Announcements Open Letter: Stop the war on Syria’s hospitals

CASE STUDY

Using a modified rabies immunoglobulin protocol in a crisis of unavailability: Ethical and practical challenges

Omesh Kumar Bharti

DOI: https://doi.org/10.20529/IJME.2019.022


Abstract

Rabies is a dreaded disease of zoonotic origin, responsible for an estimated 55,000 deaths annually, of which 20,000 deaths are in India. Some animal bite patients need rabies immunoglobulin (RIG) for post exposure prophylaxis, in addition to the vaccine against rabies. The major reason for the high death rate in India is the high cost of RIG. Until 2017, the WHO-recommended protocol required a large amount of RIG. I describe how a cost-saving protocol for RIG was implemented in Himachal Pradesh. The published results contributed to the modification of the WHO’s global recommendations on RIG use.

Background

Rabies is a disease caused by the bite of a rabid animal. An estimated 55,000 people die a painful death due to rabies every year, out of which 20,000 deaths are reported from India alone (1). The annual cost of medicines for animal bite treatment in India was estimated in 2003 at Rs 2 billion (2).

According to the World Health Organisation’s classification of animal bite wounds, intact skin if licked by rabid animals is called a Type-I bite and does not pose any threat of rabies, and requires only washing with soap and water. Bites that breach the skin surface but do not bleed are known as Type-II wounds and require only vaccination for protection after thorough wound wash with soap and water and application of antiseptic. Wounds that bleed are known as Type-III bites. In the case of Type III wounds, WHO advocates administration of the rabies vaccine along with additional injection of rabies immunoglobulin (RIG) into the wound/s to neutralise any virus present in the surface of the wound.

Until recently, WHO recommendations required injection of a certain quantity of RIG, according to the patient’s weight (3). In this report, I describe how a modified protocol was implemented in Himachal Pradesh, that contributed to modification of the WHO’s global recommendations on RIG use.

The main reason for the high rabies death rate in India has been the high cost of the rabies vaccine and RIG. Over seventy percent of patients in the state of Himachal Pradesh, where I work, use government health services. However, for a long time, the rabies vaccine was not available free to everyone in government hospitals, due to its high cost. Patients were forced to purchase it from private chemist shops. Only very poor patients were given the vaccine free.

The rabies vaccine can be given by either the intra-dermal (ID) or intramuscular (IM) route. ID administration needs one-fifth of the vaccine volume compared to when given IM, and has the same or superior efficacy. Though the WHO has, since 1992, endorsed ID administration (4), the Government of India, until 2006, continued with IM administration (5) , requiring a larger quantity of the vaccine, and this led to frequent stockouts of the vaccine.

I joined the Himachal Pradesh government health services in 1993.In 2000, I joined the state government-run Deen Dayal Upadhyaya (DDU) Hospital in the state capital of Shimla. I am a member of the Jan Swasthya Abhiyan, a network of health advocacy groups campaigning for the right to healthcare for poor patients. Our efforts contributed to the state government’s switch to ID administration of the vaccine, making it affordable (6). It is now given free by the Himachal Government, thereby saving many lives.

However, deaths due to rabies were still being reported. The high cost of RIG, which is required for Type III bites, made it unaffordable for patients, and it was not routinely stocked in all government services.

While the dose of the rabies vaccine is fixed, the dose of RIG is calculated based on the patient’s body weight. The WHO’s 2010 position paper on rabies vaccines (1) prescribed that all the RIG as calculated by body weight formula (40 IU/kg for eRIG), or as much as anatomically possible (to avoid compartment syndrome ie excess dose injection causing pressure on the arteries, blocking them and causing necrosis of the organ), should be administered into or around the wound site/s; the remaining RIG, if any, should be injected IM at a site distant from the site of vaccine administration. The estimated cost of treatment for a patient weighing 60 kg was Rs 1,200 with equine RIG and Rs 30,000 with human RIG (7).

In 2009, a 38-year-old woman died of rabies due to a dog bite in Theog block of Shimla district. As a medical professional with a knowledge of rabies epidemiology, I was asked by the government to enquire into the matter. I learnt that the victim was well-off and could have afforded the cost of treatment. She had taken the full course of vaccination, but RIG was not administered as it was not available in the Civil Hospital at Theog or in private chemist shops there. Though RIG is on the essential drugs list, because of its high cost it was stocked only in district hospitals and medical colleges. Fear of anaphylactic reaction with cheaper equine RIG further discouraged its stocking at lower level health facilities. And private chemists did not stock RIG because few patients could afford to buy it, and chemists lost money when stocks remained unsold past the expiry date. If a medicine is not widely used, chemists tend not to stock it and it becomes unavailable for even those who can afford it.

