinations are offered for free in some developed cities (e.g., Hangzhou, Shenzhen), even for unlicensed dogs, in most areas, owners must pay for dog rabies vaccinations annually, costing between 50–80 RMB (7–12 US dollars)31. However, due to the high cost and lack of awareness of dog vaccinations, limited numbers of trained veterinarians, and the existence of a large number of free-roaming dogs, dog vaccination coverage remains far below the 70% needed to interrupt rabies transmission in dogs7,32,33,34,35.

WHO indicates that rabies virus infection in rodents is very uncommon; similarly, 26 cases (0.2%) reported exposure to rodents in our analysis. These cases were clinically diagnosed cases who presented with typical clinical manifestations but were not laboratory confirmed. As such, we could not confirm that rodents caused these human rabies cases. However, rabies virus infection in rodents has been detected by laboratory testing in both the United States and China, and our results suggest that it is possible that exposure to rodents may cause human rabies20,36,37. Further investigation to confirm this transmission route requires confirmation by a detailed case reporting, alongside laboratory evidence in the future.

Our study had several limitations. We collected information on only 66% of all human rabies cases reported through the NIDRIS in China from 2006 to 2012. As such, we were unable to assess whether the exposure characteristics and clinical courses of the cases included in this analysis were representative of all cases. Additionally, if patients died before the case-investigation was completed, or the patient’s health was too compromised to complete the case-investigation, information was obtained from relatives, and therefore certain details about exposure characteristics and PEP were unavailable. Nevertheless, our large sample size and analysis provide critical information for rabies programme directors at the national and local levels in China.

Based on the recommendations of the WHO and experiences of other countries, an integrated intervention strategy including mass dog vaccinations, providing access to human rabies PEP and enhancing community awareness of rabies prevention methods and programmes, is efficacious for the control and elimination of dog-mediated human rabies38. Preventing and controlling rabies has been highlighted in the Long-Term Animal Disease Prevention and Control Plan (2012–2020), issued by the Chinese State Council as a guidance document for related departments. To achieve the goal of controlling and eliminating rabies in China, an integrated intervention strategy modelled on WHO recommendations should be adopted, which will require the collective efforts of multiple sectors, including public health departments, veterinary departments, city management offices, and education departments39.

Despite current national policy guidance in China, most cases did not begin or complete a PEP vaccination series. As such, improving adherence to PEP practices at health care facilities that treat bite wounds from animals should be addressed by rabies intervention campaigns. Additionally, based on our findings, to eliminate dog-mediated human rabies, rabies prevention campaigns targeting males, farmers and person older than 55 years should be conducted alongside general population campaigns. Since dogs, including domesticated dogs, are the primary cause of human rabies, additional approaches to increasing dog vaccinations should also be explored. Finally, in order to strengthen surveillance efforts, and accurately assess the burden of rabies and effectively monitor the impact of rabies intervention programmes, rates of laboratory-confirmation of suspected human rabies cases should be improved.

Methods

Data collection

In 2013, we administered a standard questionnaire to all 31 provinces in mainland China to collect information regarding investigations of human rabies cases with dates of onset between January 1, 2006, and December 31, 2012. The questionnaire collected data on the following: date of exposure, location of exposure, exposure route, exposure category, anatomical site of wound, vaccination history of the animal involved, the patient’s clinical characteristics, wound treatment (time, medical institution, operating steps), PEP vaccination (time, date, kind of vaccine and vaccination series), reasons for failing to complete the PEP vaccination schedule and receipt of RIG. Provincial staff treating rabies were asked to collect paper-based questionnaires in all case investigations, enter relevant data into an EpiData 3.1 dataset, and return the electronic dataset to China CDC.

Data management and analysis

Case-investigation data were imported into SAS 9.3 (Cary, NC, USA) for cleaning and analysis. We removed duplicate records and cases with onset dates outside of the 2006 to 2012 project period. We cross-referenced investigation data with rabies case reported to the NIDRIS; cases that were previously reported to the national surveillance system were retained for our analysis (see Supplementary Fig. S1). Missing data from each record were categorized as “missing”.

Before 2008, the criteria of the rabies diagnosis were unified in the National Rabies Surveillance Program published by the Chinese Ministry of Health in 2005. The criteria indicate human rabies cases were classified as clinically diagnosed cases if a patient had been licked, bitten or scratched by dog, cat or other mammal, with clinical symptoms of a prickling or itching sensation at the site of the bite, progressing within days to agitation, anxiety, confusion, hydrophobia, aerophobia, and paralysis of muscles or cranial nerves. Alternatively, human rabies cases were classified as laboratory-confirmed cases if a person had a clinical diagnosis of rabies and any one of the following: laboratory evidence of rabies infection detected by direct fluorescent antibody test (DFA), reverse-transcriptase polymerase chain reaction (RT-PCR) or rabies virus isolation testing in clinical specimens.

