Compiled by Noel Benefield

Agranulocytosis is an acute disease where there is a sudden drop in white cell production leaving the body defenceless against bacterial invasion. In the majority of cases caused bythe sensitization to drugs and chemicals that effectthe bone marrow and depress the formationof granulocytes.

Agranulocytosis and dapsone in Vietnam was distinctive in that this was the only repeat history of this effect, when using dapsone at 25mg daily with other agents.

"Although agranulocytosis has been reported rarely with dapsone when usedalone it is more common when dapsone has been used wth other agents in the prophylaxis of malaria" (Martindales 1989.)

The earliest records were McKenna W and Chalmers AC 1958.

Where agranulocytosis has been recorded with Dapsone and other agents use elsewhere, in all cases the dosage had been above 50mg daily. Dapsone alone incidences are recorded, with a dosage above 50mg daily, and the patients had used the drug for some time.

On 25th July 1966 dapsone at 25mg daily was authorized for use by selected US troops as a daily preventative. "over the next 30 months an increasing number of men were placed on dapsone prophylaxis". (Ognibene)

In 1965 Australian soldiers suffered their first of epidemics of fever at the commencement of the wet season. Epidemics of fevers of unknown origin occurred in August 1966 and 1967. The epidemics of malaria of November/December 1965,1966,1967 were accompanied by fevers of unknown origin. (Black, Fleming)

In 1967 the first reporting of agranulocytosis conditions in Vietnam (Rogoway) appeared with US troops. It's occurrence was calculated at 0.5% of 2,200cases of malaria. These cases originated from the use of dapsone at 25mg daily in a triple drug treatment regime . No deaths were recorded. This treatment regime was also deployed by the Australian Forces and none of their patients were found to have agranulocytosis.( low neutrophil count ) (Fleming)

The only distinction between US and Australian servicemen was that the former had been on a dapsone/chloroquine/primaquine preventative regime, and the latter a paludrine double dose preventative regime, prior to hospitalisation.

The origins of the 200mg daily dosage Paludrine has two explanations in the available evidence. In (Black) "Proguanil (Paludrine) 200 mg daily had been the standard chemoprophylaxis in West Malaysia and this was continued when Australian troops moved into South Vietnam." A more definative statement is recorded in questioning of (Rodgers) at the Evatt Royal Commission. "Two tablets per day were taken....The reason was to make sure at least one per day got in." New Zealand troops entered Vietnam on the NZ Ethicals recommendation of 100mg (1 Tablet per day). In some unit histories it is recorded that NZ troops were evacuated to Fire Support Bases to recover from malarial epidemics, whereas theAustralian troops in the same area were less affected. The dosage was increased to 200mg when New Zealand troops became part of the observation trial in November 1968

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NZ Ethicals of the period stated "Its actions (Paludrine) against blood forms (of malaria).....may be slow.....is not always completely effective against falciparum malaria and parasites may become resistant to it."

It is probable that the 200mg dosage of Paludrine prevented full expression of the malarial protozoan, and could explain the incidence of some of the fevers of unknown origin (FUOs) that accompanied the malarial epidemics.

The triple drug treatment regime with dapsone, pyrimethamine and quinne, issued for 25 days became standard in Australian hospitals in Vietnam on receipt of a Director General Medical Services Technical Instruction in 1967, and is recorded as been the reason for lack of malarial deaths and evacuations that occurred prior to that time. Confirmation of malaria diagnosis was carried out by a system of referral slides to Colonel Robert H Black, Consultant in Tropical Medicine to the Australian Army. (Fleming) There is disagreement between evidence on the date that the DGMS Technical instruction was issued. From the evidence of ( O'Keefe) this was on 11 October 1968, a year later than that claimed by Fleming.

In January 1968 the clinical notes of 50 patients with falciparum malaria and 10 with vivax admitted to 8 Field Ambulance Nui Dat were reviewed to an indication of the presentations and prognosis of the disease. A large number of symptoms were reported the most common been fever(100%), headaches(90%), chills(72%), anorexia(34%), vomiting(24%), backaches(22%). (Fleming) The ability to distinguish between suspected malarial and non malarial conditions had been established prior to the introduction of the Australian preventative malarial dapsone/paludrine regime.

Where no malarial association was confirmed scrub typhus, leptospirosis or Japanese encephalitis where considered. White cell count confirmation techniques were known at that time.

A practice of investigating patients whose fever persisted after five days of antimalarial therapy, and having no parasite in the blood sample, were tested for these other diseases and where returned negative, infectious mononucleosis was considered. (Fleming)

This case study alerted the investigators to three patterns of fever response after therapy. There appears to be no consideration given to the possibility that the 25 days of dapsone issue may have been a factor.

By mid 1968 an effective treatment regime, effective confirmation of malarial diagnosis and protocols for determining non malarial conditions were in place.

Chlorquine resistant malarial strains had been reported (De Gowin et al 1966 World Health Notification) and it had been reported that 25mg Dapsone daily was "effective in preventing malaria in laboratory(probably in vitro) trials, and reduced malaria where antimalarial discipline was good and no toxic effects were noted over the period of observation." (Joy1966, also Joy and Gardner 1966).

Some observers have commented that the American use of dapsone was the origin for the use by the Australians of dapsone with paludrine in combination, as a preventative regime.

In 1960 Archibald and Ross published a preliminary report on the use of dapsone in the field in Nigeria and suggested that it might be effective in combating strains of malaria resistant to Paludrine.(Smithhurst)

"There were no experimental aspects to its use. Subh(such) experiments were conducted years before." (NZDLS 15 Apr 85) appears to suggest that Archibald and Ross's trials were considered conclusive.

Two reasons were given in support of the Australian preventative trial, in the introductory document: (Bradbury)

(1)"There is every good reason to believe that dapsone taken in conjunction with Paludrine gives added protection against malaria. It is strongly emphasised that dapsone taken on its own will not give significant protection and it must be taken in conjunction with another suppressant." This evidence suggests a combination of the African trial knowledge and US forces experiences were the catalyst for the October trial.

(2)"Dapsone has been used previously in conjunction with Quinne and primaquine for the treatment of malaria and the effectiveness...is well documented" The use of dapsone with primaquine would be reevaluated by the Australians within months of this instruction been issued.

Also in (Bradbury) the trial period was recorded as "....to commence on 23 Oct 68 and continue for at least one month. Depending on the significance of the results, the number of operational days, and the areas in which the operations are conducted, it may be necessary to extend the trial period for a further one or two months, to ensure that Dapsone-Paludrine is fully tested."

In (Bradbury) the trial units were 12 Field Regiment, (excluding 161 NZ Battery ), 1st Royal Australian Regiment (excluding Victor and Whiskey Companies RNZIR), 4th Royal Australian Regiment and a planned use of the 9th Royal Australian Regiment on their arrival in South Vietnam. An increasing cohort. With the arrival of 9RAR aunit with no prior malaria, Paludrine, or theatre expeirence, a dapsone effectiveness comparision would be invetigated, this did not happen

9 RAR did not arrive in South Vietnam. There is evidence that this event was probably responsible for the decision to place the remaining members of the Task Force in Vietnam, on the dapsone / paludrine regime.

This is supported by (MacDonald) report where the malaria observation is recorded as been from October 1968 to December 1968. This is further supported by (NZDLS 15 Apr 85) where it is recorded that "The use of the drug was monitored however to determine its effectiveness in controlling malaria."

At the end of November the 3rd Royal Australian Regiment left to return home to Australia. In the previous month starting 26 October 1968 they had been placed on dapsone for their few remaining operations. "The cessation date is presumed to be the departure date to Australia..."(O'Keefe) Earlier it has been shown that operational days were a necessary factor for the trial, and given the fact that 9 RAR did not arrive to be included in the cohort, is unlikely in Nov this time requirement had been met.

In (NZDLS 17 Apr 68) it is stated "The results of this trial where so outstanding that the whole Task Force was placed on the drug.....even though Maj Gen Jame's trial was incomplete .....The decision to place the whole Force on the drug later received some criticism from the "boffins". It is apparent from the evidence that at the time the remainer of the Task Force personnel were placed on the dapsone/paludrine regime the original trial protocols had not been met.

"In addition it must be noted that in late 1968 shipments of dapsone began arriving by sea and in quantity to meet the requirements. (Ognibene)

At the height of the epidemic of falciparum in October 1968 the daily dose of dapsone 25mg and 200mg Paludrine was trialed. "The reduction in the incidence of falciparum malaria in the group taking proguanil and dapsone was so striking when compared to the incidence on those taking proguanil only that the daily dose of dapsone was added to the daily proguanil for the whole force towards the end of November". (Black) In this peer reviewed presentation in the Medical Journal of Australia, there was no indication that the trial was incomplete.

From the total evidence it can be stated that when the remainder of the Task Force personnel began the dapsone / paludrine regime until December1968, a "trial" or experimental situation still existed.

On 29 December 1968 Austforce Vietnam sent instructions to all units using dapsone to cease issue of this drug prior to issuing Chloroquine/Primaquine before personnel returned to Australia.

Methemoglobin levels were measured on servicemen returning from South East Asia between September 1968 and January 1969. Some of the respondents had received dapsone, pyrimethamine and quinne for malaria treatment, with the remainer identified as having taken Chloroquine/Primaquine. None are identified as having taken dapsone as part of a prior chemoprophylaxis. ( Sietsma) Whilst a small amount of methemoglobin (a compound formed from hemoglobin in the blood by the oxidation of the iron atom) is naturally present, greater quantities due to the toxic actions of drugs reduces the ability of the blood system to function as a efficient oxygen carrier. On withdrawal of the toxic agent a recovery is normally expected, but it is speculative as to the potential effects on the biotransformation of other agents to which soldiers were exposed, when affected by this condition.

But this may not have been the only factor that caused the AustForce to issue its instruction. A 24 year old soldier had developed jandice and felt anorexic two weeks into his Return to Australia course of chloroquine and primaquine, whilst he continued to ingest dapsone and paludrine. The physician "...had no doubt that the jaundice was haemolytic in origin, and considered the combination of dapsone and primaquine had caused it."

The reason why Chloroquine and primaquine were issued for 14 days prior to leaving Vietnam was in accordance with Ethical recommendations for Paludrine (eg 1961) "When paludrine is used and the regime has not been strictly adhered to there is the possibility of the emergence of resistant strains of the parasite.....following the withdrawal of a paludrine prophylactic regime (for falciparium malaria)... should be treated with one of the more potent schizonticides such as ....chloroquine....To achieve a radical cure of vivax (malaria)....this treatment should be combined with a 14 day course of primaquine"

US combat forces remained on 25mg dapsone daily and chloroquine/primaquine once weekly after this date, which suggests that US and Australian authorities had differing opinions on this aspect of dapsone. At a later date there was also different opinions on the relationship of agranulocytosis with dapsone issued in Vietnam.

"In February 1969 advice was given that dapsone should be discontinued because proguanil had provided sufficient protection from February until late in the year in previous years. However a command decision was taken to continue the combination throughout the year." (Black)

26 Supply Coy RAASC records show that no dapsone was issued during January, although Paludrine was reduced to 100mg, and in February 1969 returned to 200mg daily but no dapsone. In the subsequent months dapsone issues are recorded.

In the (NZDLS 15 Apr 85) evidence it is recorded "A. Dapsone issued to Aust troops during periods 17 Nov 68 to 11 Feb 69 and 5 Aug 70 to 28 Feb 71" Yet this remarkably recommended (Black) as a suitable reference on dapsone use in Vietnam

There is no explanation for the continuation of the regime, against advice in any of the published literature.

