Spontaneous Rabies in a Stray Bitch after Parturition Induced Immunosuppression —Investigating an Impending Outbreak of Rabies with One Health Approach

Background: Rabies is endemic in India and every half an hour a person dies of this dreaded disease. Stray roaming dogs, mostly unvaccinated, are most dangerous host in spread of rabies in India and in our state of Himachal Pradesh. Timely prophylaxis is the only method to save animal bite victims, including that of rabid dog bite patients. Objectives: Objective of this study was to investigate an impending outbreak of rabies in Shimla town in the absence of life saving rabies immunoglobulins (RIGs) in the market, and to know the source of infection by using one health approach and using epidemiological tools. Methods: On April 7, 2015, there was a sudden surge in cases of suspected rabid dog bites. Impending rabies outbreak was suspected as there were no RIGs available in the market. A rapid Response Team (RRT) consisting of the author, veterinary doctor, dog squad of Municipal Corporation (MC) Shimla along with the vehicles to impound rabid dogs was constituted to investigate the terror spread by two rabid dogs on biting spree in the Shimla Municipality. Results: A total of 18 people were bitten by suspected rabid dogs within three days period. A black bitch and a brown dog, on the identity of affected people, were captured by the dog squad of Municipality next day on April 8, 2015 and taken to Dog Sterilization Centre, Animal Birth Control (ABC) programme, MC Shimla for observation. The most furious Black bitch died of clinically confirmed symptoms of furious rabies after three days. The second rabid dog, brown in color, died after a month of observation due to paralytic dumb rabies. The brain of the brown dog was extracted for Fluorescent Antibody Testing (FAT) at central research Institute (CRI) Kasauli and was found to be positive for FAT. Follow up of patients was 100% by house to house visit and over telephone and no casualty was reported. Conclusion: While we were working on hypothesis of rabid dogs getting the infection from nearby forest about 8 - 10 KM away but on follow up of the patients, they reported that both the dog and bitch used to stay in the compound of their colony since the bitch was pregnant and there was no history of the bitch moving for away to forests neither any outside dog which was seen near them in the compound. This led us to think of other causes of what must had happened to the bitch that caused her to be rabid as for the past 9 years we had observed bitches becoming rabid after litter birth (Whelping) and making their pups rabid due to licking. Since the carrier state for rabies virus in bitches/dogs is known and a state of immunosuppression after whelping/parturition is also known, therefore there is a possibility of latent rabies virus getting activated due to immunosuppression after litter birth and it is thought to be as one of the probable causes of black bitch getting rabid and inflicting the infection to accompanying brown dog. We need to do further studies to ascertain this phenomenon before coming to a definite conclusion and suspect such a possibility in case a dam suddenly becomes rabid among a pack of stray dogs in rabies endemic countries like ours.

Pup Vaccination Practices in India Leave People to the Risk of Rabies — Lessons from Investigation of Rabies Deaths Due to Scratch/Bite by Pups in Remote Hilly Villages of Himachal Pradesh, India

Rabies, a zoonotic disease, kills 55,000 persons every year globally and 20,000 persons in India. Two years back, we learnt of two deaths due to Rabies in remote village Shiv Shankar Garh of Arki block of District Solan and decided to investigate the deaths. Method: A rapid response team was constituted to investigate the deaths. We interviewed the villagers & family to conduct verbal autopsy. A line list of entire population of village and household contacts of the patients, who died, were made along with the line list of dogs and cattle. Results & Discussion: A-month-old stray pup brought home by the family and had caused an abrasion with its toes on the hands of both the deceased on June 2, 2011 while playing. The lady developed paralysis of the arm on July 3, 2011 and 3 days later developed symptoms of hydrophobia. She died on July 9, 2011. Her son had developed hydrophobia 10 days after that and died on July 19, 2011. Assumption that bite or abrasion by a small pup of one month cannot be fatal proved otherwise. Lack of awareness regarding the fatality of even a scratch and lack of knowledge regarding local treatment of the wound & vaccination of both human and pups, were the main reasons for the deaths. While such incidents keep on happening, and the veterinarians in India are refusing to vaccinate pups before three months of age, as pups may not develop immunity before that age, leaving unsuspecting people to the risk of rabies. Conclusions: Humans can be exposed to rabies even by pups below 3 months of age. Recommendation: Pup vaccination schedule in rabies endemic countries like India need revision. Veterinarians and public health experts need to strongly consider vaccinating pups at first contact with humans even if they are less than 3 months of age. A booster to the pup can be given at three months of age with subsequent yearly boosters.

