Following is Prof. M S Khuroo’s keynote address to medical fraternity delivered at Nehru planitorium Mumbai.

At the outset I take this opportunity to thank the organizers of this symposium for inviting me for the keynote address on a disease and a pathogen which is so important to us in India. The occasion is to celebrate the 75th birthday of an icon, (Prof. HG Desai), in Medicine and Gastroenterology in India in general and Mumbai in particular His contributions to field of gastroenterology and gastritis are known to all.  He has been an embodiment of discipline and service to field of medicine in India and while all of you, his students and colleagues, are rejoicing this moment, I can present him this couplet “Tum jeyoo hazaroo saal, har saal kay din ho hazar”.  I bring to all of you love and regards from people of beautiful valley of Kashmir, about which you may have an occasion to hear regarding the status of the disease under focus and while doing so it may not look as beautiful as it looks on this image of “the great Mughal garden”.

 In the next 20 min I present to this August gathering how I saw the 25 years of hepatitis E since it was recognized as a disease in 1980. In 1995, I have to move out of Kashmir and had temporarily settled in a tertiary care centre in Middle East, the King Faisal Specialist Hospital Riyadh, the place which many of you may be aware of. Now that the conditions in Kashmir are just improving I have decided to settle back in the Valley and in India for good and would be watching the developments in the field of hepatitis E with great interest. I have been given the job of tracing the historical background and future of hepatitis E (the untold story) and while doing so I pay tribute to this genius (Hippocrates, 460-375 BC) who described the epidemic jaundice more than two thousand years earlier. Going through the substance of his description and the explosive nature of epidemics he described I am reasonably convinced that he was talking of a disease similar to what now we see as hepatitis E. His lucid description of fulminant hepatic failure is accurate even today and we have not improved on therapy of hepatitis E disease over his magic therapy of water and honey. To one who suffers from the disease it does not matter whether we understand better the pathogenesis of disease as long as we don’t offer him better remedy than Hippocrates had proposed (melikraton, a mixture of water & honey). It is a matter of great dismay that we can offer no better therapy to a patient with hepatitis E than Hippocrates offered many centuries ago.

I shall focus on few aspects of hepatitis E during my talk and skip the cutting edge research to done by many distinguished researchers from India and abroad. After a brief report on the first recognition of the epidemic from Kashmir, I shall highlight landmarks which helped progress of knowledge and understanding of the disease and the pathogen. Next I shall bring out the enigmatic nature of the disease and outline the frustrations which we face as care givers while managing patients. An outline of the challenges and the way to meet these challenges shall conclude my talk.

Quite a bit has been written about the discovery of hepatitis E and hepatitis E virus. I thought this may be ideal forum to uncover my personal “untold story” about how I recognized the first epidemic in Kashmir and on what basis we proposed it as a new and yet unknown disease and asked the international fraternity to look for a new agent. Story goes to eighties during which I was undergoing fellowship in gastroenterology in PGI Chandigarh. For several reasons outside the scope of today talk, during this period I transformed my understanding of the liver disease in India. At the same time it struck me that emergency room and intensive care unit of the hospital was always occupied to a considerable proportion by pregnant women with liver disease, with high mortality and autopsies of fatal patient uniformly revealed massive hepatic necrosis as the cause of fulminant hepatic failure. Late Professor DV Datta would often call me on a cup of coffee after the morning meeting and ask me on each session “Sultan, why do these pregnant women come and die”. He knew that I did not know the answer and possibly wished me to find one. It is unfortunate that even after 30 years his question as to why women in India suffer from hepatitis E, develop fulminant hepatic failure and die remains unanswered. With this ingrained in to my mind I went back to Kashmir to establish a clinical unit of gastroenterology at the Medical college Srinagar Kashmir.

THE HEPATITIS E VIRUS

A simple phone call on a cold November day in 1978 changed my course of work in Kashmir. I was told that in and around a town which is 50 km from Srinagar there is a huge commotion caused by epidemic of jaundice and pregnant women are hit the worst and many of these women have died. Inspection of the region next morning revealed no less than a mini-tsunami state of affairs. 200 villages with a population of over 200,000 were hit by the disease. In 2 days time we were organized to start a house to house survey in 16 defined villages and through the services of 500 health care workers record each and every new case of jaundice from entire valley. I funded this project from a substantial proportion (up to 30 percent of my earning) of income from my clinic income.

 I must mention that the region involved by the disease had extreme weather conditions and most primitive health care facilities and it was extremely hard to do field survey under this trying situation. Also, the laboratory facilities were nonexistent and we had to get an outreach support for serological testing for hepatitis A, the test just available by that time in few research laboratories. It also struck us that the drinking water supplies of this region were from open flowing streams and we showed that water was grossly polluted because of this phenomenon.

 Over the next few months we had accumulated data which on analysis were unbelievable and unprecedented. These data that a new form of hepatitis virus caused this epidemic were presented to annual meeting of Indian Society Gastroenterology (1979) at Pune and subsequently widely communicated.  I faced a strong skepticism from international experts who believed that this is a classical epidemic of hepatitis A and hepatitis A virus testing was faulty.  I surrendered hundreds of sera to these laboratories only to confirm that these sera lacked acute markers of HAV infection.

Over the 6 weeks period from November to December 1979, 600 deaths had occurred and majority of these deaths had hit pregnant women. In fact once the epidemic had subsided nearly all the second and third trimester pregnant women had vanished and it was difficult to find one surviving. Disease was predominantly cholestatic, self-limiting and with characteristic histology in a subgroup of patients. Of course all patients lacked acute markers of HAV and HBV; while all adults had previous exposure to hepatitis A.

Over the next few years repeated waves of epidemic of exactly same pattern hit different regions of the valley and left over fifty thousand affected with over seventeen hundred dead. Following this there was a lull for 12 years and another wave of epidemics restarted in 1993.

 We also identified a similar disease constituting over half of the endemic hepatitis and defined a gradual loss of antibodies in affected patients over 14 years follow up period. In 1995 we confirmed a long clinical suspicion that vertical transmission is nearly a universal phenomenon in hepatitis E infection causing considerable fetal morbidity and mortality.  In this endeavor we also defined a strong association between severity of hepatitis E disease in the mother and the baby and strongly suspect that fulminant disease in the mother may be reflection of the severe fetal disease. Lately we appreciated that viremia is a common occurrence in otherwise healthy persons in endemic areas and disease can be transmitted through transfusions.

 Is hepatitis E virus a new emerging infection or an ancient disease discovered recently? Several pieces of evidences point to the fact that this disease has been with us since ancient times. There have been several reports of epidemics of jaundice from the Indian subcontinent including one which hit this city of Delhi in 1955-56. Going back further reports of Campaign jaundice in the middle Ages and impact of this disease in the two World wars is part of history. I believe the disease existed in its all forms globally in the past and has become restricted in behavior in various geographical regions with change in ecological conditions especially water supplies, sewage disposal and the socioeconomic status of the societies. 

A quick word about the Delhi epidemic which affected estimated 29,300 in this city and was investigated by the ICMR, the apical national research body of India.  The field survey was started retrospectively when the epidemic had subsided and so the reported data had some limitations; yet the features of this epidemic had many characteristics resembling the Kashmir epidemic and were published in as a classical example of hepatitis A. Only after we reported on the nature of the Kashmir epidemic in Pune sera which had been stored in the “National Virology Institute, Pune” were tested and found to be negative for acute markers of hepatitis A. For reasons unknown nature of disease and pathogen was not suspected earlier.

Landmarks in hepatitis E virus research started with an example of extreme zest for human knowledge and self experimentation. While I was just thinking of using Rhesus monkeys as a animal model for transmission studies, late Dr. Balayan (from virus research laboratory in Moscow) produced incredible data after self ingesting 8 fecal samples from non-A hepatitis cases from Central Asia. A moderately severe hepatitis E developed on 35 day of ingestion (he was in hospital in ICU setting for several weeks) and virus like particles were recovered from the stool samples on immune electron microscopy. He transmitted the disease in Cyano with recovery of similar virus like particles. This set a stage for search of the agent and its further characterization.

Excellent data of animal transmission and biophysical properties of the pathogen were published from CDC during the period 1983 to 1990. However, the pathogen frustrated molecular biologist as the recoveries of VLP from stool specimens were insufficient to clone and sequence the virus. We were advised to dumb large specimens of stool samples from patients in to our deep freezers and many of us including me did it faithfully at the great wrath of the nurses and laboratory staff. A breakthrough in this area occurred with the observation that while VLP are rare in stool, the bile is loaded with the infectious material. This observation led to the cloning and sequencing of the agent and a full length genome was subsequently sequenced and a serological test developed. Improved antigen expression made the serologic test valid for clinical and epidemiological purposes.

Story of HEV and Zoonosis developed with great interest. Several pieces of data led us to move in this direction namely prevalence of antibodies in nonendemic regions of the world and presence of antibodies in several species of animals. Natural infection in several animals has been established and a swine HEV has been identified. Relation of animal HEV and human disease in endemic and nonendemic regions of the world is under scrutiny. Human disease has been traced to eating of raw deer meat in Japan has set a stage for zoonotic origin of HEV under these circumstances.  Recently HEV infection has been traced to supermarkets in Japan and the West. A substantial proportion of raw pig livers sold in such supermarkets contains live hepatitis E virus and infects humans. Many such reports have been published in Japan, USA and the Europe.

Another breakthrough which has been watched with great hope and interest is the story of vaccine development. Challenge experiments in cyno again from CDC set the stage and a recombinant candidate vaccine has passed through many phases of experimentation and we may here the final news hopefully during the deliberations of this symposium where we stand now.  Data from phase 2 trials from Nepal have shown that the HEV vaccine is efficacious and safe. Oral and DNA based vaccine also give us further hope in this area should the candidate recombinant  vaccine fail to satisfy us as care givers to control the disease.

Ladies and Gentleman, while today we have so much to rejoice on the developments in the field of hepatitis E virus through your cutting edge research, there are so many unanswered questions related to epidemiology about this enigmatic disease as listed in this slide. I may endeavor to propose hypothesis for 2 enigmatic phenomenon of hepatitis E for discussion in this symposium and this is based on data we have collected for last several years. We believe repeated epidemics are a function of cohort phenomenon and partial loss of antibodies over the time period in the community. These 2 processes as you see in the slide bring down the herd immunity of the population in every one to two decades for the next waves of epidemics. Also the important question of increased severity of hepatitis E in pregnant women is possibly related to events which happen in the fetus due to vertical transmission of the agent causing severe and fulminant fetal hepatitis. We believe the mothers are overloaded with fetal toxins due to this infection and succumb to the disease and can survive if the fetus is delivered on priority.

The agent has been no less enigmatic to us and in spite of excellent studies by all of you we the care givers lack answer to some basic questions about immune response to HEV infection, replication of HEV, immunoprophylaxis, so important to us as clinicians and vaccine development, which is crucial for the epidemiologists to control the impact of disease, to name a few.

I shall conclude my talk in identifying the challenges we face in hepatitis E as a disease. Safe potable water and proper sanitation shall remain restricted to the politician slogan in many countries for many years to come. It is a shame that even today I cannot and am not advised to drink water from the water supply scheme of metropolitan cities like Mumbai and Delhi, of this great country. So, Sir, as long as this is so, hepatitis E shall remain with us. Control of epidemics when they strike cause panic, commotion and a better national organization in affected countries shall help the poor and the needy. Millions of patients suffer from hepatitis E in developing countries and hundreds and thousands develop fulminant hepatic failure and it is painful to remark that intensive care facilities and facilities of liver transplantation have never been given a priority. I do not know of any patient or series of patients with hepatic E fulminant hepatic failure who have been transplanted in developing countries. I am sure a country like India where an expensive cardiology service has advanced so much could have developed it was it given a direction. We as hepatologists and pharmaceutical companies have lacked behind in drug development for this agent while a similar story for HCV & HBV has advanced so much.

How do we face the challenge? I believe many of us need to come together to attack the pathogen with our tools and help the patient. While this forum is ideal to bring many care givers, epidemiologists and laboratory personal together we need media, funding agencies and politician with us so that we can change the course of hepatitis E in a patient who suffers from pain and anguish. Till the time we cannot offer a patient a better option for controlling and treating hepatitis E, we have not moved much away form where Hippocrates had left us over 2 thousand years ago. Thank you for your patience.