It was this crisis that led me to discuss with my colleagues and rabies specialists in the country whether anything could be done to bring down the cost of RIG use, as had been done for the vaccine, so that it would reach the poor.

As I went through the literature for low-cost solutions to this problem, I found papers including animal studies, suggesting that injecting RIG into the wound would be sufficient to neutralise the virus, and there was no additional benefit in giving it IM; as well as papers reporting that RIG alone, when administered IM in the recommended dose, was almost undetectable in the blood (8),(9), (10), (11), (12), (13). It was evident that giving the excess RIG in an IM injection was a waste of an expensive biological, and omitting it would reduce the dose, bringing costs per patient down and making the immunoglobulin available for more patients, as it is always in short supply in the market. I was particularly influenced by a commentary by David C Anderson (14) which argued against the WHO guidelines of the time.

However, conclusive evidence from human studies of the impact of local wound infiltration without additional IM was not available. No one was ready to use this protocol as it could have been construed as a violation of WHO guidelines. If a patient given RIG wound infiltration alone died of rabies, the doctor could be held liable in a court of law.

While reading these papers, we were faced with a new crisis. In 2014, there was a complete stockout of RIG in India. Panic grew over the deaths due to rabies, where the vaccine was given but RIG was not available. I discussed the matter with the then senior medical superintendent, in May 2014, Dr PL Gaunta. We held a consultation for DDU Hospital doctors, where the issue was deliberated upon. I presented what we knew from the literature on the use of local wound infiltration of RIG. The meeting ended with the decision to use wound infiltration alone in the crisis of non-availability, after completing the necessary formalities. We apprised the then Director, Health and Family Welfare, Dr DS Gurung, of the situation, and were told to consult experts before starting the intervention.

How did we dare to use a protocol that went against WHO recommendations? Well, the alternative was to do nothing. Patients could not procure eRIG anywhere in North India, even if they could afford it. And we did not have enough eRIG to follow the WHO procedure (which used up to 10 ml of eRIG per patient – compared to what turned out to be an average of 1.26 ml with the new protocol). We felt that our intervention with this modified protocol would put patients at minimum risk and, in this situation, it was the only option to save lives.

This was not a study; it was a clinical intervention to save people’s lives. But it generated evidence that had not been collected anywhere in the world and has contributed to saving the lives of many more people around the world.

Ethical and practical barriers

Before starting the intervention, as advised by our seniors, approval was sought from an institutional ethics committee (IEC). The state government’s Department of Health and Family Welfare does not have an IEC, so research institutions in the area were approached. We found that IECs of medical colleges in Himachal do not review projects unless the principal investigator (PI) is from the college, and no one from any of these colleges was ready to be PI in this study. We were informed, verbally, that no one was ready to take up this protocol for fear of the legal consequences in case the protocol failed.

After much searching, we found a friend, a member of the IEC of Jaypee University of Information Technology, who agreed to discuss the protocol in the IEC meeting. But the IEC asked for written technical clearance of the study’s feasibility from a reputed institution or expert working on rabies. This put us in a quandary. We found that rabies experts were reluctant to go against the recommendations of the WHO. During a number of informal interactions, we asked these experts to carry out the study themselves since they had the necessary facilities, but found that they feared an adverse outcome. At the same time, they did not offer any solution to the problem of unavailability of RIG and consequent rabies deaths as observed in Himachal. After approaching many experts, I was eventually rewarded when I met Dr SN Madhusudana, an eminent neurovirologist and expert on rabies, from the National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru. NIMHANS is also a WHO Collaborating Centre for Reference and Research in Rabies. Dr Madhusudana, who was the main author of one of the papers on animal studies advocating this modified protocol (13), wrote me a letter testifying to the scientific rationale of our protocol: “This study will show us the way to manage the patients with severe dog bites but who cannot afford full course of expensive rabies immunoglobulins. Please go ahead with the study and you have my full support for laboratory investigations as and when required.” (Madhusudana SN. Letter to author, dated May 13, 2014) Above all, he also offered to do free testing of human blood samples for antibody titres.

After I made a presentation and submitted the letter of technical clearance from NIMHANS, clearance was obtained from the IEC of Jaypee University in a meeting (IEC Project No 11-2014, approval dated May 23, 2014).

