Dapsone use in Vietnam


By Noel Benefield
In the search for a new preventative malarial medication it has been claimed that US authorities investigated some 2100 agents, and Dapsone was chosen. Dapsone had been considered during World War II but was discarded as an option. Prior to its use in Vietnam there had been small experimental studies of short duration, and these have been the foundation of the consistent claims by New Zealand and Australian authorities that use in Vietnam was not experimental.

It was in 1968 that the Australians investigated the use of dapsone for the prevention or prophylaxis of malaria. Along with the Americans, the Australians had used a combination of dapsone, pyrimethamine and quinne for the treatment of falciparium malaria. As with that use, the decision to use dapsone as a preventative in a "trial" in conjunction with the existing two tablets of Paludrine, is presented in official histories as a decision taken in Vietnam in response to deteriorating conditions. The Australians did not have a malarial expert in Vietnam at that time. A British Army specialist was sent to conducted an evaluation, and whilst he was convinced that probable reason for the outbreaks of malaria were a result of poor discipline in antimalarial countermeasures, recommended the inclusion of Dapsone, in his evaluation. The involvement of another country's specialist was omitted in the later official history.

The introduction of Dapsone at 25mg daily with 200 mg of Paludrine for all members of the force was on the basis that it had been proven to be effective in suppression after a short trial period. There is no doubt that the inclusion of dapsone to the prophylaxis regime by the Australians dramatically reduced the incidence of malaria amongst Australian and New Zealand troops. But the mechanism for that turn around using dapsone was never adequately explored at that time, which is unfortunate as it can account for some long- term health affects amongst Veterans exposed.

In early 1969, or more probably late 1968 the Americans were having difficulties with their dapsone program, and given the relationship between them and Australian Medical authorities its not surprising that larger numbers in 1969 was taking dapsone. The cohort sizes for the suppression trials were of sufficient size for establishing effectiveness, but for toxicity a large number of people were required. When the decision was made to issue the drug to the whole of the force it would be later revealed that the "boffins" were unhappy with that decision. What they were unhappy about has never been revealed. But it is probably the fact that insufficient evaluation of the potential long-term effects had been carried out.

Years later the regime would remain questionable. The Evatt Commission findings when published, in 1984, claimed that there was no association with herbicides, but they placed a question mark over dapsone. It was in the following year that someone in the New Zealand Director General Medical Services Department formally accused Australian authorities in Vietnam of having conducted an "ad hoc" response to a malarial epidemic. One suspects that this was simply a reaction to the Evatt report designed to lay the blame on the Australians for New Zealand forces use of dapsone. Especially given that the Commission had suggested epidemiology studies. Certainly there is no evidence of an exploration by New Zealand authorities for any untoward long terms effects amongst those exposed.

One problem confronting the Americans was cases of agranulocytosis. Whilst rare they were indicative of something amiss because they were always thought to be associated with high doses of dapsone, as used in leprosy.

Eventually the Australians started to identify cases. The opinion was, when published a year later, that the conditions was "probably due to dapsone" It also quoted a USARV medical consultants report of October 1969. "As everybody knows by now dapsone produces agranulocytosis. This is reversible on stopping the drug". "If infection occurs the prognosis is extremely grave." But the object of the exercise was to explore for life threatening side effects, not their cause, and now that it was proven the drug was restricted to short periods of use. To make sure, the drug was removed from general issue at the store and control passed to 8 Field Ambulance.

What was missed in the analysis by both countries was the true answer. The official history in the Australian Medical Journal of 1973 by an "expert" who had never set foot in Vietnam used the explanation of leprosy specialists he consulted, that the association was unlikely.

The actual hypothesis believed by those involved in design of the regimes was never made available until I requested copies of correspondence in the late 1990's between the Australian and New Zealand DGMS of 1985. It was thought that the dapsone had somehow been degraded by heat when the ship carrying it was held up in the Panama Canal.

Amazingly here were cases of serious life threatening side effects, a product suspected of been implicated, and there is no evidence of any long- term investigations of those exposed.

Factually both "experts" were wrong. The most important comparison was that of the relationship of two different regimes, both with dapsone producing the same outcome. That outcome was the bacterial infections, sadly that killed some of the Americans, after the drug had been discontinued, and was precipitated by lock out of iron when dapsone was used resulting in a myeloperoxidase deficiency where the bacterium were isolated by could not be destroyed
. The iron release effect also occurred during an evaluation of the earlier treatment trials using dapsone, pyrimethamine and quinne, before any consideration of widespread use for preventing malaria was contemplated. There also, after dapsone was discontinued, there were unexplained fevers. There is no indication of a search for the origin of the fevers, causing one to suspect that the success of the regime was more important than a full investigation of all factors. It is probable that in these cases it was re emerging vivax malaria, because like bacteria it enjoys a renewed iron environment. Later circa mid 1969 1st Australian Field Hospital began including iron tablets to be taken in conjunction with dapsone after treatment for malaria. There is no evidence that this practice was adopted with the preventative regime suggesting that the effect was considered a result of the pyrimethamine with dapsone and not dapsone alone. Previously iron deficiency symptoms had been considered a result of inadequate diet.

In explaining the regime at the Evatt Commission one ex Australian DGMS stated it was thought that dapsone amplified Paludrine. Assumptions were a predominant factor in dapsone use in Vietnam. It is true that Paludrine is active against the plasmodium, the agent of malaria, directly, but dapsone did it by a cruder method. Because it had been used in leprosy at higher doses it was assumed that there would be no side effect. It would be decades before it was proven that in leprosy, because of dapsones high affinity, that the side effects differ greatly to those where it is used for other applications.