Immunizing Vulnerable Populations Like Rag Pickers, Garbage Collectors, Municipality Workers and Newspaper Hawkers against Rabies in Shimla Municipality, HP, India

Background: Rabies is a zoonotic disease and many vulnerable sections like rag pickers and municipality workers neglect animal bites due to ignorance of their potential deadly outcomes. Stray dogs abound in garbage pits and this population is exposed to their attacks. It should be a mandate for municipalities to help protect their sanitary workforce, especially rag pickers, from deadly infectious diseases such as Rabies, Hepatitis-B, HIV, Tetanus etc. Objectives: Objective of this study was to study methods to provide pre-exposure Rabies vaccination for such highly exposed populations by engaging them and understanding their perception of this disease through a constant dialogue with them. Methods: We started by engaging with the rag pickers to know how best to entice them to get themselves immunized. We then attempted to search literature for the most practical methods likely to succeed in reducing risk of rabies deaths in this population. Results: WHO approved 3 injections of 0.1 ml tissue culture vaccine on days 0, 7 and 21 were tried but were shown to result in many dropouts among rag pickers for repeat injections. We then followed a method where 0.1 ml of rabies vaccine was injected at 4 different anatomical sited in one setting. This proved acceptable and relatively inexpensive. A small number of subjects were studied by determination of neutralizing antibody by RFFIT, which proved immunogenic having anamnestic response on boosters given single IM or at 4 sites ID subsequently, implying that short schedule rabies pre-exposure vaccination can be done in high risk groups and may save lives if applied to the poorest that are highly exposed.

Exploring the Feasibility of a New Low Cost Intra-Dermal Pre &Post Exposure Rabies Prophylaxis Protocol in Domestic Bovine in Jawali Veterinary Hospital, District Kangra, Himachal Pradesh, India

Cattle are the backbone of household economy in rural areas of India and many of them die after bites by potentially rabid dogs, despite being given currently recommended five shots of intramuscular (IM) rabies vaccination as Post Exposure Prophylaxis (PEP). In 2016, seven of 21 bovine bitten by rabid dogs given IM rabies vaccination died due to rabies in Shimla Municipality. This scenario prompted the authors to look for a suitable protocol, based on human studies, to save animals. We tested various schedules of IDRV in bovine and found that a schedule of 0.2 ml given in middle 1/3rd of neck on day 0, 3, 7, 14 and 28 along with local wound infiltration of eRIG is sufficiently immunogenic and life saving in all of them, even if bitten by lab confirmed rabid dogs/mongoose as tested by CRI. Rabivac Vet, a Cell Culture Rabies Vaccine, available as 1 ml per vial was used off level for IDRV. While injecting the vaccine, a raised papule of ≥1 cm will appear slowly causing a peau d’orange appearance. All 60 bovine serum samples tested by RFFIT after IDRV, had titers more than 0.5 IU/ml on day 14. Thereafter, a total of 150 animals were given five doses of IDRV as PEP, with or without RIG, after their exposure to clinically or lab confirmed rabid dogs/mongoose and all survived for more than a year. Serum samples from 15 animals bitten by lab confirmed rabid dogs/mongoose were collected on day 14 and tested for RVNA by RFFIT from NIMHANS Bangalore and all had desired antibody titers above 0.5 IU/ml, without any immunosuppression. The RFFIT titers in 55% bovine in all groups were more than adequate after one year and 100% of them had anamnestic response to a single 0.2 ml booster given at one year. Few of the bovine and even one equine (Horse. Figure 4) brought for PEP at some of nearby vet hospitals were given IM rabies vaccine with local eRIG infiltration also survived. Local eRIG infiltration appeared to have covered the lacuna of longer window period required for indigenous antibodies production through IM route in bovine that are not sufficiently produced by day 14. While five times less vaccine was used in this low cost protocol and the survival was 100% compared to traditional IM protocol where survival was 66%. Pre-exposure prophylaxis was found to be effective as 0.2 ml dose of IDRV on day 0, 3, 7 and all bovine had titers higher than the desired by day seven after single 0.2 ml vaccine booster at one year. Our study points towards a possibility of having short schedules of three shots IDRV vaccination in bovine with or without local RIG (depending on presence or absence of wound/s) as PEP and single shot IDRV as PrEP, but further studies are required on a large number of animals. Our study also points out for allowing intra-dermal use in animals as well and labeling vaccines for the same as this is low cost more immunogenic and less painful compare to IM administration.