In 2008, these criteria were modified and published as the Standard of Rabies Diagnosis (WS 281-2008) by the National Health and Family Planning Commission of the People’s Republic of China40. Rabies was classified as furious rabies or paralytic rabies based on clinical symptoms. The clinical symptoms of furious rabies were similar to those defined in the criteria before 2008. However, in paralytic rabies, which lacks hyperactivity or hydrophobia, muscles gradually become paralyzed, starting at the site of the bite or scratch, and progress with systemic flaccid paralysis. A clinically diagnosed case of rabies was defined as the occurrence of typical manifestations in a patient with a history of exposure to animals with rabies5. Laboratory-confirmed cases were defined as clinically diagnosed cases with any one of the following: laboratory evidence of rabies infection detected by DFA, RT-PCR or rabies virus isolation testing in clinical specimens. Medical staff categorized wounds according to increasing severity as follows:

Category I - touching or feeding animals, licks on intact skin;

Category II - nibbling on uncovered skin or minor scratches or abrasions without bleeding;

Category III - single or multiple transdermal bites or scratches, licks on broken skin, and contamination of mucous membrane with saliva from licks6.

We verified the variable “Exposure route” to check the exposure category of wound classified by medical staff. Exposures caused by animal bites or scratches but classified as category I by medical staff were reclassified as category “II or III”. Exposures classified as category I by medical staff, but the exposure route was unknown or missing were reclassified as “unknown”. Exposures classified as category II or category III by medical staff were not reclassified (See Supplement Table S1).

We described the demographic characteristics, exposures history, and clinical characteristics of rabies cases as well as the timing and type of PEP initiated. Using cases in exposure category II or above, we performed logistic regression analysis to identify factors associated with failing to begin an appropriate PEP vaccination series. Our independent variables included sex, occupation, area (rural vs. urban) and age group. The dependent variable was dichotomized as a failing to initiate vaccination – yes or no. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Variables statistically significant in the crude univariable analyses were included in the multivariable model.

We also assessed differences in incubation period according to case definition (clinically diagnosed or laboratory-confirmed), exposure category (category II or above), the type of wound (sensitive or other wounds) and age group using T-tests and analysis of variance (general linear model [GLM]). We described the clinical course of infection and outlined reasons for failing to complete the full PEP vaccination series if initiated. An alpha level of 0.05 was used to assess statistical significance.

Ethical approval

Data analysed in this project were obtained through ongoing public health surveillance of a notifiable infectious disease. The National Health and Family Planning Commission, China, determined that the investigation of human rabies cases was part of a continuing public health surveillance activity and was exempt from institutional ethical review board assessment. The project was also determined to be a routine public health surveillance activity, in accordance with human subjects’ protection procedures of the United States CDC (CGH #2015-238). All analysed data were anonymized and thus did not include any personal identifying information.

Data Availability

The data that support the findings of this study are available from China CDC but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are, however, available from the authors upon reasonable request and with permission of China CDC.

References

  1. 1.

    What is rabies. http://www.who.int/rabies/about/en/ (2016).

  2. 2.

    Singh, R. et al. Rabies - epidemiology, pathogenesis, public health concerns and advances in diagnosis and control: a comprehensive review. Vet Q 37, 212–251 (2017).

    Article  Google Scholar 

  3. 3.

    Hampson, K. et al. Estimating the global burden of endemic canine rabies. PLoS Negl Trop Dis 9, e0003709 (2015).

    Article  Google Scholar 

  4. 4.

    WHO Expert Consultation on Rabies. (Geneva 2013).

  5. 5.

    Zhou, H. et al. Human Rabies in China, 1960-2014: A Descriptive Epidemiological Study. PLoS Negl Trop Dis 10, e0004874 (2016).

    Article  Google Scholar 

  6. 6.

    Ugolini, G. Rabies virus as a transneuronal tracer of neuronal connections. Advances in virus research 79, 165–202 (2011).

    CAS  Article  Google Scholar 

  7. 7.

    Hu, R. L., Fooks, A. R., Zhang, S. F., Liu, Y. & Zhang, F. Inferior rabies vaccine quality and low immunization coverage in dogs (Canis familiaris) in China. Epidemiology and infection 136, 1556–1563 (2008).