From June 2014, with the approval of the hospital’s senior medical superintendent, we started implementing the new protocol for all patients attending our anti-rabies clinic in DDU Hospital, Shimla. We would take informed consent from the patient or, if the patient was a minor, from the guardian. The consent form to be signed by patients included the following statements:

As discussed with the treating physician, I cannot afford the full calculated dose of immunoglobulins. Since I am told that at least local infiltration of immunoglobulin can minimize the risk of getting rabies, [emphasis in original] I agree to purchase a minimum volume of RIG required for local wound treatment. I would keep a watch on the animal that had bitten me and in case of the death of the animal, I would immediately inform the hospital of the same as in such circumstances the hospital agrees to provide the booster dose of vaccine free of cost. If animal dies within 10 days of initiation of vaccination, and local infiltration of RIGs, I am fully responsible for the delay in seeking treatment. … I know that if I still do not want to get included in this low dose immunoglobulin methodology, I can still opt out.

A lawyer, who had first gone to a private hospital for suspected rabid dog bite management where he could not get RIG and was referred to our clinic, refused to sign the consent form. He was told to procure RIG himself if he wished it to be administered as per WHO norms. When he found he could not obtain it anywhere in North India, he gave his consent, but unwillingly, threatening to sue us in case of any mishap. This incident brought home to us the risks we faced, but we decided to continue in the interest of saving patients’ lives.

From May 2014 to May 2015, more than 2,000 bite patients were treated in our hospital using this protocol. Each patient’s consent was taken along with his/her address and telephone number, and each was followed up regularly. If the biting animal was known, it too was followed up. However, many dogs could not be traced or tested for rabies. A subgroup of 26 of our patients who were bitten by lab-confirmed rabid dogs were followed for more than a year and all were found to be healthy.

In the meantime, we received the report of a man who had been badly bitten by a suspected rabid dog and was given all four doses of rabies vaccine (as recommended by WHO) but was not given eRIG, as it was not available in the market. We were informed that he had developed rabies and succumbed to it. In another case, a village woman and her daughter who were bitten by a suspected rabid dog were referred to our clinic. They were treated according to our protocol and survived. However, we were informed by the family that the woman’s cow, which was bitten by the same dog, died of suspected rabies after two weeks.

Some of the patients bitten by suspected rabid dogs would come to our clinic terrified as the reports of deaths due to unavailability of eRIG appeared in the media. I would assure them that we were giving them the correct treatment, and nothing would happen to them. But such cases would put my determination to the test in this crisis. While I had the moral support of seniors like Dr Madhusudana, Dr Henry Wilde, Dr MK Sudarshan, and Dr PL Gaunta, and the practical support of people like Sister Nirmal Gupta, staff nurse at the clinic, I felt that I alone would be held legally liable if something went wrong. I had to reassure myself that we were doing what was necessary in the interest of our patients.

We followed up patients referred to our clinic and administered our intervention. All these patients survived (15). Our clinic became one of the few centres in India offering post-exposure prophylaxis (PEP) at that time to all patients, using ID vaccine and only wound/s infiltration of eRIG. The total cost of ID vaccine along with local wound infiltration of eRIG was one fifth of the cost of just the vaccine that was being provided IM before 2008. The government is now in a position to offer complete PEP including vaccine and eRIG free to all patients in Himachal. This “Himachal Model” can help India and other countries overcome the burden of rabies in the years to come.

I have had many guides in this work. In addition to Dr SN Madhusudana, Dr Henry Wilde from Thailand directed me towards important papers on rabies PEP, helped me in drafting the protocol, and advised me on the need to obtain ethics clearance before implementing this protocol. He later kindly collaborated with me in one of the papers reporting on this intervention. Dr MK Sudarshan, former president of the Rabies in Asia Foundation and former member of the Global Alliance for Vaccines and Immunisation, also advised me, from time to time, on ethical and technical issues regarding this work.

Critical evidence towards WHO’s updated global guidelines on RIG use, 2018

The state health department gave us verbal consent to use this modified protocol in June 2014, agreeing that there was no other option in this crisis of non-availability of RIG. We began implementing the new revised protocol after that from 2014. In two years, we trained more than 50 batches of doctors, nurses and pharmacists from all over the state in the new method of local eRIG infiltration of wounds. From June 2014 to July 2016 more than 4,500 patients were treated according to this protocol. We were able to follow up about 80% of all PEP patients on the phone and through house visits (all 26 patients bitten by lab-confirmed rabid animals were followed). We also got information from all the tertiary hospitals where rabid patients are referred. No rabies death was reported of any of the people who underwent PEP in our government hospitals. Earlier free treatment was restricted to the poorest of the poor, and eRIG was only available at district headquarters. Now rabies PEP is available upto the sub-divisional hospital level, and in some cases even at the primary health centre level. Himachal Pradesh reported four deaths due to rabies last year in 2017, but none of the four people had received PEP in government hospitals and one had been given vaccine but not RIG by a private hospital. Two deaths reported this year had not availed of any PEP.