High Immunization Coverage but Delayed Immunization Reflects Gaps in Health Management Information System (HMIS) in District Kangra, Himachal Pradesh, India—An Immunization Evaluation

Background: Complete and timely childhood immunization is one of the most cost-effective interventions in improving child survival in developing countries. Computerized HMIS has been recently introduced to collect aggregated data on service beneficiaries in Himachal Pradesh. HMIS provides coverage estimates for immunization while information on timeliness is currently not available. Hence we conducted a study to validate coverage and assess the timeliness of immunization in Kangra District of Himachal Pradesh. We surveyed mothers (224) of children aged 12 - 23 months (as on January 2008) and selected 32 clusters in the district between January and March 2008. Design/Methods: We conducted a cross sectional survey and selected 32 clusters by probability proportional to size method whereas seven eligible children per cluster were randomly selected. We interviewed mothers using a structured interview schedule, examined immunization card & looked for Bacillus Calmette Guierre (BCG) Scar. Vaccination after 30 days from national schedule was considered “delayed”. We computed proportions of children completely immunized, immunization delayed, frequency of reasons for delay and 95% Confidence Interval (CI) for significance of associated factors. We conducted a case control analysis of factors associated with timely immunization by taking timely immunized children as cases and delayed immunized ones as controls. Results/Outcome: Reported coverage was universal (100%). Validated full immunization coverage was 94.2% by card/record & 99% by history. Only 29.5% (CI = 20.6% - 37.4%) of children were fully immunized as per schedule (delay less than 30 days). Median delay was 21 days for BCG, 28 days for Diptheria Pertussis Tetanus (DPT 3) and 25 days for measles. Among those with delayed vaccinations, reasons were forgetfulness (36%), lack of correct knowledge (27%) & mother gone to parents’ home (27%) & insufficient children in a camp to open full dose BCG vial (22%). Our case control analysis of timely vaccinated versus delayed vaccination revealed that “precall” (reminder) was significantly [OR = 0.1, CI = 0.2 - 0.5] protective against delayed vaccination. Logistic Regression of delay > 30 days revealed that having returned unimmunized from immunization camp earlier due to insufficient children to open vaccine vial (because of high wastage factor) was significantly associated with delayed immunization (p = 0.0000), while knowledge of date of immunization camp was significantly protective from delayed immunization (p = 0.0026). 68% of the children were having at least one immunization delayed over 30 days from recommended schedule, while the proportion of children whose immunization was delayed by over 90 days was 9.4%. Conclusions: Validated field coverage estimates are lower than reported which can be due to inclusion of children of migrants in numerator & not in the denominator. High proportion of children (>70%) were delayed, suggesting implications for WHO’s strategy of measles control & national Tuberculosis (TB) control programmes, as 4.5% of them had suffered from measles. To avoid delays we recommend (i) use of mono dose vials for BCG;(ii) precall notice to mothers;(iii) modification of HMIS software to track immunization status and timeliness of individual beneficiaries rather than aggregate numbers.

Can Non-Polio Enteroviruses Be Tamed with a Vaccine to Minimize Paralysis Caused by Them?

Background: While we are inching towards global eradication of polio, the paralysis due to non-polio viruses (NPEV) poses greater challenge. Factors responsible for causing Acute Flaccid Paralysis (AFP) were studied in 3596 AFP patients in 64 districts of Uttar-Pradesh, India, to observe indirect relationship of AFP with wild polio as well as NPEV. A recent study suggests the need to investigate polio virus negative but NPEV positive AFP cases. Methods: The lab results of the stool samples of these children were line listed and analysed to observe the association of various factors with respect to presence of paralysis on 60 follow-up days. Taking zero OPV dose AFP cases as a biological base, we studied the relationship of presence of paralysis at 60 follow-up days to that of presence of NPEV in stool samples while polio virus was present or absent. Results: 70 of the 86 AFP cases (81%) with zero OPV dose and having only NPEV isolated in stool samples were having paralysis at 60 follow-up days. There were 4.54% (162) AFP cases, which did not carry any polio virus but were having NPEV isolated in the stool samples and paralysis at 60 follow-up days. 79% (75/95) of zero OPV dose children, who were having residual weakness at 60 follow-up days, were carrying both polio virus as well as NPEV in their stool samples. Total AFP cases, having residual weakness at 60 follow-up days and having NPEV in stool samples, decreased with increase in OPV doses;a behavior similar to what wild polio viruses (WPV) have to OPV. Conclusions: Maybe polio like NPEV is active for causing severe paralysis in children and is responding to the OPV. As is evident in the studies by M. Margalith, B. Fattal et al. [1] that there is an antibody response to the enteroviruses, we can think of coming out with a vaccine against the enteroviruses. Therefore, enterovirus vaccine can be produced on similar lines to that of OPV, as now we have enough isolates of NPEV. Effective NPEV surveillance system also needs to be in place.