    CAS  Article  Google Scholar 

  8. 8.

    Bai, M. et al. Case report of the first rabies-related death in Tibet. Chin J Vector Biol & Control 27, 528 (2016).

    Google Scholar 

  9. 9.

    Song, M. et al. Human rabies surveillance and control in China, 2005–2012. BMC infectious diseases 14, 212 (2014).

    Article  Google Scholar 

  10. 10.

    Ren, J. et al. Human rabies in Zhejiang Province, China. International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 38, 77–82 (2015).

    Article  Google Scholar 

  11. 11.

    Ma, C. et al. Re-emerging of rabies in Shaanxi Province, China, 2009 to 2015. Journal of medical virology (2017).

  12. 12.

    Li, G. et al. Epidemiological characteristics of human rabies in Henan province in China from 2005 to 2013. The journal of venomous animals and toxins including tropical diseases 21, 34 (2015).

    ADS  Article  Google Scholar 

  13. 13.

    Hemachudha, T., Laothamatas, J. & Rupprecht, C. E. Human rabies: a disease of complex neuropathogenetic mechanisms and diagnostic challenges. Lancet Neurol 1, 101–109 (2002).

    Article  Google Scholar 

  14. 14.

    Ou, Z., Shi, C. & Luo, Y. Epidemiological Analysis on the out-patients of Rabies Admitted from CDC Clinic of Chengdu. Modern Preventive Medicine 39, 5404–5406 (2012).

    Google Scholar 

  15. 15.

    Zhou, H., Li, Y., Chen, R. & Tao, X. Technical Guidelined for Human Rabies Prevention and Control (2016). Chinese Journal of Epidemiology 37, 139–163 (2016).

    PubMed  Google Scholar 

  16. 16.

    Sudarshan, M. K. et al. Assessing the burden of human rabies in India: results of a national multi-center epidemiological survey. International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 11, 29–35 (2007).

    CAS  Article  Google Scholar 

  17. 17.

    Dimaano, E. M., Scholand, S. J., Alera, M. T. & Belandres, D. B. Clinical and epidemiological features of human rabies cases in the Philippines: a review from 1987 to 2006. International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 15, e495–499 (2011).

    Article  Google Scholar 

  18. 18.

    Goswami, A. et al. The real cost of rabies post-exposure treatments. Vaccine 23, 2970–2976 (2005).

    Article  Google Scholar 

  19. 19.

    Wang, C., Zhang, X. & Yu, Y. Study on the compliance and economic cost of rabies vaccination. Zhongguo yi miao he mian yi 16, 254–257 (2010).

    PubMed  Google Scholar 

  20. 20.

    Rabies vaccines: WHO position paper– April 2018. Wkly Epidemiol Rec 93, 201–220 (2018).

  21. 21.

    W, H. Research on the geographical distribution equity of China’s health resources-Based on the integrated use of two indicators Master thesis, Fudan University (2011).

  22. 22.

    Miao, Y. Accessibility to Healthcare Resources and Farmers’ Health: Evidence from Rural China. Chinese Journal of Population Science, 47–55 (2008).

  23. 23.

    Zhao, N., Wang, S., Mi, L. & C., S. In Chinese Veterinary Public Health Association second seminar. (Nanjing 2010).

  24. 24.

    Hemachudha, T. et al. Human rabies: neuropathogenesis, diagnosis, and management. Lancet Neurol 12, 498–513 (2013).

    Article  Google Scholar 

  25. 25.

    Vaish, A. K., Jain, N., Gupta, L. K. & Verma, S. K. Atypical rabies with MRI findings: clue to the diagnosis. BMJ case reports 2011 (2011).

    Google Scholar 

  26. 26.

    Ghosh, J. B., Roy, M., Lahiri, K., Bala, A. K. & Roy, M. Acute flaccid paralysis due to rabies. Journal of pediatric neurosciences 4, 33–35 (2009).

    CAS  Article  Google Scholar 

  27. 27.

    Desai, R. V., Jain, V., Singh, P., Singhi, S. & Radotra, B. D. Radiculomyelitic rabies: can MR imaging help? AJNR. American journal of neuroradiology 23, 632–634 (2002).

    PubMed  Google Scholar 

  28. 28.

    De Serres, G., Dallaire, F., Cote, M. & Skowronski, D. M. Bat rabies in the United States and Canada from 1950 through 2007: human cases with and without bat contact. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 46, 1329-1337 (2008).

    Article  Google Scholar 

  29. 29.

    Putra, A. A. et al. Response to a rabies epidemic, Bali, Indonesia, 2008–2011. Emerging infectious diseases 19, 648–651 (2013).