In December 1968 the trial started in October was completed. Reporting by (MacDonald) on 6 January 1969 identified the success of the regime during the previous period of use, and suggested "However it is recommended that research be conducted into the long term effects of this regime, particularly with regard to any toxic effect on the individual......"

In (Ognibene) it is stated that "strict enforcement of medical case reporting was first instituted in January 1969....before this time agranulocytosis was not reportable and isolated cases may have occurred..." At the same time the American focus on potential serious conditions associated with their regime began.

From February 1969, including the dry period where no malarial epidemics had been reported in the past, to February1970 the longest period of exposure to the regime occurred.

On June 26 1969 the first Australian case of agranulocytosis was admitted to 8th Field Ambulance at Nui Dat. An investigation of all possible chemical agents and drugs to which the soldier may have been exposed was carried out, and this was compared with the then current literature to ascertain if any of these products could have been responsible for the condition. The published result was "Agranulocytosis probably due to Dapsone" (Strickland)

The prior FUOs with Paludrine, coupled with the uncertainties of dapsone, probably explains (Black) the admission that "In 1969 the Central Register of Malaria Cases were commenced at the School of Public Health and Tropical Medicine and army medical officers were instructed to provide information on malaria cases for inclusion in the register".

Agranulocytosis occurred elsewhere in Vietnam at this time. "Sixteen patients with agranulocytosis who were taking dapsone prophylaxis were admitted to Army Hospitals in Vietnam during the first 10 Months of 1969" In (Ognibene) it is recorded that 16 US Soldiers in Vietnam who were receiving dapsone25mg daily and chloroquine/primaquine once weekly were admitted to hospital and eight deaths were recorded. In 6 of the 8 deaths a total absence of granulocytes on initial bone marrow examination. All patients had been on the prophylaxis from 3 weeks to 3 months. Recovery or death due to sepsis generally occurred within 9 days. This article was first received at the publisher on October 28, 1969, and the revision accepted December 24, 1969. It was published the following year in April 1970. (Ognibene) cites (Low J, Smith M), "The chemotherapy of leprosy in Nigeria" with an appendix on glandular fever and exfoliative determatitis precipitated by sulfones as source material. He made the observation " ....speculation as to whether dapsone used in Vietnam and exposed to intense heat might be subject to decomposition. The products of decomposition could be toxic to the bone marrow." and "Further investigation of the relative safety of dapsone when used as a treatment or as an intermittent prophylaxis of falciparum malaria is urgently required and presently being undertaken at the Walter Reed Army Institute of Research. The development of severe side effects from dapsone has resulted in limitations in its use for malaria prophylaxis for U.S. troops and is used only when combat manpower loss from falciparum malaria requires significant action to reduce the attack rate." The Walter Reed Army Research unit was probably the unit stationed at Saigon.

The American limitation imposed on dapsone use, was adopted by the Australians in 1970.

The next Australian agranulocytosis case admitted to 8 Field Ambulance Nui Dat occurred on January 7, 1970, with case three on February 2, 1970. The author made an observation of an accompanying condition in other patients. "The toxic side effects of sulfonamides are well known ......and an infectious mononucleosis type syndrome(Low 1952, Low and Davey ) In our own experience we have been struck with a high incidence of this latter condition in soldiers at 1 Australian Field Hospital. On Agranulocytosis the authors had reviewed available literature and concluded that "Most authors stress that this side effects of dapsone mainly occur after high sustained dosage"

The authors also made the statement "The US Forces in South Vietnam are known to have stopped the administration of dapsone and the USARV medical consultants report of October 1969 states " as everybody knows by now dapsone produces agranulocytosis, this is reversible on stopping the drug. If infection occurs the prognosis is extremely grave." (Smithhurst)

In the Australian history (Black) it is stated "....(dapsone)administered to a force of 7,000 men for just over one year there were several cases of agranuloctyosis but there are a number of features which call this causal relationship into question. Two subsequent exposures of slightly smaller numbers of men to dapsone for seven months and five months was not associated with the occurrence of agranulocytosis"

The information submitted from the (NZDLS 17 Apr 85) questioning was "Because of possible health effects resulting from prolonged administering of the drug, its use was withdrawn once the epidemic period had passed." The known epidemic period was estimated as October to December, so this evidence could only apply to the two subsequent exposure periods, which suggests that those shorter exposure periods after February 1970 were calculated from previous experience.

