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and none of the directly inoculated or enriched stool samples yielded cultures of V cholerae or any other enteric pathogens. Samples were then assayed by a highly sensitive bead ELISA which can detect less than 6 pg/ml of cholera enterotoxinl and is being evaluated in our laboratory. Enhanced sensitivity is achieved in part by the use of affinity-purified antitoxin Fab’ conjugated to horseradish peroxidase by the maleimide method2 and tetramethylbenzidine as substrate.3 All five samples were positive for cholera toxin. Optical densities were compared with a standard curve prepared with purified cholera toxin (List Biological Laboratories, Campbell, USA; lot CVX-034), and cholera toxin concentrations were found to range between 10 and over 620 pg/ml. Cholera toxin in the stool samples could be completely neutralised with 10 ug anti-cholera-toxin IgG but was only partly neutralised by 10 Ilg anti-labile-toxin IgG from E coli of human origin. These findings pointed to toxigenic V cholerae as the cause of the outbreak, and local health officials were informed. The outbreak source and vehicle of transmission are under investigation. Conventional bacteriological techniques failed to find the causal agent of this outbreak. Administration of tetracycline to the ill passengers soon after the disease was brought to the notice of the ship’s doctor on July 6 may be one of the reasons why culture isolation failed. Furthermore, over 72 hours elapsed between the collection of samples and bacteriological examination; inadequate care during transport may have resulted in death of the organism. This is the first time in the history of NICED that an outbreak of cholera has been declared, despite failure to isolate vibrios, this being possible through the use of the bead ELISA.
National Institute of Cholera and Enteric Diseases, Calcutta-700010, India
T. RAMAMURTHY AMIT PAL G. BALAKRISH NAIR S. C. PAL
National Children’s Medical Research Centre,
Tokyo
TAE TAKEDA
Department of Microbiology, Faculty of Medicine, Kyoto University, Kyoto, Japan
YOSHIFUMI TAKEDA
1. Oku Y, et al. Development of a highly sensitive bead-ELISA to detect bacterial protein toxins. Microbiol Immunol 1988; 32: 807-16 2. Imagawa M, et al. Characteristics and evaluation of antibody-horseradish peroxidase conjugates prepared by using a maleimide compound, glutaraldehyde, and periodate. J Appl Biochem 1982; 4: 41-57. 3. Ishikawa E, Imagawa M, Hadshida S. Ultrasensitive enzyme immunoassay using fluorogenic, luminogenic, radioactive and related substrates and factors to limit the sensitivity. In: Avrameas S, Druet P, Masseyeff R, Feldman G, eds. Amsterdam:
Elsevier, 1983: 219-32.
Thiamine deficiency and sudden deaths SiR,—The letters in your June 16 issue by Dr Phua and colleagues (p 1471) and Dr Thurnham (p 1472) discuss thiamine deficiency and sudden death in Thai workers and south-east Asian refugees. In my view, both letters miss the point of the biochemical lesion. Flatty one of the research pioneers in thiamine deficiency and beriberi (not by any means synonymous terms), stated that some of the beriberi deaths he described "may have been due to a biochemical lesion in the central nervous system." He believed that more attention should be paid to the potentially crucial part that this played, particularly in infantile beriberi. Indeed, it was clear that sudden infant death
the rule in infantile beriberi and that its epidemiology precise facsimile of modem sudden infant death syndrome (SIDS).2 Beriberi affects the brainstem and autonomic nervous system,3 which suggests that the mechanism of sudden death might arise from dysfunction in central adaptive control. Phua et al point out that antithiamine factors can play a part in the biochemical lesion. It is interesting to note the disease which occurs in south-east Asians is called bangungutthe Tagalog word for nightmare. Classically death occurs in sleep after a heavy, typically Filipino, meal consisting of rice and a "patis" made from fish. Fish contain thiaminase 1,5 an enzyme which splits the thiazolium ring from the pyrimidine ring in the thiamine molecule and adds a base to the pyrimidine ring to construct an analogue inhibitor of thiamine is
a
was
action. This effect may compound an initial marginal dietary thiamine deficiency and precipitate events lethal to the brainstem. Apontein his discussion of bangungut, mentions an experiment by Nolasco who administered some of the fish "patis" to dogs; the animals died from respiratory paralysis, a mechanism consistent with a biochemical lesion in the brainstem. The same author mentioned a form of sudden death in the Philippines and Hawaii after ingestion of raw mullet. This is one of the fish in which thiaminase I is found in spleen, kidney, gill, and liver. Preventive Medicine
Group,
Westlake, Ohio 44145, USA
D. LONSDALE
1. Platt BS. Thiamine
deficiency in human beriberi. In: Wolstenholme GEW, O’Connor M, eds. Thiamine deficiency. Boston: Little Brown, 1967. 135-45 2. Fehily L. Human milk intoxication due to B1 avitaminosis. Br Med J 1944; ii: 590-92. 3. Inouye K, Katsura E. Clinical signs and metabolism of benberi patients, In. Shimazono N, Katsura E, eds. Beriberi and thiamine. Tokyo: Igaku Shoin, 1965; 29-63. 4. 5.
Aponte GE. The enigma of "Bangungut". Ann Intern Med 1959; 52:
1258-63.
Fujita A. In: Nord FF, ed. Thiaminase. New York: Interscience Publishers, 1954, 15: 389-421.
Pseudomonas pseudomallei and sudden unexplained death in Thai construction workers SiR,—The report of sudden unexplained death syndrome (SUDS) among Thai construction workers in Singapore (May 12, p 1154), prompted suggestions (May 12, p 1155; June 16, p 1471) that thiamine deficiency might be the cause of these deaths as well as those reported in south-east Asian refugees. Since more than half of the SUDS cases in Singapore showed pulmonary haemorrhage at necropsy and there was histopathological evidence of myocarditis or pneumonitis in several of them, infection cannot be ruled out. Because the victims were all men from villages in north-eastern Thailand, we investigated melioidosis, which is endemic in that region and predominantly affects men, as a predisposing factor in SUDS. Melioidosis is caused by the gram-negative organism Pseudomonas pseudomallei, which is found in the soil and surface water of rice fields, especially in south-east Asia, being most prevalent in Thailand in the north-eastern region. The spectrum of diseases produced by P pseudomallei is not well known but most infections are thought to be symptomless.1 Sera were collected from healthy Thai construction workers and SUDS cases and examined for P pseudomallei infection by the indirect haemagglutination (IHA) test, with a local strain of the organism as antigen. The antigen, prepared according to the method of Rice et aJ,2 was used to sensitise tanned, glutaraldehydetreated turkey red blood cells. The sera were heat-inactivated and absorbed with non-sensitised cells before testing. An IHA antibody titre of 4 or more was considered positive. The seropositivity rate among healthy Thai workers was about 40% (table), which is close to that reported for healthy adults in that region.1 Although the number of SUDS cases tested was small, the difference in seropositivity rate between SUDS cases and healthy workers was highly significant. The results suggest that P pseudomallei infection may be associated with SUDS among Thai workers in Singapore. How infection by this organism causes death is unknown. The immediate cause of death in SUDS among south-east Asian refugees is ventricular fibrillation,3and anomalies in the cardiac conductive system have been found in these cases.’ Conduction abnormality has also been reported in a case of septicaemic melioidosis reactivated by acute influenza A.’ We suggest that P pseudomallei infection is a risk factor in SUDS among Thai workers and probably also south-east Asian refugees. Subclinical infection may PREVALENCE OF ANTIBODY TO P PSEUDOMALLEI AMONG THAI CONSTRUCTION WORKERS
*p =3910’* compared with healthy workers (Fisher’s exact test)
377
result in a cardiac conduction abnormality, and stress (and other factors) on an already compromised heart may precipitate sudden death. Department of Microbiology, Faculty of Medicine, National University of Singapore, 0511 Singapore, Quarantine and Epidemiology Department, Ministry of the Environment, Singapore; Institute of Science and Forensic Medicine,
Ministry of Health, Singapore, and Department of Pathology, Singapore General Hospital
E. H. YAP Y. C. CHAN K. T. GOH T. C. CHAO B. H. HENG T. W. THONG M. SINGH E. JACOB
1 Kanai K, Dejsirilert S Pseudomonas pseudomallei and melioidosis, with special reference to the status m Thailand. Jpn J Med Sci Biol 1988; 41: 123-57. 2 Rice CE, Koust H, Duthie RC Studies by complement-fixation methods of malleins produced in broth and synthetic media I relative immunizing activities in horse and rabbits Can J Comp Med 1951; 15: 284-91. 3 Otto CM, Tauxe RV, Cobb LA, et al. Ventricular fibrillation causes sudden death in Southeast Asian immigrants Ann Intern Med 1984, 100: 45-47. 4 Kirschner RH, Eckner FAO, Baron RC. The cardiac pathology of sudden, unexplained nocturnal death in Southeast Asian refugees. JAMA 1986, 256: 2700-05. 5. Mackowiak PA, Smith JW. Septicemic melioidosis: occurrence following acute influenza A six years after exposure in Vietnam. JAMA 1978; 240: 764-66
Distributing ivermectin S)R,—In his letter on health workers (June 23, p 1539) Dr Pond of the Kwara State Blindness Prevention Program, Nigeria, suggests that unnecessarily rigid controls on ivermectin (’Mectizan’) distribution and post-treatment monitoring in community-based programmes are being imposed by Merck and the Mectizan Expert Committee (MEC). He finds that the amount of medical supervision required by the committee in mass treatment programmes is neither realistic nor necessary in view of the drug’s safety and the ability of community health workers to provide the post-treatment monitoring and health-care services called for. Pond’s considerable contributions to ivermectin treatment in Nigeria are well known, and his views are based on personal experience. A bit of history may be useful, however, in adding a broader perspective. The MEC was created by Merck & Co early in 1988 as an independent body, experienced in tropical medicine and international public health, to devise and oversee a process for donating mectizan to medically responsible and operationally sound community-wide, mass treatment programmes. The mass treatment, public health approach was adopted, in contrast to a patient-by-patient approach, because both Merck and the MEC wanted to make the benefits of ivermectin available to as many people with onchocerciasis as possible in the shortest period of time. In handling applications for ivermectin MEC was guided both by Merck’s prescribing literature for what was a newly licensed product and by the Committee members’ experience in international public health. The Committee applied generally accepted standards of good medical care in formulating guidelines and has used the same standards in evaluating applications. There has been considerable variation among proposals with respect to how this standard of medical care was to be achieved. In some programmes, physicians would be members of the field staff and be directly involved in treatment and follow-up. In others, experienced paramedical professionals, supervised by doctors, handled field activities, physicians being available for referral of patients needing specialised care. In almost all approved applications trained community health workers, or others with local health-care responsibilities, have been members of the treatment teams. In some instances they functioned primarily in the drug distribution phase; in others, they provided on-site triage of patients reporting health problems possibly related to treatment and referred those who needed more than symptomatic care to the nearest dispensary or hospital. In evaluating applications MEC has paid special attention to the training and experience of those distributing the drug and monitoring and managing post-treatment problems; the medical supervision of all phases of the programme; and the availability of medical back-up for potentially serious adverse reactions.
From the outset, the Committee adopted a policy of accepting all reasonable applications and helping applicants bring their proposals into line with accepted standards. Since September, 1988, when the donation programme began, 40 applications have been received: 6 have been withdrawn (or otherwise become inactive), 8 recently are still under review, and all the other 26 have been approved. The 26 approved applications authorised nearly 1 million treatments in 25 of 32 countries in Africa and Latin America with onchocerciasis. 2 of the earliest applicants have had approval for a second year, additional treatments numbering more than 350 000. We agree with Pond that it is important to explore ways to expand and extend the benefits of ivermectin treatment. The flexibility in the current application process will permit it to benefit from the experiences of those in the field while continuing to ensure medically responsible mectizan treatment. Carter Center, Atlanta. Georgia 30345, USA
WILLIAM H. FOEGE, Chairman, Mectizan Expert Committee
Halofantrine to prevent falciparum malaria on return from malarious areas SIR,-In 1987, we described the principle of "radical cure" for people returning from malarious areas as a strategy to prevent imported falciparum malaria.12 Plasmodium falciparum does not cause relapses via renewed manifestation of infection from hypnozoites and any residual risk will be due to recrudescence of blood forms of the parasite. 3,4 A week after returning from a malaria area exoerythrocytic schizogony is unlikely and an effective antimalarial agent could achieve a radical cure, defined as "complete elimination of all asexual stages from the body by treatment which is .5 effective against all asexual forms present at the time" In 1989, we did a comparative study in French army units, including 758 men who had been in central Africa (Gabon and Central African Republic) for about 4 months. The objective was to compare, in people returning from malaria areas, the usual strategy of chemoprophylaxis with chloroquine and radical cure with halofantrine (’Halfan’). 480 men were given two doses of 1500 mg halofantrine on the third and on the tenth days after their return to France. The other 278 men took chloroquine 100 mg daily for 6 weeks after their return to France. While in Africa both groups had been on chloroquine prophylaxis. The P falciparum attack rate in the 5 months after the men’s return to France was 5% in the chloroquine group (14/278) and 0-2% in the halofantrine group (1/480) (p = 0-02). Transaminases were monitored in the halofantrine group and no increase was found. The only possible instance of intolerance to halofantrine was a morbilliform rash, without fever, in 1 man. No significant difference was observed for the P ovale attack rate between the two groups (halofantrine 1-9%, chloroquine 1-1%). Radical cure by halofantrine seems to be more effective than chloroquine prophylaxis in preventing imported falciparum malaria. Furthermore, the low attack rate in the men not on long-term chemoprophylaxis (ie, those on halofantrine) supports the absence of hypnozoites in P falciparum. Before a halofantrine strategy is proposed for the prevention of P,falciparum infection in people returning from malarious areas confirmation of our results and further information on tolerance are needed.
Institut de Médecine Tropicale du Service de Santé des Armées, 13998 Marseille, France
J. BERNARD
D. BAUDON J. P. MOULIA-PELAT
G. MARTET
J. SARROUY
J. E. TOUZE
A. SPIEGEL
P. LANTRADE
J. J. PICQ
D, Picq JJ. Intérêt d’une cure radicale de l’infection par Plasmodium falciparum au retour d’une zone d’endémie palustre Presse Méd 1987; 16: 586 2. Baudon D, Picq JJ Cure radicale de l’infection par Plasmodium falciparum. Presse Med 1 Baudon
1987, 16: 1600 3 Garnharn PCC Rechutes dans la malaria revue de travaux recents Ann Soc Belge Méd Trop 1985; 65: 233-45 4 Garnham PCC. Malaria parasites of man life cycles and morphology (excluding ultrastructure) In Wernsdorfer WH, McGregor 1, eds Malaria principles and practice of malariology. Edinburgh Churchill Livingstone, 1988, vol I(2) 61-96 5 Desjardins RE, Dobersty n EB, Wernsdorfer WH The treatment and prophylaxis of malaria In Wernsdorfer W H, McGregor I, eds Malaria principles and practice of malariology Edinburgh: Churchill Livingstone, 1988 Vol I(31) 827-64.