    Article  Google Scholar 

  30. 30.

    Xia, Y. & Sun, L. Discussion about the dog managment In the domestic and overseas. Shanghai Journal of Animal Husbandry and Veterinary Medicine, 47949 (2005).

  31. 31.

    Sun, B. Market survey on rabies vaccine for veterinary in China. China Health Care & Nutrition 22, 5370–5371 (2012).

    Google Scholar 

  32. 32.

    Luo, Y. et al. Complete genome sequence of a highly virulent rabies virus isolated from a rabid pig in south China. Journal of virology 86, 12454–12455 (2012).

    CAS  Article  Google Scholar 

  33. 33.

    Xiong, C., Shao, Z., Hang, Z., Chang, W. & Sun, J. Survey of rabies virus carried by domestic dogs in different endemic areas rabies in China. China Tropical Medicine 8, 364–366 (2008).

    CAS  Google Scholar 

  34. 34.

    Conan, A. et al. Population dynamics of 0wned, free-roaming dogs: implications for rabies control. PLoS Negl Trop Dis 9, e0004177 (2015).

    Article  Google Scholar 

  35. 35.

    Rabies. http://www.wpro.who.int/china/mediacentre/factsheets/rabies/en/ (2016).

  36. 36.

    Lei, Y. et al. New animal hosts of rabies virus in mountain areas in Zhejiang Province. Zhonghua Liu Xing Bing Xue Za Zhi, 349–351 (2009).

  37. 37.

    Fitzpatrick, J. L., Dyer, J. L., Blanton, J. D., Kuzmin, I. V. & Rupprecht, C. E. Rabies in rodents and lagomorphs in the United States, 1995–2010. J Am Vet Med Assoc 245, 333–337 (2014).

    Article  Google Scholar 

  38. 38.

    WHO report on intradermal application of rabies vaccines. Revista panamericana de salud publica=Pan American journal of public health 1, 73–77 (1997).

  39. 39.

    Chen, Y., Tian, J. & Chen, J. L. Challenges to eliminate rabies virus infection in China by 2020. The Lancet. Infectious diseases 17, 135–136 (2017).

    Article  Google Scholar 

  40. 40.

    Ogundare, E. O. et al. Pattern and outcome of dog bite injuries among children in Ado-Ekiti, Southwest Nigeria. The Pan African medical journal 27, 81 (2017).

    Article  Google Scholar 

Download references

Acknowledgements

We thank staff members at the hospitals, local health departments, and county-, district-, prefecture-, and province-level Chinese Centers for Disease Control and Prevention for providing assistance with field investigations, administration, and data collection. We also thank Dr. Jeanette J. Rainey and Dr. Brett W. Petersen from the United States Centers for Disease Control for their critical review of this manuscript. This study was funded by the National Science Fund for Distinguished Young Scholars of China (No. 81525023), National Science and Technology Major Project (Grant No.2018ZX10713001), and cooperative agreement (No. 5U2GGH000961) provided through the United State CDC-China Collaborative Program on Emerging and Re-emerging Infectious Diseases. S.L. is supported by the grants from the National Natural Science Fund (No. 81773498), the Ministry of Science and Technology of China (2016ZX10004222-009), and the Program of Shanghai Academic/Technology Research Leader (No. 18XD1400300). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of China CDC or US CDC.

Author information

Affiliations

Authors

Contributions

S.N. and H.Y. supervised the study. H.Y., Y.L., and W.Y. conceived the study. Y.L., D.M., Y.H., C.Y.R., S.L. and C.G. undertook data collection and cleaning. C.G. analyzed and interpreted the data. C.G. and Y.L. drafted the manuscript. Y.H., S.L., S.N. and H.Y. critically revised the manuscript. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Hongjie Yu or Shaofa Nie.

Ethics declarations

Competing Interests

H.Y. has received investigator-initiated research funding from Sanofi Pasteur, GlaxoSmithKline, bioMérieux Diagnostic Product (Shanghai), and Yichang HEC Changjiang Pharmaceutical Company. The other authors declare no potential conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Guo, C., Li, Y., Huai, Y. et al. Exposure history, post-exposure prophylaxis use, and clinical characteristics of human rabies cases in China, 2006–2012. Sci Rep 8, 17188 (2018). https://doi.org/10.1038/s41598-018-35158-0

Download citation

Keywords

  • Human Rabies Cases
  • Cases Investigators
  • Free-roaming Dogs
  • Rabies Prevention
  • Median Incubation Period

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing