OUTBREAK: VIRAL ENCEPHALITIS – More Questions Than Answers

Dr David KL Quek

dquek@pc.jaring.my

The past few months have been particularly vexatious for Malaysians. Once again it would appear that we are being thrust from one unwanted crisis into another – this time even more harrowing, more exasperating.

Another high-fatality outbreak has besieged the nation. Fear and uncertainty now consumes almost everyone although this outbreak appears to be almost exclusively confined to the pig-farming communities in Perak and Negri Sembilan. The very lethal nature of this particular epizoodemic, presenting as a viral encephalitis has stunned and shaken the people.

In less than 5 months, some 70 people have died, while more than 100 have been or are being hospitalized and are seriously ill. To complicate the already horrendous scope of death and crippling morbidity, more than 300,000 ill-fated pigs are now being culled to try and contain this mysterious but obfuscated outbreak. A further 600,000 hogs have also been earmarked for destruction.

Although, this outbreak has been labelled as Japanese Encephalitis or JE, there have now arisen new revelations and piecemeal disclosures, which have rendered this misnomer, somewhat untenable – not the least of which, is the discovery of another more probable virus, yet unnamed. This new Paramyxoviridae virus has now been cultured and isolated by Dr Chua Kaw Bing and Professor Lam Sai Kit at the University Hospital (see figure, and inside story: A new encephalitis virus).

It is believed to be related to a previously unknown equine morbillivirus first isolated in a fatal respiratory outbreak among horses in a suburb (Hendra) near Brisbane, Queensland, Australia, in 1994. In that outbreak, the horse trainer died, while his assistant became quite ill (see accompanying story: Solving the horse virus mystery – Hendra virus).

Do we now have a dual epidemic occurring side by side? In any point source outbreaks, it is extremely uncommon to have more than one cause – therefore it is quite improbable that the JE virus is now causing this outbreak with another, Hendra-like virus or whatever. Since the new virus has now been directly implicated as the cause of a sizeable number of these encephalitis patients, it seems that this must be the most likely culprit virus.

In epidemiological science, direct isolation from the patients, of a causative agent must take precedence over serological data, which are only indirect measures of infection both past and perhaps recent present. Still, one could concede that it is not totally inconceivable that perhaps not all the cases afflicted so far, are due to the newly discovered virus, and that a few might actually be due to the JE virus.

The case for this new virus as a causative agent in this lethal outbreak is strengthened by the discovery of the same Hendra-like virus in 11 out of 15 cases of infected abattoir workers in neighbouring Singapore (just recently confirmed by the CDC, USA). Importantly, few of these had any antibodies to the JE virus. In this particular scenario, one pig-handler died while the rest are in various stages of recovery. It is known that the involved abattoirs there had unknowingly imported pigs from the infected farms in Malaysia.

Are we splitting hairs? Is it that important to incriminate and pinpoint the causative agent? The answer must be a resounding yes! If for nothing else, because their modes of transmission, treatment strategies and methods to contain and eliminate the outbreak may be vastly different. Nevertheless, several other issues seem to beg more questions than answers.

What do we have so far? It would appear that this relentless epidemic began sometime in October 1998, when some pig farmers in Tambun, Ipoh came down with clinical features suggestive of encephalitis. And since Japanese encephalitis is known to be endemic among pig farming communities in the region, this was the initial logical clinical diagnosis, pending the usual viral serological confirmation from the hospital laboratories or at the IMR (Institute of Medical Research, Kuala Lumpur). Under normal circumstances this would mean that paired serological testing for viral IgM antibodies would have been the usual diagnostic criteria needed to corroborate the diagnosis of Japanese encephalitis or JE.

However, it appears that some of these unfortunate victims died rather quickly and prematurely, before a second specimen could be obtained. Hence many of the tests performed, were thought to have been single unpaired but somewhat raised levels of JE antibodies – which would have rendered the diagnosis less than definite or even probable. This is because JE antibodies are well known to be present among people who have been exposed to the virus, particularly under such occupations as pig farming.

What this means is that while the JE virus might have infected these people, in a great many, they might not necessarily have become clinically ill. Indeed, it is usually reported that for every one case of JE disease, some 300 others or so are subclinical. To confuse the scenario further, vaccination with the attenuated or killed virus, can result in antibody level elevation, which is indistinguishable from native infection. However, most authorities accept that a truly diagnostic test would have been the finding of elevated JE IgM antibodies in the cerebrospinal fluid (CSF), which would imply infection of the CNS (central nervous system). Of course, the isolation of the virus by culture or PCR testing is also definitive, but so far we have no information or confirmation that any of these has been obtained.

Another peculiar aspect in this outbreak is the age group of the victims. Most of the infected patients are adults with a few, teenagers. All have been closely linked to the close handling of pigs. Children and other related family members appear to have been spared. JE typically afflicts younger children, rarely adults, and then mainly the elderly at that. If the outbreak was truly mosquito-borne (by the Culex tritaeniorhynchus), one would have expected a less discriminatory pattern of involvement of household members. Most of the victims would have been children. Furthermore, the massive fogging operations to eradicate the mosquitoes would have had some effect on reducing the number of cases, which alas, appear to be increasing, instead.

Then what about the vaccination program which has been in full swing since last November? Many of the patients now afflicted with encephalitis have been vaccinated, with more than half having up to at least one booster. Theoretically, this would have conferred some 80% protection against JE – yet, they had succumbed. One other possibility is that the given vaccine was defective or inactive, which makes little sense, since most of the vaccines had been recently imported specially to combat this outbreak.

The other issue is that of pig infection and dying. JE typically is a non-fatal infection for pigs – most are subclinical. However, clinical manifestations include mummified stillbirths, abortions, which can afflict pregnant sows, and boars can have testicular inflammation, which can render some of them sterile. Almost never, do they fall sick. In veterinarian reports which are now being reexamined, pigs have become sick, with belabored breathing, cough, frothy nasal and oral discharge, and postmortem studies on some, have confirmed exudative even hemorrhagic pulmonary edema. These are features, which suggest another pathology rather than that caused by infection with the JE virus.

From the available but adumbrated reports received so far, in this outbreak, it would appear that the JE virus has not been conclusively proven to be the culprit in any sizable number of patients or victims treated so far. Hence, the uncertainty regarding the cause of these patients’ fatal and severe disease, remains.

What about the strategies used in containing this outbreak, thus far? The mass vaccination program for people at risk, if based of the preliminary JE diagnosis is logically correct. Mass vaccination of the hogs, on the other hand, appears less grounded on evidence, given the fact that hogs are natural hosts for the JE virus. Thankfully, this latter strategy has now been halted, in the light that the new virus might have been unwittingly transmitted via this route – from infected to uninfected pigs through shared injectors.

From the outset when local veterinarians first noticed the sick pigs, the question of whether to cull the infected pigs was raised. However, in view of the huge economic impact (RM 1.5 to 2 billion, 27% of the livestock industry) involved in such a move, no easy or premature decision could be made. This is especially so when the working diagnosis was that of JE – containing the infection spread has never been through the eradication of this almost omnipresent JE virus in any pig population.

However, the very devastating lethality of this new infection did shock our authorities from their stunned inertia, to move with increased but staggered pace, and to announce that perhaps, culling the infected pigs in infected areas may be the answer. The logistics involved are truly monumental and are now only being ironed out with improved efficiency. Bearing in mind the extreme case fatality rate, and the very lethal and morbid aspects of the infection, it would appear that culling the pig population is a necessary but painful option.

Now that the mass culling of the hogs are underway, and the infection better studied and managed, more should be done to ensure that the pig farming communities understand their sacrifice, and their misfortune. While it would be easy to all point our fingers at the hapless pig farmers and handlers and their so-called polluted environment, and blame them for the outbreak, it might be prudent to reassess the practical realities involved in this case.

One really needs to beg the question of a clean pigsty – is there ever any? However, this does not detract from the fact that the farmers have to do much more to clean up their act, and manage their animal waste much better. It would be beneficial to relocate such farming to better-monitored zones where a carefully planned waste management plant can be constructed side by side to protect the environment from unwarranted mishaps, or other potential pollution. In fact, biodegradation oxidation ponds have already been in existence in several pig farms in the Bukit Pelanduk and Sepang area.

Contrary to what one might expect, the farms that I have had a chance to visit earlier in 1997, were not as filthy or as polluted as one can imagine. Sure, they were not pristinely clean, but which if any other rural communities, villages or kampungs, where poultry such as ducks, geese and chicken are reared in the compounds, are? Uncovered ground compounds – with our year-round tropical rains – are often soggy, and puddles and stagnant ponds are part and parcel of such rural living. For sure, these should always be cleared so as to prevent mosquito breeding, but it will be a futile exercise to imagine that we can actually eradicate these pesky little insects which have survived since the Jurassic period! Periodic fogging and eradication measures such as larvicidal treatment of potential water-clogged sites, might be better options. A conscientious effort by the farmers to continually keep their environment and piggeries clean should be repeatedly instilled and enforced.

It is important to remember that sporadic outbreaks of newly emerging infections are sometimes just that – spontaneous and sudden, and without a blamable cause. Mutations, new or altered transmigration of animals, such as monkeys and rodents, or as the case maybe, flight movement changes of bats or flying foxes, are potential harbingers of potentially lethal zoonotic viral infections. Because of our ever-encroaching proximity to the edges of wild life, we become susceptible to the vagaries of hitherto unknown but infectious agents – some of which have been known to cause catastrophic outbreaks such as the Lassa or Ebola infections. Perhaps, our current outbreak is one such happenstance.

However, we still need to scrutinize our point source data. In this respect, we must naturally look at the uncanny resemblance of the so-called first case of the JE, which occurred in Tambun, Ipoh. How did it all begin? Why did it originate there in the first place? We remembered that there were some suspicious deaths among racehorses, taking place last year, coincidentally (?) at Tambun, Ipoh. Were these equine deaths and illness connected with the present outbreak? Do we have any veterinarian report and data to determine what the cause of deaths or illness were, for these horses?

Importantly, were any of these horses imported from another country, perhaps Australia, perhaps even from Brisbane, or were there any cross-national movements of these horses? These are important if tangential queries that should be addressed in earnest, and with honesty. Why? Because, the virus now implicated in our lethal outbreak appears to be closely related to the very rare Hendra virus first isolated in Australia, near Brisbane, in the suburb of Hendra. This Hendra virus has to date never been reported anywhere else in the world.

What else might we learn from our recent spate of back-to-back outbreaks, which sorely tested our healthcare resources and public health machinery? This run of bad luck and ill health has already cost us many precious human lives. It has also cost us plenty in terms of financial losses through containment measures, health care, medications, and loss of economic activity, loss of tourism dollars, and in this instant, an unprecedented destruction of the pig-farming industry – some 27% of our livestock industry!

In a changing world constantly beleaguered with such precarious and capricious natural disasters, we need a better approach. We have seen the frequent miscommunication and discord among different impassioned parties and the authorities, which naturally have their own interests at heart. We have certainly exhibited a lamentable lack of a definitive plan of action.

We sorely need an authoritative but centralized institution of excellence to direct, communicate and coordinate all such public health activities, and epidemiological measures. It is becoming abundantly clear that we should now have our own CDC or Communicable Disease Centre. We would also need a truly professional team of dedicated experts who can come together to act as one in exigent times of crisis. Also we would need one highly respected Director who can deliver the results, coordinate the highest level of clinical and microbiological research and investigations, and who understands the clinical implications of his actions and those of his team of experts.

This Director should have full and unfettered access to all data – clinical, epidemiological and laboratory investigations. He should be independent and his ranking should not be subject to bureaucratic discrimination, obfuscation or grandstanding intrigue. He or she should then be directly answerable to the Director-General or Minister of Health, without fear or favour.

At this point in time, perhaps the closest to such an ideal centre, is perhaps, the University of Malaya Medical Microbiology Department and the WHO Arbovirus Research Laboratory and Centre, under the stewardship of Prof. Lam Sai Kit. This Laboratory has consistently managed to identify and isolate the infectious agents of several outbreaks in the recent past – viz. Enterovirus 71, influenza A (H2N3) virus, chikungunya virus, and the current Hendra-like virus. Its role in dengue viral research has already made it the regional centre for WHO research and coordination. We should at least start with a tried and tested centre.

Finally, do we need a Biosafety Laboratory? Clearly we do, as this outbreak indicates. We have had to set up a makeshift P3 level Biosafety Laboratory at the University of Malaya during this outbreak. But we should seriously consider establishing a P4 level laboratory, perhaps under the funding and auspices of the WHO or even under the Ministry of Health.

Caprice in nature and disaster occurs. In Malaysia we are already lucky that we are spared the earthquakes and the typhoons which regularly afflict our neighbouring countries. Biological catastrophe, on the other hand, provides a challenge, which we should not capitulate to, despite its potentially fatal consequences. We can and should accept these testing trials in good spirit, and with a willingness to learn and improve ourselves. Petty differences and territorial turf in-fighting should not hamper the good work that we can all achieve by working together, not for self-glorification but for the good of our nation and our people.

In the Antigone, Sophocles has this to say: "All men make mistakes, but a good man yields when he knows his course is wrong, and repairs the evil. The only sin is pride." In this tragic saga of death and destruction, let us hope that we can learn from the suffering of the unfortunate victims and the experience of how to manage our outbreaks better. Another Greek poet Aeschylus has said: "In our sleep, pain which cannot forget falls drop by drop upon the heart until, in our despair, against our will, comes wisdom through the awful grace of God."

31 March 1999

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