The (NZDLS 17 Apr 85) evidence also states"....four cases of agranuloyctosis were experienced in the Force and the decision to withdraw the drug was therefore reinforced" Three cases have been identified in available literature, but no evidence of the time of the fourth case has been published. (NZDLS 15 Apr 85) indicates the relevant medical journal articles for the three known cases. Disclosure of a fourth case after a published cessation, would identify that the regime had been reintroduced.

After the three recorded cases, the dapsone/paludrine regime was never again issued for a twelve month period. Whilst some Americans were convinced of an agranulocytosis association the Australians were not. (Black) had gone so far as to have correspondence with leading leprosy specialists before discounting the association.

" A Colonel Bob (Joy) from Walter Reed Hospital undertook some research into the use of Dapsone after the US Forces were finding inconsistencies in their results. It was found that one consignment of the drug was on a freighter delayed in Panama for four weeks........The theory was expounded that this Dapsone had become degraded....."(NZDLS 17 Apr 85)

Such an effect had not been recorded with improvised storage at leprosy issuing stations, in tropical countries.

During questioning of (Rodgers) at the Evatt Royal Commission, he identified that he had regular communication with the Walter Reed Research detachment in Vietnam,

Whilst this theory might explain cases of agranulocytosis within a particular time frame, it is not a suitable answer for all cases in Vietnam. Preventative dapsone use with Americans had cases spanning10 months. The Americans cases during dapsone use as a therapeutic occurred prior to the introduction of shipping as a transport route for the drug. No cases were identified prior to January 1969 but no confirmation could be made that they had not existed. Whilst the Americans where experiencing difficulties with the therapeutic regime, no problems were encountered by the Australians. It was (Ognibene) who suggested that heat degradation of dapsone could have occurred, based on the example of one recovered patient who was reissued dapsone as part of a continuing treatment regime in Japan where agranulocytosis was not repeated. It is probable that this patient was not issued a weekly chloroquine/primaquine course there.

The cases of agranulocytosis were not the result of a one off contaminated shipment.

Indications on entry to hospital for both the American and Australian cases, showed what today would be ample evidence of dapsone sensitization. The American cases had less exposure time than the Australians, but this can be explained by the fact that both primaquine and dapsone are arylamide drugs. Such drugs are thought to induce oxidative damage to red cells and induce the formation of free radicals that attach to macromolecules. Recent research (McMillian DC, Simpson JV, and Jollow DJ) has identified a possible mechanism for these drugs, where the oxidative damage to the hemoglobin becomes bound to the inside surface of the red cells. Sites on the red blood cells external surfaces are recognised by circulating antibodies, which could explain the cases of agranulocytosis, mononucleosis and allergies experienced in Vietnam. Interestingly the effect was faster with rat cells than human.

Long term effects have been recorded with dapsone alone amongst susceptible individuals, and it has been suggested that prior exposure to this drug may promote earlier expression of some illnesses.

The only research conducted on dapsone use in Vietnam has been the Australian Institute of Health an Welfare study "Dapsone Exposure, Vietnam Service and cancer incidence".

The aim of that study is recorded as "....to assess and quantify any association between cancer incidence and exposure to dapsone and to Vietnam service among Australian Servicemen...." This study did not examine for other endpoints in addition to cancer. Whilst the study did compare those with higher exposures (cumulative dosage of 5 g) and those with lower exposure, the study did not compare between those within the historically defined exposure periods. Also this study did not investigate a comparison of those who possibly took dapsone in conjunction with chloroquine/primaquine and those who did not. The half life of dapsone varies in individuals.