Success Story of a Low Cost Intra-Dermal Rabies Vaccination (IDRV) Clinic-Lessons Learnt over Five Years of 12,000 Patient Vaccinations “Without Failure” at DDU Hospital Shimla, Himachal Pradesh, India <br/>—“Saving a Drop of Rabies Vaccine and Immunoglobulins” 12 Innovations to Make Himachal Pradesh Rabies Free State by 2020

Background: Rabies is a dreaded disease and an estimated 55,000 people die of rabies every year. Himachal Pradesh is in the North bordering China and is predominantly rural and hilly. Villages are near forests, where wild reservoirs of rabies exist. Since health facilities are not accessible easily, we need to innovate on existing schedules of rabies vaccination keeping in view the compliance of the patients and affordability so as to give them the best possible option of treatment. In the year 2006 and 2007, we, at DDU Hospital Shimla, experienced a severe shortage of rabies vaccine and patients were running from pillar to post to fetch rabies vaccine. At the same time, we learnt that some of the patients died because either they were not able to purchase the vaccine, mostly because of its high cost, $35, or they ignored the animal bites and did not seek the treatment. Since last year, we have been experiencing non-availability of rabies immunoglobulins (RIGs) in the market and have to innovate new schedules and techniques to save lives of the patients. Methods: During shortage of rabies vaccine in 2008, we contemplated to start a low cost intra-dermal (ID) clinic so as to make rabies vaccine affordable as intramuscular (IM) vaccination cost five times more than ID vaccination. But, there were three main hurdles. One hurdle was the non-availability of rabies vaccine vials having written on them “For IM/ID use” and another hurdle was only fewer animal bite patients attending the DDU Hospital, sometimes only one or two per day, which was insufficient to open a vaccine vial and distribute among them. The third problem being faced was reluctance of the hospital doctors to prescribe ID vaccine as this was not the practice at higher teaching institutions, including medical colleges. We contacted a vaccine company and few vials labeled as “For IM/ID use” were sourced from Mumbai (1200 km away from here). We asked the Chief Medical Officer, Shimla district to write a letter to all health facilities around our Hospital to give first aid to animal bite patients and then refer them to DDU Hospital for vaccination. Now we were able to pool the patients and divide a single 1 ml vaccine vial among four patients. After continuous advocacy, our stress that WHO has given its approval for ID use of rabies vaccine and that subsequent approval has been granted by Government of India was enough for doctors to prescribe the vaccine as ID. Last Year, we got ethical approval to inject rabies Immunoglobulins (RIGs) only locally in and around the wound at times of scarcity of RIGs in the market. The subsequent follow up of patients proved life saving in crisis of shortage of RIGs. Due to shortage of RIGs we innovatively vaccinated people bitten by rabid dogs or people who had consumed rabid cow’s milk and followed them for outcome, apart from having Rabies Fluorescent Focus Inhibition Test (RFFIT) was done for few of the patiens for verification of protective titers. We innovated a technique of extraction of last drop of vaccine from the vial and also saved a drop of RIGs being used for test dose before giving RIGs to the patients. Results: The first low cost anti-rabies clinic was started on August 2, 2008 after long advocacy sessions with the authorities and the doctors. Since then, we have done many innovations based on local requirements and patients’ feedback and accessibility to treatment. We have given pre and post-exposure prophylaxis to more than 12,000 animal bite victims over more than five years period in this single clinic, saving lives as well as money without any failure even in difficult rabid animal bite cases. Our innovation helped us save the vaccine and immunoglobulins till the last drop. Conclusions: Innovative ways by health providers backed by extensive literature review and scientific evidence can help patients get low cost health deliverables that increase their compliance as medicines/vaccines become affordable to them. Third world countries need to innovate their own ways to solve their problems of scanty resources and find innovative solutions to conquer them, rather than looking elsewhere for solutions.