It would be after Vietnam, that it would be noted in malarial use, that some conditions, permanent in nature, could only be a result of dapsone used for suppression of malaria. In this situation because there is no disease state some of the drug was reconverted from its metabolite, back to the parent drug, resulting in increased quantities within the body from repeated cycling.

The reason the significance of the bacterial infections was not considered was because of a prevailing untested hypothesis that dapsone, because it was related to sulphonimides, it was bactericidal. It would have to wait until after the dawn of a new century for that false assumption to be fully buried.

Another condition, which was discounted by the 1990's Australian AIHW study group, had already been investigated during the Vietnam era. Between September 1968 and January 1969 an investigation was conducted in Australia to determine the incidence of methaemeglobina in soldiers returning from South East Asia. This condition arises from a lack of oxygen transport ability in the blood, and cam be caused by insufficient iron for binding the oxygen. Whilst some of the soldiers were under the short- term treatment regime using dapsone for falciparium malaria, there is no evidence that the investigators were made aware that they had prior dapsone exposure or others on the short- term prophylaxis trial. The degree of methaemeglobina severity varied markedly across the total group.

The conclusion was that soldiers were at risk from the condition, the cause been the Return To Australia regime of Chloroquine and primaquine. But why did Austforce HQ in Saigon, in late December, before this investigation was completed, send a signal to those units in Vietnam, using dapsone to discontinue prior to starting the RTA regime? At the same time the American WRAIR people where conducting this same exercise on personnel in US Aviation units using dapsone, and weekly Chloroquine and primaquine, and obtained the same result. Dapsone and primaquine are synergistic to each other. That is the effects are magnified when both are used together.

The Australian study was not published in the Australian Medical Journal until 1971, by which time dapsone use in Vietnam had been curtailed. If a doctor in general practise had acted on this information, at the time of publishing, he would have been only able to find on a small number of cases that had a genetic predisposition to primaquine toxicity.

A simple cross indexing of known side effects in recent literature on dapsone and those of iron deficiency reveals stark similarities From concave or spotted finger nails to more serious conditions and those with potential long term implications the comparison is outstanding. Of the many lesser symptoms, they were more likely to have been dismissed as representative of active service during the Vietnam period.

But this was not a dose dependant scenario that was the foundation of the AIHW 1992 cancer study. Iron deficiency is a slow manifesting condition that would only became apparent when the drug was withdrawn from the body. By that time many exposed Veterans had returned to Australia or New Zealand. Years after my service, I had a number of discussions with a former Medical Officer who saw New Zealand returnees. He admitted that there were many occasions when diagnosis was unobtainable. I asked him if he had been aware that dapsone had been issued to soldiers, and his reply was he had not.

During many years of research, officialdom has habitually informed me that dapsone was, and is not of concern because it was issued only at 25mg daily and it was used at that time in leprosy at greater doses. All of the official literature suggests a mind set that any effects must be dose dependant. Years after use in Vietnam, in 1990 the Australian Army Tropical Medicine department could not let paludrine and dapsone as a combination go. On this occasion the dose of dapsone was reduced from 25mg to 10mg. again with a short exposure period that suggests the philosophy continued

Could the true implications of dapsone use have been established during use in Vietnam? Remarkably the answer is yes. One of the Australian battalions raised in haste was destined to be a part of the "trial" investigations of 1968, but instead became part of the total cohort when use was expanded. The significance of that battalion was that it had no prior exposure to dapsone, paludrine, malaria, active service or herbicides.
Also one must include the fact that iron tablets were introduced for those on treatment regimes in 1969, which should have prompted further investigation of the preventative regime. That practice also puts in doubt the AIHW study results based on all treatment cases, with or without iron replacement, been considered as the same.

Iron deficiency is amplified by a co-existing folate deficiency. In Vietnam there were many factors that had a potential to reduce the folate pool, ranging from bacterial infections, stress, diet, etc through to folate inhibitors such as paludrine. In fact in some of the cases reviewed by the AIHW they had exhibited symptoms of folate deficiency, but the significance was not recognised.

There are three possible scenarios where dapsone use in Vietnam could be implicated in long-term effects.

The first is an enhancement of folate deficiency. There are recorded cases during service in Vietnam with dapsone use, and there has also been a number of morbidity/mortality studies of Veterans that clearly identify and excess of conditions associated with folate deficiency. Unfortunately none have confounded for dapsone exposure. It should be also noted that folate deficiency can be a factor of aging and may indicated why symptoms previously noted during service, return at a later age.

The second scenario is interference in the biotransformation of other agents to which veterans were exposed. This could have occurred by either insufficient available oxygen for redox detoxification mechanisms, or from a reduction of iron in the liver for primary detoxification. One current anomaly in studies of TCDD and diabetes is its association with exposed Veterans but a non-association with exposed chemical worker populations. Future confounding for dapsone exposure, particular only to Vietnam Veterans, may identify the reason for this anomaly. In fact, recent studies have identified that whilst deficiency of iron does not contribute to type 2 diabetes, iron storage as would have occurred during dapsone use, does in fact initiate the disease.

The third scenario is previously undiagnosed toxic action. In recent years the US Veterans Affairs have accepted an association between motor neurone and dapsone, if the initial diagnosis was identified within two years of exposure. The probable mechanism was free radical formation during biotransformation of the hydroxylamine metabolite. Given that such by-products can also be bound to the red blood cells, and only released on cell destruction, the potential for subtle damage to other organs cannot be discounted.

In conclusion there is evidence that in Vietnam, and after Vietnam, Veterans have presented with conditions that were, directly or indirectly, a result of dapsone exposure.
There is no confirmation available of potential risk, because the few studies conducted have been structured to support the historical dose dependent hypothesis.

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