Our initial findings, showing that this reduced quantity of locally infiltrated ERIG was sufficient for protection, were published and became part of the literature reviewed by WHO’s Strategic Advisory Group of Experts (SAGE) (16) on immunisation. We were asked to provide a further analysis. Dr Madhusudana, my mentor, had passed away and my other advisor, Dr Henry Wilde was my co-researcher and author in this paper. We published a follow-up paper reporting that the 26 patients with lab-confirmed rabid bites were all healthy one year later (15). The evidence provided in both papers was reviewed by the SAGE and contributed to its updated recommendations on RIG use (2018) worldwide (17,18).

Trials and programmatic experience indicate that infiltration of RIG in and around the wound neutralises rabies virus within hours, whereas RIG administered IM distant from the wound is of limited value. These procedures allow RIG dose-sparing by calculating the maximum dose based on body weight, and injecting only the volume needed to infiltrate the wound(s).

Incidentally, the report of a 2009 WHO consultation (19) documented a heated debate on the subject of this very protocol. It noted:

Delegates … raised the need for further controlled prospective studies that would determine whether injecting the wounds alone is effective in preventing human rabies deaths. However, such studies are impossible to carry out ethically today. [emphasis added]

While the experts could not agree on how to resolve this issue, the report highlighted the doctor’s predicament when treating an animal bite victim with Type 3 bites:

The physician in an impoverished region must therefore make a decision whether to inject RIG into all wounds alone and then, either save the remnant of the calculated total dose for the next patient, or inject it intramuscularly at a site different from vaccine as is currently recommended by WHO… This clearly raises the probability that a physician, who does not use the total calculated RIG dose, may be held responsible if the patient dies of rabies. This threat further complicates decision making on how to solve the dilemma of avoiding waste of valuable excess RIG after wound injection. (19)

Then came the most important suggestion:

Animal bite centers, which experience extreme shortages of RIG and have no choice but to inject wounds only, should collect prospective data. This may allow making evidence-supported-changes in current RIG injection guidelines. [emphasis added]

In other words, as far back as 2009, experts were looking for evidence to modify the WHO rabies RIG protocol. But it was unethical to do a controlled study for this purpose. The only way to get this information was through the intervention that we were forced to implement in a situation of non-availability of RIG, despite fearing the repercussions of violating the WHO protocol.

Conclusion

We started our intervention in order to save patients in a crisis of RIG shortage. We had no idea of its potential global implications. Our initiative led to a major change in WHO guidelines on RIG use. It is evident that if creative minds are encouraged and supported by their superiors, they have the capacity to contribute to critical national and international policy decisions even while working in small institutions in resource-poor settings. It is also evident that when doctors are sensitive to the plight of poor patients and the circumstances that lead to such unnecessary deaths, they can be energised to challenge any protocol, to save lives not only in their own setting but even worldwide.