Conversely given that claims had previously been made of an association with a possible bone marrow suppressant, in the form of a degraded dapsone in Vietnam, one has to question why there is no indication in the study that shows a comparison been made of those who served during that perceived event and those who did not.

Black. Consultant in Tropical Medicine to the Australian Army, former Colonel Royal Australian Army Medical Corps. "Malaria in the Australian Army in South Vietnam" Medical Journal of Australia June 1973.

Fleming. Formerly Physician Australian Force, Vietnam. Probably at 8 Field Ambulance Nui Dat. "Experiences with Malaria in the early phase of the Australian Army involvement in South Vietnam." Medical Journal of Australia December 1974. At the time of publication Deputy Chief Director (Medical Services) Department of Repatriation and Compensation, Canberra

Ognibene. Lt. Col. United States Marine Corps Physician. "Agranulocytosis Due to Dapsone" Annals of Internal Medicine 1970. Written from Headquarters US Army Long Binh Vietnam.(Field Force HQ)

Joy. Colonel US Army. Member USArmy Medical Research Team Vietnam. "Medical chemoprophylaxis with di-amino di-phenyl sulfone: Field Trial with 1st Brigade Calvary Division". Published in WRAIR (Medical Research Team) Annual Progress Report 1 September 1965 to 31 August 1966.

Bradbury. Australian Army Colonel Chief of Staff Australian Force Vietnam. "AFV(Army Component) Trial Instruction No 9/68, Effectiveness of Dapsone-Paludrine as a Malaria Suppressant." dated 16 October 1968

Sietsma. Medical Registrar 2 Military Hospital Ingleburn NSW. "Methaemoglobin levels in Soldiers receiving Antimalarial Drugs" Medical Journal of Australia February 27 1971.

MacDonald. Major General, Commander Australian Force Vietnam. "Final Report on AFV Army Component) Trial No 9/68, Effectiveness of Dapsone-Paludrine Suppressant" dated 6 January 1969.

Rogoway. US Army. "Granulocytopenia complicating falciparum malaria therapy" USARV Medical Bulletin 1967

Strickland. Resident Medical Officer Military Repatriation General Hospital, Heidleberg, Victoria. "Agranulocytosis probably due to Dapsone in an Infantry Soldier" Medical Journal of Australia May 1970.

Smithurst. Lt.Col. Medical and Specialist Physician Australian Army. Officer Commanding 1st Australian Field Hospital, Vung Tau, Vietnam. "Dapsone induced agranulocytosis complicated by gram-negative septicaemia" Medical Journal of Australia March 1971. Probably written in Vietnam early 1970.

(NZDLS 15 Apr 85) Unclassified signal from New Zealand Defence Liaison Staff Canberra to NZ Defence HQ.

(NZDLS 17 Apr 85) "Safe Hand" courier delivered communication between NZDLS and NZ Defence HQ containing supplementary answers from Brig Rodgers and his staff, to be read in association with the answers given in (NZDLS 15 Apr 85)

(O'Keefe) Chief Archivist Australian Military Archives Canberra. Primary source of evidence for the Australian Institute of Health and Welfare, and the Evatt Royal Commission . Coauthor with Professor F. Smith "Medicine at War", Allan & Urwin, St.Leonards, Australia 1994.

(Rodgers) Medical exploration Vietnam 1963. Director of Army Medical Services (Aust) in Vietnam 1966-1967. Returned to Vietnam probably to the same post, May 1969 to 1970. Provided information to NZDLS and made a personal submission and representation at the Evatt Royal Commission. His submission, which included FUOs, was received during a closed session, making it unavailable for scrutiny. In 1985 Director General Medical Services for the Australian Army.

The writer wishes to express his thanks to the Vietnam Veterans Association of New Zealand for the copies of the Austforce Vietnam signal of December 1968, Bradbury, MacDonald and Rodgers evidence.

Thanks is also expressed to the Hon. Max Bradford, Minister of Defence, New Zealand who supplied the NZDLS evidence.