References

  1. World Health Organisation. Rabies vaccines: WHO position paper; Weekly Epidemiological Record. 2010 Aug 6 [cited 2018 Nov 28]; 32(85): 309–20. Available from: http://www.who.int/wer/2010/wer8532.pdf?ua=1
  2. Association for Prevention and Control of Rabies in India. Assessing burden of rabies in India. WHO sponsored National Multi-centric Rabies Survey 2003. 2004 May [cited 2018 Nov 28]. Available from:: http://www.apcri.org/pdf/WHO-APCRI%20Survey%20Report.pdf
  3. World Health Organisation. WHO guide for rabies pre and post exposure prophylaxis in humans. Geneva: WHO; Updated 2014[cited 2018 Nov 27]. Available from:http://www.who.int/rabies/PEP_Prophylaxis_guideline_15_12_2014.pdf
  4. WHO Expert Committee on Rabies. Eighth Report. WHO Technical Report Series 824. Geneva: WHO; 1992 [cited 2018 Nov 27]. Available from:http://apps.who.int/iris/bitstream/handle/10665/39308/WHO_TRS_824_eng.pdf?sequence=1&isAllowed=y
  5. National Rabies Control Programme, National Centre for Disease Control. National guidelines on rabies prophylaxis. New Delhi: NCDC;2015 [cited 2018 Nov 27]. Available from: http://clinicalestablishments.gov.in/WriteReadData/238.pdf
  6. Rahim A, Kuppuswamy K, Thomas B, Raphael L. Intradermal cell culture rabies vaccine: a cost effective option in anti rabies treatment. Indian J Community Med. 2010 Jul [cited 2018 Nov 27];35(3): 443-4. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2963893/
  7. Bharti OK, Madhusudana SN, Gaunta PL, Belludi AY. Local infiltration of rabies immunoglobulins without systemic intramuscular administration: An alternative cost-effective approach for passive immunization against rabies. Hum Vaccin Immunother. 2016; 12(3): 837-42. Available from:https://www.ncbi.nlm.nih.gov/pubmed/26317441
  8. Dean DJ, Baer GM, Thompson WR. Studies on the local treatment of rabies infected wounds. Bull Wld Hlth Org. 1963 [cited 2018 Nov 27]; 28:477-86. Available from:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2554747/pdf/bullwho00303-0083.pdf
  9. Wilde H, Sirikawin S, Sabcharoen A, Kingnate D, Tantawichien T, Harischandra PAL, et al. Failure of postexposure treatment of rabies in children. Clin Infect Dis. 1996 Feb 1 [cited 2018 Nov 28];22(2):228-32. Available from:http://cid.oxfordjournals.org/content/22/2/228.full.pdf
  10. Chomchay P, Khawplod P, Wilde H. Neutralizing antibodies to rabies following injection of rabies immune globulin into gluteal fat or deltoid muscle. J Travel Med. 2000 Jul-Aug [cited 2018 Nov 27];7:187-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11003730
  11. Servat A, Lutsch C, Delore V, Lang J, Veitch K, Cliquet F. Efficacy of rabies immunoglobulins in an experimental post-exposure prophylaxis rodent model. Vaccine. 2003 Dec 12; 22: 244–9.
  12. Wilde H, Shantavasinkul P, Hemachudha T, Tepsumethanon V, Lumlertacha B, Wacharapluesadee S, et al; New knowledge and new controversies in rabies. J Infect Dis Antimicrob Agents. 2009 [cited 2018 Nov 27]; 26:63-74. Available from: http://www.idthai.org/Publication/pdf/Vol26-2/p.63-74.pdf
  13. Madhusudana SN, Ashwin BY, Sudarshan S. Feasibility of reducing rabies immunoglobulin dosage for passive immunization against rabies; results of in vitro and in vivo studies. Hum Vaccine Immunother, 2013 Sep 1 [cited 2018 Nov 27]; 9:1914-7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906356/
  14. Anderson DC. WHO guidelines dealing with immunoglobulin use impede rabies prevention. Asian Biomed. 2007 Jun [cited 2018 Nov 28]; 1(1):103-107. Available from:https://pdfs.semanticscholar.org/5dca/196b5e952af49fba56119e307857c6ff830e.pdf
  15. Bharti OK, Madhusudana SN, Wilde H. Injecting rabies immunoglobulin (RIG) into wounds only: A significant saving of lives and costly RIG. Hum Vaccin Immunother. 2017 Apr 3 [cited 2018 Nov 28];13(4):762-5.https://www.ncbi.nlm.nih.gov/pubmed/28277089
  16. World Health Organisation. Weekly epidemiological record; No 48. 2017;92,729–48; 2017 Dec 1[cited 2018 Dec 12]. Available from:http://apps.who.int/iris/bitstream/handle/10665/259533/WER9248.pdf?sequence=1
  17. World Health Organisation. Rabies vaccines and immunoglobulins: WHO position. Summary of 2017 updates [cited 2018 Nov 28]. Available from:http://apps.who.int/iris/bitstream/handle/10665/259855/WHO-CDS-NTD-NZD-2018.04-eng.pdf?sequence=1
  18. World Health Organisation. WHO Expert Consultation on Rabies: WHO TRS N°1012, Third report; 2017 Apr [cited 2018 Nov 27]. Available from: http://apps.who.int/iris/bitstream/handle/10665/272364/9789241210218-eng.pdf?ua=1
  19. Commentary. Proposed new WHO rabies control guidelines (Highlights from the WHO consultation on human and dog rabies prevention and control, Veyrier du Lac, France, October 7-9, 2009). Asian Biomed. 2009 Dec;3(6):751-4. Available from: http://www.asianbiomed.org/htdocs/previous/A20093751.pdf
About the Authors

Omesh Kumar Bharti ([email protected])

State Epidemiologist, State Institute of Health and Family Welfare and Master Trainer, Intra-dermal Rabies Vaccination, State Intra-dermal Anti-rabies Clinic and Research Centre, Deen Dayal Upadhyaya Hospital, Shimla, Himachal Pradesh 171 001

Keywords

N/A

Refbacks

There are currently no refbacks.

Click here to support US